Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

Pre-exercise protein intake is associated with reduced time in hypoglycaemia among adolescents with type 1 diabetes.

AIM: Secondary analyses were conducted from a randomized trial of an adaptive behavioural intervention to assess the relationship between protein intake (g and g/kg) consumed within 4 h before moderate-to-vigorous physical activity (MVPA) bouts and glycaemia during and following MVPA bouts among adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: Adolescents (n = 112) with T1D, 14.5 (13.8, 15.7) years of age and 36.6% overweight/obese, provided measures of glycaemia using continuous glucose monitoring [percentage of time above range (>180 mg/dl), time in range (70-180 mg/dl), time below range (TBR; <70 mg/dl)], self-reported physical activity (previous day physical activity recalls), and 24 h dietary recall data at baseline and 6 months post-intervention. Mixed effects regression models adjusted for design (randomization assignment, study site), demographic, clinical, anthropometric, dietary, physical activity and timing covariates estimated the association between pre-exercise protein intake on percentage of time above range, time in range and TBR during and following MVPA. RESULTS: Pre-exercise protein intakes of 10-19.9 g and >20 g were associated with an absolute reduction of -4.41% (p = .04) and -4.83% (p = .02) TBR during physical activity compared with those who did not consume protein before MVPA. Similarly, relative protein intakes of 0.125-0.249 g/kg and ≥0.25 g/kg were associated with -5.38% (p = .01) and -4.32% (p = .03) absolute reductions in TBR during physical activity. We did not observe a significant association between protein intake and measures of glycaemia following bouts of MVPA. CONCLUSIONS: Among adolescents with T1D, a dose of ≥10 g or ≥0.125 g/kg of protein within 4 h before MVPA may promote reduced time in hypoglycaemia during, but not following, physical activity.

Enterococcus faecalis in secondary apical periodontitis: Mechanisms of bacterial survival and disease persistence.

Enterococcus faecalis is a commensal bacterium commonly found in the human gastrointestinal tract. However, in individuals with compromised immune systems, the pathogen can lead to severe illness. This opportunistic pathogen is associated with secondary apical diseases and is adept at resisting antibiotics and other forms of treatment because of its numerous virulence factors. Enterococcus faecalis is capable of disrupting the normal functions of immune cells, thereby hindering the body's ability to eradicate the infection. However, intensive research is needed in further understanding the adverse immunomodulatory effects of E. faecalis. Potential strategies specific for eradicating E. faecalis have proven beneficial in the treatment of persistent secondary apical periodontitis.

Enhancing Methotrexate Delivery in the Brain by Mesoporous Silica Nanoparticles Functionalized with Cell-Penetrating Peptide using in Vivo and ex Vivo Monitoring.

The blood-brain barrier (BBB) acts as a physical/biochemical barrier that protects brain parenchyma from potential hazards exerted by different xenobiotics found in the systemic circulation. This barrier is created by "a lipophilic gate" as well as a series of highly organized influx/efflux mechanisms. The BBB bottleneck adversely affects the efficacy of chemotherapeutic agents in treating different CNS malignancies such as glioblastoma, an aggressive type of cancer affecting the brain. In the present study, mesoporous silica nanoparticles (MSNs) were conjugated with the transactivator of transcription (TAT) peptide, a cell-penetrating peptide, to produce MSN-NH-TAT with the aim of improving methotrexate (MTX) penetration into the brain. The TAT-modified nanosystem was characterized by Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and N2 adsorption-desorption analysis. In vitro hemolysis and cell viability studies confirmed the biocompatibility of the MSN-based nanocarriers. In addition, in vivo studies showed that the MTX-loaded MSN-NH-TAT improved brain-to-plasma concentration ratio, brain uptake clearance, and the drug's blood terminal half-life, compared with the use of free MTX. Taken together, the results of the present study indicate that MSN functionalization with TAT is crucial for delivery of MTX into the brain. The present nanosystem represents a promising alternative drug carrier to deliver MTX into the brain via overcoming the BBB.

LP2, a stable lanthipeptide derived from cAng-(1-7), exerts myeloprotective action in mice.

OBJECTIVES: Linear unstable angiotensins stimulate hematopoiesis. Here we address: (1) Is cyclic angiotensin-(1-7) myeloprotective in mice? (2) Is cyclic angiotensin-(1-7) stable in rat? (3) Does LP2, a cyclic angiotensin-(1-7) with an N-terminal d-lysine, exert myeloprotective action in tumor-bearing mice? MATERIALS AND METHODS: Cyclic angiotensin-(1-7)'s capacity to restore levels of blood platelets and white blood cells was studied in gemcitabine-treated mice. The stability of cyclic angiotensin-(1-7) in rat was measured in blood samples taken after injection or infusion. The capacity of LP2 to restore total bone marrow cell levels in mice after treatment with 5-fluoruracil was measured. In addition, the capacity of LP2 to counter anemia in tumor-bearing mice treated with erlotinib was measured. RESULTS: Cyclic angiotensin-(1-7) dose-dependently restored blood platelet levels in gemcitabine-treated mice, whereas its capacity to restore levels of white blood cells was less. In vivo aminoterminal breakdown of cyclic angiotensin-(1-7) yielded cyclic angiotensin-(2-7) and cyclic angiotensin-(3-7). LP2 significantly (p < .0001 at 100 µg/kg/day) restored bone marrow cell counts in mice after treatment with 5-fluoruracil. LP2 also significantly (p < .05) countered anemia in tumor-bearing mice treated with erlotinib. CONCLUSIONS: LP2 exerts myeloprotective action with perspectives for continuation of its clinical development.

Nanostructures for prevention, diagnosis, and treatment of viral respiratory infections: from influenza virus to SARS-CoV-2 variants.

Viruses are a major cause of mortality and socio-economic downfall despite the plethora of biopharmaceuticals designed for their eradication. Conventional antiviral therapies are often ineffective. Live-attenuated vaccines can pose a safety risk due to the possibility of pathogen reversion, whereas inactivated viral vaccines and subunit vaccines do not generate robust and sustained immune responses. Recent studies have demonstrated the potential of strategies that combine nanotechnology concepts with the diagnosis, prevention, and treatment of viral infectious diseases. The present review provides a comprehensive introduction to the different strains of viruses involved in respiratory diseases and presents an overview of recent advances in the diagnosis and treatment of viral infections based on nanotechnology concepts and applications. Discussions in diagnostic/therapeutic nanotechnology-based approaches will be focused on H1N1 influenza, respiratory syncytial virus, human parainfluenza virus type 3 infections, as well as COVID-19 infections caused by the SARS-CoV-2 virus Delta variant and new emerging Omicron variant.

Development and validation of a method for creating incomplete vertical root fracture in extracted teeth.

The present study reported a method for inducing incomplete root fracture in human extracted teeth for the purpose of evaluating the merits of different diagnostic imaging techniques. Thirty-five single-rooted teeth were inspected under magnification and transillumination to exclude previously fractured teeth. Tooth crowns were removed, and the root canals were prepared up to the ProTaper Next X4 (40.06) file. Each root was lined with wax and embedded in a polystyrene resin block. The setup was attached to a universal testing machine for pressing a customized conical wedge (diameter at tip: 0.6 mm; taper: 0.2 mm/mm) into the instrumented canal with a 2 kN load at 5 mm/min. The machine was programmed to stop after a sudden 10% drop in loading force. Each specimen was removed from the resin block and inspected under × 20 magnification and transillumination to identify the fracture characteristics (pattern, surfaces and root-third affected). The gap width of each specimen was measured at different locations along the fracture line. The protocol induced incomplete vertical root fractures in all specimens. Fracture widths were < 100 µm in all specimens (mean gap width: 34.9 µm). The proposed methodology was successful in inducing incomplete vertical root fractures with characteristics that resemble the clinical presentation of these conditions. The method is easy to execute, highly reproducible and helps to minimize bias in laboratory studies that aims to mimic vertical root fractures.

Altered transcriptional responses in the lungs of aged mice after influenza infection.

BACKGROUND: Influenza causes a serious infection in older individuals who are at the highest risk for mortality from this virus. Changes in the immune system with age are well known. This study used transcriptomic analysis to evaluate how aging specifically affects the functional host response to influenza in the lung. Adult (12-16 weeks) and aged (72-76 weeks) mice were infected with influenza and lungs were processed for RNA analysis. RESULTS: Older mice demonstrated a delayed anti-viral response on the level of transcription compared to adults, similar to the immunologic responses measured in prior work. The transcriptional differences, however, were evident days before observable differences in the protein responses described previously. The transcriptome response to influenza in aged mice was dominated by immunoglobulin genes and B cell markers compared to adult animals, suggesting immune dysregulation. Despite these differences, both groups of mice had highly similar transcriptional responses involving non-immune genes one day after inoculation and T cell genes during resolution. CONCLUSIONS: These results define a delayed and dysregulated immune response in the lungs of aged mice infected with influenza. The findings implicate B cells and immunoglobulins as markers or mechanisms of immune aging. In addition to discovering new therapeutic targets, the findings underscore the value of transcription studies and network analysis to characterize complex biological processes, and serve as a model to analyze the susceptibility of the elderly to infectious agents.

Anifrolumab for treatment of refractory cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is a spectrum of skin changes related to systemic lupus erythematosus (SLE), a family of autoimmunity manifesting characteristic multisystem inflammation and damage. Treatment of CLE continues to evolve, especially for patients with moderate to severe disease. Type 1 interferon (IFN-1) plays a significant role in CLE pathogenesis. Anifrolumab, a fully humanized monoclonal antibody, selectively binds and inhibits the IFN-α receptor 1. Evidence from multiple Phase II and III randomized trials resulted in approval for anifrolumab for treatment of moderate to severe SLE. We present a case series of three patients with refractory CLE significantly improved with anifrolumab. The patients were recruited via clinic interaction and treated with anifrolumab from January 2021 to April 2022. Each patient received at least 12 weeks of therapy. Treatment and follow-up is ongoing. Patients were eligible for the study if they were a patient of the UNC Hospital System with resistant CLE, defined as having received inadequate disease control with standard therapies, including antimalarials, disease-modifying agents and biologics. Outcome measures were improvement in patient-reported symptoms and physician observation of erythema and pigmentary changes. All cases demonstrated significant improvement in disease appearance, cutaneous involvement, and symptomology after treatment with 2 months of anifrolumab infusions. Anifrolumab shows great potential for improving CLE in patients who have failed standard of care and multiple treatment options, including those that have failed belimumab or those who smoke. This report highlights the value of anifrolumab in managing patients with refractory CLE.

Immunogenicity and Efficacy of Live-Attenuated Salmonella Typhimurium Vaccine Candidate CVD 1926 in a Rhesus Macaque Model of Gastroenteritis.

Salmonella Typhimurium is a common cause of foodborne gastroenteritis and a less frequent but important cause of invasive disease, especially in developing countries. In our previous work, we showed that a live-attenuated S. Typhimurium vaccine (CVD 1921) was safe and immunogenic in rhesus macaques, although shed for an unacceptably long period (10 days) postimmunization. Consequently, we engineered a new strain, CVD 1926, which was shown to be safe and immunogenic in mice, as well as less reactogenic in mice and human cell-derived organoids than CVD 1921. In this study, we assessed the reactogenicity and efficacy of CVD 1926 in rhesus macaques. Animals were given two doses of either CVD 1926 or saline perorally. The vaccine was well-tolerated, with shedding in stool limited to a mean of 5 days. All CVD 1926-immunized animals had both a serological and a T cell response to vaccination. At 4 weeks postimmunization, animals were challenged with wild-type S. Typhimurium I77. Unvaccinated (saline) animals had severe diarrhea, with two animals succumbing to infection. Animals receiving CVD 1926 were largely protected, with only one animal having moderate diarrhea. Vaccine efficacy in this gastroenteritis model was 80%. S. Typhimurium vaccine strain CVD 1926 was safe and effective in rhesus macaques and shed for a shorter period than other previously tested live-attenuated vaccine strains. This strain could be combined with other live-attenuated Salmonella vaccine strains to create a pan-Salmonella vaccine.

Nonspherical Metal-Based Nanoarchitectures: Synthesis and Impact of Size, Shape, and Composition on Their Biological Activity.

Metal-based nanoentities, apart from being indispensable research tools, have found extensive use in the industrial and biomedical arena. Because their biological impacts are governed by factors such as size, shape, and composition, such issues must be taken into account when these materials are incorporated into multi-component ensembles for clinical applications. The size and shape (rods, wires, sheets, tubes, and cages) of metallic nanostructures influence cell viability by virtue of their varied geometry and physicochemical interactions with mammalian cell membranes. The anisotropic properties of nonspherical metal-based nanoarchitectures render them exciting candidates for biomedical applications. Here, the size-, shape-, and composition-dependent properties of nonspherical metal-based nanoarchitectures are reviewed in the context of their potential applications in cancer diagnostics and therapeutics, as well as, in regenerative medicine. Strategies for the synthesis of nonspherical metal-based nanoarchitectures and their cytotoxicity and immunological profiles are also comprehensively appraised.

Stimuli-responsive transdermal microneedle patches.

Microneedle (MN) patches consisting of miniature needles have emerged as a promising tool to perforate the stratum corneum and translocate biomolecules into the dermis in a minimally invasive manner. Stimuli-responsive MN patches represent emerging drug delivery systems that release cargos on-demand as a response to internal or external triggers. In this review, a variety of stimuli-responsive MN patches for controlled drug release are introduced, covering the mechanisms of action toward different indications. Future opportunities and challenges with respect to clinical translation are also discussed.

Baseline reward processing and ventrostriatal dopamine function are associated with pramipexole response in depression.

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.

Bioactive Carboxymethyl Starch-Based Hydrogels Decorated with CuO Nanoparticles: Antioxidant and Antimicrobial Properties and Accelerated Wound Healing In Vivo.

In this study, nanocomposite hydrogels composed of sodium carboxymethylated starch (CMS)-containing CuO nanoparticles (CMS@CuO) were synthesized and used as experimental wound healing materials. The hydrogels were fabricated by a solution-casting technique using citric acid as a crosslinking agent. They were characterized by Fourier-transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and thermogravimetric analysis (TGA) to evaluate their physicochemical properties. In addition, swelling, antibacterial activities, antioxidant activities, cytotoxicity, and in vivo wound healing were investigated to evaluate the wound healing potential of the CMS@CuO nanocomposite hydrogels. Growth inhibition of the Gram-positive and Gram-negative pathogens, antioxidant activity, and swelling were observed in the CMS@CuO nanocomposite hydrogels containing 2 wt.% and 4 wt.% CuO nanoparticles. The hydrogel containing 2 wt.% CuO nanoparticles displayed low toxicity to human fibroblasts and exhibited good biocompatibility. Wounds created in rats and treated with the CMS@2%CuO nanocomposite hydrogel healed within 13 days, whereas wounds were still present when treated for the same time-period with CMS only. The impact of antibacterial and antioxidant activities on accelerating wound healing could be ascribed to the antibacterial and antioxidant activities of the nanocomposite hydrogel. Incorporation of CuO nanoparticles in the hydrogel improved its antibacterial properties, antioxidant activity, and degree of swelling. The present nanocomposite hydrogel has the potential to be used clinically as a novel wound healing material.

The Molecular Basis of COVID-19 Pathogenesis, Conventional and Nanomedicine Therapy.

In late 2019, a new member of the Coronaviridae family, officially designated as "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), emerged and spread rapidly. The Coronavirus Disease-19 (COVID-19) outbreak was accompanied by a high rate of morbidity and mortality worldwide and was declared a pandemic by the World Health Organization in March 2020. Within the Coronaviridae family, SARS-CoV-2 is considered to be the third most highly pathogenic virus that infects humans, following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Four major mechanisms are thought to be involved in COVID-19 pathogenesis, including the activation of the renin-angiotensin system (RAS) signaling pathway, oxidative stress and cell death, cytokine storm, and endothelial dysfunction. Following virus entry and RAS activation, acute respiratory distress syndrome develops with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In this review, blockers of angiotensin II receptor and/or PARP, PARG, and TRPM2, including vitamin D3, trehalose, tannins, flufenamic and mefenamic acid, and losartan, have been investigated for inhibiting RAS activation and quenching oxidative burst. Moreover, the application of organic and inorganic nanoparticles, including liposomes, dendrimers, quantum dots, and iron oxides, as therapeutic agents for SARS-CoV-2 were fully reviewed. In the present review, the clinical manifestations of COVID-19 are explained by focusing on molecular mechanisms. Potential therapeutic targets, including the RAS signaling pathway, PARP, PARG, and TRPM2, are also discussed in depth.

Disparate outer membrane exclusionary properties underlie intrinsic resistance to hydrophobic substances in Pseudomonas spp. isolated from surface waters under triclosan selection.

Representative members of surface water microbiota were obtained from three unrelated municipal sites in Oklahoma by direct plating under selection by the hydrophobic biocide triclosan. Multiple methods were employed to determine if intrinsic triclosan resistance reflected resistance to hydrophobic molecules by virtue of outer membrane impermeability. While all but one organism isolated in the absence of triclosan were able to initiate growth on MacConkey agar, only one was able to initiate significant growth with triclosan present. In contrast, all bacteria selected with triclosan were identified as Pseudomonas spp. using 16S RNA gene sequencing and exhibited growth comparable to Pseudomonas aeruginosa controls in the presence of hydrophobic antibacterial agents to include triclosan. Two representative bacteria isolated in the absence of triclosan allowed for greater outer membrane association with the fluorescent hydrophobic probe 1-N-phenylnapthylamine than did two triclosan-resistant isolates. Compound 48/80 disruption of outer membrane impermeability properties for hydrophobic substances either partially or fully sensitized nine of twelve intrinsically resistant isolates to triclosan. These data suggest that outer membrane exclusion underlies intrinsic resistance to triclosan in some, but not all Pseudomonas spp. isolated by selection from municipal surface waters and implicates the involvement of concomitant triclosan resistance mechanisms.

Effect of transcranial direct current stimulation (tDCS) on food craving and eating when using a control method that minimizes guessing of the real vs. control condition.

PURPOSE: Validation of transcranial direct current stimulation (tDCS) to treat obesity is hampered by evidence that participants can distinguish real from the traditional-control condition. Correctly guessing the real condition precludes knowing if it is neuromodulation or expectation that suppresses food craving and eating. Therefore, this study tested the putative efficacy of tDCS to the dorsolateral prefrontal cortex (DLPFC) to reduce food craving and eating when an alternative control condition was used that would be difficult to distinguish from the real condition. METHODS: N = 28 adults with a 26-50 BMI range received a typical 20-min 2 mA current session of tDCS targeting the DLPFC as the real condition and a same duration/current tDCS session targeting the sensorimotor cortex (SMC), a region not expected to affect appetite, as the control. Food image craving ratings, in-lab food consumption, and momentary ratings of physical sensations were measured. RESULTS: DLPFC failed to reduce food craving and consumption compared to SMC stimulation. When interviewed, 71% of participants were unable to guess real from control conditions. Those who guessed DLPFC tDCS as real attributed their guess to increased number and frequency of sensations. However, their sensation ratings during tDCS did not differ between conditions. CONCLUSIONS: The results question if tDCS suppresses craving and eating at all, or if the DLPFC is the best target to do so. The results also indicate that alternate-site constant stimulation as the control method may strengthen the scientific evaluation of tDCS to treat obesity. LEVEL OF EVIDENCE: Level I, experimental study.

Enterococcus faecalis Induces Differentiation of Immune-Aberrant Dendritic Cells from Murine Bone Marrow-Derived Stem Cells.

Enterococcus faecalis, long implicated in serious systemic infections and failure of root canal treatment, is a persistent inhabitant of oral periapical lesions. Dendritic cells (DCs) and other innate immune cells patrol the oral mucosa for infecting microbes. Dendritic cells are efficient at capturing microbes when immature, whereupon they can transform into potent antigen-presenting cells upon full maturation. Autophagy, a sophisticated intracellular process first described for elimination of damaged organelles, regulates DC maturation and other important immune functions of DCs. The present study examined how E. faecalis influences the differentiation of murine bone marrow-derived stem cells (BMSCs) into functional DCs in the presence of the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Although the viability and differentiation of DCs were not affected by E. faecalis, expression of the autophagy-related proteins ATG7, Beclin1, and LC3bI/II were significantly suppressed in an mTOR-dependent manner. Ultrastructurally, E. faecalis was identified in single-membrane vacuoles, some of which were in the process of binary fission. Bacterium-containing autophagosomes were absent within the cytoplasm. Accessory molecules (major histocompatibility complex class II [MHC-II], CD80, and CD86) and anti-inflammatory cytokine (transforming growth factor ß1 [TGF-ß1]) were suppressed in E. faecalis-induced DCs, while IL-1ß, tumor necrosis factor alpha (TNF-α), and IL-12 levels were upregulated. When pulsed with ovalbumin (OVA), the E. faecalis-induced DCs showed reduction in CD4+ OVA-specific OT-II T cell proliferation. It is concluded that E. faecalis promotes the differentiation of bone marrow stem cells into CD11c-positive DCs with aberrant immune functions while retaining the capability of proinflammatory cytokine induction.

The SENIEUR protocol and the efficacy of hepatitis B vaccination in healthy elderly persons by age, gender, and vaccine route.

BACKGROUND: Reduced response to hepatitis B vaccines is associated with aging, confounding and comorbid conditions, as well as inadvertent subcutaneous (SC) inoculation. We hypothesized that the antibody and T cell-mediated immune responses (T-CMI) of elderly adults to a vaccine intended for intramuscular (IM) administration would be attenuated when deposited into SC fat, independent of confounding conditions. RESULTS: Fifty-two healthy, community dwelling elderly adults (65-82 years), seronegative for HBV, were enrolled in the SENIEUR protocol as a strictly healthy population. These seniors were randomized to receive a licensed alum-adjuvanted recombinant HBV vaccine either SC or IM, with the inoculum site verified by imaging. The response rates, defined as hepatitis B surface antibodies (HBsAb) ≥10 IU/L, were significantly lower in the elderly than in young adults, a group of 12, healthy, 21-34-year-old volunteers. Moreover, elderly participants who received the vaccine IM were significantly more likely to be responders than those immunized SC (54% versus 16%, p = 0.008). The low seroconversion rate in the IM group progressively declined with increasing age, and responders had significantly lower HBsAb titers and limited isotype responses. Moreover, T-CMI (proliferation and cytokine production) were significantly reduced in both percentage of responders and intensity of the response for both Th1 and Th2 subsets in the elderly. CONCLUSIONS: Our data demonstrate the blunted immunogenicity of SC inoculation as measured by peak titers and response rates. Further, the qualitative and quantitative deficits in B- and T-CMI responses to primary alum adjuvanted protein antigens persisted even in strictly healthy elderly populations with verified IM placement compared to younger populations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04162223. Registered 14 November 2019. Retrospectively registered.

Borate bioactive glass prevents zoledronate-induced osteonecrosis of the jaw by restoring osteogenesis and angiogenesis.

OBJECTIVES: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of systemic nitrogen-containing bisphosphonate (N-BP) administration, which leads to osteonecrosis, pain, and infection. Despite much effort, effective remedies are yet to be established. This study aimed to investigate potential recovery effect of borate bioactive glass (BBG) in vitro and in vivo. METHODS: The effect of BBG on zoledronate-treated bone marrow mesenchymal cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) was explored by cell counting kit-8, EdU assay, flow cytometry, alkaline phosphatase staining, alizarin red staining, angiogenesis experiment, and real-time quantitative polymerase chain reaction. The preventive effect of BBG on zoledronate-induced osteonecrosis of the jaw in rat model was examined by micro-CT, HE staining, and immunohistochemistry. RESULTS: Exposure of BBG to BMSCs and HUVECs increased cell proliferation and restored their osteogenesis and angiogenesis potential in vitro. The BRONJ lesions were satisfactorily repaired and bone mineral density, bone volume/tissue volume, trabecula number, OCN-positive cells, and CD31-positive cells were increased in the BBG-treated groups compared with saline-treated groups. CONCLUSIONS: Exposure of BMSCs and HUVECs to BBG restores osteogenesis and angiogenesis inhibited by zoledronate. BBG successfully restores extraction socket healing of BRONJ in rat model.