The Covert Impact of Chiari Network and Eustachian Valves on Stroke: A Scoping Review and Meta-Analysis.
The role of Chiari network (CN) and Eustachian valves (EVs) in cardioembolic strokes is still unclear. There is inconsistency in the literature regarding clinical approach to these lesions to reduce stroke risk. We aimed to describe clinical presentation, neuroimaging and cardioimaging features, as well as management approaches for CN and EV in stroke context. A systemic search was carried out using PubMed and Web of Science following PRISMA guidelines, Supplemental Digital Content 1 (http://links.lww.com/NRL/A123). We retrieved 4 case-control studies, 2 cross sectional studies as well 8 case reports, with a total of 883 patients with a mean age of 44.6 years (±13.8). The combined prevalence of EV/CN in stroke-related patent foramen ovale (PFO) patients was 50% (95% CI: 31-68). With isolated prevalence for EV and CN of 43% (95% CI: 25-63), 18% (95% CI: 12-25), respectively. Patients with history of stroke had higher prevalence of EV/CN compared with controls odds ratio=2.45 (95% CI: 1.2-5, P<0.01). All case-control and cross-sectional studies defined EV/CN by transesophageal echocardiography or intracardiac cardiography. In the 8 case reports, 7 cases were diagnosed by transesophageal echocardiography, while only 1 case was diagnosed postmortem. EV/CN are relatively common findings in stroke patients with PFO. While it appears that presence of EV/CN with a PFO increases the risk of cardioembolic stroke, they remain underrecognized. EV/CN should be considered as high-risk PFO features. There is a scarcity of research emphasizing their role in clinical decision making, especially PFO closure and antithrombotic therapy choice.


Tycho Brahe's 1572 supernova as a standard type Ia as revealed by its light-echo spectrum.
Type Ia supernovae are thermonuclear explosions of white dwarf stars in close binary systems. They play an important role as cosmological distance indicators and have led to the discovery of the accelerated expansion of the Universe. Among the most important unsolved questions about supernovae are how the explosion actually proceeds and whether accretion occurs from a companion or by the merging of two white dwarfs. Tycho Brahe's supernova of 1572 (SN 1572) is thought to be one of the best candidates for a type Ia supernova in the Milky Way. The proximity of the SN 1572 remnant has allowed detailed studies, such as the possible identification of the binary companion, and provides a unique opportunity to test theories of the explosion mechanism and the nature of the progenitor. The determination of the hitherto unknown spectroscopic type of this supernova is crucial in relating these results to the diverse population of type Ia supernovae. Here we report an optical spectrum of Tycho's supernova near maximum brightness, obtained from a scattered-light echo more than four centuries after the direct light from the explosion swept past the Earth. We find that SN 1572 belongs to the majority class of normal type Ia supernovae.


Gender differences in heritability of depressive symptoms in the elderly.
The present study aimed to investigate the relative importance of genetic and environmental influences on depressive symptoms in the elderly. Depressive symptoms were assessed through the Center for Epidemiological Studies-Depression (CES-D) scale. The CES-D scale was administered to 959 twin pairs (123 female MZs, 90 male MZs, 207 same-sex female DZs, 109 same-sex male DZs and 430 opposite-sex DZs) aged 50 years or older (mean age 72 years). A dichotomous depressed state variable was constructed based on CES-D cut-offs and self-reported use of antidepressant medication. Structural equation models were fitted to the data to dissect genetic and environmental variance components. The sex-specific heritability estimates for depressive symptoms were 14% for males and 29% for females and 23% when constrained to be equal for men and women. The prevalence of clinically significant depressive symptoms was 16% for men and 24% for women. Heritability estimates for the dichotomous depressed state measure were 7% for males and 49% for females in the full model and 33% when constrained to be equal. Our results suggest that depressive symptoms in the elderly are moderately heritable, with a higher heritability for women than men, although differences in heritability estimates were not statistically significant.


Identification and sequence of the gene encoding gpIII, a major glycoprotein of varicella-zoster virus.
The genome of varicella-zoster virus (VZV) encodes three major glycoproteins, two (gpI and gpII) having been mapped and sequenced, which carry epitopes capable of eliciting neutralizing antibodies. The product of the third major glycoprotein gene (gpIII) was purified, and seven consecutive amino acids at its N-terminus were identified. A degenerate pool of oligonucleotides based upon this sequence was used as a probe to localize the gpIII gene to the HindIII B fragment of the VZV genome. An analysis of the DNA sequence from this region revealed an open reading frame (ORF) encoding 841 amino acids. Rabbit antisera against three synthetic peptides derived from the putative gpIII gene recognized a protein which comigrated with gpIII in Western blots and immunoprecipitation analysis. Preclearing with a monoclonal antibody to gpIII specifically abolished immunoprecipitation of this protein. Also a polypeptide translated from mRNA selected by the putative gpIII gene could be immunoprecipitated by the anti-peptide sera. Therefore, we conclude that gpIII is encoded by the identified ORF in HindIII B. In addition, gpIII is implicated as essential for the cell-to-cell spread of VZV.


Transcriptomics analysis of Psidium cattleyanum Sabine (Myrtaceae) unveil potential genes involved in fruit pigmentation.
Psidium cattleyanum Sabine is an Atlantic Forest native species that presents some populations with red fruits and others with yellow fruits. This variation in fruit pigmentation in this species is an intriguing character that could be related to species evolution but still needs to be further explored. Our goal was to provide genomic information for these morphotypes to understand the molecular mechanisms of differences in fruit colour in this species. In this study, we performed a comparative transcriptome analysis of red and yellow morphotypes of P. cattleyanum, considering two stages of fruit ripening. The transcriptomic analysis performed encompassing leaves, unripe and ripe fruits, in triplicate for each morphotype. The transcriptome consensus from each morphotype showed 301,058 and 298,310 contigs from plants with yellow and red fruits, respectively. The differential expression revealed important genes that were involved in anthocyanins biosynthesis, such as the anthocyanidin synthase (ANS) and UDP-glucose:flavonoid-o-glucosyltransferase (UFGT) that were differentially regulated during fruit ripening. This study reveals stimulating data for the understanding of the pathways and mechanisms involved in the maturation and colouring of P. cattleyanum fruits and suggests that the ANS and UFGT genes are key factors involved in the synthase and pigmentation accumulation in red fruits.


[Sarcoma centres : a necessary tool in the management of patients and for research.]
Sarcomas are rare diseases, the treatment of which requires an appropriate technical plateform and a broad spectrum of multidisciplinary specialists. Many are initially treated by unplanned excision, and then referred to specialized centres. Secondary treatments may lead to higher complication rates and local recurrence, with lower functional outcome, life quality and possibly overall survival. In order to improve the accessibility for referral to a specialist centre, the coordination of clinical and research activities, and the quality of the management of sarcomas in general, Lausanne University Hospital (CHUV) has opened a Sarcoma centre on October 1st 2016. The objective of the present paper is to illustrate the concept and provide useful clinical recommendations.


[Web-based education: learning surgical procedures step-by-step with 3D visualization].
There is a need for more uniform, structured education focused on surgical procedures. We offer a standardized, step-by-step, web-based procedural training method with which surgeons can train more interns efficiently. The basis of this learning method is formed by 3D films in which surgical procedures are performed in clearly defined steps and the anatomic structures behind the surgical operating planes are further dissected. This basis is supported by online modules in which, aside from the operation, preparation and postoperative care are also addressed. Registrars can test their knowledge with exams. Trainers can see what the registrars studied, how they scored and how they progressed with their clinical skills. With the online portfolio we offer building blocks for certification and accreditation. With this clearly structured research method of constant quality, registrars are less dependent on the local trainer. In addition, through better preparation, the operation capacity can be used more efficiently for the training.


NF-kappaB RelB forms an intertwined homodimer.
The X-ray structure of the RelB dimerization domain (DD) reveals that the RelBDD assumes an unexpected intertwined fold topology atypical of other NF-kappaB dimers. All typical NF-kappaB dimers are formed by the association of two independently folded immunoglobulin (Ig) domains. In RelBDD, two polypeptides reconstruct both Ig domains in the dimer with an extra beta sheet connecting the two domains. Residues most critical to NF-kappaB dimer formation are invariant in RelB, and Y300 plays a positive role in RelBDD dimer formation. The presence of RelB-specific nonpolar residues at the surface removes several intradomain surface hydrogen bonds that may render the domain fold unstable. Intertwining may stabilize the RelBDD homodimer by forming the extra beta sheet. We show that, as in the crystal, RelB forms an intertwined homodimer in solution. We suggest that the transiently stable RelB homodimer might prevent its rapid degradation, allowing for heterodimer formation with p50 and p52.


Mortality and health care burden of Budd Chiari syndrome in the United States: A nationwide analysis (1998-2017).
The Budd Chiari syndrome (BCS) is a rare and potentially fatal disease, but there is a paucity of data on the in- hospital mortality as well its economic burden on the health care system. To evaluate trends in mortality, length of hospital stays and resource utilization among inpatients with BCS. Data on all adult patients with a diagnosis of BCS were extracted from the National Inpatient Sample (NIS) from 1998 to 2017. To make inferences regarding the national estimates for the total number of BCS discharges across the study period, sample weights were applied to each admission per recommendations from the NIS. During the study period, there were 3591 (8.73%) in-patient deaths. The overall in-hospital mortality rates among BCS patients decreased from 18% in 1998 to 8% in 2017; the mortality decreased by 4.41% (P < 0.0001) every year. On multivariate analysis, older age, higher comorbidity score, acute liver failure, acute kidney injury, acute respiratory failure, hepatic encephalopathy, hepatorenal syndrome, inferior vena cava thrombosis, intestinal infarct, sepsis/septic shock and cancer were associated increased risk of mortality. The average of length of stay was 8.8 d and it consistently decreased by 2.04% (95%CI: -2.67%, -1.41%, P < 0.001) from 12.7 d in 1998 to 7.6 d in 2017.The average total charges after adjusted for Medical Care Consumers Price Index to 2017 dollars during the time period was $94440 and the annual percentage change increased by 1.15% (95%CI: 0.35%, 1.96%, P = 0.005) from $95515 in 1998 to $103850 in 2017. The in-hospital mortality rate for patients admitted with BCS in the United States has reduced between 1998 and 2017 and this may a reflection of better management of these patients.


Efficacy of the Repetitions in Reserve-Based Rating of Perceived Exertion for the Bench Press in Experienced and Novice Benchers.
Ormsbee, MJ, Carzoli, JP, Klemp, A, Allman, BR, Zourdos, MC, Kim, J-S, and Panton, LB. Efficacy of the repetitions in reserve-based rating of perceived exertion for the bench press in experienced and novice benchers. J Strength Cond Res 33(2): 337-345, 2019-Autoregulation (AR) is the practice of adjusting training variables in response to athlete feedback. One component of AR postulated to enhance resistance training adaptations involves implementing a resistance training-specific rating of perceived exertion (RPE) scale measuring repetitions in reserve (RIR). The purpose of this study was to examine the efficacy of this method using the bench press exercise. Twenty-seven college-aged men were assigned to one of 2 groups based on training age: experienced benchers (EB) (n = 14, training age: 4.7 ± 2.0 years) and novice benchers (NB) (n = 13, training age: 1.1 ± 0.6 years). Subjects performed 1 repetition maximum (1RM) followed by single-repetition sets with loads corresponding to 60, 75, and 90% of 1RM and an 8-repetition set at 70% of 1RM. Subjects reported a corresponding RPE, based on RIR, for every set. Average velocity was recorded for each single-repetition set along with the first and last repetitions of the 8-repetition set at 70% of 1RM. Average velocity at 100% of 1RM in EB was slower (0.14 ± 0.04 m·s) compared with NB (0.20 ± 0.05 m·s) (p < 0.001). Experienced benchers recorded greater RPE than NB at 1RM (EB: 9.86 ± 0.14 vs. NB: 9.35 ± 0.36) (p = 0.011). No between-group differences existed for average velocity or RPE at any other intensity. Both EB (r = 0.85, p < 0.001) and NB (r = 0.85, p < 0.001) had strong inverse significant correlations between average velocity and RPE at all intensities. Our findings suggest that the RIR-based RPE scale may be an efficacious approach for AR of bench press training load and volume in college-aged men.


Heat inactivation of Listeria monocytogenes and Salmonella enterica serovar Typhi in a typical bologna matrix during an industrial cooking-cooling cycle.
The heat resistance of Salmonella enterica serovar Typhi PF-724 and Listeria monocytogenes 2812 was determined in a commercial bologna batter. The heat inactivation of the two bacterial species was also studied in a semiautomatic pilot smokehouse under cooking conditions that reproduced an industrial bologna process. S. enterica serovar Typhi PF-724 was less heat resistant than L. monocytogenes 2812. The D-values (times required to reduce the population by 1 logarithmic cycle) for S. enterica serovar Typhi PF-724 ranged from 10.11 to 0.04 min for temperatures of 50 to 70 degrees C, while for L. monocytogenes 2812, the D-values were 2.5-, 4.9-, 3.8-, 3.3-, and 2-fold higher at 50, 55, 60, 65, and 70 degrees C, respectively, than for S. enterica serovar Typhi PF-724. However, the z-value (temperature required to reduce log D by 1 logarithmic cycle) for S. enterica serovar Typhi PF-724 (5.72 degrees C) was not significantly different from the z-value for L. monocytogenes 2812 (7.04 degrees C), indicating that a given increase in temperature would have a similar effect on the decimal reduction time for both bacterial species in that meat emulsion. Our data on experimentally inoculated batter also showed that processing bologna at a cooking-cooling cycle commonly used in the industry resulted in a minimum 5-log reduction for both S. enterica serovar Typhi PF-724 and L. monocytogenes 2812.


Treatment of previable premature ruptured membranes.
We have gained significant experience in the clinical understanding and treatment of PPROM in the last 5 years. From our work we can conclude that iatrogenic PPROM is not only a different entity etiologically, it is also different than spontaneous PPROM in its clinical behavior and response to therapeutic measures. Our current success rate with the amniopatch allows us to suggest that iatrogenic PPROM should no longer be viewed as a devastating complication of pregnancy. Instead, as other investigators corroborate our successful experience with the amniopatch, this procedure might become standard treatment for this unusual but frustrating complication of prenatal intervention. Regarding spontaneous PPROM, our work suggests that perhaps, in a select group of patients (in whom infection has not set in and in whom a smaller and better defined membrane defect might exist), there is the potential for developing a surgical technique that might graft the defect successfully and allow the integrity of the amniotic membrane to be restored. The actual surgical technique, the materials to be used, and the approach (transabdominal versus transcervical) are areas of research for the future. Meanwhile, continued efforts are warranted to decipher whether or not this obstetrical complication can one day be conquered.


Targeting osteosarcoma vasculature with peptide obtained by phage display.
Tumour endothelial cells have been proven to have molecular markers distinct from normal endothelial cells. These specific molecular markers allow for targeting of the tumour vasculature with specific pharmacological vehicles to direct diagnostic or therapeutic modalities at the endothelial cells. By performing a phage display-based screening, this study aimed to identify a certain short peptide that could specifically bind to osteosarcoma vasculature. We performed in vivo screening in the murine models of osteosarcoma with annular Ph.D.-C7C library in the present study. To explore the in vivo binding specificity of the retrieved peptide, we conjugated the peptide with fluorescein isothiocyanate (FITC) and injected it intravenously into osteosarcoma-bearing BALB-c mice. CTKPDKGYC was the dominant sequence isolated from in vivo screening and was named as NF-1. Fluorescence staining found that FITC-NF-1 peptide could be specifically homed to osteosarcoma vasculature while being almost undetectable in the heart, brain, lung and liver. Simultaneously, a small amount of fluorescence could also be detected in the renal glomerulus and renal tubule but not in renal vascular endothelium, indicating that FITC-NF-1 peptide might be excreted mainly through the renal-urinary route. Our data suggest that, with high binding specificity to osteosarcoma vasculature, peptide NF-1 may have potential value in early diagnosis or targeted therapy for osteosarcoma.


Kinetics of reduction by substrate or dithionite and heme-heme electron transfer in the multiheme hydroxylamine oxidoreductase.
Hydroxylamine oxidoreductase of Nitrosomonas catalyzes the dehydrogenation of NH2OH. It contains hemes c553, c559 and P460 in the ratio 5:2:1. At equilibrium four or five c hemes are reduced by NH2OH or NH2NH2, respectively. Heme P460 is the site of electron entry into the enzyme; electrons exit via P460 to O2 or H2O2 with rate constants of 30s-1. We report that hydroxylamine oxidoreductase has two categories of electron-accepting sites: (a) heme P460, an H2O2-sensitive site, which is reactive with NH2OH (2.2 hemes c557 and 2 hemes c559 are reduced) or NH2NH2 (3.3 heme c 553 and 2 heme c559 are reduced) and (b) an H2O2-insensitive site(s) which is reactive with H2O2 (approximately 0.15 heme c553 is reduced); hydroquinone, pyrogallol, N-methyl hydroxylamine, pyocyanine, and ascorbate (approximately 0.8 heme c553 is reduced); or Na2S2O4 or EDTA-photoreduction with proflavin, deazalumiflavin or acridine orange and methylviologen (all hemes are reduced). The rate constants at 19 degrees C for reduction by dithionite were: 0.7 heme c553 (7s-1), 4.3 hemes c553 (0.07 s-1), 0.7 heme c559 (0.8s-1), 1.3 hemes c559 (0.1s-1), P460 (0.013s-1). At 2 degrees C the rate constant for 0.8 heme c559 was 1.7s-1. The data indicate that one heme c552 is reduced by dithionite at the same rate as mammalian cytochrome c; other hemes are reduced much more slowly and are possibly inaccessible to the solvent. The rate constants at 2 degrees C for reduction by NH2OH were: 1.8 hemes c553 (30s-1), 0.2 heme c553 (2.4s-1), 1.7 hemes c559 (19s-1), 0.3 heme c559 (1.4s-1). For reduction by NH2NH2 the values were: 2.6 hemes c553 (23s-1), 0.7 heme c553 (1.6s-1), 1.3 hemes c559 (22s-1), 0.7 heme c559 (4.2s-1). Thus reduction by NH2OH at the substrate site was at least an order of magnitude faster than reduction of hydroxylamine oxidoreductase heme by Na2S2O4. Comparison of rates of heme-heme electron transfer on the enzyme during reoxidation by O2 or H2O2, reduction by Na2S2O4 and reduction by NH2OH or NH2NH2 indicates that the enzyme can exist in distinct states which result in different rates of heme-heme electron transfer. Comparison of the rate of substrate reduction of c hemes of hydroxylamine oxidoreductase (HAO) with the turnover of the enzyme in vivo is consistent with the electron path NH2OH----HAO P460----HAO c hemes----biological electron acceptor.


Chronic antagonism of Mig inhibits cellular infiltration and promotes survival of class II MHC disparate skin allografts.
The goal of the current study was to test the ability of monokine induced by IFN-gamma (Mig)-specific antibodies to inhibit long-term T cell infiltration into class II major histocompatibility complex (MHC) disparate skin allografts and to test cellular and molecular changes in the graft during the rejection observed following cessation of treatment. C57BL/6 recipients of B6.H-2bm12 skin grafts were treated with normal rabbit serum (NRS) or rabbit Mig antiserum (Mig AS) every other day from day 7 until day 21 posttransplant and then weekly thereafter. Allografts were retrieved during the course of treatment and following cessation. Tissue sections were prepared and stained to compare infiltration by macrophages and CD4+ and CD8+ T cells and to assess collagen deposition in the grafts. RNA was prepared and tested by ribonuclease protection assay for intragraft levels of Mig, monocyte chemotactic protein-1 (MCP-1) and regulated on activation normal T-cell expressed and secreted (RANTES). T cell and macrophage infiltration into allografts was inhibited and graft survival maintained as long as Mig-specific antibodies were given. Following cessation of treatment, T cells and macrophages infiltrated the allografts. In contrast to the histology of acute rejection observed in allografts from NRS-treated recipients, the resulting rejection of the allografts from Mig AS-treated recipients was accompanied by dense collagen deposition and high level expression of Mig and RANTES. Mig directs T cell infiltration into B6.H-2bm12 skin allografts on C57BL/6 recipients. Delayed T cell and macrophage infiltration and rejection of the grafts following cessation of Mig AS treatment results in rejection that is histologically and molecularly distinct from acute rejection.


Comprehensive analysis of ubiquitin-proteasome system genes related to prognosis and immunosuppression in head and neck squamous cell carcinoma.
The ubiquitin-proteasome system (UPS) with a capacity of degrading multiple intracellular proteins is an essential regulator in tumor immunosurveillance. Tumor cells that escape from recognition and destruction of immune system have been consistently characterized an important hallmark in the setting of tumor progression. Little know about the exact functions of UPS-related genes (UPSGs) and their relationships with antitumor immunity in head and neck squamous cell carcinoma (HNSCC) patients. In this study, for the first time, we comprehensively identified 114 differentially expressed UPSGs (DEUPSGs) and constructed a prognostic risk model based on the eight DEUPSGs (BRCA1, OSTM1, PCGF2, PSMD2, SOCS1, UCHL1, UHRF1, and USP54) in the TCGA-HNSCC database. This risk model was validated using multiple data sets (all P < 0.05). The high-risk score was found to be an independently prognostic factor in HNSCC patients and was significantly correlated with T cells suppression. Accordingly, our risk model can act as a prognostic signature and provide a novel concept for improving the precise immunotherapy for patients with HNSCC.


Preparation and development of solid phase radioimmunoassay system for determination of cortisol.
The goal of this article was oriented to prepare stable polystyrene coated tubes for direct radioimmunoassay (RIA) of human cortisol. Coating process was performed using rabbit polyclonal antisera specific for cortisol. The stability study showed that these tubes could be stored for up to one year at 4ºC without any appreciable reduction in their binding. Labeling of cortisol was carried out using chloramin-T method and the 125I-cortisol tracer was purified using HPLC column. Preparation of polyclonal antibodies (anti-cortisol) was carried out in host rabbit animals against cortisol-21-hemisuccinate:Bovine serum albumin conjugate. The statistical analysis revealed good correlations between the results from the present study and the commercial IZOTOP RIA kit. The local may be extremely helpful in diagnosis and proper management of adrenal cortex disorders.


A DNA unwinding factor involved in DNA replication in cell-free extracts of Xenopus eggs.
Alteration of chromatin structure is a key step in various aspects of DNA metabolism. DNA unwinding factors such as the high mobility group (HMG) proteins are thought to play a general role in controlling chromatin structure and a specific role in controlling DNA replication. For instance, in the in vitro simian virus 40 replication system, minichromosomes containing HMG-17 replicate more efficiently than those without it, suggesting that HMG-17 enhances the rate of replication of a chromatin template by unfolding the higher-order chromatin structure. At present, however, only limited data suggest an involvement of DNA unwinding factors in DNA replication. We purified from Xenopus eggs a novel heterodimeric factor, termed DNA unwinding factor (DUF), that consists of 87 kDa and 140 kDa polypeptides. DUF unwinds closed-circular duplex DNA in the presence of topoisomerase I, but it does not possess a DNA gyrase activity: it does not introduce negative supercoils into DNA at the expense of ATP hydrolysis. Cloning and sequencing of the cDNAs encoding the two polypeptides revealed that the 87 kDa polypeptide is homologous to a mammalian HMG protein, T160/structure-specific recognition protein. The 140 kDa polypeptide is homologous to yeast Cdc68, a protein that controls the expression of several genes during the G1 phase of the cell cycle by modulating chromatin structure. Immunodepletion of DUF from Xenopus egg extracts drastically reduced the ability of the extract to replicate exogenously added sperm chromatin or plasmid DNA. We propose that DUF plays a role in DNA replication in Xenopus egg extracts.


Neuroprotective effect of phosphocreatine on oxidative stress and mitochondrial dysfunction induced apoptosis in vitro and in vivo: Involvement of dual PI3K/Akt and Nrf2/HO-1 pathways.
Methylglyoxal (MGO), an active metabolite of glucose, is observed in high levels in the tissues and blood of diabetic patients. Phosphocreatine (PCr), a high-energy phosphate compound, exhibits a range of pharmacological actions but little is well known of its neuroprotective action. The aim of the present study was to investigate the neuroprotective effects and the possible mechanisms of PCr. Diabetes is closely associated with neurodegenerative diseases, leading not only to the peripheral nervous system (PNS) and but also to central nervous system (CNS) damage. Therefore, we established two rat models of diabetes in vivo induced by MGO and streptozocin (STZ) respectively, while utilized differentiated PC-12 cells in vitro. Treatment of PC-12 cells with PCr markedly attenuated MGO-induced change of viability, apoptosis, accompanied by decreased levels of caspase-3, casapse-9 and Bcl-2/Bax protein ratio. Determination of cellular respiratory function was performed with intact PC-12 cells and homogenized hippocampal neuron tissue of rat. Reactive oxygen species (ROS) generation was assessed by membrane permeable fluorescent probe DCFH-DA. The expressions of Akt, Nrf2 and HO-1 were examined by Western blot. PCr pretreatment significantly reduced oxidative stress-induced high LDH, MDA level, and ROS production of PC-12 cells. PCr pretreatment also significantly decreased mitochondrial dysfunction in vitro and in vivo. In addition, PCr pretreatment increased the expression of p-Akt, Nrf2 and HO-1, and reduced the apoptosis. Moreover, the expression of Cleaved caspase3 was partially increased and the p-Akt, Nrf2 and HO-1 was partially reduced by a PI3K inhibitor (LY294002). While, compared with LY294002 groups, pre-treatment with PCr at the concentrations of 20 mM significantly reduced the expression of Cleaved caspase3 and increased the expression of p-Akt, Nrf2 and HO-1. Molecular docking assay showed that PCr possessed powerful affinity towards to Akt with lower binding energy. In conclusion, the neuroprotective effects of PCr in vitro and in vivo rely on normalizing mitochondrial function and reducing oxidative stress via Akt mediated Nrf2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the treatment of diabetes-associated neurodegenerative diseases.


Impact of remote monitoring and supervision on resident training using new ACGME milestone criteria.
The study objective was to determine the impact of remote monitoring and supervision (RMS) in integrated endourology suites (IES) on residents achieving endoscopic training milestones. Twenty-one urology residents evaluated RMS in IES using a 25-question survey. IES provided audio-visual communication for faculty to supervise residents remotely. Questionnaire used a linear visual scale of 1-10 to assess acceptability (8 questions), impact on training (10 questions), supervision level (1 question), and pre- and post-training milestone self-assessments (6 questions). Improvements in Patient Care Milestone #7 (upper/lower tract endoscopic procedures) and Patient Care Milestone #9 (office-based procedures) were analyzed. Twenty-one urology residents (out of potential 23) evaluated RMS in IES using a 25-question survey (91.3% response rate). Overall RMS acceptability and satisfaction was high (mean score = 9.1/10) with a majority (95.2%) feeling comfortable being alone with the patient. Residents reported positively on the following parameters: autonomy without compromising safety (8.7), supervision level (8.6), achieving independence (8.4), education quality (8.3), learning rate (8.1), clinical decision-making (8.0), and reducing case numbers to achieve proficiency (7.6). Residents perceived no issues with under- or over-supervision, and a majority (76.2%) expressed that RMS should be standard of training in residency programs. Residents reported mean level increases of 2.5 and 2.8 (out of 5) in Patient Care Milestones for endoscopic procedures and office-based procedures, respectively (p < 0.0001). RMS in integrated endourology suites may enhance resident education and endoscopic training. The study demonstrated an increase in competency levels reported by residents trained using RMS.


A collection of genetic mouse lines and related tools for inducible and reversible intersectional mis-expression.
Thanks to many advances in genetic manipulation, mouse models have become very powerful in their ability to interrogate biological processes. In order to precisely target expression of a gene of interest to particular cell types, intersectional genetic approaches using two promoter/enhancers unique to a cell type are ideal. Within these methodologies, variants that add temporal control of gene expression are the most powerful. We describe the development, validation and application of an intersectional approach that involves three transgenes, requiring the intersection of two promoter/enhancers to target gene expression to precise cell types. Furthermore, the approach uses available lines expressing tTA/rTA to control the timing of gene expression based on whether doxycycline is absent or present, respectively. We also show that the approach can be extended to other animal models, using chicken embryos. We generated three mouse lines targeted at the Tigre (Igs7) locus with TRE-loxP-tdTomato-loxP upstream of three genes (p21, DTA and Ctgf), and combined them with Cre and tTA/rtTA lines that target expression to the cerebellum and limbs. Our tools will facilitate unraveling biological questions in multiple fields and organisms.


Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM.
The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro-apoptotic response of glioma cells treated with alkylating anticancer drugs.


Psychometric Evaluation of the Screener for Intensifying Community Referrals for Health.
This study examined the psychometric properties of the Screener for Intensifying Community Referrals for Health (SINCERE), a 10-item, low literacy screening tool developed to elicit social needs (e.g., transportation, housing) impacting patients' ability to engage in health-related activities. Patients seeking care in a tertiary care emergency department (ED) were invited to complete the SINCERE as part of registration processes, and were asked about their desire for follow-up by a partnering service provider offering low- and no-cost community resource referrals. A total of 5,081 patients completed screenings were included in this sample. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) identified and verified one-factor structure, suggesting that the SINCERE's 10-items are homogenous and measure one construct. The reliability of Cronbach's α and McDonald's ω were 0.89. Item Response Theory (IRT) suggested the SINCERE can effectively identify patients wishing referrals, or who have social needs. Moreover, patients who had two or more social needs were those willing to receive referrals after discharge. The SINCERE is a valid and reliable tool for measuring social needs for health, and should be considered as a screening option for practice interventions seeking to address social needs.


Postnatal fetal and adult hemoglobin synthesis is preterm infants whose birth weight was less than 1,000 grams.
To determine if environmental factors could effect the switchover from fetal hemoglobin (HbF) to adult hemoglobin (HbA) synthesis, studies were carried out on blood samples from eight infants born at less than 1,000 g, when they had reached their postconceptional age corresponding to term. All of these infants required prolonged intensive care, multiple blood transfusions, and two required exchange transfusions. Several were ventilated mechanically for 60 d and two infants had bronchopulmonary dysplasia at the time of the study. The blood samples were incubated in an amino acid mixture containing [14C]leucine followed by column chromatography on DEAE Sephadex for separation of radioactive HbA and HbF. In spite of the extreme prematurity and poor growth of these sick infants, the proportional synthesis of HbF and HbA, as determined by the incorporation of [14C]leucine during the erythrocyte incubations, was characteristic of the period of human development from which the erythrocytes were obtained.


Using Data Science and a Health Equity Lens to Identify Long-COVID Sequelae Among Medically Underserved Populations.
Understanding how post-acute COVID-19 syndrome (PACS or long COVID) manifests among underserved populations, who experienced a disproportionate burden of acute COVID-19, can help providers and policymakers better address this ongoing crisis. To identify clinical sequelae of long COVID among underserved populations treated in the primary care safety net, we conducted a causal impact analysis with electronic health records (EHR) to compare symptoms among community health center patients who tested positive (n=4,091) and negative (n=7,118) for acute COVID-19. We found 18 sequelae with statistical significance and causal dependence among patients who had a visit after 60 days or more following acute COVID-19. These sequelae encompass most organ systems and include breathing abnormalities, malaise and fatigue, and headache. This study adds to current knowledge about how long COVID manifests in a large, underserved population.


Awake Flexible Fiberoptic Laryngoscopy to diagnose glossoptosis in Robin Sequence patients.
Robin Sequence (RS) is usually defined as the combination of micrognathia, glossoptosis and upper airway obstruction. No objective criteria to diagnose RS exist. To compare management strategy results, a single RS definition using objective criteria is needed. The most frequently used primary diagnostic tool for glossoptosis is awake Flexible Fiberoptic Laryngoscopy (aFFL). To determine the reliability of the aFFL videos as an independent diagnostic tool itself, rather than on the complete evaluation of a patient. All RS individuals from an existing cohort with an available aFFL video were included retrospectively. Thirty age-matched patients without pathologic findings on aFFL were used as controls. aFFL videos were scored by six otolaryngologists as: a. Marked glossoptosis, b. Mild glossoptosis, c. Severity unknown, d. No glossoptosis, e. Insufficient video quality. Videos were anonymised and rated twice, in altered sequences, after a washout period of minimally 2 weeks. Inter-rater and intrarater agreement. Twenty-six videos of 16 RS patients and 30 videos of controls were included. Inter-rater agreement was fair in the whole group (κ: 0.320) and RS group (κ: 0.226), and fair to moderate in determining presence of glossoptosis (total group κ: 0.430; RS κ: 0.302; controls κ: 0.212). The intrarater agreement for the presence of glossoptosis in RS was moderate (κ: 0.541). aFFL offers fair to moderate inter-rater agreement, with moderate intrarater agreement, in evaluating glossoptosis in RS. Using aFFL as the single tool in choosing management strategies in RS seems insufficient. There is need for a more reliable, patient friendly diagnostic tool or an internationally accepted aFFL scoring system, to diagnose glossoptosis in RS.


Anatomy in dentistry: From the beginnings to contemporary reality.
The history of dentistry and medicine has a deep and ancient bond with the history of anatomy. From the ancient times to the present, the study of the human body represents the basis for research and clinical therapy. The historical contribution of anatomists to the development of dental medicine also helped in its characterization as an integrated but special and independent branch of medicine. From Galen's studies on animals to the discoveries of dental hard tissues characteristics using a microscope, this paper provides a brief literature review of how anatomy broadly contributed to the development of the dental sciences and how it still allows us to direct critical and fundamental anatomical-clinical paths for modern patient care. The history of the anatomy of teeth, description of skull bones, maxillary sinus characterization, the salivary glands, the tongue and labial musculature, and the microscopic anatomy of dental hard tissues will be examined. Historical research on the understanding of and progress in the oral field is of utmost importance in current clinical practice, thus inducing a future orientation in research. Most of the research especially that connected to the more distant historical periods has seen as main characters great personalities of morphological sciences, which contributes constituted fundamental basis for dental clinical aspects. Through a punctual and continuous historical assay, the ancient insights are reconnected to more recent knowledge and distinct research, thus permitting a detailed reconstruction of the historical-anatomical course in the progress of knowledge regarding the oral cavity and related anatomical structures.


[The Role of Distinctiveness of Stimulus in Memory Distrust as a Function of Repeated Checking].
Recent literature proposes that repeated checking increases familiarity with the material, making recollections less vivid and detailed and promoting distrust in memory. The aim of the current study is to investigate the possible underlying mechanisms of low confidence in memory. The Padua Inventory-Washington State University Revision (PI-WSUR) was applied in a cohort of university students. Among the students who completed the PI-WSUR, 84 participants were selected and assigned to low Obsessive-Compulsive Symptomatology (OCS) group or high OCS group according to their PI-WSUR scores. An interactive computer animation was developed to test repeated checking behavior. Participants were randomly assigned to two experimental conditions: "Feedback condition" and "no feedback condition". The participants were all asked to carry out checking rituals on a virtual gas ring. However, half of the participants were given feedback indicating that checking activity was successful and complete and half of the participants were not. While there was no significant difference in terms of memory accuracy, memory detail and memory vividness between feedback condition and no feedback condition, there was a significant difference in terms of memory confidence between two experimental groups. Results are discussed in the light of a different explanation offering that the level of distinctiveness of recollections plays crucial role in memory distrust rather than the explanation of low confidence hypothesis.


Deep UV Microscopy Identifies Prostatic Basal Cells: An Important Biomarker for Prostate Cancer Diagnostics.
Objective and Impact Statement. Identifying benign mimics of prostatic adenocarcinoma remains a significant diagnostic challenge. In this work, we developed an approach based on label-free, high-resolution molecular imaging with multispectral deep ultraviolet (UV) microscopy which identifies important prostate tissue components, including basal cells. This work has significant implications towards improving the pathologic assessment and diagnosis of prostate cancer. Introduction. One of the most important indicators of prostate cancer is the absence of basal cells in glands and ducts. However, identifying basal cells using hematoxylin and eosin (H&E) stains, which is the standard of care, can be difficult in a subset of cases. In such situations, pathologists often resort to immunohistochemical (IHC) stains for a definitive diagnosis. However, IHC is expensive and time-consuming and requires more tissue sections which may not be available. In addition, IHC is subject to false-negative or false-positive stains which can potentially lead to an incorrect diagnosis. Methods. We leverage the rich molecular information of label-free multispectral deep UV microscopy to uniquely identify basal cells, luminal cells, and inflammatory cells. The method applies an unsupervised geometrical representation of principal component analysis to separate the various components of prostate tissue leading to multiple image representations of the molecular information. Results. Our results show that this method accurately and efficiently identifies benign and malignant glands with high fidelity, free of any staining procedures, based on the presence or absence of basal cells. We further use the molecular information to directly generate a high-resolution virtual IHC stain that clearly identifies basal cells, even in cases where IHC stains fail. Conclusion. Our simple, low-cost, and label-free deep UV method has the potential to improve and facilitate prostate cancer diagnosis by enabling robust identification of basal cells and other important prostate tissue components.


Breast symptoms in adolescents and young adults presenting to a specialist breast clinic.
While breast cancer is rare in adolescents and young adults (AYAs), breast symptoms are common. The aim of this study was to report breast symptoms that prompted referral of AYAs and to examine diagnoses and treatment. A retrospective study of AYAs aged ≤25 years who presented in a specialist breast clinic (2007-18) was conducted. Data regarding presentation, diagnosis and management were collected. One hundred and thirty-four (128 female, six male) AYAs, with a median age of 21 years, attended the breast clinic in the study period. There was one case of breast cancer (incidence 0.8%). In females, the most frequent presenting symptoms were 'lump' (n = 68, 53.1%), 'nipple/areola symptom' (n = 14, 10.9%) and 'discuss risk of breast cancer' (n = 10, 8.3%). In males, 'lump' was the most common presenting symptom (n = 5, 83%) and all were cases of gynaecomastia. A range of breast symptoms are found in AYAs and most can be treated conservatively. Awareness of symptoms and their management will help general practitioners treat young people with breast issues.


[Eco-environment and nutrient accumulation of sharptooth oak stands in southern slope of Mt. Qinling].
Based on the date from chemical analysis of 10,785 botanical and 1489 edaphic samples, the amount of nutrients accumulated in soil layer (0-60 cm) of sharptooth oak stands, the total biomass of the stands and their contents of accumulated nutrients, and the amount of litter and its contents of accumulated nutrients in southern slope of Mt. Qinling were calculated. To a certain extent, the biomass and the nutrient accumulation of the stands were increased with stand densities and stand ages from thin to high or from young to old, similar to the utilization efficiency of the stands to soil nutrient elements and the trunk canopy ratio. The tree composition of the stands much more influenced nutrient accumulation contents than the biomass. The more broad-leaved tree of species composition, the higher nutrient accumulation contents of stands. In the same region biomass and its nutrient contents of the stands with similar site factors and stand factors had not remarkably difference among different forest-types, but had a difference among various forest types and species composition. In different region, biomass and its nutrient contents of the stands with similar site factors and stand factors had a difference with the sequence of south slope > north slope, middle section > east section or west section. The utilization efficiency of soil nutrient elements by the stands was decreased from lower to higher elevation, from the south to north slope, from middle to east and west section.


[The development of the ethical thinking in children and the teaching of ethics in pediatrics].
The child's ethical thinking is not installed in his mind as a single act, but as a consequence of an evolving process. Kohlberg, based on Piaget's studies, described three main developmental stages: preconventional, conventional and post conventional. However, Vigostky and others emphasized the importance of the environment for the moral sculpture of children. Three models can be recognised for teaching ethics in children: the deontological way, the descriptive way, and the only one morally acceptable: the one used by Socrates, by which ethics becomes not merely an adjective, but an institutionalised social practice built on axiological basis.


Characteristics of non-melanoma skin cancers in Native American patients treated with Mohs micrographic surgery.
Despite the lower incidence of non-melanoma skin cancers in skin of color populations, greater morbidity and mortality have been reported. Literature describing non-melanoma skin cancers in Native Americans is scarce. We designed a retrospective review study aimed to evaluate the characteristics of non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) in Native American patients treated with Mohs micrographic surgery between January 2015 and August 2020, at a single academic center. Twenty-six patients with 28 tumors were identified; 12 squamous cell carcinomas (92% well-differentiated) and 16 basal cell carcinomas (94% nodular). Most tumors were on the head and neck, with mean size of 563mm2 (squamous cell carcinomas) and 350mm2 (basal cell carcinomas). Tumor clearance was achieved in one stage for 75% of tumors. Recurrence was seen in two patients with squamous cell carcinoma. No mortality reported, although follow up was limited. Few Native Americans patients underwent Mohs micrographic surgery for non-melanoma skin cancers. Squamous cell cancers were larger, lower risk while basal cell carcinomas were predominantly nodular. Average time from biopsy to Mohs micrographic surgery was three months. Further studies are needed to better characterize non-melanoma skin cancers in Native Americans and to identify barriers to prompt care.


Traumatic Brain Injury Disrupts Pain Signaling in the Brainstem and Spinal Cord.
Chronic pain is a common consequence of traumatic brain injury (TBI) that can increase the suffering of a patient and pose a significant challenge to rehabilitative efforts. Unfortunately, the mechanisms linking TBI to pain are poorly understood, and specific treatments for TBI-related pain are still lacking. Our laboratory has shown that TBI causes pain sensitization in areas distant to the site of primary injury, and that changes in spinal gene expression may underlie this sensitization. The aim of this study was to examine the roles that pain modulatory pathways descending from the brainstem play in pain after TBI. Deficiencies in one type of descending inhibition, diffuse noxious inhibitory control (DNIC), have been suggested to be responsible for the development of chronic pain by allowing excess and uncontrolled afferent nociceptive inputs. Here we expand our knowledge of pain after TBI in two ways: (1) by outlining the neuropathology in pain-related centers of the brain and spinal cord involved in DNIC using the rat lateral fluid percussion (LFP) model of TBI, and (2) by evaluating the effects of a potent histone acetyl transferase inhibitor, anacardic acid (AA), on LFP-induced pain behaviors and neuropathology when administered for several days after TBI. The results revealed that TBI induces transient mechanical allodynia and a chronic persistent loss of DNIC. Further, while short-term AA treatment can block acute nociceptive sensitization and some early neuropathological changes, this treatment neither prevented the loss of DNIC nor did it alter long-term neuropathological changes in the brain or spinal cord.


Gene and cell replacement via neural stem cells.
Neural stem cells (NSCs) are operationally defined by their ability to self-renew, to differentiate into cells of all glial and neuronal lineages throughout the neuraxis, and to populate developing or degenerating central nervous system (CNS) regions. Thus their use as graft material can be considered analogous to hematopoietic stem cell-mediated reconstitution and gene transfer. The recognition that NSCs propagated in culture could be reimplanted into mammalian brain, where they might integrate appropriately throughout the mammalian CNS and stably express foreign genes, has unveiled a new role for neural transplantation and gene therapy and a possible strategy for addressing the CNS manifestations of diseases that heretofore had been refractory to intervention. NSCs additionally have the appealing ability to home in on pathology, even over great distances. Such observations help to advance the idea that NSCs--as a prototype for stem cells from other solid organs--might aid in reconstructing the molecular and cellular milieu of maldeveloped or damaged CNS.


Time-Dependent Changes of Klotho and FGF-23 Levels after Kidney Transplantation: Role of Cold Ischemia Time, Renal Function and Graft Inflammation.
We investigated the evolution of serum klotho (s-Kl) and FGF-23 during the first two years post-kidney transplantation (KT), considering the cold ischemia time (CIT), glomerular filtration rate (GFR) and graft subclinical inflammation (SCI). We undertook a prospective, cohort, multicenter study of consecutive patients between April 2018 and January 2021 (with follow-up at 24 months). Subgroups were analyzed according to the median CIT (<14 vs. ≥14 h), the median GFR (≤40 vs. >40 mL/min/1.73 m2) and the presence of SCI at month 3. A total of 147 patients were included. s-Kl and fibroblast growth factor-23 (FGF-23) levels were measured at baseline and at months 3, 12 and 24. Graft biopsies (n = 96) were performed at month 3. All patients had low s-Kl levels at month 3. Patients with CIT < 14 h exhibited a significant increase in s-Kl at month 24. In patients with CIT ≥ 14 h, s-Kl at month 3 fell and lower s-Kl levels were seen at month 24. Patients with a GFR > 40 had a lesser decrease in s-Kl at month 3. FGF-23 fell significantly at months 3 and 12 in both GFR groups, a reduction maintained during follow-up. There were significant inter-group differences in s-Kl from months 3 to 24. CIT, GFR at 3 months and SCI were significantly associated with s-KI at month 3. A reduction in s-Kl at month 3 post-KT could be explained by longer CIT and delayed graft function as well as by impaired graft function. Early SCI may regulate s-Kl increase post-KT.


Severe Cutaneous Adverse Reaction to Piperacillin-Tazobactam: A Case of Stevens-Johnson Syndrome.
Stevens-Johnson syndrome (SJS) is a rare condition characterized by an exaggerated immune system response to triggers such as infections or drugs. It is characterized by blistering and exfoliation of the skin and affects mucosal surfaces, including the eyes, buccal cavity, and genitals. We report a case of a 50-year-old male who developed symptoms of SJS following a recent hospital admission for acute appendicitis The patient presented with fever, erythematous patches on the palms, abdomen, groins, and oral mucosa. The onset of symptoms occurred approximately four days after discharge from the hospital, where the patient had received treatment including intravenous antibiotics (Piperacillin-Tazobactam), ranitidine, tramadol, and intravenous fluids. He was diagnosed with SJS based on clinical and histopathological findings and was treated with supportive care and corticosteroids. He recovered after one week of hospitalization. This case highlights the importance of recognizing the potential risk of developing SJS following drug administration and the need for prompt identification and management of the condition to prevent complications and improve patient outcomes.


Study on Redox Properties and Cytotoxicity of Anthraquinone Derivatives to Understand Antitumor Active Anthracycline Substances.
This study demonstrates the relation between the redox properties and cytotoxicity of anthraquinone derivatives with a hydroxyl and methoxy group. The redox behavior of the anthraquinone derivatives was initially observed via cyclic voltammetry and their characteristics were investigated using molecular orbital calculations. The cytotoxicity of the anthraquinone derivatives was then evaluated using human leukemia HL-60 and H2O2 resistant HP100 cells, and its correlation with the redox properties of these compounds was investigated. Therefore, it was suggested that the anthraquinone derivatives express cytotoxicity through H2O2 production, and that generation of the oxidized radical form influences their cytotoxicity.


Lymphocytic tumours of the conjunctiva.
Twenty-six cases of lymphocytic tumour of the conjunctiva, which were originally classified as benign lymphoma and lymphosarcoma, were followed up for more than five years, They were then reclassified into non-disseminating and disseminating groups. Only when germinal follicles are present can a histological diagnosis of benign lymphoma be made. Moreover, it is only when lymphoblasts are seen to be infiltrating the tissues that a definitive diagnosis of lymphosarcoma can be made. The remaining tumours, which represent the large majority of lesions, show a very similar or identical histological picture, and a diagnosis of benignity or malignancy can only be made after a prolonged follow up. The possible nature of the non-disseminating lymphocytic tumours is briefly discussed.


Traumatic unilateral internuclear ophthalmoplegia.
A 23-year-old man was admitted for a closed head injury following a fall from a height of 5 meters from a ladder. Because of a C-7 burst fracture, a halo and halo vest were applied approximately 9 hours following the fall. Approximately 21 hours after the accident, the patient complained of diplopia. On neuro-ophthalmology evaluation, a unilateral internuclear ophthalmoplegia was noted. MRI of the brain, performed 3 days after application of the halo and vest, showed a small infarct at the posterior aspect of the inferior midbrain, slightly left of midline. At 9.5 weeks there was 90% improvement of the internuclear ophthalmoplegia noted. Of the reported cases in the medical literature of traumatic internuclear ophthalmoplegia, 30 (83.33%) cases were male and 6 (16.67%) were female. The mean age was 31.7. 54% of the cases were bilateral; 46% unilateral. Mechanisms include: motor vehicle accident: 28 (41.79%), fall: 7 (10.45%), blunt trauma: 11 (16.42%), penetrating trauma 1: (1.49%), bike accident 3: (4.48%), other: 1 (1.49%), Unknown: 16 (23.88%).


Clinical characteristics and outcome of left ventricular ballooning syndrome in a European population.
We assessed the clinical characteristics and determinants of the prognosis of patients with left ventricular ballooning syndrome (LVBS) in an European population. A total of 128 patients with LVBS (98% women, age 67 ± 11 years) were prospectively followed up for a median of 13 months. A trigger event was identifiable in 58% of the patients. Anterior ST-segment elevation was documented in 38% and negative T waves in 41% of the patients. Apical ballooning was present in 82% and midventricular ballooning in 18%. The initial LV ejection fraction was 41 ± 9%. In-hospital events included the death of 1 patient (0.8%), LV failure in 13 (10%), LV thrombi in 4 (3.1%), sustained ventricular or supraventricular tachyarrhythmias in 6 (4.7%) and asystole in 2 patients (1.6%). The extent of wall motion abnormalities (odds ratio 4.16, p = 0.012), dyspnea at presentation (odds ratio 3.42, p = 0.01), and treatment with nitrates (odds ratio 0.30, p = 0.015) were significant univariate predictors of in-hospital events. The recovery of regional wall motion abnormalities occurred within 1 month of the event in 73% of patients. During follow-up, events occurred in 7 (6%) of 121 patients, including noncardiac death in 1 (0.8%), recurrent LVBS in 2 (1.6%), heart failure in 1 (0.8%), and recurrent chest pain in 3 (2.5%). In conclusion, in a European population, LVBS was characterized by a significant rate of in-hospital events, mainly related to pump failure, and low short-term mortality. The extent of wall motion abnormalities was the best predictor of acute events. Contractile recovery occurred within 1 month in most patients. The long-term prognosis was good, with a recurrence rate of <2%/year.


Cytotoxic activity of lymphocytes. V. Role of soluble toxin in macrophage-inhibited cultures of tumor cells.
Macrophage cell-mediated cytolysis (M-CMC) of tumor cells may be measured by culturing target cells on macrophage monolayers and determining target cell survival by either Rb or H-thymidine incorporation. Using these techniques, one can demonstrate cytotoxicity of nonimmune human and rat macrophages to a variety of tumor cell lines. Toxicity becomes maximal 8 to 16 hr after attaching macrophages to plastic surfaces and disappears after 36 to 48 hr. Addition of Escherichia coli endotoxin at 48 hr restores macrophage toxicity. Culture of macrophages on plastic surfaces also results in the release, nonspecifically, of a soluble cytotoxin whose kinetics of release, disappearance, and reappearance after endotoxin all parallel the M-CMC. The amount of toxin released into cultures containing target cells is markedly reduced, suggesting that it is the mediator of the M-CMC and that it is utilized or absorbed during target destruction. Sephadex G-100 chromatography and treatment with heterologous anti-lymphotoxin can distinguish this toxin from lymphotoxin.


Modeling the Transmission of Measles and Rubella to Support Global Management Policy Analyses and Eradication Investment Cases.
Policy makers responsible for managing measles and rubella immunization programs currently use a wide range of different vaccines formulations and immunization schedules. With endemic measles and rubella transmission interrupted in the region of the Americas, all five other regions of the World Health Organization (WHO) targeting the elimination of measles transmission by 2020, and increasing adoption of rubella vaccine globally, integrated dynamic disease, risk, decision, and economic models can help national, regional, and global health leaders manage measles and rubella population immunity. Despite hundreds of publications describing models for measles or rubella and decades of use of vaccines that contain both antigens (e.g., measles, mumps, and rubella vaccine or MMR), no transmission models for measles and rubella exist to support global policy analyses. We describe the development of a dynamic disease model for measles and rubella transmission, which we apply to 180 WHO member states and three other areas (Puerto Rico, Hong Kong, and Macao) representing >99.5% of the global population in 2013. The model accounts for seasonality, age-heterogeneous mixing, and the potential existence of preferentially mixing undervaccinated subpopulations, which create heterogeneity in immunization coverage that impacts transmission. Using our transmission model with the best available information about routine, supplemental, and outbreak response immunization, we characterize the complex transmission dynamics for measles and rubella historically to compare the results with available incidence and serological data. We show the results from several countries that represent diverse epidemiological situations to demonstrate the performance of the model. The model suggests relatively high measles and rubella control costs of approximately $3 billion annually for vaccination based on 2013 estimates, but still leads to approximately 17 million disability-adjusted life years lost with associated costs for treatment, home care, and productivity loss costs of approximately $4, $3, and $47 billion annually, respectively. Combined with vaccination and other financial cost estimates, our estimates imply that the eradication of measles and rubella could save at least $10 billion per year, even without considering the benefits of preventing lost productivity and potential savings from reductions in vaccination. The model should provide a useful tool for exploring the health and economic outcomes of prospective opportunities to manage measles and rubella. Improving the quality of data available to support decision making and modeling should represent a priority as countries work toward measles and rubella goals.


Impact of replacing conventional complete dentures with implant-supported fixed complete dentures.
The aim of this study was to assess the impact of replacing conventional mandibular complete dentures with implant-supported fixed complete dentures (ISFDs) on the oral health-related quality of life (OHQOL) of edentulous patients and on the associated kinesiographic parameters. The patients had their complete dentures replaced by ISFDs and were assessed after 1, 2, 3, 6, and 12 months. An improvement of general OHQOL was observed 2 months after treatment with ISFDs. Kinesiographic recordings revealed significant mandibular vertical and horizontal opening increases and a greater vertical intrusion of the maxillary complete dentures during clenching after the treatment with ISFD.


Effect of Quorum Quenching Lactonase in Clinical Isolates of Pseudomonas aeruginosa and Comparison with Quorum Sensing Inhibitors.
Pseudomonas aeruginosa is a Gram negative pathogenic bacterium involved in many human infections including otitis, keratitis, pneumonia, and diabetic foot ulcers. P. aeruginosa uses a communication system, referred to as quorum sensing (QS), to adopt a group behavior by synchronizing the expression of certain genes. Among the regulated traits, secretion of proteases or siderophores, motility and biofilm formation are mainly involved in the pathogenicity. Many efforts have been dedicated to the development of quorum sensing inhibitors (QSI) and quorum quenching (QQ) agents to disrupt QS. QQ enzymes have been particularly considered as they may act in a catalytic way without entering the cell. Here we focus on the lactonase SsoPox which was previously investigated for its ability to degrade the signaling molecules, acyl-homoserine lactones, in particular on the engineered variant SsoPox-W263I. We highlight the potential of SsoPox-W263I to inhibit the virulence of 51 clinical P. aeruginosa isolates from diabetic foot ulcers by decreasing the secretion of two virulence factors, proteases and pyocyanin, as well as biofilm formation. We further compared the effect of SsoPox-W263I to the comprehensively described QSI, 5-fluorouracil and C-30. We found the lactonase SsoPox-W263I to be significantly more effective than the tested QSI at their respective concentration optimum and to retain its activity after immobilization steps, paving the way for future therapeutic applications.


Standard therapeutic regimens in H. pylori infection leads to activation of transitory fungal flora in gastric mucus.
Administration of broad-spectrum antibiotics with antisecretory agents in treatment of H. pylori-associated diseases results in decreased representation of normal intestinal microflora and growth of transitory microflora, whose representatives are yeast-like fungi (Candida). This mayprimarily be caused by disordered microbial biocenosis in stomach, conditioned by eradication of H. pylori. Studies over recent years have yielded reliable information confirming that H. pylori is a source of peptides possessing a potent fungicidal activity. It still remains unclear whether there takes place an activation of fungal flora pre-existing in intestine, or drug-induced disorders of microbiocenosis in stomach. We carried out a histological and bacterioscopic study of biopsy materials obtained from gastric antral mucosa in 679 patients with H. pylori-associated erosive or/and ulcerative gastric lesions, chronic gastritis and gastroesophageal reflux disease (GERD), with erosive or/and ulcerative duodenal lesions before and after eradication therapy. Prior to treatment, the yeast-like fungi in stomach were revealed in 112 patients (16.5%). Eradication of H. pylori was achieved in 85% of patients, with large growth of elements resembling yeast-like fungi and pseudomycelium being detected in gastric mucosa in 33% of case. The findings obtained suggest that an increased influx of yeast-like fungi from stomach into the gut may play role in proliferation of intestinal fungal microflora following antihelicobacter therapy. Under the conditions of decreased acidity of gastric juice on the background of antisecretory therapy and the lack of microbial antagonism on behalf of H. pylori in gastric mucus, Candida-genus fungi receive optimal conditions for development and subsequent passage to the intestine.


Carbon nanotube reinforced polylactide-caprolactone copolymer: mechanical strengthening and interaction with human osteoblasts in vitro.
This study proposes the use of carbon nanotubes (CNTs) as reinforcement to enhance the mechanical properties of a polylactide-caprolactone copolymer (PLC) matrix. Biological interaction of PLC-CNT composites with human osteoblast cells is also investigated. Addition of 2 wt % CNT shows very uniform dispersion in the copolymer matrix, whereas 5 wt % CNT shows severe agglomeration and high porosity. PLC-2 wt % CNT composite shows an improvement in the mechanical properties with an increase in the elastic modulus by 100% and tensile strength by 160%, without any adverse effect on the ductility up to 240% elongation. An in vitro biocompatibility study on the composites shows an increase in the viability of human osteoblast cells compared to the PLC matrix, which is attributed to the combined effect of CNT content and surface roughness of the composite films.


Melatonin pre-treatment mitigates SHSY-5Y cells against oxaliplatin induced mitochondrial stress and apoptotic cell death.
Oxaliplatin (Oxa) treatment to SH-SY5Y human neuroblastoma cells has been shown by previous studies to induce oxidative stress, which in turn modulates intracellular signaling cascades resulting in cell death. While this phenomenon of Oxa-induced neurotoxicity is known, the underlying mechanisms involved in this cell death cascade must be clarified. Moreover, there is still little known regarding the roles of neuronal mitochondria and cytosolic compartments in mediating Oxa-induced neurotoxicity. With a better grasp of the mechanisms driving neurotoxicity in Oxa-treated SH-SY5Y cells, we can then identify certain pathways to target in protecting against neurotoxic cell damage. Therefore, the purpose of this study was to determine whether one such agent, melatonin (Mel), could confer protection against Oxa-induced neurotoxicity in SH-SY5Y cells. Results from the present study found Oxa to significantly reduce SH-SY5Y cell viability in a dose-dependent manner. Alternatively, we found Mel pre-treatment to SH-SY5Y cells to attenuate Oxa-induced toxicity, resulting in a markedly increased cell viability. Mel exerted its protective effects by regulating reactive oxygen species (ROS) production and reducing superoxide radicals inside Oxa-exposed. In addition, we observed pre-treatment with Mel to rescue Oxa-treated cells by protecting mitochondria. As Oxa-treatment alone decreases mitochondrial membrane potential (Δψm), resulting in an altered Bcl-2/Bax ratio and release of sequestered cytochrome c, so Mel was shown to inhibit these pathways. Mel was also found to inhibit proteolytic activation of caspase 3, inactivation of Poly (ADP Ribose) polymerase, and DNA damage, thereby allowing SH-SY5Y cells to resist apoptotic cell death. Collectively, our results suggest a role for melatonin in reducing Oxa induced neurotoxicity. Further studies exploring melatonin's protective effects may prove successful in eliciting pathways to further alter the neurotoxic pathways of platinum compounds in cancer treatment.


Clinical pharmacokinetic of celecoxib in healthy Thai volunteers.
Celecoxib, a nonsteroidal antiinflammatory drug exhibits its antiinflammatory effect by selective inhibition of cyclooxygenase-2 (COX-2) enzyme. Its efficacy has been accepted for the treatment of arthritic pain with superior gastrointestinal side effect profile compared with other conventional NSAIDs. To elucidate clinical pharmacokinetic of celecoxib following an oral dose administration. Eighteen healthy Thai male volunteers were enrolled in the present study. Their mean age was 20.94 +/- 1.21 years and their mean weight was 63 +/- 5.17 kg. They were orally administered 200 mg celecoxib after an over night fasting, serial blood samples were drawn before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours after dosing. Plasma celecoxib was analysed by reversed-phase HPLC. Following a 200 mg celecoxib oral administration, the drug was absorbed into the systemic circulation and reach maximum concentration (Tmax) within 2.50 +/- 1.22 hrs by average with the mean peak concentration (Cmax) of 686.83 +/- 211.35 ng/ml. The extent of absorption (area under the curve, AUC) was approximately 5157.12 +/- 1499.46 and 5911.48 +/- 1363.51 ng hr/ml for AUC(0-->t) and AUC(0-->infinity) respectively. The apparent volume of distribution (Vd) was found to be 458.93 +/- 323.28 L/hr. Celecoxib was eliminated after biotransformation and the metabolites were excreted in both urine and feces. The elimination half-life (t(1/2)) of celecoxib appeared to be 8.79 +/- 5.49 hrs with the apparent clearance (CL) of 35.91 +/- 9.85 L. The elimination rate constant for celecoxib obtained from this present study was about 0.11 +/- 0.05 hr(-1). Pharmacokinetic parameters following an oral dose of 200 mg celecoxib administration were characterized, including Cmax, Tmax, Vd, kel, CL, AUC. These parameters reflected absorption, distribution, biotransformation and excretion of celecoxib in healthy Thai volunteers.


Atrial Fibrillation and Transient Ischemic Attack Encountered in the Management of Snake Bite.
Thousands of snake bites occur in the world each year, with hundreds of patients receiving antivenom. Incidence rates for immediate hypersensitivity reactions associated with the use of antivenom range vary. This is a case report of a patient with atrial fibrillation (AF) and transient ischemic attack (TIA) induced by vigrous snake bite that was suspected to be caused by the treatment of subcutaneous epinephrine, due to immediate hypersensitivity reaction following the administration of antivenom treatment.


Serum circRNA_100199 is a Prognostic Biomarker in Acute Myeloid Leukemia.
An aberrant level of serum microRNA expression has been demonstrated to be a prognostic marker for acute myeloid leukemia (AML). The therapeutic relevance of serum circRNA 100199 remained unknown, however. This research aimed to investigate the probable prognostic significance of serum circRNA_100199 for AML. This study included a total of 200 participants consisting of 114 AML-diagnosed patients and 86 healthy people. Blood samples were taken, and the level of circRNA_100199 in the serum was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) to explore its potential clinical significance. Our study demonstrated that circRNA_100199 expression in the serum was substantially higher in AML subjects than in healthy persons. This increase in serum circRNA_100199 levels was particularly noticeable in M4/M5 subtype AML patients, and those with poor cytogenetic risk or higher white blood cell counts. Using receiver operating characteristic (ROC) analysis, AML cases were effectively differentiated from healthy persons based on the level of serum circRNA_100199. Furthermore, it was found that high serum circRNA_100199 expression was strongly linked with shorter survival times and more severe clinical features. Our study also confirmed that high serum circRNA_100199 expression was an independent predictor of relapse-free survival (RFS) and overall survival (OS) in AML patients. Interestingly, the serum expression level of circRNA_100199 was significantly reduced following treatment, and its levels were substantially lower in AML patients who achieved complete remission (CR) than those who did not. Overall, these findings suggest that serum circRNA_100199 has the potential to be a favorable prognostic biomarker for AML.


Potentiation of 5-fluorouracil, chromomycin A3, and bleomycin by amphotericin B or polymyxin B in transformed fibroblastic cells.
By using cultured, transformed fibroblastic cells, antitumor agents including cytosine arabinoside, thio-tepa, nitrogen mustard N-oxide, mitomycin C, chromomycin A3, 5-fluorouracil, daunomycin, vinblastine, vincristine, and bleomycin A2 were screened for the potentiation of their activity by amphotericin B or polymyxin B. Among them, the action of 5-fluorouracil and chromomycin A3 on ribonucleic acid synthesis was potentiated in their action by amphotericin B, not by polymyxin B. Bleomycin A2 was potentiated in its action on deoxyribonucleic acid and ribonucleic acid synthesis only by polymyxin B.


Combined radiotherapy and chemotherapy in the management of local-regionally advanced vulvar cancer.
To determine, in a retrospective single institutional study, the role of concurrent radiotherapy and chemotherapy in the treatment of local-regionally advanced vulvar cancer. From 1984 to 1991, 20 patients with locally extensive primary or recurrent carcinoma of the vulva were treated with initial combined radiotherapy and chemotherapy. Seven patients had Federation Internationale de Gynecologie et d'Obstretrique Stage III disease, 10 had Stage IV disease, and three were treated for recurrent disease. None of these patients were considered candidates for primary radical vulvectomy and groin node dissection. Median radiation doses to regions of microscopic disease and gross tumor were 40 Gy (range 30-54 Gy) and 54 Gy (34-70.4 Gy), respectively. All patients received 2 or 3 cycles of 5-Fluorouracil concurrently with radiotherapy. In addition, five patients received Cis-platinum, and one Mitomycin-C. Median at-risk follow-up interval was 37 months. Ten patients had complete resolution of tumor to initial chemoradiotherapy, and eight of these have remained free of tumor relapse. Eight other patients had partial responses, with tumor bulk reduced by > 50%, while the remaining two patients had local-regionally progressive disease. Six of the patients with partial responses had residual tumor successfully resected, although four subsequently recurred. For the entire group of 20 patients, the actuarial 3- and 5-year local control rates were 48% each, and the corresponding disease-specific survival rates were 59% and 49%. There was a suggestion that better local control was obtained in patients who received gross tumor radiation doses > or = 50 Gy. Skin reaction was the major acute toxicity and responded well to conservative management. Long-term sequalae were limited to skin and subcutaneous atrophy. These results indicate that initial combined radiotherapy and chemotherapy is effective in the management of advanced vulvar cancer.


Assessment of CMV load in solid organ transplant recipients by pp65 antigenemia and real-time quantitative DNA PCR assay: correlation with pp67 RNA detection.
After bone marrow (BM) or solid-organ (SO) transplantation viremic Cytomegalovirus (CMV) infection is observed frequently. Quantitative assay of CMV in blood helps the management of this clinical condition. In the present report, 83 samples from 39 solid organ recipients, three CMV assays were compared simultaneously for the first time: the Nuclisens CMV pp67 assay (nucleic acid sequence-based amplification, NASBA), an "in-house" quantitative real-time PCR assay (TaqMan) for CMV DNA, and pp65 antigenemia. The relation between CMV DNA and pp65 antigenemia, the quantitative assays, was evaluated on a larger group including 251 blood samples from 118 solid organ recipients. Real-time PCR provided the best results; > or =130 CMV DNA copies/2 x 10(5) peripheral blood leukocytes (PBLs) predicted > or =1 pp65 antigen positive (Ag+) cell/2 x 10(5) PBLs. By taking pp65 antigenemia as the "gold standard," the sensitivity of CMV DNA quantitation and of the pp67 RNA assay were 0.95 and 0.20, respectively, while the corresponding specificity values were 0.50 and 0.93. When real-time PCR was considered as the "gold standard," the sensitivity and specificity of the pp65 antigenemia were 0.65 and 0.91, respectively. Among the three tests examined, the sensitivity of the pp67 RNA assay was the lowest. On the other hand, the pp67 RNA assay was highly specific and effective in pinpointing high viremia patients. The present report, by providing predictive values for all three diagnostic profiles, DNA load, antigenemia, and pp67RNA, is a contribution for validation of real-time PCR as a new standard for quantitative assessment of CMV viremia in clinical settings.


Familial hypertrophic cardiomyopathy. Cardiac ultrasonic abnormalities in genetically affected subjects without echocardiographic evidence of left ventricular hypertrophy.
It is not known whether the apparent normality of echocardiographic examination results, in subjects bearing a mutation for hypertrophic cardiomyopathy but without ultrasonic left ventricular hypertrophy, is due to incomplete phenotypic expression, or inaccurate echocardiographic criteria. The aim of this study was to search for echocardiographic abnormalities in these patients. Echocardiography was performed in 100 subjects from two families with a mutation in the beta-MHC (720) or My-BPC (714) genes. We compared genetically affected subjects with an apparently normal left ventricle (thickness < 13 mm) (20 patients), and nonaffected first-degree relatives (61 normal subjects). (1) Patients had a thicker left ventricular wall (9.7 +/- 1.4 vs 8.9 +/- 1.4 mm, P = 0.03), a greater indexed mass (107 +/- 18 vs 97 +/- 17 g. m-2, P = 0.03), a larger left atrium (27 +/- 9 vs 23 +/- 10 mm3, P = 0.09) and lower wall stress (78 +/- 11 vs 89 +/- 15 10(3) dynes. cm-2, P = 0.002); these differences were highly significant after adjustment for height, age and systolic blood pressure either for wall thickness (P = 0.000003), mass (P = 0.005) or atrial volume (P = 0.001), and the ventricular systolic dimension appeared smaller (P = 0.01); (2) results remained significant (P < 0.01) when a lower cut-off value (< or = 11 mm) or only adults (> or = 18 years) were considered; (3) a subanalysis of Family 714 (13 patients, 25 normals matched for sex, age and height) showed the same trends. In familial hypertrophic cardiomyopathy, genetically affected subjects with an apparently normal heart by echocardiography show slight ultrasonic structural and functional left ventricular modifications, suggesting that the phenotype of the disease is a continuous spectrum from normal structure to typical hypertrophy.


Moving bed biofilm reactor technology: process applications, design, and performance.
The moving bed biofilm reactor (MBBR) can operate as a 2- (anoxic) or 3-(aerobic) phase system with buoyant free-moving plastic biofilm carriers. These systems can be used for municipal and industrial wastewater treatment, aquaculture, potable water denitrification, and, in roughing, secondary, tertiary, and sidestream applications. The system includes a submerged biofilm reactor and liquid-solids separation unit. The MBBR process benefits include the following: (1) capacity to meet treatment objectives similar to activated sludge systems with respect to carbon-oxidation and nitrogen removal, but requires a smaller tank volume than a clarifier-coupled activated sludge system; (2) biomass retention is clarifier-independent and solids loading to the liquid-solids separation unit is reduced significantly when compared with activated sludge systems; (3) the MBBR is a continuous-flow process that does not require a special operational cycle for biofilm thickness, L(F), control (e.g., biologically active filter backwashing); and (4) liquid-solids separation can be achieved with a variety of processes, including conventional and compact high-rate processes. Information related to system design is fragmented and poorly documented. This paper seeks to address this issue by summarizing state-of-the art MBBR design procedures and providing the reader with an overview of some commercially available systems and their components.


Childhood lead poisoning from commercially manufactured French ceramic dinnerware--New York City, 2003.
Lead poisoning adversely affects children worldwide. During 1999-2000, an estimated 434,000 children aged 1-5 years in the United States had elevated blood lead levels (BLLs) >/=10 microg/dL. Glazes found on ceramics, earthenware, bone china, and porcelain often contain lead and are a potential source of lead exposure. Children are especially vulnerable to the neurotoxic effects of lead. Exposures to lead in early childhood can have adverse effects on the developing nervous system, resulting in decreased intelligence and changes in behavior. In addition, certain behaviors (e.g., thumb sucking) place children at greater risk for exposure to lead. In 2003, the New York City Department of Health and Mental Hygiene's Lead Poisoning Prevention Program (LPPP), and the Mount Sinai Pediatric Environmental Health Specialty Unit (PEHSU) investigated a case of lead poisoning in a boy aged 20 months. This report summarizes that case investigation, which identified ceramic dinnerware imported from France as the source of lead exposure. This case underscores the susceptibility of children to a toxic exposure associated with 1) the high proportion of time spent in the home and 2) dietary habits that promote exposure to lead leached from ceramic ware.


NODULE INCEPTION antagonistically regulates gene expression with nitrate in Lotus japonicus.
Legumes produce root nodules as symbiotic organs where nitrogen-fixing bacteria are accommodated. Lotus japonicus NODULE INCEPTION (NIN) is an essential factor that specifically and positively regulates nodulation processes, and has evolved from a member of the NIN-like proteins, of which Arabidopsis homologs target nitrate-responsive elements (NREs), and activate gene expression in response to nitrate. It is therefore assumed that the NIN-mediated transcriptional network overlaps with those regulated by NLPs, because of their common DNA-binding RWP-RK domains. However, nodulation is inhibited in the presence of nitrate, and involvement of NIN in nitrate responses has remained largely unknown. Here we determined a consensus of NIN-binding nucleotide sequences (NBSs) by in vitro experiments, and revealed that the sequence pattern was very similar to those of NREs. Chromatin immunoprecitiation (ChIP)-PCR analyses showed that NIN targeted NREs in L. japonicus nitrate-inducible gene promoters, including LjNIR1, LjNRT2.1 and LjNRT2.2. Affinities of NIN binding to the NREs were comparable with that to NBS-yB1a, an NBS on the symbiotic LjNF-YB1 promoter, indicating that NREs are potential targets of NIN. However, rhizobial infection did not activate LjNIR1, LjNRT2.1 and LjNRT2.2. NIN ectopic expression interfered with nitrate-dependent activation of these genes. Nitrate treatment followed by NIN activation down-regulated expression of symbiotic NIN target genes. Our results showed that NIN and nitrate antagonistically regulate expression of genes that are activated by nitrate and NIN, respectively. We propose that this antagonistic relationship prevents inappropriate activation of genes in response to nitrate and rhizobial infection.


Multicenter, randomized study to optimize bowel preparation for colon capsule endoscopy.
To assess the cleansing efficacy and safety of a new Colon capsule endoscopy (CCE) bowel preparation regimen. This was a multicenter, prospective, randomized, controlled study comparing two CCE regimens. Subjects were asymptomatic and average risk for colorectal cancer. The second generation CCE system (PillCam® COLON 2; Medtronic, Yoqneam, Israel) was utilized. Preparation regimens differed in the 1st and 2nd boosts with the Study regimen using oral sulfate solution (89 mL) with diatrizoate meglumine and diatrizoate sodium solution ("diatrizoate solution") (boost 1 = 60 mL, boost 2 = 30 mL) and the Control regimen oral sulfate solution (89 mL) alone. The primary outcome was overall and segmental colon cleansing. Secondary outcomes included safety, polyp detection, colonic transit, CCE completion and capsule excretion ≤ 12 h. Both regimens had similar cleansing efficacy for the whole colon (Adequate: Study = 75.9%, Control = 77.3%; P = 0.88) and individual segments. In the Study group, CCE completion was superior (Study = 90.9%, Control = 76.9%; P = 0.048) and colonic transit was more often < 40 min (Study = 21.8%, Control = 4%; P = 0.0073). More Study regimen subjects experienced adverse events (Study = 19.4%, Control = 3.4%; P = 0.0061), and this difference did not appear related to diatrizoate solution. Adverse events were primarily gastrointestinal in nature and no serious adverse events related either to the bowel preparation regimen or the capsule were observed. There was a trend toward higher polyp detection with the Study regimen, but this did not achieve statistical significance for any size category. Mean transit time through the entire gastrointestinal tract, from ingestion to excretion, was shorter with the Study regimen while mean colonic transit times were similar for both study groups. A CCE bowel preparation regimen using oral sulfate solution and diatrizoate solution as a boost agent is effective, safe, and achieved superior CCE completion.


Perspective-taking with affected others to promote climate change mitigation.
Prior evidence suggests that perspective-taking may promote pro-environmental behavior, at least for low-cost behaviors or local environmental problems. Climate change, however, requires costly mitigation efforts and is a global problem. Thus, in this study, we examine whether perspective-taking in the context of climate change is effective in promoting mitigation behaviors, including actual and/or costly behaviors, the mechanisms through which perspective-taking works, and if the distance to the person adversely affected by climate change matters for the effect. We conducted an online experiment with a non-student sample from Germany (n = 557), utilizing a 2 × 2 factorial design, to investigate the impact of perspective-taking and distance on three outcome measures: a climate donation, signing a petition, and approval of mitigation policies. We find that perspective-taking does not promote these mitigation behaviors, yet it raises the degree perspective-takers value and - for close others - feel connected with the affected person. Exploratory analysis shows that dispositional perspective-taking and empathic concern are correlated with mitigation behaviors.


Legionella pneumophila infection activates bystander cells differentially by bacterial and host cell vesicles.
Extracellular vesicles from eukaryotic cells and outer membrane vesicles (OMVs) released from gram-negative bacteria have been described as mediators of pathogen-host interaction and intercellular communication. Legionella pneumophila (L. pneumophila) is a causative agent of severe pneumonia. The differential effect of bacterial and host cell vesicles in L. pneumophila infection is unknown so far. We infected THP-1-derived or primary human macrophages with L. pneumophila and isolated supernatant vesicles by differential centrifugation. We observed an increase of exosomes in the 100 k pellet by nanoparticle tracking analysis, electron microscopy, and protein markers. This fraction additionally contained Legionella LPS, indicating also the presence of OMVs. In contrast, vesicles in the 16 k pellet, representing microparticles, decreased during infection. The 100 k vesicle fraction activated uninfected primary human alveolar epithelial cells, A549 cells, and THP-1 cells. Epithelial cell activation was reduced by exosome depletion (anti-CD63, or GW4869), or blocking of IL-1β in the supernatant. In contrast, the response of THP-1 cells to vesicles was reduced by a TLR2-neutralizing antibody, UV-inactivation of bacteria, or - partially - RNase-treatment of vesicles. Taken together, we found that during L. pneumophila infection, neighbouring epithelial cells were predominantly activated by exosomes and cytokines, whereas myeloid cells were activated by bacterial OMVs.


Identifying the Effect of Celastrol Against Ovarian Cancer With Network Pharmacology and In Vitro Experiments.
Aim: We aimed to reveal the function of celastrol in the treatment of ovarian cancer using network pharmacology and molecular docking. Background: Ovarian cancer is a growth of cells that forms in the ovaries. Celastrol is a useful bioactive compound derived from the root of the thunder god vine. Method: Celastrol and ovarian cancer targets were determined by analyzing datasets. Protein-protein interaction (PPI) networks were obtained with network pharmacology. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Molecular docking using SWISS-MODEL, CB-Dock and Discovery Studio was conducted. A methylthiazolyltetrazolium bromide (MTT) assay was performed to evaluate cell proliferation. Cell apoptosis and cell cycle were measured with a fluorescence assay. Reverse transcription PCR (RT-PCR) and Western blot were performed to measure the expression of core targets. Result: Celastrol possessed 29 potential targets, while ovarian cancer possessed 471 potential targets. The core PPI network contained 163 nodes and 4,483 edges. The biological processes identified in the GO analysis indicated that the targets were related with the cellular response to DNA damage stimulus, DNA recombination, and cell proliferation, among other processes. The KEGG analysis indicated that the pathways were related with the cell cycle, viral carcinogenesis, and MAPK signaling pathway, among others. The three core targets shared between the core PPI network and celastrol targets were MYC, CDC37, and FN1. Celastrol directly combined with the targets according to the results from CB-Dock and Discovery Studio. Celastrol inhibited ovarian cancer cell proliferation and promoted ovarian cancer cell apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses showed that celastrol inhibited core target expression. In addition, celastrol also influenced the related inflammatory signaling pathways in ovarian cancer cells. Conclusion: Celastrol exerts effective antitumor activity toward ovarian cancer. Celastrol regulated cell proliferation, DNA repair and replication, apoptotic processes, and inflammatory responses in ovarian cancer cells.


Setting standards using integrated care pathways.
An integrated care pathway is a tool that can help to deliver clinical governance objectives if implemented well. Key factors of successful implementation are: effective project management; communication and training; and top-down and bottom-up support for the process.


Genotypic diversity among multidrug resistant Pseudomonas aeruginosa and Acinetobacter species at Mulago Hospital in Kampala, Uganda.
Multidrug resistant Pseudomonas aeruginosa and Acinetobacter species are common causes of nosocomial infections worldwide. Recently we reported the occurrence of carbapenem resistant Enterobacteriaceae, P. aeruginosa and Acinetobacter species at Mulago National Referral Hospital in Kampala, Uganda, but the isolates were not analyzed for genetic relatedness. Herein we report the intra-species genotypic diversity among P. aeruginosa and Acinetobacter baumannii isolated from hospitalized patients and the environment at Mulago Hospital, using repetitive elements-based PCR (Rep-PCR) genotyping. A total of 736 specimens from hospitalized patients were processed for culture and sensitivity testing yielding 9 (1.2%) P. aeruginosa and 7 (0.95%) A. baumannii. Similarly, 100 samples from the hospital environment were processed yielding 33 (33%) P. aeruginosa and 13 (13%) A. baumannii. Altogether, 62 non-repetitive isolates were studied (42 P. aeruginosa and 20 A. baumannii), of which 38% (16/42) P. aeruginosa and 40% (8/20) A. baumannii were multidrug resistant (isolates resistant to three or more classes of antimicrobials). Carbapenem resistance prevalence was 33 and 21% for P. aeruginosa from patients and the environment, respectively, while it was 14 and 86% for A. baumannii from patients and environment, respectively. Cluster analysis of the Rep-PCR fingerprints revealed a high level of genetic diversity among the isolates within each species as few isolates were clustered (at 100% level of similarity). More to this, the clustered isolates revealed a complex nature of multidrug resistant P. aeruginosa and A. baumannii clones circulating at Mulago Hospital. Importantly, certain isolates from the environment and patients were clustered, implying that hospitalized patients at Mulago were probably infected with strains from the environment. The prevalence of multidrug resistant P. aeruginosa and A. baumannii is high at Mulago Hospital but carbapenem resistance prevalence remains relatively low in isolates from hospitalized patients. Importantly, the prevalence of carbapenem resistance in isolates from the environment is high implying the infection control practices at the hospital might be inadequate.


Revisiting acrania: same phenotype, different aetiologies.
To evaluate the contribution of prenatal and postmortem examinations in establishing the aetiology of acrania. Retrospective evaluation of 14 cases of acrania managed through elective termination of pregnancy. The median maternal age was 30 years (range 18-40) and median gestational age at diagnosis was 13 weeks (range 12-15). One mother had epilepsy and was taking anticonvulsants and another had uncontrolled type II diabetes mellitus. Only 3 women were using folic acid at conception. Chromosomal abnormalities were detected in 3 of 8 cases analyzed. Unilateral anopthalmia, cervical rachischisis, midline facial and limb defects coexisted with acrania in 4 cases. Acrania with craniofacial dysmorphism and asymmetrical finger amputation were observed in a case of amniotic band syndrome. A previous history of anencephaly was documented in 1 case. Acrania is a characteristic phenotypic expression of a variety of different aetiologies. Investigation with cytogenetic studies and postmortem are essential to provide a definitive answer. This will provide a better understanding of the underlying aetiology and help establish the recurrence risk for future pregnancies.