Miracle-dz/UniFAR-FTUs huggingface dataset:
The potential gonadoprotective effects of grape seed extract against the histopathological alterations elicited in an animal model of cadmium-induced testicular toxicity.

BACKGROUND Grape seed extract (GSE) is a powerful antioxidant containing high levels of bioflavonoids, vitamin C and vitamin E. The aim of the work is to study the possible protective and ameliorative effects of grape seed extract in an animal model of cadmium (Cd)-induced testicular toxicity in rats. MATERIALS AND METHODS A thirty-day oral gavage study in adult male albino rats was performed using 32 animals, randomly divided into 4 equal groups; negative control, cadmium (5 mg/k/day), grape seed extract (100 mg/k/day), and cadmium + GSE. Testicular weights were measured. Hematoxylin & eosin (H&E) staining and proliferating nuclear cell antigen (PCNA) immunohistochemistry, as a marker for proliferation were done. Morphometric parameters were assessed and subjected to statistical analysis. RESULTS The H&E results showed atrophy and distortion of the seminiferous tubules (STs) with sloughing of the spermatogenic epithelium in cadmium group. The interstitial spaces were widened and showed edema and mononuclear cell infiltrations. No remarkable changes were observed in the grape-seed-only group when compared to the control group. In both combined group, maintaining of the STs and their lining cells was evident. The immunohistochemical results showed marked positive PCNA immunoreactivity in both control and GSE groups, while negative immunoreaction was noticed in Cd group. Limited positive PCNA immunoreactivity was ameliorated in Cd+ GSE group. CONCLUSIONS GSE protected against cadmium-induced testicular toxicity in rats, reducing induced histopathological changes, and maintaining testicular histoarchitecture.
Mechanosensitive Ca2+ signaling and coordination is diminished in osteocytes of aged mice during ex vivo tibial loading

ABSTRACT Purpose: The osteocyte is considered the major mechanosensor in bone, capable of detecting forces at a cellular level to coordinate bone formation and resorption. The pathology of age-related bone loss, a hallmark of osteoporosis, is attributed in part to impaired osteocyte mechanosensing. However, real-time evidence of the effect of aging on osteocyte responses to mechanical load is lacking. Intracellular calcium (Ca2+) oscillations have been characterized as an early mechanosensitive response in osteocytes in systems of multiple scales and thus can serve as a real-time measure of osteocyte mechanosensitivity. Our objective was to utilize an ex vivo model to investigate potentially altered mechanosensing in the osteocyte network with aging. Methods: Tibiae were explanted from young-adult (5 mo) and aged (22 mo) female mice and incubated with Fluo-8 AM to visualize osteocyte intracellular Ca2+. Whole tibiae were cyclically loaded while in situ osteocyte Ca2+ dynamics were simultaneously imaged with confocal microscopy. Responsive osteocyte percentage and Ca2+ peak characteristics were quantified, as well as signaling synchrony between paired cells in the field of view. Results: Fewer osteocytes responded to mechanical loading in aged mice compared to young-adult and did so in a delayed manner. Osteocytes from aged mice also lacked the well-correlated relationship between Ca2+ signaling synchrony and cell-cell distance exhibited by young-adult osteocytes. Conclusions: We have demonstrated, for the first time, real-time evidence of the diminished mechanosensing and lack of signaling coordination in aged osteocyte networks in tibial explants, which may contribute to pathology of age-induced bone loss.
Tuberculoid leprosy: An in vivo microvascular evaluation of cutaneous lesions

Tuberculoid leprosy (TT) is characterized by cutaneous lesions called plaques. Although microvascular ultrastructure of TT patients’ skin is well-documented, little is known about functional aspects of their microcirculation. We aimed, for the first time, to evaluate, in vivo, the microcirculation of TT cutaneous lesions. Seven TT patients, males, under treatment were included in the study. The spectral analysis of frequency components of flowmotion (endothelial, sympathetic, myogenic, cardiac and respiratory) was performed using laser Doppler flowmetry (LDF). Endothelial dependent and independent vasodilatations were assessed by LDF associated to acetylcholine (ACh) and sodium nitroprusside (SNP) iontophoresis, respectively. Vessel density (VD), perfused vessel density (PVD), proportion of perfused vessels (PPV%), microvascular flow index (MFI) and flow heterogeneity index (FHI), reflecting tissue perfusion and oxygenation, were evaluated through sidestream dark field (SDF) imaging. All microvascular analysis were performed in TT lesions and in healthy skin in the contralateral limb of the same patient, used as control skin. VD, PVD and PPV% and MFI were significantly lower in the cutaneous lesion compared to contralateral healthy skin. The contribution of different frequency components of flowmotion, endothelial dependent and independent vasodilatations and FHI were not statistically different between control skin and cutaneous lesion. Our results suggest that TT cutaneous lesions have a significant impairment of tissue perfusion, which may aggravate peripheral nerve degeneration caused by Mycobacterium leprae infection.
Utilization of echocardiography during septic shock was associated with a decreased 28-day mortality: a propensity score-matched analysis of the MIMIC-III database.

Background Hemodynamic management is of paramount importance in patients with septic shock. Echocardiography has been increasingly used in assessing volume status and cardiac function. However, whether the utilization of echocardiography has an impact on prognosis is unknown. Thus, we intended to explore its effect on the outcomes of patients with septic shock. Methods The study was based on the Medical Information Mart for Intensive Care (MIMIC) III database. Septic shock patients were divided into two groups according to the usage of echocardiography during the onset of septic shock. The primary outcome was 28-day mortality. Secondary outcomes included the usage of inotropes, ventilation-free and norepinephrine-free time, and fluids input. Propensity-score matching was used to reduce the imbalance. Results Among 3,291 eligible patients, 1,289 patients who underwent echocardiography (Echo), and 1,289 who did not receive the Echo, had similar propensity scores and were included in the analyses. After matching, the Echo group had a significantly lower 28-day mortality (33.2% vs. 37.7%, P=0.019). More patients in the Echo group received pulmonary artery catheter (PAC) (4.2% vs. 0.2%, P<0.001) and inotropes (17.8% vs. 7.1%, P<0.001). In the survival analysis, Echo utilization was associated with improved 28-day mortality [hazard ratio (HR): 0.83; 95% confidence interval (CI), 0.73-0.95, P=0.005]. A reduced likelihood of 28-day mortality in patients with Echo vs. those without Echo was maintained either when excluding patients receiving multiple echocardiography scans (HR, 0.82; 95% CI, 0.72-0.94; P=0.004) or when excluding patients undergoing PAC or pulse index continuous cardiac output (PiCCO) (HR, 0.87; 95% CI, 0.76-0.99; P=0.034). Conclusions Utilization of echocardiography was associated with improved 28-day outcomes in patients with septic shock.
Effects of Prehypnotic Instructions on Hypnotizability and Relationships Between Hypnotizability, Absorption, and Empathy

Although hypnotizability exhibits high across-time and across-test consistencies, it is not clear (a) how different preambles to a hypnotic procedure (metasuggestions) influence responsiveness to suggestions and the strength of the association between two hypnotizability scales and (b) how hypnotizability relates to absorption and empathy. In Experiment 1, nonclinical participants (N = 152 women) were administered the Modified Tellegen Absorption Scale (MODTAS), Interpersonal Reactivity Index (IRI), Hypnotic Induction Profile (HIP), and Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C). In Experiment 2, nonclinical participants (N = 188; 105 women and 83 men) were administered the MODTAS, IRI, and Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A). The induction scores of the HIP (HIP-IND) and the SHSS:C scores showed a significantly stronger correlation when the HIP was introduced to the participants after hypnosis metasuggestion (HIP-H-IND) than after imagination metasuggestion (HIP-I-IND). Metasuggestion was a moderator of the association between HIP-IND and SHSS:C scores. Participants with low and medium, but not with high, hypnotizability levels on the SHSS:C showed significantly higher scores on the HIP-I-IND than on the HIP-H-IND. The strong correlations between the SHSS:C, HIP-H-IND, and HIP eye-roll (HIP-ER) scores indicate that both the HIP-H-IND and HIP-ER are robust measures of hypnotizability. Absorption and empathy were not significantly associated with hypnotizability. Women were more hypnotizable than men, as assessed by the HGSHS:A. The clinical relevance of metasuggestions, intended to increase responsiveness to suggestions, is discussed as a strategy to improve treatment outcomes.
Costs and Cost-Utility of Critical Care and Subsequent Health Care: A Multicenter Prospective Study*

Supplemental Digital Content is available in the text. Objectives: The number of critical care survivors is growing, but their long-term outcomes and resource use are poorly characterized. Estimating the cost-utility of critical care is necessary to ensure reasonable use of resources. The objective of this study was to analyze the long-term resource use and costs, and to estimate the cost-utility, of critical care. Design: Prospective observational study. Setting: Seventeen ICUs providing critical care to 85% of the Finnish adult population. Patients: Adult patients admitted to any of 17 Finnish ICUs from September 2011 to February 2012, enrolled in the Finnish Acute Kidney Injury (FINNAKI) study, and matched hospitalized controls from the same time period. Interventions: None. Measurements and Main Results: We primarily assessed total 3-year healthcare costs per quality-adjusted life-years at 3 years. We also estimated predicted life-time quality-adjusted life-years and described resource use and costs. The costing year was 2016. Of 2,869 patients, 1,839 (64.1%) survived the 3-year follow-up period. During the first year, 1,290 of 2,212 (58.3%) index episode survivors were rehospitalized. Median (interquartile range) 3-year cumulative costs per patient were $49,200 ($30,000–$85,700). ICU costs constituted 21.4% of the total costs during the 3-year follow-up. Compared with matched hospital controls, costs of the critically ill remained higher throughout the follow-up. Estimated total mean (95% CI) 3-year costs per 3-year quality-adjusted life-years were $46,000 ($44,700–$48,500) and per predicted life-time quality-adjusted life-years $8,460 ($8,060–8,870). Three-year costs per 3-year quality-adjusted life-years were $61,100 ($57,900–$64,400) for those with an estimated risk of in-hospital death exceeding 15% (based on the Simplified Acute Physiology Score II). Conclusions: Healthcare resource use was substantial after critical care and remained higher compared with matched hospital controls. Estimated cost-utility of critical care in Finland was of high value.
Effects of symmetric and asymmetric rapid maxillary expansion treatments on pharyngeal airway and sinus volume: A cone-beam computed tomography study.

OBJECTIVE To evaluate pharyngeal airway and maxillary sinus volumes following symmetric rapid maxillary expansion (RME) and asymmetric rapid maxillary expansion (ARME) treatment using cone-beam computed tomography (CBCT). MATERIALS AND METHODS The study consisted of 60 patients presenting to the orthodontics clinic with an indication that they required symmetric or asymmetric rapid maxillary expansion treatment. Individuals were included if they were aged 12-15 years and had symmetric (RME group; 14 girls, 16 boys) or asymmetric (ARME group; 16 girls, 14 boys) maxillary deficiency. Maxillary sinus volume (mm3) and pharyngeal airway volume (upper, lower, and total; mm3) were evaluated using CBCT records. The parameters were compared before treatment (T1) and after 3 months in retention (T2). RESULTS All measurements at T2 were increased significantly compared with T1 in the RME group (P < .05). In the ARME group, changes in the lower pharyngeal airway and the nonaffected maxillary sinus volumes (non-affected side of maxillary sinus volumes) were not significant; however, the other measurements increased significantly from T1 to T2 (P < .05). Intergroup comparisons revealed that total pharyngeal airway volume and total maxillary sinus volume changes were significantly greater in the RME group. CONCLUSIONS Pharyngeal airway and maxillary sinus volumes increased with both RME and ARME treatment. Both were found to be effective for treating transverse maxillary deficiency.
Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke

Objective We evaluated the interaction of serum folate and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on the risk of first ischemic stroke and on the efficacy of folic acid treatment in prevention of first ischemic stroke. Methods A total of 20,702 hypertensive adults were randomized to a double-blind treatment of daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months. Results Median values of folate and B12 concentrations at baseline were 8.1 ng/mL and 280.2 pmol/L, respectively. Over a median of 4.5 years, among those not receiving folic acid, participants with baseline serum B12 or serum folate above the median had a significantly lower risk of first ischemic stroke (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57–0.96), especially in those with MTHFR 677 CC genotype (wild-type) (HR, 0.49; 95% CI, 0.31–0.78). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B12 below the median (2.3% in enalapril-folic acid group vs 3.6% in enalapril-only group; HR, 0.62; 95% CI, 0.46–0.86), particularly in MTHFR 677 CC carriers (1.6% vs 4.9%; HR, 0.24; 95% CI, 0.11–0.55). However, TT homozygotes responded better with both folate and B12 levels above the median (HR, 0.28; 95% CI, 0.10–0.75). Conclusions The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B12. Effect of folic acid treatment was greatest in patients with low folate and B12 with the CC genotype, and with high folate and B12 with the TT genotype.
Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment

Chemotherapy resistance has become a hold back and major clinical challenge in osteosarcoma cancer. The alteration and subcellular distribution of apurinic/apyrimidinic endonuclease 1 (APE1) has been reported to be involved in chemotherapy resistance in many cancers. Here, we report that the cytoplasmic distribution of APE1 plays a key role in the sensitivity of combination platinum chemotherapy in osteosarcoma. Interestingly, the prevalence of cisplatin‐induced DNA damage and apoptosis in low cytoplasmic APE1 osteosarcoma cell lines was higher than in high expression of cytoplasmic APE1 cell lines. Overexpression of cytoplasmic APE1 protected the osteosarcoma cells from CDDP‐induced apoptosis. In addition, clinical data also show that the level of cytoplasmic APE1 was negatively associated with sensitivity to combination chemotherapy of cisplatin in osteosarcoma patients. Our findings suggest that cytoplasmic APE1 plays a significant role in chemotherapy resistance. This role is a supplement to the extranuclear function of APE1, and cytoplasmic APE1 expression level could be a promising predictor of platinum treatment prognosis for osteosarcoma patients.
Relative potency factor approach enables the use of in vitro information for estimation of human effect factors for nanoparticle toxicity in life-cycle impact assessment

Abstract The major theme of the NRC report “Toxicity Testing in the Twenty-first Century” is to replace animal testing by using alternative in vitro methods. Therefore, it can be expected that in the future in vivo data will be replaced with in vitro data. Hence, there is a need for new strategies to make use of the increasing amount of in vitro data when developing human toxicological effect factors (HEF) to characterize the impact category of human toxicity in life cycle assessment (LCA). Here, we present a new approach for deriving HEF for manufactured nanomaterials (MNMs) based on the combined use of in vitro toxicity data and a relative potency factor (RPF) approach. In vitro toxicity tests with nano-CuO, nano-Ag and nano-ZnO and their corresponding ions were performed on THP-1, CaCo-2 and Hep-G2 cell lines. The ratio of the here calculated EC50 of the ionic form and the nanoform corresponds to the Relative Potency Factor (RPF). Using this approach, HEFs (case/kgintake) for the aforementioned nanoparticles were obtained. Non-carcinogenic HEFs (case/kgintake) for exposure via ingestion of 5.9E-01, 7.5E-03 and 2.5 E-02 were calculated for nano-Ag, nano-CuO and nano-ZnO, respectively. The HEF values here proposed were compared with HEF values extrapolated from in vivo toxicity data reported in the literature. The here presented procedure is the most appropriate approximation currently available for using in vitro toxicity data on MNM for application in the field of LCIA.
Association of More Intensive Induction With Less Acute Rejection Following Intestinal Transplantation: Results of 445 Consecutive Cases From a Single Center

Background. In intestinal transplantation, acute cellular rejection (ACR) remains a significant challenge to achieving long-term graft survival. It is still not clear which are the most important prognostic factors. Methods. We performed a Cox multivariable analysis of the hazard rates of developing any ACR, severe ACR, and cause-specific graft loss during the first 60 months posttransplant among 445 consecutive intestinal transplant recipients at our institution since 1994. Of particular interest was to determine the prognostic influence of induction type: rabbit antithymocyte globulin (rATG; 2 mg/kg × 5)/rituximab (150 mg/m2 × 1; begun in 2013), alemtuzumab (2001–2011), and less intensive forms. Results. First ACR and severe ACR occurred in 61.3% (273/445) and 22.2% (99/445) of cases. The following 3 multivariable predictors were associated with significantly lower hazard rates of developing ACR and severe ACR: transplant type modified multivisceral or full multivisceral (P = 0.0009 and P < 0.000001), rATG/rituximab induction (P < 0.000001 and P < 0.01), and alemtuzumab induction (P = 0.004 and P = 0.07). For both ACR and severe ACR, the protective effects of rATG/rituximab and alemtuzumab were highly significant (P ≤ 0.000005 for ACR; P ≤ 0.01 for severe ACR) but only during the first 24 days posttransplant (when the ACR hazard rate was at its peak). The prognostic effects of rATG/rituximab and alemtuzumab on ACR/severe ACR disappeared beyond 24 days posttransplant (ie, nonproportional hazards). While significant protective effects of both rATG/rituximab and alemtuzumab existed during the first 6 months posttransplant for the hazard rate of graft loss-due-to-rejection (P = 0.01 and P = 0.003), rATG/rituximab was additionally associated with a consistently lower hazard rate of graft loss-due-to-infection (P = 0.003). All significant effects remained after controlling for the propensity-to-be-transplanted since 2013. Conclusions. More intensive induction was associated with a significant lowering of ACR risk, particularly during the early posttransplant period.
The Monoclonal Antibody NEO-201 Enhances Natural Killer Cell Cytotoxicity Against Tumor Cells Through Blockade of the Inhibitory CEACAM5/CEACAM1 Immune Checkpoint Pathway.

Background: Natural killer (NK) cells are essential to innate immunity and participate in cancer immune surveillance. Heterophilic interactions between carcinoembryonic antigen (CEA) on tumor cells and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on NK cells inhibit NK cell cytotoxicity against tumor cells. NEO-201 is a humanized IgG1 monoclonal antibody that recognizes members of CEACAM family, expressed specifically on a variety of human carcinoma cell lines and tumor tissues. This investigation was designed to determine whether the binding of NEO-201 with CEACAM5 on tumor cells can block the CEACAM5/CEACAM1 interaction to restore antitumor cytotoxicity of NK cells. Materials and Methods: In vitro functional assays, using various human tumor cell lines as target cells and NK-92 cells as effectors, were conducted to assess the ability of NEO-201 to block the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to enhance the in vitro killing of tumor cells by NK-92. NK-92 cells were used as a model of direct NK killing of tumor cells because they lack antibody-dependent cellular cytotoxicity activity. Results: Expression profiling revealed that various human carcinoma cell lines expressed different levels of CEACAM5+ and NEO-201+ cells. Addition of NEO-201 significantly enhanced NK-92 cell cytotoxicity against highly CEACAM5+/NEO-201+ expressing tumor cells, suggesting that its activity is correlated with the level of CEACAM5+/NEO-201+ expression. Conclusions: These findings demonstrate that NEO-201 can block the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to reverse CEACAM1-dependent inhibition of NK cytotoxicity.
Endothelial cells support osteogenesis in an in vitro vascularized bone model developed by 3D bioprinting

Bone is a highly vascularized tissue, in which vascularization and mineralization are concurrent processes during skeletal development. Indeed, both components should be included in any reliable and adherent in vitro model platform for the study of bone physiology and pathogenesis of skeletal disorders. To this end, we developed an in vitro vascularized bone model, using a gelatin-nanohydroxyapatite (gel-nHA) three-dimensional (3D) bioprinted scaffold. First, we seeded human mesenchymal stem cells (hMSCs) on the scaffold, which underwent osteogenic differentiation for 2 weeks. Then, we included lentiviral-GFP transfected human umbilical vein endothelial cells (HUVECs) within the 3D bioprinted scaffold macropores to form a capillary-like network during 2 more weeks of culture. We tested three experimental conditions: condition 1, bone constructs with HUVECs cultured in 1:1 osteogenic medium (OM): endothelial medium (EM); condition 2, bone constructs without HUVECs cultured in 1:1 OM:EM; condition 3: bone construct with HUVECs cultured in 1:1 growth medium:EM. All samples resulted in engineered bone matrix. In conditions 1 and 3, HUVECs formed tubular structures within the bone constructs, with the assembly of a complex capillary-like network visible by fluorescence microscopy in the live tissue and histology. CD31 immunostaining confirmed significant vascular lumen formation. Quantitative real-time PCR was used to quantify osteogenic differentiation and endothelial response. Alkaline phosphatase and runt-related transcription factor 2 upregulation confirmed early osteogenic commitment of hMSCs. Even when OM was removed under condition 3, we observed clear osteogenesis, which was notably accompanied by upregulation of osteopontin, vascular endothelial growth factor, and collagen type I. These findings indicate that we have successfully realized a bone model with robust vascularization in just 4 weeks of culture and we highlighted how the inclusion of endothelial cells more realistically supports osteogenesis. The approach reported here resulted in a biologically inspired in vitro model of bone vascularization, simulating de novo morphogenesis of capillary vessels occurring during tissue development.