Miracle-dz/UniFAR-FTUs huggingface dataset:
Vitamin C protects rat cerebellum and encephalon from oxidative stress following exposure to radiofrequency wave generated by a BTS antenna model

Abstract Radio frequency wave (RFW) generated by base transceiver station has been reported to produce deleterious effects on the central nervous system function, possibly through oxidative stress. This study was conducted to evaluate the effect of RFW-induced oxidative stress in the cerebellum and encephalon and the prophylactic effect of vitamin C on theses tissues by measuring the antioxidant enzymes activity, including: glutathione peroxidase, superoxide dismutase, catalase, and malondialdehyde (MDA). Thirty-two adult male Sprague-Dawley rats were randomly divided into four equal groups. The control group; the control-vitamin C group received L-ascorbic acid (200 mg/kg of body weight/day by gavage) for 45 days. The RFW group was exposed to RFW and the RFW+ vitamin C group was exposed to RFW and received vitamin C. At the end of the experiment, all groups were killed and encephalon and cerebellum of all rats were removed and stored at −70 °C for measurement of antioxidant enzymes activity and MDA. The results indicate that exposure to RFW in the test group decreased antioxidant enzymes activity and increased MDA compared with the control groups (p < 0.05). The protective role of vitamin C in the treated group improved antioxidant enzymes activity and reduced MDA compared with the test group (p < 0.05). It can be concluded that RFW causes oxidative stress in the brain and vitamin C improves the antioxidant enzymes activity and decreases MDA.
Obesity Affects the Liver – The Link between Adipocytes and Hepatocytes

The incidence of obesity has dramatically increased in recent years. Consequently, obesity and associated disorders such as nonalcoholic fatty liver disease (NAFLD) constitute a serious threat. Therefore, the contribution of visceral adipose tissue to metabolic homeostasis has become a focus of interest. Visceral adipose tissue secretes free fatty acids (FFAs) and hormones, known as adipokines, and thus seems to play a major role in the development of NAFLD. Apoptotic cell death is a prominent feature in nonalcoholic steatohepatitis (NASH). Indeed, toxic FFAs can activate the intrinsic apoptosis pathway in hepatocytes via c-Jun N-terminal kinase (JNK). JNK activates the proapoptotic protein Bim, resulting in Bax activation and enhanced apoptosis, termed ‘lipoapoptosis’. Reduced adiponectin levels may establish a proinflammatory milieu, thus increasing vulnerability to lipotoxicity, which promotes progression from simple steatosis to NASH and even advanced hepatic fibrosis. Moreover, obesity seems to be a risk factor for hepatocellular carcinoma, the most frequent liver cancer subtype. Even in acute liver failure, a high body mass index is associated with poor outcome, and recent data suggest a major role of obesity in the progression of chronic hepatitis C and B. This review summarizes current knowledge – highlighting the inflammatory and cytokine view – of the intimate relationship between adipose and liver tissue.
Homeobox B9 Mediates Resistance to Anti-VEGF Therapy in Colorectal Cancer Patients

Purpose: The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab. Experimental Design: HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoietin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFβ1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test. Results: HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly (P < 0.05) reduced Angptl2, CXCL1, IL8, and TGFβ1 levels, reverted their mesenchymal phenotype, reduced CD11b+ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006–4.125; P = 0.048). Conclusions: These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy. Clin Cancer Res; 23(15); 4312–22. ©2017 AACR.
Receipt of guideline-concordant pharmacotherapy among children with new diagnoses of bipolar disorder.

OBJECTIVE This study examined the extent to which children with bipolar I disorder received recommended treatment of mood-stabilizer or second-generation antipsychotic monotherapy and factors associated with its receipt. METHODS Administrative claims data collected from January 1, 2005, to December 31, 2007, were used to construct a cohort of 412 privately insured children with bipolar I disorder. The primary outcome measure was the receipt of mood-stabilizer or second-generation antipsychotic monotherapy within 90 days of an index diagnosis of bipolar disorder. RESULTS Only 82 (20%) children received recommended first-line treatment for bipolar I disorder within 90 days of the index diagnosis, and 130 (32%) received no psychotropic medications. Of children receiving any medications, 200 (71%) received nonrecommended pharmacotherapy, most commonly antidepressant monotherapy (N=67, 24%) and combination pharmacotherapy (N=51, 18%). Youths who had been treated by a psychiatrist on the day of or 180 days before the fill date of medication were more likely to receive guideline-recommended care (risk ratio [RR]=1.64, 95% confidence interval [CI]=1.10-2.45) and to receive any psychotropic medications (RR=1.13, CI=1.02-1.24). Nevertheless, only 51 of the 209 (24%) children who visited a psychiatrist and 31 of the 203 (15%) who visited a nonpsychiatrist received recommended pharmacotherapy. CONCLUSIONS This study highlights significant gaps in the treatment of pediatric bipolar disorder. Most children in this sample received either no medications or nonrecommended pharmacotherapies. Additional research is needed to further assess factors related to the nonuse of recommended psychotropic medications and to the persistent use of nonrecommended pharmacotherapies for children with bipolar disorder.
Comparative Effectiveness of Two Tiotropium Formulations: A Retrospective Cohort Study

Abstract The effectiveness of the tiotropium Respimat® formulation in routine clinical practice is still an open issue due to concern about the generalizability of the Tiotropium Safety and Performance in Respimat® (TIOSPIR) trial findings. Our aim was to compare the incidence of acute respiratory events between new users of tiotropium Respimat® and HandiHaler®. The study population comprised patients aged ≥45 years resident in two Italian regions who received a first tiotropium prescription (HandiHaler® or Respimat®) between 1 July 2011 and 30 November 2013. The cohort was identified within the database of drug prescriptions reimbursed by the Italian National Health Service. Clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for respiratory events, including chronic obstructive pulmonary disease (COPD) exacerbation, respiratory failure, hypoxemia/hyperventilation and pneumonia, during the exposure period. The hazard ratios were estimated for the propensity score matched groups with Cox regression. After matching, 31,334 patients with incident tiotropium prescriptions were included. Similar incidence rates of the primary outcome between the Respimat® and HandiHaler® users were identified (adjusted hazard ratio 0.95, 95% CI 0.84–1.07). No differences emerged in the subgroup analyses conducted according to the baseline characteristics of the tiotropium users. This study confirms the findings observed in the TIOSPIR trial in a more heterogeneous population that included patient subgroups with severe respiratory disease and unstable COPD.
Foliar and stem epidermal anatomy of the tribe Cynoglosseae (Boraginaceae) and their taxonomic significance

Foliar and stem epidermal anatomical features of the tribe Cynoglosseae have been studied in detail for the taxonomic identification using light microscopy (LM) and scanning electron microscopic (SEM) techniques. A comparative study was conducted on different plant parts (leaf and stem epidermal anatomy) of 25 species belonging to eight genera of the tribe Cynoglosseae (Boraginaceae) collected from different phytogeographical regions of Iran for the first time. Different qualitative and quantitative characteristics were observed in detail using LM and SEM. Results showed that although generally the stem and leaf anatomical traits were similar, but some diagnostic features were examined for distinguishing the closely related genera in the tribe. The ratio of cortex/diameter of stem and phloem/xylem, the average row number of collenchyma, palisade and spongy cells, structure of trichomes, type of indumentum and palisade arrangement were found taxonomically important. The anatomical characters were statistically analyzed using cluster analysis and principal component analysis. The study found that stem and leaf eccentrics are variable in the genus but constant within species of the same genus. Most species had typical isobilateral leaves, but some showed an incipient dorsoventrally symmetry with a layer of abaxial palisade tissue. Eglandular trichomes were observed found in all the studied species, which were recognized based on structure and function. In present study some novel characters have been observed which are of great interest to the taxonomist for the correct identification some genera delimitations. The characters studied here are of less taxonomic value and delimitating at species level.
of patient global assessment on achieving remission in patients with rheumatoid arthritis: a multinational study using the METEOR database.

Objectives : There is an on-going debate about excluding patient global assessment (PGA) from composite and Boolean-based definitions of rheumatoid arthritis (RA) remission. This study aimed at i) determining the influence of PGA on RA disease states, exploring differences across countries, and ii) understanding the association between PGA, measures of disease impact (symptoms) and markers of disease activity (inflammation). Methods : Cross-sectional data from the METEOR international database were used. We calculated the proportion of patients failing ACR/EULAR Boolean-based remission (4v-remission) solely due to PGA (PGA-near-remission) in the overall sample and in the most representative countries (i.e. with over 3,000 patients in the database). Multivariable linear regression models were used to identify the main determinants of PGA, grouped in (predominantly) inflammatory (28-tender and 28-swollen joint counts and C-reactive protein) and disease impact factors (pain and function). Results : This study included 27,768 patients. Excluding PGA from the Boolean-based definition (3v-remission) increased remission rate from 5.8% to 15.8%. near-remission varied considerably between countries, from 1.7% in India to 17.9% in Portugal. One third of patients in PGA-near-remission scored PGA>4/10. Pain and function were the main correlates of PGA, with inflammation-related variables contributing less to the model (R 2 =0.57). Conclusions: PGA is moderately related to joint inflammation overall, but only weekly so in low levels of disease activity. A considerable proportion of patients otherwise in biological remission still perceive high PGA, putting them at risk of excessive immunosuppressive treatment.
AIP and MEN1 mutations and AIP immunohistochemistry in pituitary adenomas in a tertiary referral center

Background Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy. Aims We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center. Methods Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response. Results Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen. Conclusions Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients.
A novel 3′ untranslated region mutation in the SLC29A3 gene associated with pigmentary hypertrichosis and non‐autoimmune insulin‐dependent diabetes mellitus syndrome

Pigmentary hypertrichosis and non‐autoimmune insulin‐dependent diabetes mellitus (PHID) is one of the rare H syndrome diseases mainly characterized by hyperpigmentation, hypertrichosis, sensorineural hearing loss, cardiac complications, developmental delay, and diabetes mellitus (DM). Mutations in the coding regions of the SLC29A3 gene that encodes for an equilibrative nucleoside transporter (ENT3) have been reported to cause the phenotypic spectrum of the H syndrome. Disease‐causing mutations in the untranslated regions (UTRs) of the SLC29A3 gene have not been previously described in the literature. The aim of the study is to describe and assess the pathogenicity of a novel 3’UTR mutation in the SLC29A3 gene associated with the PHID phenotype in two Turkish patients.
Tridimensional Retinoblastoma Cultures as Vitreous Seeds Models for Live-Cell Imaging of Chemotherapy Penetration

A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core (p < 0.05). Importantly, topotecan penetration correlated with its cytotoxic activity. Therefore, the studied tridimensional cell model recapitulated several characteristics of vitreous seeds observed in patients with retinoblastoma and were successfully used to assess live-cell imaging of chemotherapy penetration for drug distribution studies.
Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning

Significance Gaucher disease is a rare genetic disorder that has crippling health consequences. Mutations in the GBA1 gene are known to disrupt the enzyme glucocerebrosidase-1, but it is not known, at atom-level detail, as to how enzyme function is lost. This study uses multiscale simulations and deep learning to define precisely the mechanism underlying the disruption of glucocerebrosidase-1 and, in particular, its interaction with the facilitator protein, saposin C. The lysosomal enzyme glucocerebrosidase-1 (GCase) catalyzes the cleavage of a major glycolipid glucosylceramide into glucose and ceramide. The absence of fully functional GCase leads to the accumulation of its lipid substrates in lysosomes, causing Gaucher disease, an autosomal recessive disorder that displays profound genotype–phenotype nonconcordance. More than 250 disease-causing mutations in GBA1, the gene encoding GCase, have been discovered, although only one of these, N370S, causes 70% of disease. Here, we have used a knowledge-based docking protocol that considers experimental data of protein–protein binding to generate a complex between GCase and its known facilitator protein saposin C (SAPC). Multiscale molecular-dynamics simulations were used to study lipid self-assembly, membrane insertion, and the dynamics of the interactions between different components of the complex. Deep learning was applied to propose a model that explains the mechanism of GCase activation, which requires SAPC. Notably, we find that conformational changes in the loops at the entrance of the substrate-binding site are stabilized by direct interactions with SAPC and that the loss of such interactions induced by N370S and another common mutation, L444P, result in destabilization of the complex and reduced GCase activation. Our findings provide an atomistic-level explanation for GCase activation and the precise mechanism through which N370S and L444P cause Gaucher disease.
TNFAIP3, TNIP1, and MyD88 Polymorphisms Predict Septic-Shock-Related Death in Patients Who Underwent Major Surgery

Background: In many immune-related diseases, inflammatory responses and several clinical outcomes are related to increased NF-κB activity. We aimed to evaluate whether SNPs related to the NF-κB signaling pathway are associated with higher susceptibility to infection, septic shock, and septic-shock-related death in European patients who underwent major surgery. Methods: We performed a case-control study on 184 patients with septic shock and 212 with systemic inflammatory response syndrome, and a longitudinal substudy on septic shock patients. Thirty-three SNPs within genes belonging to or regulating the NF-κB signaling pathway were genotyped by Agena Bioscience’s MassARRAY platform. Results: No significant results were found for susceptibility to infection and septic shock in the multivariate analysis after adjusting for multiple comparisons. Regarding septic-shock-related death, patients with TNFAIP3 rs6920220 AA, TNIP1 rs73272842 AA, TNIP1 rs3792783 GG, and TNIP1 rs7708392 CC genotypes had the highest risk of septic-shock-related death in the first 28 and 90 days. Also, the MyD88 rs7744 GG genotype was associated with a higher risk of death during the first 90 days. Haplotype analysis shows us that patients with the TNIP1 GAG haplotype (composed of rs73272842, rs3792783, and rs7708392) had a lower risk of death in the first 28 days and the TNIP1 AGC haplotype was associated with a higher risk of death in the first 90 days. Conclusions: The SNPs in the genes TNFAIP3, TNIP1, and MyD88 were linked to the risk of septic-shock-related death in patients who underwent major surgery.
Comparing invasive with MRI‐derived intracranial pressure measurements in healthy elderly and brain trauma cases: A pilot study

Intracranial pressure (ICP) is an important physiological parameter in several neurological disorders. Considerable effort has been made to measure ICP noninvasively. MR‐based ICP (MR‐ICP) is a nonempirical method based on principles of cerebrospinal fluid (CSF) physiology, where ICP is obtained from measurements of blood and CSF flows to and from the cranium during the cardiac cycle.
Chinese One-shot Dilation versus Sequential Fascial Dilation for Percutaneous Nephrolithotomy: A Feasibility Study and Comparison.

PURPOSE Nephrostomy tract creation is a key step to perform a successful percutaneous nephrolithotomy (PCNL). In an attempt to improve the conventional technique of the tract dilation, a Chinese one-shot dilation was developed and compared with the sequential fascial dilation. MATERIALS AND METHODS We retrospectively reviewed medical records of 116 patients who had undergone 116 PCNL in our department from January 2012 to December 2012. The nephrostomy tracts had been created by using Chinese one-shot (one-shot group, 59 cases) or sequential fascial dilation technique (sequential group, 57 cases). Tract creation time, hemorrhage loss, overall renal function, tract dilation failure and major complications were compared between the two groups. RESULTS The one-shot group had a significantly shorter mean (SD) tract creation time (1.9±0.4 vs 4.6±0.9 min, P<0.001) and lower mean (SD) decrease in hemoglobin concentration (0.59±0.32 vs 0.68±0.37 g/dL, P=0.0009) compared to the sequential group, respectively. There were no significant differences in mean (SD) value changes of pre- and post-operative serum creatine concentrations (4.6±11.3 vs 4.9±14.7 ? mol/L, P=0.259) between the one-shot and sequential group. No tract dilation failure or major complications occurred in both of the groups. CONCLUSION This study demonstrated that the Chinese one-shot dilation technique is as safe and feasible as the conventional sequential fascial dilation. Furthermore, a greater reduction in tract creation time and blood loss was achieved using this technique.
Effects of Low-Dose Sacubitril/Valsartan on Different Stages of Cardiac Hypertrophy in Salt-Loaded Hypertensive Rats

Background: Sacubitril/valsartan was shown to attenuate the development of cardiac hypertrophy with enhanced blood pressure reduction compared with valsartan alone in animal models. We investigated whether a low-dose sacubitril/valsartan has blood pressure–independent effects on cardiac hypertrophy and pulmonary edema using a rat model of hypertension and obesity. Methods and Results: In plan 1, male SHR/NDmcr-cp rats fed normal or phase-increased high salt were treated with vehicle, 6-mg/kg sacubitril/valsartan or 3-mg/kg valsartan, for 6 months. In plan 2, after high-salt loading for 6 months, drugs were administered for 4 months. Antihypertensive effects of the 2 drugs were similar during all study periods. In plan 1 with normal salt, there were no differences between treatments in the left ventricle weight/body weight (BW), or lung weight/BW as an index of cardiac hypertrophy or pulmonary edema, respectively. These indexes were smaller in high-salt-fed rats with sacubitril/valsartan than vehicle. In plan 2, both indexes did not differ between vehicle and sacubitril/valsartan. Ventricle weight/BW was lower in valsartan than sacubitril/valsartan. In plan 2, gene markers of cardiac dysfunction were upregulated by sacubitril/valsartan compared with the other groups. Conclusions: Low-dose sacubitril/valsartan may have different effects depending on the stage of cardiac hypertrophy in rats.