Miracle-dz/UniFAR-FTUs huggingface dataset:
Diosmin protects rat retina from ischemia/reperfusion injury.

OBJECTIVE Diosmin, a natural flavone glycoside, possesses antioxidant activity and has been used to alleviate ischemia/reperfusion (I/R) injury. The aim of this study was to clarify whether the administration of diosmin has a protective effect against I/R injury induced using the high intraocular pressure (IOP) model in rat retina, and to determine the possible antioxidant mechanisms involved. METHODS Retinal I/R injury was induced in the rats by elevating the IOP to 110 mmHg for 60 min. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. The levels of malondialdehyde (MDA) and the activities of total-superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in the retinal tissues were determined 24 h after I/R injury. At 7 days post-I/R injury, electroretinograms (ERGs) were recorded, and the density of surviving retinal ganglion cells (RGCs) was estimated by counting retrograde tracer-labeled cells in whole-mounted retinas. Retinal histological changes were also examined and quantified using light microscopy. RESULTS Diosmin significantly decreased the MDA levels and increased the activities of T-SOD, GSH-Px, and CAT in the retina of rats compared with the ischemia group (P<0.05), and suppressed the I/R-induced reduction in the a- and b-wave amplitudes of the ERG (P<0.05). The thickness of the entire retina, inner nuclear layer, inner plexiform layer, and outer retinal layer and the number of cells in the ganglion cell layer were significantly less after I/R injury (P<0.05), and diosmin remarkably ameliorated these changes on retinal morphology. Diosmin also attenuated the I/R-induced loss of RGCs of the rat retina (P<0.05). CONCLUSION Diosmin protected the retina from I/R injury, possibly via a mechanism involving the regulation of oxidative parameters.
Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non‐small cell lung cancer

Limited treatment options are available for stage IIIB/IV non‐small cell lung cancer (NSCLC). Nivolumab, a programmed cell death‐1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site‐assessed ORR, overall survival (OS), progression‐free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC‐assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site‐assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4–25.4), 2.7 (range 1.2–5.5) and 4.2 (95% CI 1.4–7.1) months, respectively. The IRC‐assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment‐related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy. Clinical trial registration number: JapicCTI‐132072
Insulin regulation of protein translation repressor 4E-BP1, an eIF4E-binding protein, in renal epithelial cells.

BACKGROUND Augmented protein translation by insulin involves activation of eukaryotic initiation factor 4E (eIF4E) that follows release of eIF4E from a heterodimeric complex by phosphorylation of its inhibitory binding protein, 4E-BP1. We examined insulin regulation of 4E-BP1 phosphorylation in murine proximal tubular epithelial cells. METHODS AND RESULTS Insulin (1 nmol/L) increased de novo protein synthesis by 58 +/- 11% (P < 0.001). Insulin also augmented 4E-BP1 phosphorylation and phosphatidylinositol 3-kinase (PI 3-kinase) activity in antiphosphotyrosine immunoprecipitates. This could be prevented by PI 3-kinase inhibitors, Wortmannin, and LY294002. Insulin also activated Akt that lies downstream of PI 3-kinase. Rapamycin abrogated 4E-BP1 phosphorylation in response to insulin, suggesting involvement of mammalian target of rapamycin (mTOR), a kinase downstream of Akt. Insulin-stimulated phosphorylation of 4E-BP1 was also inhibited by PD098059, implying involvement of Erk-1/-2 mitogen-activated protein (MAP) kinase. An increase in Erk-1/-2 type MAP kinase activity by insulin was directly confirmed in an immunokinase assay and was found to be PI 3-kinase dependent. CONCLUSIONS In proximal tubular epithelial cells, insulin augments 4E-BP1 phosphorylation, which is PI 3-kinase and mTOR dependent. The requirement for Erk-1/-2 MAP kinase activation for 4E-BP1 phosphorylation by insulin suggests a cross-talk between PI 3-kinase and Erk-1/-2-type MAP kinase pathways.
Safety and performance of a novel embolic deflection device in patients undergoing transcatheter aortic valve replacement: results from the DEFLECT I study.

AIMS This study aimed to evaluate the safety and performance of the TriGuard™ Embolic Deflection Device (EDD), a nitinol mesh filter positioned in the aortic arch across all three major cerebral artery take-offs to deflect emboli away from the cerebral circulation, in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS The prospective, multicentre DEFLECT I study (NCT01448421) enrolled 37 consecutive subjects undergoing TAVR with the TriGuard EDD. Subjects underwent clinical and cognitive follow-up to 30 days; cerebral diffusion-weighted magnetic resonance imaging (DW-MRI) was performed pre-procedure and at 4±2 days post procedure. The device performed as intended with successful cerebral coverage in 80% (28/35) of cases. The primary safety endpoint (in-hospital EDD device- or EDD procedure-related cardiovascular mortality, major stroke disability, life-threatening bleeding, distal embolisation, major vascular complications, or need for acute cardiac surgery) occurred in 8.1% of subjects (VARC-defined two life-threatening bleeds and one vascular complication). The presence of new cerebral ischaemic lesions on post-procedure DW-MRI (n=28) was similar to historical controls (82% vs. 76%, p=NS). However, an exploratory analysis found that per-patient total lesion volume was 34% lower than reported historical data (0.2 vs. 0.3 cm3), and 89% lower in patients with complete (n=17) versus incomplete (n=10) cerebral vessel coverage (0.05 vs. 0.45 cm3, p=0.016). CONCLUSIONS Use of the first-generation TriGuard EDD during TAVR is safe, and device performance was successful in 80% of cases during the highest embolic-risk portions of the TAVR procedure. The potential of the TriGuard EDD to reduce total cerebral ischaemic burden merits further randomised investigation.
Structure of a slow processing precursor penicillin acylase from Escherichia coli reveals the linker peptide blocking the active-site cleft.

Penicillin G acylase is a periplasmic protein, cytoplasmically expressed as a precursor polypeptide comprising a signal sequence, the A and B chains of the mature enzyme (209 and 557 residues respectively) joined by a spacer peptide of 54 amino acid residues. The wild-type AB heterodimer is produced by proteolytic removal of this spacer in the periplasm. The first step in processing is believed to be autocatalytic hydrolysis of the peptide bond between the C-terminal residue of the spacer and the active-site serine residue at the N terminus of the B chain. We have determined the crystal structure of a slowly processing precursor mutant (Thr263Gly) of penicillin G acylase from Escherichia coli, which reveals that the spacer peptide blocks the entrance to the active-site cleft consistent with an autocatalytic mechanism of maturation. In this mutant precursor there is, however, an unexpected cleavage at a site four residues from the active-site serine residue. Analyses of the stereochemistry of the 260-261 bond seen to be cleaved in this precursor structure and of the 263-264 peptide bond have suggested factors that may govern the autocatalytic mechanism.
Safety and benefit considerations for menopausal hormone therapy

ABSTRACT Introduction: While benefits and risks of hormone therapy (HT) have been shown in rigorous randomized, controlled trials, clinical use and further study have discovered effects of age, time of HT initiation, and differential effects of various regimens and administration routes on its safety profile. Areas covered: The safety of HT with regard to cardiovascular disease, thrombosis, the endometrium, the breast, and cognition was reviewed. Differential safety effects of estradiol versus conjugated equine estrogens, and progesterone versus synthetic progestins are reported. Expert opinion: Perceived safety of HT has evolved based on data from observational studies, the Women’s Health Initiative and its subsequent analyses, more recent randomized, controlled trials, and studies examining the differences between different estrogens and between different progestogens. Unexpected safety concerns with HT became apparent with release of the first results from WHI. Differences between estrogen-alone versus estrogen-progestogen therapies, estradiol versus conjugated equine estrogens, and progesterone versus progestins were found in subsequent WHI analyses and studies examining components of various regimens. The decision to use HT depends on balancing risks and benefits for each individual and determining the most appropriate choice of therapy, dosing, and route of administration, while also considering the safety evidence of different estrogens and progestogens.
Outcomes of two-phase orthodontic treatment of deepbite malocclusions.

OBJECTIVE The objective of this prospective controlled study was to assess the outcomes of two-phase treatment of deepbite patients revaluated at the end of circumpubertal growth, 1 year after the end of a phase-2 treatment. MATERIALS AND METHODS A sample of 58 subjects with deepbite (mean age 9.7 years, overbite greater than 4.5 mm) was treated consecutively with a two-phase protocol. Lateral cephalograms were taken before treatment (T1), at the completion of phase 1 (T2), and 1 year after the completion of phase 2 with fixed appliances (T3, mean age 15.8 years). The T1-T2, T2-T3, and T1-T3 changes were compared with those of the 29 subjects (mean age at T1 = 9.1 years) with untreated deepbite (t-tests for independent samples). Prevalence rates for improved overbite during the T1-T3 interval and for corrected overbite at T3 were contrasted in the treated vs untreated groups (z tests on proportions). RESULTS Overbite was reduced by 1.9 mm in the treated group as a result of overall treatment; this group also displayed a significant reduction in the interincisal angulation (-6.6°) due to a significant proclination of upper incisors (4.1°) and a significant increase in the projection of the lower incisors (2.0 mm). CONCLUSIONS The average amount of deepbite correction 1 year into retention was modest, and it was mainly due to a significant proclination of the incisors. The prevalence rate of subjects with a corrected overbite in the treated sample at T3 (74%) was not significantly different from that of the untreated sample (52%).
Oxidative Damage of Sulfur Dioxide on Various Organs of Mice: Sulfur Dioxide Is a Systemic Oxidative Damage Agent

Cu,Zn-superoxide dismutase (SOD), Se-dependent glutathione peroxidase (GSH-Px), catalase (CAT), and glutathione (GSH) play an important role in attenuating free radical-induced oxidative damage. The purpose of this research was to determine (1) whether sulfur dioxide (SO 2) increases levels of lipid peroxidation and alters intracellular redox status in multiple organs of mice, and (2) whether SO 2 is a systemic toxic agent. The effect of SO 2 on levels of thiobarbituric acid-reactive substances (TBARS) and GSH and activities of SOD, GSH-Px, and CAT were investigated in nine organs (brain, lung, heart, liver, stomach, intestine, spleen, kidney, and testis) of Kunming albino mice of both sexes. SO 2 at 20 ppm (56 mg/m 3) was administrated to the animals of SO 2 groups in an exposure chamber for 6 h/day for 7 days while control groups were exposed to filtered air in the same condition. Results show that SO 2 inhalation decreased significantly activities of SOD and GSH-Px in all organs tested in all SO 2 groups, with respect to their corresponding control groups; CAT activities in all organs tested of both sexual mice were significantly unaltered, except CAT activities in livers were significantly lowered by SO 2; SO 2 exposure decreased significantly GSH contents and significantly increased TBARS levels of all organs tested, in comparison with their respective control groups. These results lead to two conclusions: (1) SO 2 is a systemic oxidative damage agent. It results in a significant increase in the lipid peroxidation process in all organs tested of mice of both sexes, which is accompanied by changes of antioxidant status in these organs. (2) SO 2 may cause toxicological damage to multiple organs of animals, and it is suggested that the oxidative damage produced by SO 2 inhalation may influence or promote the progression or occurrence of some disease states of various organs, not only to respiratory system. Further work is required to understand the toxicological role of SO 2 on multiple or even all organs in mammals.
Sex trafficking and the involvement of organised crime: a study of the Australian context

Trafficking in human beings for the purpose of sex work has been estimated as the second most lucrative transnational crime, equal to illegal arms trading and second only to drug trafficking. Australia is viewed as an attractive destination country for trafficked persons given its wealth, stable economy and geographical proximity to countries of the Asia-Pacific region. However, like many other transnational crimes, trafficking in persons is a recent phenomenon and there was insufficient research to confidently make a claim about the involvement of organised crime syndicates in Australia in respect of trafficking persons into sex work. This research project studied the context of involvement of organised crime groups in trafficking persons into sex work in Australia. A qualitative study of twentyone known cases of human trafficking in Australia was undertaken. The study involved examination of documents, transcripts, case files and intelligence reports contained within individual investigations conducted by the Australian Federal Police between 2004 and 2013. From this a detailed description of the context of organised crime involvement in sex trafficking in Australia has been generated. This study argues that organised crime syndicates are extensively involved in sex trafficking operations in Australia. It was found in this study that overseas agents preyed on vulnerable females from source countries, especially Thailand, South Korea and China. In essence, they were deceptively recruited and the cost of their travel to Australia held against them as a highly inflated debt, where they found themselves forced into sex work to repay it. This study examined the attributes of the organised crime syndicates involved in the trafficking of persons for the purpose of sexual exploitation and discussed the context in which they operate in Australia. In particular, the study concluded the use of the Sleipnir model as an analytical tool for identifying and breaking down the attributes of organised crime is of benefit as it provides consistency and context; and is particularly beneficial for comparing different crime groups. This study also contains analysis of victimological factors that exist within each case. To achieve this analysis an integrated victimological framework was developed to identify victimological indicators at each phase of the trafficking process. It was identified that the type of victimisation varies during the recruitment, harbouring and exploitation phases of the human trafficking process.
Risk Factors for Infection After Spinal Surgery

Study Design. A retrospective case control analysis of 48 cases of postoperative infection following spinal procedures. Objectives. Spinal procedures that became infected after surgery were analyzed to identify the significance of preoperative and intraoperative risk factors. Characterization of the nature and timing of the infections was also performed. Summary of Background Data. The rate of postoperative infection following spinal surgery varies widely depending on the nature of the procedure and the patient’s diagnosis. Preoperative comorbidities and risk factors also influence the likelihood of infection. Methods. A review of 1629 procedures performed on 1095 patients revealed that a postoperative infection developed in 48 patients (4.4%). Data regarding preoperative and intraoperative risk factors were gathered from patient charts for these and a randomly selected control group of 95 uninfected patients. For analysis, these patient groups were further divided into adult and pediatric subgroups, with an age cutoff of 18 years. Preoperative risk factors reviewed included smoking, diabetes, previous surgery, previous infection, steroid use, body mass index, and alcohol abuse. Intraoperative factors reviewed included staging of procedures, estimated blood loss, operating time, and use of allograft or instrumentation. Results. The majority of infections occurred during the early postoperative period (less than 3 months). Age >60 years, smoking, diabetes, previous surgical infection, increased body mass index, and alcohol abuse were statistically significant preoperative risk factors. The most likely procedure to be complicated by an infection was a combined anterior/posterior spinal fusion performed in a staged manner under separate anesthesia. Infections were primarily monomicrobial, although 5 patients had more than 4 organisms identified. The most common organism cultured from the wounds was Staphylococcus aureus. All patients were treated with surgical irrigation and débridement, and appropriate antibiotics to treat the cultured organism. Conclusions. Aggressive treatment of patients undergoing complex or prolonged spinal procedures is essential to prevent and treat infections. Understanding a patient’s preoperative risk factors may help the physician to optimize a patient’s preoperative condition. Additionally, awareness of critical intraoperative parameters will helpto optimize surgical treatment. It may be appropriate to increase the duration of prophylactic antibiotics or implement other measures to decrease the incidence of infection for high risk patients.
Repulsion between Lys258 and upstream arginines explains the missorting of the AQP2 mutant p.Glu258Lys in nephrogenic diabetes insipidus

Regulation of body water homeostasis occurs by the vasopressin‐dependent sorting of aquaporin‐2 (AQP2) water channels to and from the apical membrane of renal principal cells. Mutations in AQP2 cause autosomal nephrogenic diabetes insipidus (NDI), a disease that renders the kidney unresponsive to vasopressin, resulting in polyuria and polydipsia. The AQP2 mutant c.772G>A; p.Glu258Lys (AQP2–E258K) causes dominant NDI by oligomerizing with wild‐type AQP2 and missorting of this AQP2 complex to multivesicular bodies instead of the apical membrane. The motif causing this missorting of AQP2–E258K was identified here. Functional analyses and plasma membrane expression studies of truncation mutants in oocytes revealed that AQP2–E258K shortened to Leu259 is still intracellular retained. Alanine scanning and glutamic acid to arginine exchanges revealed increased function and plasma membrane expression for AQP2–E258K mutants with the following additional changes: Leu259Ala, Arg252Glu, Arg253Glu, or Arg252Ala–Arg254Ala, or for the AQP2 mutant p.Glu258Ala, indicating that the motif RRRxxxK258L confers AQP2–E258K retention. Fusion of this motif to aquaporin‐1 also resulted in missorting of that water channel, indicating that this retention motif is transferable. In conclusion, our data reveal that the RRRxxxKL motif and repulsion between K258 and the arginine‐triplet within this motif are the primary cause of missorting of AQP2–E258K in NDI. Hum Mutat 30:1–10, 2009. © 2009 Wiley‐Liss, Inc.
Modulation of prelanding lower-limb muscle responses in athletes with multiple ankle sprains.

PURPOSE The objective of this study was to investigate modulation in prelanding muscle responses and its associated impact force on landing from unexpected and self-initiated drops in male basketball players with a history of bilateral multiple ankle sprains (BMAS). METHODS Prelanding EMG responses were recorded in four lower-limb muscles, together with the impact force on landing, while 20 healthy and 19 basketball players with BMAS performed unexpected, self-initiated drops from a height of 30 cm. RESULTS Group differences were detected after self-initiated but not unexpected drops. Two main changes in prelanding EMG responses were observed in the injured basketball players during the self-initiated drops. First, tibialis anterior (TA) was activated significantly earlier in the injured group, whereas left tensor fascia latae appeared closer to the moment of landing (P < 0.025) than in the healthy players. Second, cocontraction indexes between left TA and peroneus longus, and left TA and medial gastrocnemius, were significantly greater in the injured than in the healthy players (P < 0.025). On landing, higher magnitude-of-impact forces were observed in the injured players on the right leg (by 23%, P = 0.012). CONCLUSION In basketball players with BMAS, modulation of prelanding muscle response latencies occurred in injured (ankle) and uninjured (hip) joints during self-initiated but not unexpected drops. Greater cocontraction index between the left ankle muscle pairs in preparation for landing from self-initiated drops, and a significantly higher magnitude of impact force in the right leg on landing, were observed in the injured players.