Miracle-dz/UniFAR-FTUs huggingface dataset:
The development of a humanised mouse model of ANCA associated vasculitis

2 Anti-neutrophil cytoplasmic autoantibodies (ANCA), targeting the neutrophil protein granules myeloperoxidase (MPO) and proteinase 3 (PR3), activate neutrophils in vitro, and are associated with a systemic autoimmune vasculitis, in which a pauci-immune crescentic glomerulonephritis is common. The in vivo study of ANCA pathogenesis is severely limited, both by the lack of a robust anti-PR3 IgG induced disease model, and by the differences found between human and mouse biology. Therefore the development of a disease model based on humanised mice, defined as mice possessing human immune cells, has the potential to overcome these limitations, while also allowing the direct study of human ANCA in vivo. The aims of this thesis were 1) to establish in vitro assays of ANCA induced neutrophil activation, and thus allow the study of ANCA:neutrophil interactions and 2) to establish a humanised mouse model of ANCA vasculitis. ANCA were purified from patient plasma, and two human neutrophil respiratory burst assays were developed. Subsequently, it was shown that Granulocyte Colony Stimulating Factor (GCSF) primes neutrophils for an anti-MPO induced respiratory burst, and the inhibition of phosphoinositol 3-kinase β/δ abrogates the ANCA induced release of superoxide. Humanised mice were produced by the engraftment of human haematopoietic stem cells into irradiated, adult NOD-scid IL2rγ mice. At least 8 weeks later a population of human neutrophils were identified by flow cytometry, and this population was expanded by treatment with GCSF. It was shown that these cells could respond to inflammatory stimuli in vivo, by modulating their expression of activation markers, and in vitro, by undergoing respiratory burst and degranulation. Patient derived ANCA was passively transferred into humanised mice that had been primed with GCSF and lipopolysaccharide. Mice were culled 7 days later, but there was no histological or biochemical evidence of disease. Thus, this work has identified GCSF and phosphoinositol-3-kinase β/δ as molecules of potential importance in ANCA vasculitis. Furthermore, the passive transfer of patient ANCA into humanised mice did not prove pathogenic in this study, and possible reasons for this are discussed. The demonstration of functional responses in human neutrophils does, however, suggest that this humanised mouse model has the potential be useful for the study of human neutrophils in vivo.
Cleft lip repair: are outcomes between unilateral and bilateral clefts comparable?

Abstract This study sought to compare patient demographics, operative course, and peri-operative outcomes between unilateral and bilateral cleft patients. Primary cleft lip repairs were isolated from the National Surgical Quality Improvement Program Pediatric Database (NSQIP-P). Unilateral and bilateral cases of primary cleft lip were identified by ICD codes. Demographics, comorbidities, and post-operative outcomes were compared between cohorts. Patients were propensity matched to control for differences before repeating the analysis. About 4550 cleft lip repairs were evaluated over the 5-year period. Of the cases where the cleft type was identifiable, 75.5% were unilateral clefts and 24.5% were bilateral clefts. The bilateral cleft population had significantly more comorbidities including higher rates of ventilator dependence (1.0% versus 0.4%, p = 0.02), asthma (1.6% versus 0.7%, p = 0.011), tracheostomy (1.6% versus 0.5%, p < 0.001), gastrointestinal disease (16.9% versus 12.7%, p < 0.001), previous cardiac surgery (3.6% versus 2.2%, p = 0.015), developmental delay (9.9% versus 4.6%, p < 0.001), structural central nervous system abnormalities (5.0% versus 2.5%, p < 0.001), and nutritional support (8.0% versus 3.2%, p < 0.001). Following propensity matching, there were no significant differences in complications, readmissions, or reoperations between the cohorts. Patients with bilateral cleft lip have significantly more comorbidities than unilateral cleft lip patients. However, peri-operative outcomes are comparable between the groups.
Stressful Life Events and Negative Emotions on Delinquency Among Korean Youth: An Empirical Test of General Strain Theory Assessing Longitudinal Mediation Analysis

The current study examines the extent to which the argument of Agnew’s general strain theory extends to a sample of South Korean youth to be able to explain the hypothesized direct and indirect/mediated effects of negative emotions derived from various negative life experiences of strain on delinquent behaviors. These experiences can include bullying victimization, parental abuse, poor friend quality, and poor physical functioning. Data for this study were compiled from the Korean Welfare Panel Study (KOWEPS), which is a longitudinal study among 7,027 Korean households surveyed from 2006 through 2012. This study utilizes the longitudinal mediation models for temporal precedence. Results reveal that adolescents with poor-quality friends during the previous year are more likely to engage in later delinquency, and adolescents who experience bullying victimization, child abuse, and poor friendship quality during the previous year are more likely to later feel negative emotions. Furthermore, early feelings of negative emotions are significantly related to later delinquent behaviors and partially mediate the link between poor friend quality and later delinquent behaviors. Finally, bullying victimization, child abuse, and poor friend quality generated negative emotions, which led to a greater likelihood of delinquent behavior later.
Only minor stem cell mobilization in head and neck irradiated patients treated with hyperbaric oxygen.

INTRODUCTION Hyperbaric oxygen, (HBO) is used to treat several conditions including late radiation tissue injury. Previous studies have suggested that HBO mobilizes bone marrow derived stem/progenitor cells (SPC) to the peripheral blood, however possible cumulative effects were highly variable. METHODS We have investigated a possible HBO-induced mobilization of SPCs by determining CD34+CD45dim cell numbers, as well as SPCs in general. The latter were characterized by high aldehyde dehydrogenase (ALDH) activity by use of the Aldefluor® assay. We included ten patients admitted for HBO treatment of radiation tissue injury. Six patients completed the 29-30 HBO treatment exposures. We also investigated possible HBO-induced effects on platelet activation as measured by flow cytometry and functional analyses. RESULTS We found a weak and insignificant tendency toward mobilization of CD34+CD45dim cells after a single HBO exposure versus before. Additionally, we found an additive effect of 15 HBO exposures on the increase in CD34+CD45dim cells relative to the pre-1st-HBO values. These changes were significantly more than zero but less than a doubling. We could not demonstrate a significant effect of HBO on the content of Aldefluor® positive SPCs in peripheral blood. There was no significant effect on platelet activation overall. However, in patients with increased expression of activation markers at baseline, we found a decrease after one exposure although this was not reflected in functional tests. CONCLUSION We found a minor statistically significant mobilizing effect of HBO treatment on the bone marrow derived stem/progenitor cell content in peripheral blood after 15 treatments (n = 10 patients), but no effect after 30 treatments (n = 6 patients). However, because of the low number of patients we cannot confidentially prove or disprove the null hypothesis. The possibility that HBO treatment reduces the number of activated platelets could not be demonstrated nor excluded.
Mitomycin and 5‐fluorouracil for second‐line treatment of metastatic squamous cell carcinomas of the anal canal

Metastatic squamous cell carcinomas (SCC) of the anal canal are rare and there is no international consensus on their second‐line management. 5‐Fluorouracil (5‐FU) and mitomycin in combination with radiotherapy is the standard for locally advanced forms but its efficacy in metastatic stage has never been evaluated.
Muscle Architecture and Neuromuscular Changes After High-Resistance Circuit Training in Hypoxia

Abstract Ramos-Campo, DJ, Martínez-Guardado, I, Rubio-Arias, JA, Freitas, TT, Othalawa, S, Andreu, L, Timón, R, and Alcaraz, PE. Muscle architecture and neuromuscular changes after high-resistance circuit training in hypoxia. J Strength Cond Res 35(11): 3035–3040, 2021—This study aimed to analyze the effect of 8 weeks of high-resistance circuit (HRC) training in hypoxia on muscle architecture, strength, and neuromuscular variables. Twenty-eight resistance-trained subjects were assigned to a hypoxia (FiO2 = 15%; HG: n = 15; age: 24.6 ± 6.8 years; height: 177.4 ± 5.9 cm; and mass: 74.9 ± 11.5 kg) or normoxia group (FiO2 = 20.9%; NG: n = 13; age: 23.2 ± 5.2 years; height: 173.4 ± 6.2 cm; and mass: 69.4 ± 7.4 kg). Each training session consisted of 2 blocks of 3 exercises (block 1: bench press, leg extension, and front lat pulldown; block 2: deadlift, elbow flexion, and ankle extension). Each exercise was performed with a 6 repetition maximum load. Subjects exercised twice weekly and, before and after the training program, vastus lateralis muscle thickness and pennation angle, knee extensors electromyographic activity, maximum voluntary contraction (MVC), and rate of force development (RFD) and H-Reflex (Hmax), M-wave of the soleus muscle were assessed. Both training groups showed similar improvements in muscle thickness (effect size [ES] = HG: 0.23; NG: 0.41), pennation angle (ES = HG: 0.86; NG: 0.15), MVC (ES HG: 0.63; NG: 0.61), Hmax (ES = HG: 0.96; NG: 0.40), RFD at 200 milliseconds (ES = HG: 0.31; NG: 0.61) and peak RFD (ES = HG: 0.21; NG: 0.66). No significant between-group differences were found. In conclusion, similar morphological and neuromuscular adaptations can be achieved after 8 weeks of HRC training under hypoxic or normoxic conditions.
Metabolic Syndrome and Mortality in Continuous Ambulatory Peritoneal Dialysis Patients: A 5-Year Prospective Cohort Study

Background/Aims: Metabolic syndrome (MS) has been widely proved as a predictor of cardiovascular disease, all-cause, and cardiovascular mortality in general population. But its effects on mortality and technique failure have not been well illustrated in peritoneal dialysis (PD) patients. We aimed to investigate the association of MS and clinical outcomes in Chinese continuous ambulatory PD (CAPD) patients. Methods: A single-center, prospective, observational cohort study was conducted in CAPD patients enrolled from September 1 to December 31, 2011, and followed up until December 31, 2016. Demographic, clinical, biochemical and anthropological data were collected. The relationships between MS and mortality and technique failure were assessed using Kaplan-Meier and Cox Regression Survival Functions. Results: A total of 511 patients were enrolled. The baseline mean age was 48.4 ± 14.4 years, 282 patients (55.2%) were male, and 130 patients (25.4%) were diabetic. In total, 213 patients (41.7%) met the diagnostic criterion of MS. During a median of 4.4 years (interquartile range 2.3–5.3 years) follow-up period, 114 patients died, of whom, 65 patients (48%) died in MS group versus 49 patients (30%) in non-MS group. Patients who died tended to be older, higher in inflammation markers and with poorer nutritional state. Kaplan-Meier Survival Functions found patients with MS had a significant rising of all-cause mortality (log-rank test = 12.811, p < 0.001) and cardiovascular mortality (log-rank test = 14.529, p < 0.001) in all patients, and a significant rising of cardiovascular mortality (log-rank test = 4.486, p = 0.034) in non-diabetic patients. After adjusting for confounders, Cox Regression showed that MS was significantly associated with higher cardiovascular mortality in all patients (hazard ratio [HR] 2.21, 95% CI 1.12–4.36, p = 0.022) and in non-diabetic patients (HR 2.60, 95% CI 1.07–6.35, p = 0.036), but it has no significant effect on technique failure. Conclusion: In CAPD patients, MS predicted mortality, especially cardiovascular mortality. No relationship was found between MS and technique survival.
R3hdml regulates satellite cell proliferation and differentiation

In this study, we identified a previously uncharacterized skeletal satellite cell‐secreted protein, R3h domain containing‐like (R3hdml). Expression of R3hdml increases during skeletal muscle development and differentiation in mice. Body weight and skeletal muscle mass of R3hdml knockout (KO) mice are lower compared to control mice. Expression levels of cell cycle‐related markers, phosphorylation of Akt, and expression of insulin‐like growth factor within the skeletal muscle are reduced in R3hdml KO mice compared to control mice. Expression of R3hdml increases during muscle regeneration in response to cardiotoxin (CTX)‐induced muscle injury. Recovery of handgrip strength after CTX injection was significantly impaired in R3hdml KO mice, which is rescued by R3hdml. Our results indicate that R3hdml is required for skeletal muscle development, regeneration, and, in particular, satellite cell proliferation and differentiation.
Relationship Between Subjective Reports of Temporary Threshold Shift and the Prevalence of Hearing Problems in Military Personnel

Traditional hearing conservation programs are based on the premise that noise dose, as measured by the time-weighted average noise level, is the primary risk factor associated with occupational hearing loss and that permanent threshold shifts are the most relevant outcome measures for determining when a noise-related hearing loss has occurred. However, recent studies in animal models have suggested that significant neurological damage to the hearing system can occur from noise exposures even when they are not severe enough to result in permanent threshold shifts. This has led to a number of studies attempting to relate subjective measures of noise exposure to subjective measures of hearing difficulty and suprathreshold measures of hearing performance (e.g., speech-in-noise tests). In this study, 3,330 U.S. service members volunteered to complete a survey on noise exposure, subjective hearing complaints, and tinnitus in conjunction with their annual hearing tests. Two questions were also included about the frequency and duration of temporary hearing losses that may have been experienced by the service member. The results show that subjective reports of temporary threshold shifts were substantially more predictive of tinnitus and other hearing complaints than more traditional questions based on the frequency of noise exposure.
Alcohol's dysregulation of maternal-fetal IL-6 and p-STAT3 is a function of maternal iron status.

BACKGROUND Prenatal alcohol exposure (PAE) causes long-term growth and neurodevelopmental deficits that are worsened by maternal iron deficiency (ID). In our preclinical rat model, PAE causes fetal anemia, brain ID, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron-fortified (IF) diet. Here, we hypothesize that iron status and PAE dysregulate the major upstream pathways that govern hepcidin production - EPO/BMP6/SMAD and IL-6/JAK2/STAT3. METHODS Pregnant, Long-Evans rat dams consumed ID (2-6ppm iron), iron-sufficient (IS, 100ppm iron), or IF (500ppm iron) diets and received alcohol (5 g/kg) or isocaloric maltodextrin daily from gestational days (GD) 13.5-19.5. Protein and gene expression were quantified in the six experimental groups at GD 20.5. RESULTS PAE did not affect Epo or Bmp6 expression, but reduced p-SMAD1/5/8/SMAD1/5/8 protein ratios in both IS and ID maternal and fetal liver (all P's<0.01). In contrast, PAE stimulated maternal hepatic expression of Il-6 (P=0.03), and elevated p-STAT3/STAT3 protein ratios in both IS and ID maternal and fetal liver (all P's<0.02). PAE modestly elevated maternal Il-1β, Tnf-α, and Ifn-γ. Fetal cytokine responses to PAE were muted compared with dams, and PAE did not affect hepatic Il-6 (P=0.78) in IS and ID fetuses. Dietary iron fortification sharply attenuated Il-6 expression in response to PAE, with IF driving a 150-fold decrease (P<0.001) in maternal liver and a 10-fold decrease (P<0.01) in fetal liver. The IF diet also normalized p-STAT3/STAT3 ratios in both maternal and fetal liver. CONCLUSIONS These findings suggest that alcohol-driven stimulation of the IL-6/JAK2/STAT3 pathway mediates the elevated hepcidin observed in the PAE dam and fetus. Normalization of these signals by IF suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL-6/JAK2/STAT3 pathway. Prenatal dietary IF represents a potential therapeutic approach for PAE that warrants further investigation.
Metabolically healthy obesity: facts and fantasies.

Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered "metabolically healthy. " However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO - specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.
Using a Composite Graft of Natural 15% Chitosan Gel in the Management of Intrabony Defects: A Case Series.

INTRODUCTION The purpose of this study was to compare effects of smoking and smokeless forms of tobacco consumption (tobacco chewing) on periodontal disease parameters and response of these subjects to non-surgical periodontal therapy. MATERIALS AND METHODS Ten patients aged between 30 and 55 years with intrabony defects greater than or equal to 3 mm and pocket probing depth (PPD) greater than or equal to 5 mm were selected. All participants received chitosan gel (15% w/v) plus bovine porous bone mineral as a composite bone graft. Clinical and radiographic measurements were recorded at baseline, 3 months after healing and at 6 and 9 months. Significance was set at 0.05. RESULTS After nine months, all the defects treated with this combination showed PPD reduction of 5.30 ± 0.822 mm, relative clinical attachment level (CAL) gain of 5.80 ± 0.499 mm, reduction in intrabony defect (IBD) depth of 3.00 ± 0.497 mm and defect resolution of 78.32 ± 5.80 %, all of which were statistically significant. CONCLUSION Within the limits of this study, this case series study suggests that chitosan gel, along with bovine porous bone mineral, has a promising role to play in periodontal regeneration.
Anti-nociceptive and anti-inflammatory effect of imperatorin: evidences for involvement of COX-2, iNOS, NFκB and inflammatory cytokines

Abstract Aim: The objective of the current investigation was to explore the analgesic effect of naturally occurring furanocoumarin, imperatorin and the involvement of inducible cyclooxygenase (COX-2), inducible nitric oxide synthase (iNOS), NFκB and cytokines in the observed effect. Materials and methods: Anti-nociceptive effect was explored by inducing chemical hyperalgesia using acetic acid and formalin in mice. ED50 of imperatorin was calculated in acetic acid model. Modulation of cyclooxygenase and nitric oxide pathway by imperatorin was examined by stimulator/precursor challenge with substance P and L-arginine, respectively and quantification of COX-2, iNOS and NFκB expression by immunohistochemical analysis in spinal tissues. Involvement of inflammatory cytokines TNF-α and IL-1β was investigated using LPS challenge and subsequent ELISA analysis of these inflammatory mediators in serum. Carrageenan inflicted paw edema was employed to explore the anti-inflammatory activity of imperatorin. Results: A significant reduction in the nociceptive behaviour was observed with imperatorin treatment in acetic acid and formalin test. ED50 of imperatorin was found to be 4.53 mg/kg. Pre-treatment with substance P and L-arginine significantly attenuated the anti-nociceptive activity of imperatorin in formalin test. Immunohistochemical findings revealed marked decrease in spinal COX-2, iNOS and NFκB expression. Imperatorin administration significantly reduced LPS induced rise in level of TNF-α and IL-1β dose dependently. In carrageenan-induced paw edema test, maximum possible anti-inflammatory effect of imperatorin was evident after 240 min of carrageenan administration. Conclusion: Current investigation revealed that anti-nociceptive and anti-inflammatory potential of imperatorin is probably mediated through the attenuation of COX-2, iNOS, NFκB activity and reduction in circulatory cytokines.
In a Search of Pressure Which Optimizes Autoregulation of Cerebral Blood Flow.

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