Simultaneous Administration Research Articles

Effect of uniform capacitively coupled electric fields on matrix metabolism of osteoarthritic cartilage

BackgroundOsteoarthritis (OA) is a common and debilitating condition characterized by degeneration of hyaline cartilage. Currently, there is no treatment for OA that directly targets degradation of cartilage matrix. Capacitively coupled electric fields (CCEFs) represent a noninvasive and cost-effective treatment modality that can potentially restore articular cartilage homeostasis. Previous studies showed that stimulation of articular cartilage with CCEFs resulted in upregulation of anabolic factors and downregulation of catabolic factors. These studies didn’t explain the derivation of the CCEFs or verify their uniformity and field strength, so it’s possible that cartilage wasn’t exposed to uniform field strength. The present study aims to employ CCEFs with verified uniform field strength in two in-vitro models of OA to investigate its potential to preserve cartilage matrix and validate the results of the aforementioned studies.MethodsRabbit hyaline chondrocytes and full-thickness bovine articular cartilage explants were cultured in the absence or presence of CCEF and in the absence or presence of Interleukin1-B (IL-1B). Quantitative polymerase chain reaction (QPCR) was performed on chondrocytes to measure gene expression of ADAM-TS4, MMP3, MMP9, IL-6, TIMP1, and TIMP2. QPCR was performed on explants to measure gene expression of MMP3, Aggrecan, Collagen-2, and TIMP1. Aggrecan concentration in explants was measured with histology. Statistical analysis was performed using one-way analysis of variance and Tukey–Kramer multiple comparison test.ResultsThe treatment of chondrocytes with IL-1B resulted in upregulated expression of ADAM-TS4, MMP3, MMP9, and IL-6, while simultaneous administration of IL-1B and CCEF led to a relative decrease in ADAM-TS4, MMP3, MMP9, and IL-6 expression and a relative increase in TIMP1 and TIMP2 expression. Application of IL-1B and CCEF to the explants resulted in decreased expression of MMP3 and increased expression of Aggrecan, Collagen-2, and TIMP1 when compared to application of IL-1B alone.ConclusionThe data indicate that application of a CCEF with verified uniformity may result in upregulation of cartilage anabolic factors even in the presence of IL-1B while attenuating IL-1B induced upregulation of catabolic factors in both monolayer culture and whole tissue. These results demonstrate the potential of CCEFs to suppress the progression of OA and regenerate articular cartilage matrix.

In Vitro Synergistic Inhibitory Activity of Natural Alkaloid Berberine Combined with Azithromycin against Alginate Production by Pseudomonas aeruginosa PAO1.

Background Berberine (BER) is a natural isoquinoline alkaloid which extensively been applied to treat bacterial infection in TCM for a long time. Alginate is an important component of Pseudomonas aeruginosa biofilm. Herein, we investigated the effects of berberine and azithromycin (AZM) on alginate in the biofilm of P. aeruginosa PAO1. Methods The MIC and synergistic activity of BER and AZM against PAO1 were determined using the micro broth dilution and checkerboard titration methods, respectively. The effect of BER on PAO1 growth was evaluated using a time-kill assay. Moreover, the effects of BER, AZM, and a combination of both on PAO1 biofilm formation, kinesis, and virulence factor expression were evaluated at subinhibitory concentrations. The alginate content in the biofilm was detected using ELISA, and the relative expression of alginate formation-related genes algD, algR, and algG was detected by qRT-PCR. Results Simultaneous administration of berberine significantly reduced the MIC of azithromycin, and berberine at a certain concentration inhibited PAO1 growth. Moreover, combined berberine and azithromycin had synergistic effects against PAO1, significantly reducing biofilm formation, swarming, and twitching motility, and the production of virulence factors. The relative expression of alginate-related regulatory genes algG, algD, and algR of the combined treatment group was significantly lower than that of the control group. Conclusion In summary, berberine and azithromycin in combination had a significant synergistic effect on the inhibition of alginate production by P. aeruginosa. Further molecular studies are in great need to reveal the mechanisms underlying the synergistic activity between berberine and azithromycin.

Effect of temporary cessation of milking and estradiol combination on the antimicrobial components in goat milk

A temporary cessation of milking is widely used in Japan to treat mastitis in dairy cows. Exogenous administration of estradiol (E2) is known to inhibit milk production in dairy cows. Therefore, we aimed to evaluate the effects of the temporary cessation of milking in combination with E2 administration on the antimicrobial components of goat milk. Twelve goats, divided into two groups—with and without E2 injection (E2 and control group, respectively), were subjected to cessation of milking in both udder halves for 3 d (day 0–2). Milk yield in the E2 group was significantly lower than that in the control group on days 7 to 10. The concentrations of cathelicidin-2, IgA, and lactoferrin in the E2 group were significantly higher than those in the control group. These results suggest that the temporary cessation of milking with simultaneous E2 administration leads to a higher concentration of certain antimicrobial components in milk than that observed after using cessation of milking alone. Thus, this combination may contribute to a stronger innate immune system and a faster recovery from mastitis, and might prove to be an alternative to antibiotic treatment upon further research.

Thiosemicarbazones and selected tyrosine kinase inhibitors synergize in pediatric solid tumors: NDRG1 upregulation and impaired prosurvival signaling in neuroblastoma cells.

Tyrosine kinase inhibitors (TKIs) are frequently used in combined therapy to enhance treatment efficacy and overcome drug resistance. The present study analyzed the effects of three inhibitors, sunitinib, gefitinib, and lapatinib, combined with iron-chelating agents, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) or di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). Simultaneous administration of the drugs consistently resulted in synergistic and/or additive activities against the cell lines derived from the most frequent types of pediatric solid tumors. The results of a detailed analysis of cell signaling in the neuroblastoma cell lines revealed that TKIs inhibited the phosphorylation of the corresponding receptor tyrosine kinases, and thiosemicarbazones downregulated the expression of epidermal growth factor receptor, platelet-derived growth factor receptor, and insulin-like growth factor-1 receptor, leading to a strong induction of apoptosis. Marked upregulation of the metastasis suppressor N-myc downstream regulated gene-1 (NDRG1), which is known to be activated and upregulated by thiosemicarbazones in adult cancers, was also detected in thiosemicarbazone-treated neuroblastoma cells. Importantly, these effects were more pronounced in the cells treated with drug combinations, especially with the combinations of lapatinib with thiosemicarbazones. Therefore, these results provide a rationale for novel strategies combining iron-chelating agents with TKIs in therapy of pediatric solid tumors.

Electrochemotherapy: An Alternative Strategy for Improving Therapy in Drug-Resistant SOLID Tumors.

Simple SummaryChemotherapy is becoming an increasingly difficult antitumor therapy to practice due to the multiple mechanisms of drug resistance. To overcome the problem, it is possible to use alternative techniques, such as electrochemotherapy, which involves the simultaneous administration of the electrical pulse (electroporation) and the treatment with the drug in order to improve the effectiveness of the drug against the tumor. Electroporation has improved the efficacy of some chemotherapeutic agents, such bleomycin, cisplatin, mitomycin C, and 5-fluorouracil. The results of in vitro, veterinary, and clinical oncology studies are promising on various cancers, such as metastatic melanoma. The purpose of this review is to give an update on the state of the art of electrochemotherapy against the main solid tumors in the preclinical, clinical, and veterinary field.Electrochemotherapy (ECT) is one of the innovative strategies to overcome the multi drug resistance (MDR) that often occurs in cancer. Resistance to anticancer drugs results from a variety of factors, such as genetic or epigenetic changes, an up-regulated outflow of drugs, and various cellular and molecular mechanisms. This technology combines the administration of chemotherapy with the application of electrical pulses, with waveforms capable of increasing drug uptake in a non-toxic and well tolerated mechanical system. ECT is used as a first-line adjuvant therapy in veterinary oncology, where it improves the efficacy of many chemotherapeutic agents by increasing their uptake into cancer cells. The chemotherapeutic agents that have been enhanced by this technique are bleomycin, cisplatin, mitomycin C, and 5-fluorouracil. After their use, a better localized control of the neoplasm has been observed. In humans, the use of ECT was initially limited to local palliative therapy for cutaneous metastases of melanoma, but phase I/II studies are currently ongoing for several histotypes of cancer, with promising results. In this review, we described the preclinical and clinical use of ECT on drug-resistant solid tumors, such as head and neck squamous cell carcinoma, breast cancer, gynecological cancer and, finally, colorectal cancer.

Antioxidant Supplementation with N-Acetylcysteine as a Protection Against Cisplatin-Induced Motor Impairment in Rats

Abstract The aim of this study was to estimate a potential beneficial influence of N-acetylcysteine (NAC) in the treatment of cisplatin-induced motor impairment. We included 32 male Wistar albino rats, divided into 4 equal groups: control (received saline on the 1st and 5th day), cisplatin – CIS (received saline on the 1st and cisplatin 7.5 mg/kg i.p. on the 5th day), NAC (received NAC on the 1st and 5th day, 500 mg/kg i.p.), and CIS+NAC (received NAC on the 1st and 5th day, 500 mg/kg i.p. and cisplatin 7.5 mg/kg i.p. on the 5th day) group. Motor performance was estimated by rotarod, grip wire, open field (OF), elevated plus maze (EPM) and beamwalking (BW) tests on the 10th day. Cisplatin administration resulted in decreased motor performance in all tests, except for BW test, compared to the control group. NAC supplementation on its own had no significant effect on motor performance parameters. However, simultaneous administration of NAC along with cisplatin reversed negative impact of cisplatin in rotarod, OF and EPM tests, with no significant effect on the results obtained in grip wire test. The results of this study confirmed numerous motoric manifestations of cisplatin-induced neurotoxicity in rats. However, the decline in most of the estimated parameters was successfully prevented by antioxidant supplementation with NAC.

CLEC5A is critical in Pseudomonas aeruginosa-induced NET formation and acute lung injury.

Pseudomonas aeruginosa is one of the most common nosocomial infections worldwide, and it frequently causes ventilator-associated acute pneumonia in immunocompromised patients. Abundant neutrophil extracellular traps (NETs) contribute to acute lung injury, thereby aggravating ventilator-induced lung damage. While pattern recognition receptors (PRRs) TLR4 and TLR5 are required for host defense against P. aeruginosa invasion, the PRR responsible for P. aeruginosa-induced NET formation, proinflammatory cytokine release, and acute lung injury remains unclear. We found that myeloid C-type lectin domain family 5 member A (CLEC5A) interacts with LPS of P. aeruginosa and is responsible for P. aeruginosa-induced NET formation and lung inflammation. P. aeruginosa activates CLEC5A to induce caspase-1-dependent NET formation, but it neither causes gasdermin D (GSDMD) cleavage nor contributes to P. aeruginosa-induced neutrophil death. Blockade of CLEC5A attenuates P. aeruginosa-induced NETosis and lung injury, and simultaneous administration of anti-CLEC5A mAb with ciprofloxacin increases survival rate and decreases collagen deposition in the lungs of mice challenged with a lethal dose of P. aeruginosa. Thus, CLEC5A is a promising therapeutic target to reduce ventilator-associated lung injury and fibrosis in P. aeruginosa-induced pneumonia.

Hepatoprotective and nephroprotective efficacy of Cichorium intybus following imidacloprid induced subchronic toxicity in WLH cockerels

The current research work was undertaken to evaluate the hepatoprotective and nephroprotective potential of Cichorium intybus following subchronic exposure of imidacloprid in white leghorn (WLH) chicks. Thirty, 6 to 8 weeks old chicks of 300-350 g weight were randomly and equally divided into five groups. Group I served as control and was fed normal grower ration and other were fed medicated ration containing Cichorium intybus leaf powder @ 5000 ppm in Group II, imidacloprid @ 100 ppm in Group III, imidacloprid @ 100 ppm + silymarin @ 100 ppm in Group IV and imidacloprid @ 100 ppm + Cichorium intybus leaf powder @ 5000 ppm in Group V, respectively, for 8 weeks. Biochemical parameters at 4th and 8th week revealed a significant increase in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, indirect bilirubin, creatinine, blood urea nitrogen (BUN) with an increase in absolute and relative organ weights of liver and kidney after 8 weeks and a significant decline in total protein, albumin and globulin in imidacloprid treated Group III as compared to control (Group I). However, the simultaneous administration of Cichorium intybus leaf powder (CILP) in Group V revealed amelioration in these parameters at par with Groups I and IV. Thus, amelioration of imidacloprid induced hepatotoxic and nephrotoxic effects following simultaneous CILP administration indicates hepatoprotective and nephroprotective potential of Cichorium intybus in imidacloprid intoxicated cockerels.

Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy.

Androgen deprivation therapy (ADT) has been the standard of care for advanced hormone-sensitive prostate cancer (PC), yet tumors invariably develop resistance resulting in castrate-resistant PC. The acute response of cancer cells to ADT includes apoptosis and cell death, but a large fraction remains arrested but viable. In this study, we focused on intensively characterizing the early metabolic changes that result after ADT to define potential metabolic targets for treatment. A combination of mass spectrometry, optical metabolic imaging which noninvasively measures drug responses in cells, oxygen consumption rate, and protein expression analysis was used to characterize and block metabolic pathways over several days in multiple PC cell lines with variable hormone response status including ADT sensitive lines LNCaP and VCaP, and resistant C4-2 and DU145. Mass spectrometry analysis of LNCaP pre- and postexposure to ADT revealed an abundance of glycolytic intermediates after ADT. In LNCaP and VCaP, a reduction in the optical redox ratio [NAD(P)H/FAD], extracellular acidification rate, and a downregulation of key regulatory enzymes for fatty acid and glutamine utilization was acutely observed after ADT. Screening several metabolic inhibitors revealed that blocking fatty acid oxidation and synthesis reversed this stress response in the optical redox ratio seen with ADT alone in LNCaP and VCaP. In contrast, both cell lines demonstrated increased sensitivity to the glycolytic inhibitor 2-Deoxy- d-glucose(2-DG) and maintained sensitivity to electron transport chain inhibitor Malonate after ADT exposure. ADT followed by 2-DG results in synergistic cell death, a result not seen with simultaneous administration. Hormone-sensitive PC cells displayed altered metabolic profiles early after ADT including an overall depression in energy metabolism, induction of a quiescent/senescent phenotype, and sensitivity to selected metabolic inhibitors. Glycolytic blocking agents (e.g., 2-DG) as a sequential treatment after ADT may be promising.

The effect of beetroot juice on airway inflammation in a murine model of asthma.

The effects of beetroot juice on airways inflammation, cytokine levels, and oxidative stress biomarkers were evaluated using an allergen-induced murine model of asthma. Ovalbumin (OVA)-sensitized and challenged BALB/c mice were used as an asthma model. BALB/c mice were randomly assigned into four groups: control (Ova sensitization and normal saline challenge), control and beetroot (Ova sensitization and normal saline challenge plus beetroot juice), Ova S/C [Ova sensitization and challenge (Ova S/C)], Ova S/C and beetroot juice (Ova S/C plus beetroot juice). The bronchoalveolar lavage fluid (BALF) was analyzed for total and differential inflammatory cells count. The levels of cytokines [interleukin (IL)-10, IL-13, and IL-18], and oxidative stress biomarkers [glutathione peroxidase (GPx), catalase, and thiobarbituric acid reactive substances (TBARS)] were analyzed in the lung tissue. Simultaneous administration of beetroot juice and Ova S/C significantly increased the total inflammatory cells compared to the control (p=.0001) and Ova S/C (p=.013) groups and significantly increased the number of eosinophils (p ˂ .0001) and macrophages (p ˂ .0001) compared to the control. Moreover, the simultaneous administration of beetroot juice and Ova S/C did not affect the level of IL-10, IL-13, IL-18, GPx, or TBARS compared to the control (p > .05), but it significantly increased the level of catalase (p=.002). Results suggest that beetroot juice aggravates asthma by enhancing airway inflammation. However, it does not affect airway inflammation in healthy mice. PRACTICAL APPLICATIONS: Asthma is a chronic airway inflammatory disease that is characterized by variable degrees of airways inflammation and obstruction. Paradox data are reported in the literature regarding beetroot and asthma. The present study revealed that beetroot juice exacerbates asthma by enhancing airway inflammation. However, it is safe and has no effects on airway inflammation in healthy mice. Patients having asthma or a history of asthma are advised to avoid the consumption of beetroot.

RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability–high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX–CRT regimen. CRT can promote proteomic diversity via RNA editing.

Effect of Central Venous Nutrition Infusion, Intravenous Fat Emulsion, and Therapeutic Agents on the Particle Size of Fat Emulsion for Simultaneous Administration of Three Drugs

Background: In Japan, therapeutic agents are often administered through the side tube of a central venous line or mixed with a total parenteral nutrition (TPN) infusion. This is expected to result in the mixture of three drugs in the infusion line: the infusion product for TPN, the fat emulsion, and the therapeutic agent. Therefore, we investigated whether various therapeutic agents affect the particle size of the fat emulsion. Methods: In model of administration A, the TPN infusion formulation was administered through the main tube, and the fat emulsion and therapeutic agents were simultaneously administered through the side tube; 21 therapeutic agents were used. In model of administration B, the TPN infusion formulation mixed with therapeutic agents was administered through the main tube, and the fat emulsion was simultaneously administered through the side tube; 20 therapeutic agents were used. The number of fine particles for each particle size range in the mixed solution was measured over time using a light-shielding automatic fine-particle measuring device. Results: In model A, the number of fine particles in the fat emulsion changed rapidly for five therapeutic agents and slowly for two therapeutic agents. In model B, this change occurred drastically for five therapeutic agents and slowly for one therapeutic agent. Conclusions: Some therapeutic agents may contribute to fat particle aggregation. Therefore, these therapeutic agents should not be concurrently administered with fat emulsions.

Effect of Coriander on H2O2-induced Oxidative Stress in PC12 Cells

Objective: Coriander (Coriandrum sativum), a member of the Apiaceae family of plants, is traditionally used as a spice and medicinal plant which has anti-aging, anti-inflammatory, and anti-anxiety effects and is used for the treatment of diabetes. The present study aimed to investigate the effects of coriander on H2O2-induced neurotoxicity in PC12 cells. Methods: PC12 cells were cultured in Dulbecco’s modified Eagle’s medium, and the effects of various treatments were analyzed using cytotoxicity assay, morphological evaluation of neurite outgrowth, and western blotting. Results: The cytotoxicity assay showed increased levels of LDH in cells treated above 10-5 M H2O2, however there was no significant change in the coriander administration group. Morphological evaluation showed significantly increased neurite outgrowth in the nerve growth factor (NGF) treatment group after 72 h. Treatment of NGF-stimulated cells with H2O2 reversed the effect of NGF on neurite outgrowth, which returned to the levels of the control group. Simultaneous administration of H2O2, NGF and 0.1 or 0.01 µg/mL of coriander significantly increased neurite outgrowth after 72 h. Western blot showed that phosphorylated ERK levels were significantly increased in the NGF group compared with H2O2+NGF group, and no significant differences were found compared to the H2O2+NGF+0.1 µg/mL coriander administration group. Conclusion: Coriander reversed the reduction in neurite outgrowth following treatment of NGF-stimulated PC12 cells with H2O2. This suggests that coriander may help prevent oxidative stress-induced neurodegeneration.

Immunogenicity and safety of concomitant administration of the chinese inactivated poliovirus vaccine with the diphtheria-tetanus-acellular pertussis (DTaP) vaccine in children: A multicenter, randomized, non-inferiority, controlled trial.

Key pointConsidering that vaccination with the sIPV and DTaP overlap at the ages of 3 and 4 months in China, to reduce the burden of treatment on parents and increase vaccination coverage rates, we designed a postmarket clinical study of co-administration.BackgroundThe Sabin-strain-based inactivated poliovirus vaccine (sIPV) and the diphtheria-tetanus-acellular pertussis vaccine (DTaP) have been licensed in China for many years. To conduct a clinical study on the safety and immunogenicity of the sIPV when administered concomitantly with the DTaP.MethodsThe study population was divided into three groups: group 1 was the sIPV+ DTaP concomitant administration group, group 2 was the sIPV inoculation group, and group 3 was the DTaP inoculation group. Blood samples were collected prevaccination and 30 days postvaccination, and serum antibody levels were detected.ResultsThis study showed that the seropositive and seroconversion rates of type 1, 2 and 3 poliovirus in group 1 were higher than those in group 2, with no statistically significant difference after vaccination (P>0.05). Groups 1 and 3 also showed similar responses for all vaccine antigens except anti-FHA (97.65 (94.09-99.36) vs. 100 (97.89-100)). The geometric mean titers (GMTs) for the DTaP and sIPV among the groups were comparable, and the non-inferiority t test result was P<0.001. The number of local adverse events (AEs) reported in group 1 (29.91%) were larger than those in group 2 (12.39%) and group 3 (21.93%), among which the most common was redness. Similarly, the most common systemic AE was fever. All 5 severe AE (SAE) cases were determined by experts to be unrelated to the vaccines during the study.ConclusionsThe evidence of similar seroconversion and safety with co-administered DTaP and sIPV supports the co-administration supports the introduction of a strategy of simultaneous administration of both vaccines into routine infant immunization, and it could increase vaccination coverage and protect more infants from morbidity and mortality from these related diseases.Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT04054882?term=NCT04054882&cntry=CN&draw=2&rank=1, identifier NCT04054882.

Start, Stop, Continue? The Benefit of Overlapping Intravenous Thrombolysis and Mechanical Thrombectomy

ObjectiveHere we compare the procedural and clinical outcome of patients undergoing thrombectomy with running thrombolysis to matched controls with completed intravenous therapy and an only marginally overlapping activity.MethodsPatients from 25 sites in Germany were included, who presented with an acute ischemic stroke. Patients’ baseline characteristics (including ASPECTS, NIHSS and mRS), grade of reperfusion, and functional outcome 24 h and at day 90 after intervention were extracted from the German Stroke Registry (n = 2566). In a case-control design we stepwise matched the groups due to age, sex and time to groin puncture and time to flow restoration.ResultsIn the initial cohort (overlap group n = 864, control group n = 1702) reperfusion status (median TICI in overlap group vs. control group: 3 vs. 2b), NIHSS after 24 h, early neurological improvement parameters, mRS at 24 h and at day 90 were significantly better in the overlap group (p < 0.001) with a similar risk of bleeding (2.9% vs. 2.4%) and death (18% vs. 22%). After adjustment mRS at day 90 still showed a trend for lower disability scores in the overlap group (3 IQR 1-5 vs. 3 IQR 1-6, p = 0.09). While comparable bleeding risk could be maintained (4% in both groups), there were significantly more deaths in the control group (18% vs. 30%, p = 0.006).ConclusionThe presented results support the approach of continuing and completing a simultaneous administration of intravenous thrombolysis during mechanical thrombectomy procedures.

Static and Electromagnetic Fields Differently Affect Proliferation and Cell Death Through Acid Enhancement of ROS Generation in Mesenchymal Stem Cells.

Magnetic fields remotely influence cellular homeostasis as a physical agent through the changes in cell physicochemical reactions. Magnetic fields affect cell fate, which may provide an important and interesting challenge in stem cell behaviors. Here, we investigated the effects of the static magnetic field (SMF, 20 mT) and electromagnetic field (EMF, 20 mT-50 Hz) on reactive oxygen species (ROS) production and the acidic pH conditions as stimuli to change cell cycle progression and cell death in mesenchymal stem cells. Results show that SMF, EMF, and their simultaneous (SMF+EMF) administration increase ROS and expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and glutathione-S-transferase (GST) as an antioxidant defense system. Besides, intracellular pH (pHi) decreases in presence of either EMF or SMF+EMF, but not SMF. Decreased ROS content using ascorbic acid in these treatments leads to increased pH compared to the magnetic field treatments alone. Furthermore, each magnetic field has different effects on the cellular process of stem cells, including cell cycle, apoptosis and necrosis. Moreover, treatment by SMF enhances the cell viability after 24 h, while EMF or SMF+EMF decreases it. These observations indicate that fluctuations of ROS generation and acid enhancement during SMF and EMF treatments may reveal their beneficial and adverse effects on the molecular and cellular mechanisms involved in the growth, death, and differentiation of stem cells.

Reactogenicity of Simultaneous COVID-19 mRNA Booster and Influenza Vaccination in the US

COVID-19 and seasonal influenza vaccines are essential in preventing respiratory infections and their potentially severe complications. Simultaneous administration of vaccines is efficient and may improve coverage with each vaccine. However, the safety of simultaneous administration of COVID-19 and influenza vaccines has not been well described. To evaluate adverse events and health impacts associated with simultaneously administered COVID-19 mRNA booster and seasonal influenza vaccines in the US population. In this retrospective cohort study, self-reported vaccine data were collected on days 0 to 7 after vaccination from September 22, 2021, through May 1, 2022, through v-safe, a voluntary smartphone-based monitoring system established by the Centers for Disease Control and Prevention. Participants were persons who voluntarily registered in v-safe following COVID-19 vaccination. Receipt of simultaneously administered COVID-19 mRNA booster and seasonal influenza vaccines or COVID-19 mRNA booster alone. Local injection site and systemic reactions (eg, fatigue, headache, and myalgia) and health impacts reported by v-safe respondents in the week following COVID-19 mRNA booster vaccination. Adjusted odds ratios (aORs) were estimated for simultaneous administration compared with booster dose alone, controlling for sex, age, and week of vaccination. Of a total of 981 099 persons aged 12 years or older registered with v-safe, simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines was reported by 92 023 (9.4%) v-safe respondents; of these respondents, 54 926 (59.7%) were female, 36 234 (39.4%) were male, and sex was unknown for 863 (0.9%). In the week following vaccination, any systemic reactions were reported by 36 144 (58.9%) of 61 390 respondents who simultaneously received Pfizer-BioNTech booster and influenza vaccines and 21 027 (68.6%) of 30633 respondents who simultaneously received Moderna booster and influenza vaccines. Respondents who simultaneously received influenza and Pfizer-BioNTech booster vaccines (aOR, 1.08; 95% CI, 1.06-1.10) or influenza and Moderna booster vaccines (aOR, 1.11; 95% CI, 1.08-1.14) were slightly more likely to report any systemic reaction in the week following simultaneous vaccination than respondents who received only a COVID-19 mRNA vaccine booster. In this study, compared with administration of COVID-19 mRNA booster vaccines alone, simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines was associated with significant increases in reports of systemic reactions during days 0 to 7 following vaccination. These results may help better characterize the outcomes associated with simultaneously administered COVID-19 booster and influenza vaccines in the US population.

A bivalent SARS-CoV-2 monoclonal antibody combination does not affect the immunogenicity of a vector-based COVID-19 vaccine in macaques.

Human monoclonal antibodies (mAbs) that target the spike glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) offer a promising approach for the prevention and treatment of coronavirus disease 2019 (COVID-19). Given suboptimal global vaccination rates, waning immunity in vaccinated individuals, and the emergence of SARS-CoV-2 variants of concern, the use of mAbs for COVID-19 prevention may increase and may need to be administered together with vaccines in certain settings. However, it is unknown whether administration of mAbs will impact the immunogenicity of SARS-CoV-2 vaccines. Using an adenovirus vector-based SARS-CoV-2 vaccine, we show that simultaneous administration of the vaccine with SARS-CoV-2 mAbs does not diminish vaccine-induced humoral or cellular immunity in cynomolgus macaques. These results suggest that SARS-CoV-2 mAbs and viral vector-based SARS-CoV-2 vaccines can be administered together without loss of potency of either product. Additional studies will be required to evaluate co-administration of mAbs with other vaccine platforms.

Simultaneous Bilateral Frontal and Bilateral Cerebellar Transcranial Direct Current Stimulation in Treatment-Resistant Depression-Clinical Effects and Electrical Field Modelling of a Novel Electrodes Montage.

Depressive disorders are one of the leading causes of disability worldwide. Transcranial direct current stimulation (tDCS) is a safe, simple, non-invasive brain stimulation technique showing considerable effectiveness in improving depressive symptoms. Most studies to date have applied anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC), in line with the hypothesis that depressed patients exhibit relative hypoactivity in the left DLPFC compared to the right. Considering the emerging role of the cerebellum in emotional processes, we aimed to study the effect of combining bilateral cerebellar tDCS with the commonly used bifrontal stimulation in patients with severe depression. This open-label pilot study entailed the simultaneous administration of bilateral cerebellar (anode over the left cerebellum, cathode over the right cerebellum) and bilateral frontal (anode over the left DLPFC, cathode over the right DLPFC) tDCS to patients (N = 12) with treatment-resistant depression. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck’s Depression Inventory-II (BDI-II) were selected as outcome measures. Electric fields distribution originating from this novel electrode montage was obtained by a computational method applied to a realistic human head model. We observed a 30% reduction of both clinician-rated and self-reported severity of depressive symptoms after only five days (10 sessions) of treatment. Younger age was associated with greater clinical improvement. Adverse events were similar to those of the conventional electrodes montage. The modelling studies demonstrated that the electric fields generated by each pair of electrodes are primarily distributed in the cortical areas under the electrodes. In conclusion, the cerebellum could represent a promising adjunctive target for tDCS interventions in patients with TRD, particularly for younger patients.

Same lung deposited dose in dog dosing a fine and coarse aerosol indicates no difference in intranasal filtration

A novel inhalation exposure system was developed with the aim to increase the efficiency of pharmacokinetic (PK) evaluations of inhaled drugs in a large species such as the dog. It enables collecting PK data for multiple drug candidates in a single experiment by simultaneous administration of the drugs to the same animal. This facilitates a direct PK comparison of the same lung dose of different drugs using the same blood samples, which can be considered to be a refinement measure from an animal research perspective. The system design was inspired by a clinical precision dosing dosimeter systems, which enhance dosing precision by synchronizing the aerosol delivery from the jet nebulizer with the inhalation to maximize the inhaled fraction of the nebulized dose.The performance of the novel system was validated in an in-vivo study, which included a comparison of the same nebulized dose delivered as a fine and a coarse aerosol. The drugs selected for this study were developed for local treatment of the lung via inhalation and were known to have low oral bioavailability due to being extremely poorly soluble and therefore expected to also have low nasal bioavailability. This would result in systemic exposure derived primarily from pulmonary absorption, which facilitated the PK assessment applied to determine the lung deposited dose.The jet nebulizer selected to generate a fine aerosol was designed for alveolar lung deposition and approved by U.S. Food and Drug Administration for lung ventilation imaging, and the nebulizer selected to generate a coarse aerosol was a standard nebulizer. The drugs were wet milled to a particle size considerably smaller than the nebulized droplets and the dispersed drug particles were therefore homogenously distributed in the droplet size distribution.Higher initial plasma concentrations were observed for the fine aerosol. This was expected, as the smaller droplets should deposit more efficiently in the peripheral regions of the lung, which consequently should lead to a faster absorption compared with the coarse aerosol from the standard nebulizer that should deposit more centrally. The fact that this could be observed supports that the novel system is an excellent tool in PK evaluations.Our study indicated that there was no difference in the systemic exposure between the fine and the coarse aerosol for the same nebulized dose, and thus the lung deposition was also the same. The considerable difference in the nebulized size distribution within the range relevant for available inhalation devices resulted in a negligible difference in intranasal filtration. The fraction of the nebulized dose that deposited in the lung was observed to be high in this study (mean of 21–30% and about 50% for one dog with a distinguished slow and deep breathing), which supports that the intranasal filtration was low. That a high fraction of the nebulized dose deposited in the lung indicates that an enhanced dosing precision was obtained with the novel system. The similar achieved lung doses of all three drugs, shows that the simultaneous administration of multiple drugs worked well.That the intranasal filtration was low is an important finding considering that devices for oropharyngeal delivery in dogs are applied in order to eliminate intranasal filtration. Oropharyngeal dosing is more invasive compared with oronasal dosing and avoiding utilizing that method can be considered a refinement measure from an animal research perspective.