Outcomes of root canal treatment in Dental Practice-Based Research Network practices.
This study sought to quantify the incidence of root canal treatment (RCT) failure and identify its predictors in root canals that were performed or referred by general dentistry practices in a practice-based research network (PBRN). This retrospective cohort study involved 174 endodontically treated teeth. Mean duration from initial therapy to follow-up was 8.6 years. Permanent restorations were ultimately placed in 89% of teeth, although 18% of teeth were ultimately extracted anyway. Receiving a permanent restoration was a significant predictor of treatment failure (in other words, patients who did not receive a permanent restoration were more likely to experience RCT failure), whether failure was determined clinically or radiographically. This study of PBRN practices suggests a higher failure rate compared with studies that utilized highly controlled environments or populations with high levels of dental insurance.


Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab.
Most patients with primary central nervous system (CNS) lymphoma or systemic non-Hodgkin's lymphoma (NHL) involving the CNS relapse after an initial response to treatment, often presenting with leptomeningeal disease. Since the majority of these lymphomas are B-cell neoplasms expressing the CD20 surface antigen treatment with the chimeric monoclonal antibody (Mab) rituximab might be a new therapeutic option. Here, we report on 6 patients with relapsed CNS B-cell lymphoma who were treated with intraventricular or intrathecal applications of rituximab. One of these cases has already been reported.


Ionizing radiation up-regulates cyclooxygenase-2 in I407 cells through p38 mitogen-activated protein kinase.
The epithelial cell line I407 up-regulates cyclooxygenase-2 (COX-2) mRNA and protein expression following ionizing radiation exposure. Prostaglandin E2 (PGE2) production is concomitantly up-regulated. Irradiation of I407 cells also results in phosphorylation of the p38 mitogen-activated protein kinase and the p38 inhibitor SB203580 abrogates radiation-induced PGE2 synthesis. Wild-type p38alpha (p38alphaWT) and dominant-negative p38alpha (p38alphaDN) stable-transfectant clones of I407 cells were used to examine the role of the p38 mitogen-activated protein kinase pathway in the events controlling PGE2 synthesis after ionizing radiation. Treatment of p38alphaWT clones with gamma-radiation resulted in increased COX-2 protein levels and PGE2 synthesis similar to treated control-transfected cells. In contrast, the p38alphaDN clones failed to up-regulate COX-2 protein or increase PGE2 synthesis when irradiated. Exogenous arachidonate did not restore PGE2 synthesis by p38alphaDN cells. Radiation increased COX-2 mRNA stability and the p38 inhibitor SB203580 attenuated COX-2 mRNA stability in irradiated I407 cells. In contrast, irradiation had no effect on transcription from a COX-2 promoter/luciferase reporter plasmid in the presence or absence of SB203580. The data demonstrate a crucial role for p38alpha in COX-2 expression and PGE2 synthesis in an irradiated transformed epithelial cell line. Furthermore, they indicate that p38 activity is required at a step distal to arachidonate release, most probably COX-2 up-regulation, since exogenous arachidonate did not restore PGE2 synthesis.


The Pex6 N1 domain is required for Pex15 binding and proper assembly with Pex1.
The heterohexameric AAA-ATPase Pex1/Pex6 is essential for the formation and maintenance of peroxisomes. Pex1/Pex6, similar to other AAA-ATPases, uses the energy from ATP hydrolysis to mechanically thread substrate proteins through its central pore, thereby unfolding them. In related AAA-ATPase motors, substrates are recruited through binding to the motor's N-terminal domains or N-terminally bound co-factors. Here we use structural and biochemical techniques to characterize the function of the N1 domain in Pex6 from budding yeast, S. cerevisiae. We found that although Pex1/ΔN1-Pex6 is an active ATPase in vitro, it does not support Pex1/Pex6 function at the peroxisome in vivo. An X-ray crystal structure of the isolated Pex6 N1 domain shows that the Pex6 N1 domain shares the same fold as the N terminal domains of PEX1, CDC48, or NSF, despite poor sequence conservation. Integrating this structure with a cryo-EM reconstruction of Pex1/Pex6, AlphaFold2 predictions, and biochemical assays shows that Pex6 N1 mediates binding to both the peroxisomal membrane tether Pex15 and an extended loop from the D2 ATPase domain of Pex1 that influences Pex1/Pex6 heterohexamer stability. Given the direct interactions with both Pex15 and the D2 ATPase domains, the Pex6 N1 domain is poised to coordinate binding of co-factors and substrates with Pex1/Pex6 ATPase activity.


Evaluation of the Initial Optical Coherence Tomography Parameters in Anticipating the Final Visual Outcome of Central Retinal Vein Occlusion.
To evaluate the predictive and associated factors in determining the visual outcome in patients having central retinal vein occlusion (CRVO)-related macular edema (ME). The charts of the patients who were treated due to CRVO-related visual disturbance were reviewed. The optical coherence tomography (OCT) images of eyes were analyzed, and disorganization of retinal inner layers (DRILs), ellipsoid zone (EZ) and external limiting membrane (ELM) disruption length, hyper-reflectivity of retinal inner layer (HRIL) existence, baseline and final visual acuity (VA), subfoveal thickness (SFT), subretinal fluid (SRF), and injection numbers were noted. The regression and correlation analyses were applied. Thirty eyes of thirty patients were included in the study. The mean follow-up time was 17.5 ± 11 (8-47) months. The mean baseline VA was 1.4 ± 0.7 (0.2-3.1) logMAR. A total of 87 intravitreal injections were applied for the treatment of ME during the follow-up. The initial mean central subfield thickness was 795 ± 264 (1470-398) μm. HRIL and SRF were observed in 16 and 23 eyes at the initial visit, respectively. The final mean VA was 1.2 ± 0.9 (0.1-3.1) logMAR. At the final visit, additional OCT parameters were evaluated. The mean DRIL length was 463 ± 324 μm. The mean disruption length of EZ and ELM was 367 ± 247 μm and 414 ± 327 μm, respectively. The final mean SFT was 290 ± 91 μm. SRF presence at the initial visit was found to be associated with elongated EZ and ELM disruption length at the final visit (P = 0.03 and P = 0.04, respectively). On linear regression analyses, none of the baseline features (SRF, SFT, and HRIL) except baseline poor best corrected visual acuity were found to be predictive in anticipating the final visual outcome (P = 0.04). On linear bivariate analysis, the final poor visual outcome was found to be affected by EZ disruption length of ≥500 μm at the last visit (P = 0.02). Baseline VA was the only predictive factor in anticipating the final visual outcome. At the final visit, extensive disruption length of EZ in the subfoveal area was associated with a poor visual outcome.


The effects of magnetic resonance imaging on surgical staples: an experimental analysis.
Surgical staples are commonplace in repairing surgical incisions. Staples allow for expeditious closure and removal compared with suture materials. However, there are clinical concerns when obtaining a magnetic resonance imaging (MRI) scan with staples present. This study examined two issues related to MRI scanning in the presence of surgical staples: skin surface temperature change and staple displacement. Thirty pig feet had 3-cm surgical incisions repaired with five surgical staples. Once placed, each skin staple position was marked for later referencing. A surface temperature laser device recorded prescan skin surface temperature. A 35-minute MRI scan was performed with a 1.5-Tesla magnet and standard knee coil for each pig foot. Immediately afterward, the skin surface temperature and displacement measurements were recorded. The paired t test was used to analyze temperature change from prescan to postscan. The prescan mean temperature was 16.45°C (standard deviation: 0.70°C), and the range was 14.60°C to 18.20°C. After scanning, the mean temperature was 16.02°C (standard deviation: 0.63°C), and the range was 15.00°C to 17.60°C. The decrease of 0.43°C in skin surface temperature was statistically significant (p=0.001). No change in staple position was measurable or evident by visual inspection for any of the pig feet. This study found no increase in skin surface temperature or displacement of staple position after a standard extremity MRI scan. Based on our findings, MRI scanning in the presence of stainless steel surgical staples seems safe.


Computation and NMR crystallography of terbutaline sulfate.
This article addresses, by means of computation and advanced experiments, one of the key challenges of NMR crystallography, namely the assignment of individual resonances to specific sites in a crystal structure. Moreover, it shows how NMR can be used for crystal structure validation. The case examined is form B of terbutaline sulfate. CPMAS (13)C and fast MAS (1)H spectra have been recorded and the peaks assigned as far as possible. Comparison of (13)C chemical shifts computed using the CASTEP program (incorporating the Gauge Including Projector Augmented Wave principle) with those obtained experimentally enable the accuracy of the two distinct single-crystal evaluations of the structure to be compared and an error in one of these is located. The computations have substantially aided in the assignments of both (13)C and (1)H resonances, as has a series of two-dimensional (2D) spectra (HETCOR, DQ-CRAMPS and proton-proton spin diffusion). The 2D spectra have enabled many of the proton chemical shifts to be pinpointed. The relationships of the NMR shifts to the specific nuclear sites in the crystal structure have therefore been established for most (13)C peaks and for some (1)H signals. Emphasis is placed on the effects of hydrogen bonding on the proton chemical shifts.


Redox switching in ethenyl-bridged bisphospholes.
A 2e(-) /2H(+) redox platform has been implemented in the ethenyl-bridged bisphosphol-3-ol 1 to afford the first phospholes that feature chemically reversible oxidations. Oxidation of the title compounds to the corresponding bisphosphol-3-one 2 leads to a change in conjugation topology and a concomitant hypsochromic shift of the lowest-energy absorption maximum by 100 nm. Electrochemical oxidation proceeds without any detectable intermediates, whereas the deprotonated form of 1 can be observed in an aprotic medium during the reduction of 2. This dianionic intermediate 3 is characterized by end absorptions that are bathochromically shifted by circa 200 nm compared to those of 2.


Analysis of Verticillium dahliae Suggests a Lack of Correlation Between Genotypic Diversity and Virulence Phenotypes.
Verticillium dahliae causes severe wilt and recurring losses in numerous agricultural and ornamental hosts worldwide. Two virulence phenotypes (races) have been identified based on the Ve resistance gene and its homologs but their distribution and evolutionary history are unknown. Sequence analyses of the intergenic spacer of the ribosomal DNA and amplified fragment length polymorphism markers suggested an absence of correlation between genotypic diversity and virulence phenotypes. Additionally, both race 1 and 2 phenotypes were isolated in various geographic regions and hosts. Sustained levels of migration of both virulence phenotypes among various geographic regions were evident, and the study also suggested that both virulence phenotypes infect a variety of hosts, regardless of the availability of resistant cultivars. Given the high genotypic diversity observed in V. dahliae, more than the two known virulence phenotypes may be present in nature but not yet identified because of the current lack of sources of resistance other than the Ve gene and its homologs. The inclusion of various genotypes exhibiting the same virulence phenotype may greatly improve the long-term effectiveness of resistance to race 2 of V. dahliae regardless of the host. This study also confirms the transcontinental gene flow and high genotypic diversity of V. dahliae affecting lettuce in coastal California regardless of the molecular markers employed.


Evaluation of decellularized esophagus as a scaffold for cultured esophageal epithelial cells.
Recently, decellularized tissue has been reported to have the potential to regenerate a variety of tissues. However, the optimal protocol for a decellularized esophagus has not been studied. Here, we investigated the effect of different decellularization protocols on the histology and biocompatibility of decellularized esophagi in view of future applications to tissue engineering. The esophageal mucosal epithelium (EP) from 4-week-old Wistar rats was enzymatically dissociated and cultured with growth-arrested feeder cells. Two methods for decellularization using deoxycholic acid (DEOX) or Triton X-100 (TRITON) were compared on esophagi from adult Wistar rats. Those treated with DEOX showed superior mechanical properties, maintenance of extracellular matrix, and lower DNA content than those treated with TRITON. To evaluate the biocompatibility of the scaffold, cultured (passage 3) esophageal epithelial cells were seeded inside the decellularized esophagus and cultured for 7 days. The cells seeded onto the decellularized esophagus were examined histologically and immunocytochemically. Esophageal epithelial cells were stratified into three to four cellular layers in vitro inside the decellularized esophagus, to show polarity. The results from immunocytochemistry indicated that the seeded epithelial cells expressed characteristic marker proteins for native esophageal EP. Decellularized esophagus showed suitable compatibility as a scaffold material for esophageal tissue engineering.


Early postoperative intraperitoneal chemotherapy with mitomycin C, 5-fluorouracil and cisplatin for advanced gastric cancer.
The long-term survival of patients who undergo surgery for stage IV gastric cancer is poor, due to metastatic spread of the tumor. Intraperitoneal chemotherapy (IPT) as a possible treatment for peritoneal dissemination has been investigated in a number of different tumors. The aim of this study was to investigate the toxicity and impact of early postoperative IPT on the survival of patients with advanced gastric cancer. Between 1993 and 1997, a total of 91 patients with stage IV gastric cancer who underwent potentially curative or palliative resection received intraperitoneal mitomycin C before closure of the abdominal wound. 5-Fluorouracil and cisplatin were administered intraperitoneally on postoperative days 1-4, and this was repeated at 4-week intervals. All patients received a median of 3 IPT perfusions. There were 24 (26.4%) postoperative complications and 1 (1.1%) mortality. The most frequent hematologic toxicity (grade 3-4) was leukopenia. The major nonhematologic toxicities (grade 3-4) were emesis and nephrotoxicity. After a median follow-up period of 26 months, 14 patients remain alive without evidence of recurrence, whereas 75 patients died due to recurrence or progression of disease. The median survival period for all 91 patients was 15.4 months. When survival according to the residual tumor was analyzed, median survival was 36.0 months in the R0 (curative resection) group, 20.6 months in the R1 group (margins of resected specimens showing microscopic residual tumor or diameter of each residual tumor less than 3 mm) and 9.0 months in the R2 group (macroscopic residual tumor larger than 3 mm) (p < 0.001). IPT was found to be safe, and it appears to improve the prognosis in patients with minimal residual tumors. However, complete cytoreductive surgery is mandatory for achieving the beneficial effect of IPT.


Neurocognitive deficits in schizophrenia. Are we making mountains out of molehills?
Most original studies and all meta-analyses conducted to date converge on the conclusion that patients with schizophrenia display rather generalized neurocognitive deficits. For the present study, we reopen this seemingly closed chapter and examine whether important influences, such as lack of motivation and negative attitudes towards cognitive assessment, result in poorer secondary neuropsychological performance. A sample of 50 patients with an established diagnosis of schizophrenia were tested for routine neurocognitive assessment and compared to 60 nonclinical volunteers. Before and after the assessment, subjective momentary influences were examined (e.g. motivation, concerns about assessment, fear about poor outcome) for their impact on performance using a new questionnaire called the Momentary Influences, Attitudes and Motivation Impact (MIAMI) on Cognitive Performance Scale. As expected, patients performed significantly worse than controls on all neurocognitive domains tested (large effect size, on average). However, patients also displayed more subjective momentary impairment, as well as more fears about the outcome and less motivation than controls. Mediation analyses indicated that these influences contributed to (secondary) poorer neurocognitive performance. Differences in neurocognitive scores shrank to a medium effect size, on average, when MIAMI scores were accounted for. The data argue that performance on measures of neurocognition in schizophrenia are to a considerable extent due to secondary factors. Poor motivation, fears and momentary impairments distinguished patients from controls and these variables heavily impacted performance. Before concluding that neurocognitive deficits in psychiatric patients are present, clinicians should take these confounding influences into account. Although patients with schizophrenia achieved, on average, worse test scores than controls, a large subgroup displayed spared performance.


Terpene-loaded Liposomes and Isopropyl Myristate as Chemical Permeation Enhancers Toward Liposomal Gene Delivery in Lung Cancer cells; A Comparative Study.
Gene therapy is in its development stage as a novel method for cancer treatment. Liposomes look promising as gene delivery vectors; however, investigations have shown that these vesicles are not doing well in some cases. It was decided here to investigate the possibility of augmentation of liposomal gene delivery by chemical penetration enhancers. Cationic liposome containing antisense oligonucleotide (AsODN) against lung cancer was prepared by ethanol injection method. Liposomal cineole and limonene (as enhancers) were prepared by film hydration method. Isopropyl myristate (IPM) was also investigated as penetration enhancer. Liposomes were evaluated for their size, zeta potential and encapsulation efficiency. Cancer cells (A549) were pretreated with liposomal terpenes prior to treatment with liposomal antisense or scrambled oligonucleotide. Cell viability was evaluated by MTT assay. Oligonucleotide -containing liposome showed particle size of about115 nm and zeta potential of 0.6 mV. Liposomal cineole significantly (P<0.05) increased specific activity of liposomal antisense but limonene didn't show such an effect. IPM increased both specific and non-specific cytotoxicity of Oligonucleotide. These results show that penetration enhancers (such as cineole) may be used for improving liposomal gene delivery and to reduce non-specific toxicity. Concentration and chemical nature of enhancer has prominent effect in their efficacy.


Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs), premalignant precursors of pancreatic adenocarcinomas.
Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.


Eco-evolution in size-structured ecosystems: simulation case study of rapid morphological changes in alewife.
Over the last 300 years, interactions between alewives and zooplankton communities in several lakes in the U.S. have caused the alewives' morphology to transition rapidly from anadromous to landlocked. Lakes with landlocked alewives contain smaller-bodied zooplankton than those without alewives. Landlocked adult alewives display smaller body sizes, narrower gapes, smaller inter-gill-raker spacings, reach maturity at an earlier age, and are less fecund than anadromous alewives. Additionally, landlocked alewives consume pelagic prey exclusively throughout their lives whereas anadromous alewives make an ontogenetic transition from pelagic to littoral prey. These rapid, well-documented changes in the alewives' morphology provide important insights into the morphological evolution of fish. Predicting the morphological evolution of fish is crucial for fisheries and ecosystem management, but the involvement of multiple trophic interactions make predictions difficult. To obtain an improved understanding of rapid morphological change in fish, we developed an individual-based model that simulated rapid changes in the body size and gill-raker count of a fish species in a hypothetical, size-structured prey community. Model parameter values were based mainly on data from empirical studies on alewives. We adopted a functional trait approach; consequently, the model explicitly describes the relationships between prey body size, alewife body size, and alewife gill-raker count. We sought to answer two questions: (1) How does the impact of alewife populations on prey feed back to impact alewife size and gill raker number under several alternative scenarios? (2) Will the trajectory of the landlocked alewives' morphological evolution change after 150-300 years in freshwater? Over the first 250 years, the alewives' numbers of gill-rakers only increased when reductions in their body size substantially improved their ability to forage for small prey. Additionally, alewives' gill-raker counts increased more rapidly as the adverse effects of narrow gill-raker spacings on foraging for large prey were made less severe. For the first 150-250 years, alewives' growth decreased monotonically, and their gill-raker number increased monotonically. After the first 150-250 years, however, the alewives exhibited multiple evolutionary morphological trajectories in different trophic settings. In several of these settings, their evolutionary trajectories even reversed after the first 150-250 years. Alewives affected the abundance and morphology of their prey, which in turn changed the abundance and morphology of the alewives. Complex low-trophic-level interactions can alter the abundance and characteristics of alewives. This study suggests that the current morphology of recently (∼300 years)-landlocked alewives may not represent an evolutionarily stable state.


Generation of doubly charged vortex beam by concentrated loading of glass disks along their diameter.
We show that a system of glass disks compressed along their diameters enables one to induce a doubly charged vortex beam in the emergent light when the incident light is circularly polarized. Using such a disk system, one can control the efficiency of conversion of the spin angular momentum to the orbital angular momentum by a loading force. The consideration presented here can be extended for the case of crystalline materials with high optical damage thresholds in order to induce high-power vortex beams.


Modifiable Risk Factors for Common Ragweed (Ambrosia artemisiifolia) Allergy and Disease in Children: A Case-Control Study.
Ragweed allergy is a major public health concern. Within Europe, ragweed is an introduced species and research has indicated that the amounts of ragweed pollen are likely to increase over Europe due to climate change, with corresponding increases in ragweed allergy. To address this threat, improving our understanding of predisposing factors for allergic sensitisation to ragweed and disease is necessary, specifically focusing upon factors that are potentially modifiable (i.e., environmental). In this study, a total of 4013 children aged 2⁻13 years were recruited across Croatia to undergo skin prick tests to determine sensitisation to ragweed and other aeroallergens. A parental questionnaire collected home environment, lifestyle, family and personal medical history, and socioeconomic information. Environmental variables were obtained using Geographical Information Systems and data from nearby pollen, weather, and air pollution stations. Logistic regression was performed (clustered on school) focusing on risk factors for allergic sensitisation and disease. Ragweed sensitisation was strongly associated with ragweed pollen at levels over 5000 grains m⁻3 year−1 and, above these levels, the risk of sensitisation was 12⁻16 times greater than in low pollen areas with about 400 grains m⁻3 year−1. Genetic factors were strongly associated with sensitisation but nearly all potentially modifiable factors were insignificant. This included measures of local land use and proximity to potential sources of ragweed pollen. Rural residence was protective (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.55⁻0.98), but the factors underlying this association were unclear. Being sensitised to ragweed doubled (OR 2.17, 95% CI 1.59⁻2.96) the risk of rhinoconjunctivitis. No other potentially modifiable risk factors were associated with rhinoconjunctivitis. Ragweed sensitisation was strongly associated with ragweed pollen, and sensitisation was significantly associated with rhinoconjunctivitis. Apart from ragweed pollen levels, few other potentially modifiable factors were significantly associated with ragweed sensitisation. Hence, strategies to lower the risk of sensitisation should focus upon ragweed control.


Household cardiovascular screening of high-risk families: a school-based study.
A parental history of cardiovascular disease has a strong relationship with risk factor clusters in the offspring. This study was performed to identify major cardiovascular risk factors in middle school-aged children and their parents in both high and low-risk families. A school-based, cross-sectional study. The middle schools of the 6th district of Tehran were divided randomly into two groups. A total of 169 high-risk children with their families were recruited from the first group and 105 low-risk children with their families were recruited from the second group of schools. Anthropometric and metabolic measurements were performed. The means of the waist circumference and waist-to-hip ratio were significantly higher in high-risk fathers. The means of total and low-density lipoprotein (LDL) cholesterol were significantly higher in both parents and children of the high-risk group. The means of the fasting plasma glucose were significantly higher in fathers and offspring of high-risk families. More fathers in high-risk families were smokers. The prevalence of increased total cholesterol, LDL-cholesterol and hyperglycemia (> or = 100 mg/dl) were higher in high-risk parents and children. The prevalence of increased body mass index (> or = 25 kg/m for parents and 85th percentile for children) was higher in fathers and children of high-risk families. Cardiovascular risk factors are more prevalent and clustered in high-risk families. The screening of high-risk families is essential to prevent the progression of atherosclerosis from childhood and reduce the burden of cardiovascular disease in adulthood.


An Extra Cue Is Beneficial for Native Speakers but Can Be Disruptive for Second Language Learners: Integration of Prosody and Visual Context in Syntactic Ambiguity Resolution.
It has long been debated whether non-native speakers can process sentences in the same way as native speakers do or they suffer from certain qualitative deficit in their ability of language comprehension. The current study examined the influence of prosodic and visual information in processing sentences with a temporarily ambiguous prepositional phrase ("Put the cake on the plate in the basket") with native English speakers and Japanese learners of English. Specifically, we investigated (1) whether native speakers assign different pragmatic functions to the same prosodic cues used in different contexts and (2) whether L2 learners can reach the correct analysis by integrating prosodic cues with syntax with reference to the visually presented contextual information. The results from native speakers showed that contrastive accents helped to resolve the referential ambiguity when a contrastive pair was present in visual scenes. However, without a contrastive pair in the visual scene, native speakers were slower to reach the correct analysis with the contrastive accent, which supports the view that the pragmatic function of intonation categories are highly context dependent. The results from L2 learners showed that visually presented context alone helped L2 learners to reach the correct analysis. However, L2 learners were unable to assign contrastive meaning to the prosodic cues when there were two potential referents in the visual scene. The results suggest that L2 learners are not capable of integrating multiple sources of information in an interactive manner during real-time language comprehension.


Etiology of Moldy Core, Core Browning, and Core Rot of Fuji Apple in China.
'Fuji' apple fruit were collected in Shaanxi Province, China, and 186 fungal isolates were obtained from the fruit core region. Fungi were isolated from fruit with symptomless core regions, as well as from the core regions of fruit showing browning, typical moldy core, or core rot. Based on phylogenetic and morphological analysis, all fungi were identified to species. Pathogenicity was determined by cutting apple fruit into halves and daubing spore suspensions containing 1 × 104 up to 1 × 108 spores/ml on the carpel in the core region. Pathogenicity varied significantly among genera, with Alternaria and Cladosporium spp. causing core browning at lower spore concentrations and moldy core at higher spore concentrations. Combinations of pathogens initiated more browning and moldy core than the pathogens applied alone. Epicoccum and Phoma spp. predominated in dry core rot, whereas primarily Trichothecium but also Fusarium and Penicillium spp. caused wet core rot. Core browning was introduced as a new type of core symptom, along with moldy core, dry core rot, and wet core rot. Alternaria alternata, A. tenuissima, A. arborescens, Cladosporium cladosporioides, and C. tenuissimum were the main pathogens causing core browning and moldy core.


Perioperative music and its effects on anxiety, hemodynamics, and pain in women undergoing mastectomy.
There is increasing interest in evaluating the use of nonpharmacologic interventions such as music to minimize potential adverse effects of anxiety-reducing medications. This study used a quasi-experimental design to evaluate the effects of a perioperative music intervention (provided continuously throughout the preoperative, intraoperative, and postoperative periods) on changes in mean arterial pressure (MAP), heart rate, anxiety, and pain in women with a diagnosis of breast cancer undergoing mastectomy. A total of 30 women were assigned randomly to a control group or to the music intervention group. Findings indicated that women in the intervention group had a greater decrease in MAP and anxiety with less pain from the preoperative period to the time of discharge from the recovery room compared with women in the control group. Music is a noninvasive and low-cost intervention that can be easily implemented in the perioperative setting, and these findings suggest that perioperative music can reduce MAP, anxiety, and pain among women undergoing mastectomy for breast cancer.


Urothelial carcinoma of the urinary bladder mixed with squamous differentiation or squamous cell carcinoma in areas with schistosomiasis is showing high risk of recurrence and poor survival.
In schistosomiasis haematobium areas endemic, bladder cancer is the first cause of malignancy in men and fourth in women. The chronic schistosomiasis would lead to variant histologic patterns which manifest in squamous cell carcinoma (SCC) or squamous differentiation (SqD). This study evaluated the clinical outcome after radical cystectomy (RC) in patients with urothelial carcinoma (UC) mixed with SCC or SqD, Comparison was done with two arms of pure UC and pure SCC, indication for RC was muscle-invasive-disease, and evaluation included recurrence, metastases, and overall survival. The data of patients treated with RC for muscle-invasive-disease, selection was revised for 127 patients with urothelial carcinoma mixed with SCC/SqD, two comparative arms were 100 patients with pure UC, and 100 patients had pure SCC. Follow up was on 8 months, 3 years, and 5 years to detect recurrence, metastasis, and overall survival in the three groups. The results showed that by comparison of disease aggressiveness in the three groups regarding recurrence, metastasis, and overall survival was analysed. Overall survival with mixed tumours was significantly lower than pure UC or SCC, recurrence and metastases were higher in mixed tumour which was an independent factor for poor prognosis and low survival.


The role of executive functions, social cognition and intelligence in predicting social adaptation of vulnerable populations.
This study sought to evaluate the roles of and interactions between cognitive processes that have been shown to exhibit impact from socioeconomic status (SES) and living conditions in predicting social adaptation (SA) in a population of adults living in socially vulnerable conditions. Participants included 226 people between the ages of 18 and 60 who have been living in vulnerable contexts throughout life in Santiago, Chile. Data was collected through a battery of psychological assessments. A structural equation model (SEM) was implemented to examine the interrelationships among cognitive and social variables. Results indicate a significant relationship between executive function (EF) and SA through both social cognition (SC) and intelligence. Theory of Mind (ToM), a component of SC, was shown to exhibit a significant relationship with affective empathy; interestingly, this was negatively related to SA. Moreover, fluid intelligence (FI) was found to exhibit a positive, indirect relationship with SA through crystallized intelligence (CI). Evaluation of these results in the context of research on the impacts of SES and vulnerable living conditions on psychological function may allow for the development of more effective clinical, political, and social interventions to support psychosocial health among socially vulnerable populations.


Photon-mediated interactions between distant artificial atoms.
Photon-mediated interactions between atoms are of fundamental importance in quantum optics, quantum simulations, and quantum information processing. The exchange of real and virtual photons between atoms gives rise to nontrivial interactions, the strength of which decreases rapidly with distance in three dimensions. Here, we use two superconducting qubits in an open one-dimensional transmission line to study much stronger photon-mediated interactions. Making use of the possibility to tune these qubits by more than a quarter of their transition frequency, we observe both coherent exchange interactions at an effective separation of 3λ/4 and the creation of super- and subradiant states at a separation of one photon wavelength λ. In this system, collective atom-photon interactions and applications in quantum communication may be explored.


EID3 is a novel EID family member and an inhibitor of CBP-dependent co-activation.
EID1 (E1A-like inhibitor of differentiation 1) functions as an inhibitor of nuclear receptor-dependent gene transcription by directly binding to co-regulators. Alternative targets include the co-repressor small heterodimer partner (SHP, NR0B2) and the co-activators CBP/p300, indicating that EID1 utilizes different inhibitory strategies. Recently, EID2 was characterized as an inhibitor of muscle differentiation and as an antagonist of both CBP/p300 and HDACs. Here, we describe a third family member designated EID3 that is highly expressed in testis and shows homology to a region of EID1 implicated in binding to CBP/p300. We demonstrate that EID3 acts as a potent inhibitor of nuclear receptor transcriptional activity by a mechanism that is independent of direct interactions with nuclear receptors, including SHP. Furthermore, EID3 directly binds to and blocks the SRC-1 interacting domain of CBP, which has been implicated to act as the interaction surface for nuclear receptor co-activators. Consistent with this idea, EID3 prevents recruitment of CBP to a natural nuclear receptor-regulated promoter. Our study suggests that EID-family members EID3 and EID1 act as inhibitors of CBP/p300-dependent transcription in a tissue-specific manner.


Quality of Life in Patients with Vestibular Schwannomas Following Gross Total or Less than Gross Total Microsurgical Resection: Should We be Taking the Entire Tumor Out?
The goal of microsurgical removal of a vestibular schwannoma is to completely remove the tumor, to provide long-term durable cure. In many cases, less than gross total resection (GTR) is performed to preserve neurological, and especially facial nerve function. To analyze long-term quality of life (QoL) in a cohort of patients who received either GTR or less than GTR. Patients operated for vestibular schwannoma less than 3.0 cm in posterior fossa diameter at 1 of 2 international tertiary care centers were surveyed using generic and disease-specific QoL instruments. A total of 143 patients were analyzed. GTR was performed in 122, and 21 underwent less than GTR. QoL was assessed at a mean of 7.7 yr after surgery (interquartile range: 5.7-9.6). Patients who underwent GTR had smaller tumors; otherwise, there were no baseline differences between groups. Patients who underwent GTR, after multivariable adjustment for baseline features and facial nerve and hearing outcomes, reported statistically significantly better Short Form Health Survey-36 (SF-36) physical and mental scores, Patient-Reported Outcomes Measurement Information System (PROMIS-10) physical and mental scores, and Penn Acoustic Neuroma Quality of Life (PANQOL) facial, energy, general health, and total scores compared to patients receiving less than GTR. GTR is associated with better QoL using the general QoL measures SF-36 and PROMIS-10 and the disease-specific PANQOL, even after controlling for baseline and outcome differences. This is especially significant in the assessment of mental health, indicating there may indeed be a psychological advantage to the patient that translates to overall well-being to have the entire tumor removed if microsurgical resection is undertaken.


Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination.
Crossover recombination facilitates the accurate segregation of homologous chromosomes during meiosis. In mammals, poorly characterized regulatory processes ensure that every pair of chromosomes obtains at least one crossover, even though most recombination sites yield non-crossovers. Designation of crossovers involves selective localization of the SUMO ligase RNF212 to a minority of recombination sites, where it stabilizes pertinent factors such as MutSγ (ref. 4). Here we show that the ubiquitin ligase HEI10 (also called CCNB1IP1) is essential for this crossover/non-crossover differentiation process. In HEI10-deficient mice, RNF212 localizes to most recombination sites, and dissociation of both RNF212 and MutSγ from chromosomes is blocked. Consequently, recombination is impeded, and crossing over fails. In wild-type mice, HEI10 accumulates at designated crossover sites, suggesting that it also has a late role in implementing crossing over. As with RNF212, dosage sensitivity for HEI10 indicates that it is a limiting factor for crossing over. We suggest that SUMO and ubiquitin have antagonistic roles during meiotic recombination that are balanced to effect differential stabilization of recombination factors at crossover and non-crossover sites.


Cryptic stage of sleeping-sickness trypanosome developing in choroid plexus epithelial cells.
Electronmicrographs of the choroid plexus from rats infected with Trypanosoma brucei rhodesiense showed that trypomastigotes from the perivascular spaces may penetrate and undergo multiple division in the ependymal cells which locally constitute the blood-brain barrier. Progressive degeneration of the ependymal cell liberates trypomastigotes back into the perivascular space, from which re-entry into the blood may occur. Re-entry to the blood does not take place from any tissues other than the brain and its membranes. These findings suggest that the ependymal cells of the choroid plexus are the site of the cryptic stage of the sleeping-sickness trypanosome.


The Australasian Resuscitation In Sepsis Evaluation: Fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand.
To describe haemodynamic resuscitation practices in ED patients with suspected sepsis and hypotension. This was a prospective, multicentre, observational study conducted in 70 hospitals in Australia and New Zealand between September 2018 and January 2019. Consecutive adults presenting to the ED during a 30-day period at each site, with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation, were eligible. Data included baseline demographics, clinical and laboratory variables and intravenous fluid volume administered, vasopressor administration at baseline and 6- and 24-h post-enrolment, time to antimicrobial administration, intensive care admission, organ support and in-hospital mortality. A total of 4477 patients were screened and 591 were included with a mean (standard deviation) age of 62 (19) years, Acute Physiology and Chronic Health Evaluation II score 15.2 (6.6) and a median (interquartile range) systolic blood pressure of 94 mmHg (87-100). Median time to first intravenous antimicrobials was 77 min (42-148). A vasopressor infusion was commenced within 24 h in 177 (30.2%) patients, with noradrenaline the most frequently used (n = 138, 78%). A median of 2000 mL (1500-3000) of intravenous fluids was administered prior to commencing vasopressors. The total volume of fluid administered from pre-enrolment to 24 h was 4200 mL (3000-5661), with a range from 1000 to 12 200 mL. Two hundred and eighteen patients (37.1%) were admitted to an intensive care unit. Overall in-hospital mortality was 6.2% (95% confidence interval 4.4-8.5%). Current resuscitation practice in patients with sepsis and hypotension varies widely and occupies the spectrum between a restricted volume/earlier vasopressor and liberal fluid/later vasopressor strategy.


Expression of myogenic regulatory factors in the muscle-derived electric organ of Sternopygus macrurus.
In most groups of electric fish, the current-producing cells of electric organs (EOs) derive from striated muscle fibers but retain some phenotypic characteristics of their precursor muscle cells. Given the role of the MyoD family of myogenic regulatory factors (MRFs) in the transcriptional activation of the muscle program in vertebrates, we examined their expression in the electrocytes of the gymnotiform Sternopygus macrurus. We estimated the number of MRF genes in the S. macrurus genome and our Southern blot analyses revealed a single MyoD, myogenin, myf5 and MRF4 gene. Quantitative RT-PCR showed that muscle and EO transcribe all MRF genes. With the exception of MyoD, the endogenous levels of myogenin, myf5 and MRF4 transcripts in electrocytes were greater than those detected in muscle fibers. These data indicate that MRF expression levels are not sufficient to predict the level to which the muscle program is manifested. Qualitative expression analysis of MRF co-regulators MEF2C, Id1 and Id2 also revealed these genes not to be unique to either muscle or EO, and detected similar expression patterns in the two tissues. Therefore, the partial muscle program of the EO is not associated with a partial expression of MRFs or with apparent distinct levels of some MRF co-factors. In addition, electrical inactivation by spinal cord transection (ST) resulted in the up-regulation of some muscle proteins in electrocytes without an accompanying increase in MRF transcript levels or notable changes in the co-factors MEF2C, Id1 and Id2. These findings suggest that the neural regulation of the skeletal muscle program via MRFs in S. macrurus might differ from that of their mammalian counterparts. Together, these data further our understanding of the molecular processes involved in the plasticity of the vertebrate skeletal muscle program that brings about the muscle-like phenotype of the non-contractile electrogenic cells in S. macrurus.


Development of Morphologically Discrete PEG-PDLLA Nanotubes for Precision Nanomedicine.
Precise control over the morphological features of nanoparticles is an important requisite for their application in nanomedical research. Parameters such as size and shape have been identified as critical features for effective nanotherapeutic technologies due to their role in circulation, distribution, and internalization in vivo. Tubular PEG-PDLLA polymersomes (nanotubes) exhibit an interesting morphology with potential for immunotherapeutics, as the elongated shape can affect cell-particle interactions. Developing methodologies that permit control over the precise form of such nanotubes is important for their biomedical implementation due to the stringent physicochemical constraints for efficacious performance. Through careful control over the engineering process, we demonstrate the generation of well-defined nanotubes based on polymersomes as small as 250 and 100 nm, which can be successfully shape transformed. The quality of the resulting nanostructures was established by physical characterization using AF4-MALS and cryo-TEM. Moreover, we show the successful loading of such nanotubes with model payloads (proteins and drugs). These findings provide a promising platform for implementation in biomedical applications in which discrete structure and functionality are essential features.


Efficacy and safety of 120-W thulium:yttrium-aluminum-garnet vapoenucleation of prostates compared with holmium laser enucleation of prostates for benign prostatic hyperplasia.
This study compared the efficacy and safety between 120-W thulium:yttrium-aluminum-garnet (Tm:YAG) vapoenucleation of prostates (ThuVEP) and holmium laser enucleation of prostates (HoLEP) for patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). A retrospective analysis of 88 consecutive patients with symptomatic BPH was carried out, who underwent either 120-W ThuVEP or HoLEP nonrandomly. Patient demographics and peri-operative and 12-month follow-up data were analyzed with the International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum flow rate (Qmax), postvoid residual urine volume (PVR), and rates of peri-operative and late complications. The patients in each group showed no significant difference in preoperative parameters. Compared with the HoLEP group, patients in the 120-W ThuVEP group required significantly shorter time for laser enucleation (58.3 ± 12.8 min vs. 70.5 ± 22.3 min, P = 0.003), and resulted in a significant superiority in laser efficiency (resected prostate weight/laser enucleation time) for 120-W Tm:YAG laser compared to holmium:YAG laser (0.69 ± 0.18 vs. 0.61 ± 0.19, P = 0.048). During 1, 6, and 12 months of follow-ups, the procedures did not demonstrate a significant difference in IPSS, QoL score, Qmax, or PVR (P > 0.05). Mean peri-operative decrease of hemoglobin in the HoLEP group was similar to the ThuVEP group (17.1 ± 12.0 g/L vs. 15.2 ± 10.1 g/L, P = 0.415). Early and late incidences of complications were low and did not differ significantly between the two groups of 120-W ThuVEP and HoLEP patients (P > 0.05). 120-W ThuVEP and HoLEP are potent, safe and efficient modalities of minimally invasive surgeries for patients with LUTS due to BPH. Compared with HoLEP, 120-W ThuVEP offers advantages of reduction of laser enucleation time and improvement of laser efficiency.


Dopaminergic Modulation of Decision Making and Subjective Well-Being.
The neuromodulator dopamine has a well established role in reporting appetitive prediction errors that are widely considered in terms of learning. However, across a wide variety of contexts, both phasic and tonic aspects of dopamine are likely to exert more immediate effects that have been less well characterized. Of particular interest is dopamine's influence on economic risk taking and on subjective well-being, a quantity known to be substantially affected by prediction errors resulting from the outcomes of risky choices. By boosting dopamine levels using levodopa (l-DOPA) as human subjects made economic decisions and repeatedly reported their momentary happiness, we show here an effect on both choices and happiness. Boosting dopamine levels increased the number of risky options chosen in trials involving potential gains but not trials involving potential losses. This effect could be better captured as increased Pavlovian approach in an approach-avoidance decision model than as a change in risk preferences within an established prospect theory model. Boosting dopamine also increased happiness resulting from some rewards. Our findings thus identify specific novel influences of dopamine on decision making and emotion that are distinct from its established role in learning.


Oral Health Beliefs, Attitudes, and Practices of South Asian Migrants: A Systematic Review.
Oral health is a burden among all populations and is linked with major chronic diseases such as cardiovascular diseases. Migrants, in particular South Asians, have poor oral health which requires further understanding to better inform oral health interventions by targeting specific aspects of this heterogenous South Asian population. This review is undertaken to systematically synthesize the evidence of oral health understandings, knowledge, attitudes, beliefs, practices, and behaviors of South Asian migrants residing in high-income countries. A comprehensive systematic search of seven electronic databases and hand-searching for peer-reviewed studies was conducted. All study designs were included, and quality assessment conducted. Of the 1614 records identified, 17 were included for synthesis and 12 were quantitative in design. These studies were primarily conducted in the UK, USA, Canada, and Europe. South Asian migrants had inadequate oral health knowledge, attitudes, and practices-influenced by culture, social norms, and religiosity. In the absence of symptoms, preventive oral hygiene practices were limited. Barriers to access varied with country of origin; from lack of trust in dentists and treatment cost in studies with India as the country of origin, to religiosity, among poorer nations such as Bangladesh. Fewer studies focused on recent arrivals from Bhutan or the Maldives. Culturally and socially appropriate strategies must be developed to target oral health issues and a "one-size" fits all approach will be ineffective in addressing the needs of South Asian migrants.


Effects of haptoglobin polymorphisms and deficiency on susceptibility to inflammatory bowel disease and on severity of murine colitis.
Haptoglobin (Hp) is a haemoglobin-binding protein with immunomodulatory properties. Its gene (16q22) harbours a common polymorphism with two different alleles: Hp1 and Hp2. Genotype Hp22 has been shown to be over-represented in different immune diseases. Results in Crohn's disease (CD) are contradictory. To determine whether Hp plays a role in inflammatory bowel disease, both genetically and functionally. 1061 patients with CD, 755 with ulcerative colitis (UC) and 152 with primary sclerosing cholangitis, as well as 452 healthy controls, were genotyped using touch-down PCR. To confirm association results, 464 CD trios and 151 UC trios were genotyped. Serum Hp concentrations were determined in 62 individuals of different genotype. Colitis was induced in mice with dextran sulphate sodium (DSS) and oxazolone (Oxa). Cytokine production was evaluated by mRNA quantification in colonic tissue and ELISA on supernatants of mesenteric lymph node cells. Prevalence of Hp2 was higher in CD and UC than in controls. In the confirmatory cohorts, Hp2 was over-transmitted to the affected offspring. Serum Hp concentrations were higher in individuals with genotypes Hp11 and Hp21 than in those with Hp22 (1.38 vs 0.89 g/l). DSS- and Oxa-induced colitis were more severe in Hp-deficient mice than in control mice and accompanied by higher concentrations (although not statistically significantly different) of tissue mRNA for cytokines. Interleukin-17 production was significantly higher in the presence of Hp-deficient serum compared with wild-type serum. The Hp gene may play a role in susceptibility to inflammatory bowel disease. Its implication in other immune diseases underscores the common pathways between these diseases. Experimental models of colitis showed that Hp has a protective role in inflammatory colitis, most likely by inhibiting the production of Th1 and Th17 cytokines.


Regulation of steroid sulphatase expression and activity in breast cancer.
Steroid sulphatase (STS) catalyzes the conversion of oestrone sulphate (E1S) to oestrone (E1) and its action in breast tumours makes a major contribution to in situ oestrogen production in this tissue. Although expression of STS mRNA and STS activity are increased in malignant breast tissues compared with that in non-malignant tissues, little is known about the regulation of its expression or activity. In the present study we have used a RT-PCR technique to investigate the regulation of STS mRNA expression in cultured breast tissue fibroblasts and MCF-7 cells. STS mRNA expression was readily detectable in fibroblasts derived from breast tissue proximal to tumours, breast tumour tissue and reduction mammoplasty tissue. For two pre-menopausal subjects, STS mRNA expression was similar in proximal and tumour fibroblasts whereas for a third, post-menopausal subject, expression in breast tumour fibroblasts was 2.4-fold that in proximal fibroblasts. The cytokine tumour necrosis factor alpha (TNFalpha) or the STS inhibitor, 2-methoxyoestrone-3-O-sulphamate, had no effect on STS mRNA expression in fibroblasts. STS mRNA was detectable in MCF-7 cells but neither TNFalpha nor interleukin 6 (IL-6) affected its expression. Transient transfection of COS-1 and MCF-7 cells with a STS cDNA lacking STS 5' and 3' sequences increased activity 17-fold and 2-fold, respectively. TNFalpha plus IL-6 increased STS activity in mock transfected MCF-7 cells and further increased STS activity in transfected MCF-7 cells. This indicates that activation can occur independently of STS promoter and enhancer elements. In conjunction with the lack of regulation of STS mRNA it suggest that TNFalpha and IL-6 may increase STS activity via a post-translational modification of the enzyme or by increasing substrate availability.


The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis.
Activated Wnt signalling with decreased expression of endogenous inhibitors has recently been characterised as a central pathomechanism in systemic sclerosis (SSc). Aberrant epigenetic modifications also contribute to the persistent activation of SSc fibroblasts. We investigated whether increased Wnt signalling and epigenetic changes in SSc are causally linked via promoter hypermethylation-induced silencing of Wnt antagonists. The methylation status of endogenous Wnt antagonists in leucocytes and fibroblasts was evaluated by methylation-specific PCR. 5-aza-2'-deoxycytidine was used to inhibit DNA methyltransferases (Dnmts) in cultured fibroblasts and in the mouse model of bleomycin-induced skin fibrosis. Activation of Wnt signalling was assessed by analysing Axin2 mRNA levels and by staining for β-catenin. The promoters of DKK1 and SFRP1 were hypermethylated in fibroblasts and peripheral blood mononuclear cells of patients with SSc. Promoter hypermethylation resulted in impaired transcription and decreased expression of DKK1 and SFRP1 in SSc. Treatment of SSc fibroblasts or bleomycin-challenged mice with 5-aza prevented promoter methylation-induced silencing and increased the expression of both genes to normal levels. Reactivation of DKK1 and SFRP1 transcription by 5-aza inhibited canonical Wnt signalling in vitro and in vivo and effectively ameliorated experimental fibrosis. We demonstrate that hypermethylation of the promoters of DKK1 and SFRP1 contributes to aberrant Wnt signalling in SSc and that Dnmt inhibition effectively reduces Wnt signalling. These data provide a novel link between epigenetic alterations and increased Wnt signalling in SSc and also have translational implications because Dnmt inhibitors are already approved for clinical use.


Homologous elements hs3a and hs3b in the 3' regulatory region of the murine immunoglobulin heavy chain (Igh) locus are both dispensable for class-switch recombination.
Immunoglobulin heavy chain (IgH) genes are formed, tested, and modified to yield diverse, specific, and high affinity antibody responses to antigen. The processes involved must be regulated, however, to avoid unintended damage to chromosomes. The 3' regulatory region of the Igh locus plays a major role in regulating class-switch recombination (CSR), the process by which antibody effector functions are modified during an immune response. Loss of all known enhancer-like elements in this region dramatically impairs CSR, but individual element deletions have no effect on this process. In the present study, we explored the hypothesis that an underlying functional redundancy in the homologous elements hs3a and hs3b was masking the importance of either element to CSR. Several transgenic mouse lines were generated, each carrying a bacterial artificial chromosome transgene that mimicked Igh locus structure but in which hs3a was missing and hs3b was flanked by loxP sites. Matings to Cyclization Recombination Enzyme-expressing mice established "pairs" of lines that differed only in the presence or absence of hs3b. Remarkably, CSR remained robust in the absence of both hs3a and hs3b, suggesting that the remaining two elements of the 3' regulatory region, hs1.2 and hs4, although individually dispensable for CSR, are, together, sufficient to support CSR.


What too strict a method obscures about the validity of outcome measures.
Objective: To assess the outcome of psychotherapeutic treatments, psychotherapy researchers often compare pre- and post-treatment scores on self-report outcome measures. In this paper, the common assumption is challenged that pre-to-post decreasing and increasing outcome scores are indicative of successful and failed therapies, respectively.Method: The outcome of 29 psychotherapeutic treatments was evaluated by means of quantitative analysis of pre- and post-treatment scores on commonly used outcome measures (such as the Symptom Checklist-90-R, the Inventory of Interpersonal Problems, and the General Health Questionnaire-12), as well as through consensual qualitative research.Results: Overall, a moderate to low convergence between qualitative and quantitative evaluations of outcome was observed. Detailed analyses of six cases are presented in which pre-to-post comparisons of outcome measures proved misleading.Conclusions: It is concluded that psychotherapy outcome research might benefit from assessment strategies that are sensitive to the singularities of individual treatments and to the complexity of the phenomenon of therapeutic outcome. Furthermore, classical psychometric evaluations of the validity of outcome measures might be supplemented with less-systematic evaluations that take any contingent source of information on outcome into account.


Improvement in left ventricular intrinsic dyssynchrony with cardiac resynchronization therapy.
Cardiac resynchronization therapy (CRT) has been shown to induce a structural and electrical remodeling; the data on whether left ventricle (LV) reverse remodeling is associated with restitution of intrinsic contraction pattern are unknown. In this study, we investigated the presence of improvement in left ventricular intrinsic dyssynchrony in patients with CRT. A total of 45 CRT recipients were prospectively studied. Dyssynchrony indexes including interventricular mechanical delay (IVMD) and tissue Doppler velocity opposing-wall delay (OWD) as well as QRS duration on 12-lead surface electrocardiogram were recorded before CRT device implantation. After 1 year, patients with chronic biventricular pacing were reprogramed to VVI 40 to allow the resumption of native conduction and contraction pattern. After 4-6 h of intrinsic rhythm, QRS duration and all echocardiographic measurements were recorded. Dyssynchrony was defined as IVMD >40 ms and OWD >65 ms. CRT response was defined by a ≥15% reduction in left ventricular end-systolic volume (LVESV) at a 12-month follow-up. Thirty-two patients (71%) showed response to CRT. The native QRS duration reduced significantly from 150±12 ms to 138±14 ms (p<0.001), and dyssynchrony indexes showed a significant improvement only in responders. The mean OWD reduced from 86±37 ms to 50±29 ms (p<0.001), and the mean IVMD decreased from 55±22 ms to 28±22 ms (p<0.001) in responders. The reduction in LVESV was significantly correlated with ΔOWD (r=0.47, p=0.001), ΔIVMD (r=0.45, p=0.001), and ΔQRS (r=0.34, p=0.022). Chronic CRT significantly improves LV native contraction pattern and causes reverse remodeling in dyssynchrony.


Extended active optical lattice filters: filter synthesis.
In this paper, we study the synthesis of asymptotically stable filters from a unit cell of a two-dimensional tunable lattice filter architecture consisting of four four-port couplers and four waveguides containing semiconductor optical amplifiers. Upper bounds on the number of gains that will produce a filter with a priori prescribed poles, for a specific system, are obtained. We also provide sufficient conditions on the reflection-type coefficients, characterizing each four-port coupler, which ensure that real-valued gains, taking values in [0,1], exist so that the filter is asymptotically stable. Finally, we motivate the notion of a transmission zero of a filter and discuss the possibility of simultaneously placing both poles and transmission zeros for the unit cell.


Effect of Sleep Deprivation on the Male Reproductive System in Rats.
There has been no study reporting on the influence of sleep deprivation on the male reproductive system including sperm quality. In this study, we hypothesized that sleep deprivation could lead to adverse effect on the male reproductive system. The rats were divided into three groups: 1) control (home-cage, n = 10); 2) SD4 (sleep deprivation for 4 days, n = 10); and 3) SD7 (sleep deprivation for 7 days, n = 10). Sleep deprivation was performed by a modified multiple platform method. Sperm quality (sperm motion parameters and counts), hormone levels (corticosterone and testosterone), and the histopathology of testis were evaluated and compared between the three groups. A statistically significant reduction (P = 0.018) was observed in sperm motility in the SD7 group compared to those of the control group. However, there were no significant differences in other sperm motion parameters, or in sperm counts of the testis and cauda epididymis between three groups. Compared with the control group, the SD4 (P = 0.033) and SD7 (P = 0.002) groups exhibited significant increases of corticosterone levels, but significant decreases of testosterone levels were found in the SD4 (P = 0.001) and SD7 (P < 0.001) groups. Seminiferous tubular atrophy and/or spermatid retention was partially observed in the SD4 and SD7 groups, compared with the normal histopathology of the control group. Sleep deprivation may have an adverse effect on the male reproductive system in rats.


Recent advances in Brucella abortus vaccines.
Brucella abortus vaccines play a central role in bovine brucellosis control/eradication programs and have been successfully used worldwide for decades. Strain 19 and RB51 are the approved B. abortus vaccines strains most commonly used to protect cattle against infection and abortion. However, due to some drawbacks shown by these vaccines much effort has been undertaken for the development of new vaccines, safer and more effective, that could also be used in other susceptible species of animals. In this paper, we present a review of the main aspects of the vaccines that have been used in the brucellosis control over the years and the current research advances in the development of new B. abortus vaccines.


Pharmacokinetic study of radioactive antineoplaston A10 following oral administration in rats.
Radiolabelled (3H-labelled) Antineoplaston A10 was administered in a single dose of 220 mg to 230 mg/kg to female Sprague Dawley rats. Blood and urine samples for determination of radioactivity were collected one hour prior to, and then at different time intervals after, the administration of the drug. Rats were sacrificed 6 h or 36 h later for the study of radioactivity in the various organs. The concentration of radioactivity in blood reached a maximum after 2 to 3 h after the administration of Antineoplaston A10, whereas the highest concentration of radioactivity in urine was observed in the 3.5-h to 4-h samples. It was observed by quantitative HPLC analysis that in rats sacrificed 6 h after Antineoplaston A10 administration, between 61% to 69% of the drug was absorbed, whereas between 37% to 28% was found in the stomach and between 2% to 3% was present in the intestinal contents and faeces. After 36 h, none could be detected in the stomach, intestinal contents or faeces. Organ distribution studies indicated greater accumulation of radioactivity in ileum, bladder, duodenum, kidneys and jejunum, and relatively low accumulation in the heart, lung, liver and brain. The concentration of radioactivity after 36 h was very low. By quantitative measurement, between 40% to 42% of the drug was excreted in the urine in 6 h and 75% of the radioactive material was in the form of Antineoplaston A10. The identification of the major radioactive material as Antineoplaston A10 was confirmed by TLC and analysis of the products of acid hydrolysis and by determination of melting range.


Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-mediated diseases: record-linkage studies.
Subarachnoid hemorrhage (SAH) is a devastating cause of stroke, occurring in relatively young people. It has been suggested that some immune-mediated diseases may be associated with an increased risk of SAH. We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999-2011). Rate ratios for SAH were determined, comparing immune-mediated disease cohorts with comparison cohorts. There were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn's disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, SLE and thyrotoxicosis. Elevated risks that were greater than 2-fold were found for Addison's disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura (RR = 2.42, 1.86-3.11), primary biliary cirrhosis (RR = 2.21, 1.43-3.16) and SLE (RR = 3.76, 3.08-4.55). Our findings strongly support the suggestion that patients with some immune-mediated diseases have an increased risk of SAH. Further studies of the mechanisms behind this association are warranted.


An adjunctive preventive treatment for cancer: ultraviolet light and ginkgo biloba, together with other antioxidants, are a safe and powerful, but largely ignored, treatment option for the prevention of cancer.
Cancer has surpassed heart disease as the leading cause of death in the United States. The mortality rate for cancer is high (roughly 42%), and it increases dramatically with increasing age, especially in patients between the ages of 40 and 60 years old. Currently, the efforts at cancer prevention have been minimal. The drugs developed so far are expensive and have serious side effects. There are at least 18 vitamin D-sensitive cancers. Ultraviolet light, and specifically ultraviolet B (UVB), could reduce cancer by the limited exposure of suitable skin areas to UVB of an intensity and duration insufficient to produce skin cancer. An irrational fear of skin cancer is preventing this idea from being implemented. Though skin cancer incidence is significant, mortality from skin cancer is relatively rare. Roughly 1,000,000 Americans will be affected by skin cancer but only 10,000 deaths are expected in 2005 (a 1% mortality rate). Skin cancer is easily detected and often cured by excisional biopsy alone. Current practice among practicing clinicians is to use a prescription drug substitute for UV light, calcitriol (1-25 dihydroxycholcalciferol). However, high levels of (calcitriol) are dangerous, and there is no consensus on just what a high dose or a safe dose is. Apart from skin cancer, UV light exposure possesses few risks. Additionally, a number of botanical agents such as ginkgo biloba, vitamins E and C, carotenoids, selenium and proanthocyanidins can prevent the risk of skin cancer. Ginkgo biloba also possess the following additional cancer chemopreventive qualities: (1) promoting apoptosis of cancer cells; (2) an anti-clastogenic effect on chromosomes by repairing and reconstituting broken and damaged chromosomes; (3) a powerful therapeutic effect on the treatment of fibrosis-related cancer; (4) a therapeutic effect on free radical-induced cancer; (5) a therapeutic effect on the treatment of cancer incident to the result of numerous carcinogens; (6) a therapeutic effect on preventing free radical-induced cancer; (7) an enhancing effect on radiation therapy in the treatment of cancer; and (8) a therapeutic effect on reducing the size of cancer tumors. Ginkgo biloba is widely-used and has few adverse effects. The proposed preventive treatment for cancer consists of short intermittent exposure of the least sensitive areas of the body to sunlight and/or artificial ultraviolet light. The routine testing of plasma vitamin D levels help monitor the effectiveness of the treatment and periodic checkups with a dermatologist help monitor the safety.


The expression of anti-poly(LGlu60, LPhe40) idiotypic determinants dictated by the gene products in the major histocompatibility complex.
Antibodies raised in SWR/J mice (H-2q, Igc) to the random copolymer poly(LGlu60, LPhe40) (GPhe) were purified by immunoadsorbent chromatography and used to immunize a New Zealand red rabbit. The rabbit anti-idiotypic antiserum thus produced strongly inhibited the binding of 125I-GPhe by anti-GPhe antisera produced only in mice of H-2q haplotype, and had no effect on the binding of GPhe by anti-GPhe antisera produced in mice of other haplotypes, namely, H-2k and H-2p. The anti-idiotypic antiserum also inhibited the binding of GPhe by anti-GPhe-methylated bovine serum albumin antisera produced only in mice of H-2q haplotype. No linkage to Ig allotype was observed. The anti-GPhe antisera produced in F1 mice the anti-idiotypic antiserum demonstrating the dominant presence in these F1 mice of idiotypic determinants whose expression is dictated by the H-2q major histocompatibility complex (MHC). The anti-idiotypic antiserum also inhibited the binding of 125I-poly)LGlu56, LLys35, LPhe9) and 125I-GPhe antisera produced only in mice of H-2q haplotype. These specificities were also confirmed by the inhibition of the plaque-forming cells. It was concluded that the antibodies produced in mice of H-2q haplotype against GPhe and GLPhe share common idiotypic determinants that are recognized by the anti-idiotypic antiserum. A possible explanation for the unique findings that the expression of anti-GPhe idiotypic determinants in mice of H-2q haplotype are dictated by the gene product in the MHC is that the macrophages in mice of H-2q haplotype present unique determinants of GPhe polymer in the response process to GHphe.


The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease.
Among the pathophysiological derangements operating in the chronic phase of Chagas disease, parasite persistence is likely to constitute the main mechanism of myocardial injury in patients with chronic chagasic cardiomyopathy. The presence of Trypanosoma cruzi in the heart causes a low-grade, but relentless, inflammatory process and induces myocardial autoimmune injury. These facts suggest that trypanocidal therapy may positively impact the clinical course of patients with chronic Chagas heart disease. However, the experimental and clinical evidence currently available is insufficient to support the routine use of etiologic treatment in these patients. The BENEFIT project--Benznidazole Evaluation for Interrupting Trypanosomiasis--is an international, multicenter, double-blind, placebo-controlled trial of trypanocidal treatment with benznidazole in patients with chronic Chagas heart disease. This project is actually comprised of two studies. The pilot study investigates whether etiologic treatment significantly reduces parasite burden, as assessed by polymerase chain reaction-based techniques and also determines the safety and tolerability profile of the trypanocidal drug in this type of chagasic population. The full-scale study determines whether antitrypanosomal therapy with benznidazole reduces mortality and other major cardiovascular clinical outcomes in patients with chronic Chagas heart disease.


Photon entanglement signatures in difference-frequency-generation.
In response to quantum optical fields, pairs of molecules generate coherent nonlinear spectroscopy signals. Homodyne signals are given by sums over terms each being a product of Liouville space pathways of the pair of molecules times the corresponding optical field correlation function. For classical fields all field correlation functions may be factorized and become identical products of field amplitudes. The signal is then given by the absolute square of a susceptibility which in turn is a sum over pathways of a single molecule. The molecular pathways of different molecules in the pair are uncorrelated in this case (each path of a given molecule can be accompanied by any path of the other). However, entangled photons create an entanglement between the molecular pathways.We use the superoperator nonequlibrium Green's functions formalism to demonstrate the signatures of this pathway-entanglement in the difference frequency generation signal. Comparison is made with an analogous incoherent two-photon fluorescence signal.


Importance of pre-transplant colonoscopy in renal transplant recipients.
Current recommendations for colorectal cancer screening for kidney transplant candidates are the same as for the general population. However, few studies have established the prevalence and characteristics of colorectal polyps in this population. The aim of this study is to describe the prevalence and characteristics of colonic lesions detected by pre-transplant colonoscopies in our kidney transplant population. A retrospective study was conducted from January 2007 to December 2009 at the Centre Hospitalier de l'Universite de Montreal (Canada). Inclusion criteria are all renal transplant recipients with a test for colorectal cancer screening in the 5 years preceding the transplantation. Patients benefiting of a second transplantation were excluded. The files were reviewed for clinical data, including colonoscopy indication, endoscopic and pathologic results. Advanced lesions were defined as adenomas of 10 mm or greater or with a villous component. Polyps were considered proximal if they were at the level of or above the splenic angle. This study includes 159 patients. A pre-transplant colonoscopy was performed in 40% (n = 64). Polyps were present in 32.8% (n = 21) of colonoscopies and 66.7% of them showed adenomas. Advanced lesions were present in 6.25% of the exams. Finally, 66.7% of patients with polyps had at least one proximal lesion. The prevalence of colorectal polyps before transplant is high among renal transplant recipients. The high prevalence of proximal lesions supports the need for total colonoscopy.


Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial.
Chronic rhinosinusitis with nasal polyps affects approximately 2-4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians -0·73, 95% CI -1·11 to -0·34; p<0·0001) and nasal obstruction VAS score during weeks 49-52 also significantly improved (-3·14, -4·09 to -2·18; p<0·0001). Adverse events considered related to study treatment were reported in 30 (15%) of 206 patients receiving mepolizumab and 19 (9%) of 201 receiving placebo. On-treatment serious adverse events occurred in 12 (6%) patients receiving mepolizumab and 13 (6%) receiving placebo; none were considered related to treatment in those receiving mepolizumab. One death was reported in the placebo group (myocardial infarction; death occurred 99 days after the last dose) and was considered unrelated to the treatment. Mepolizumab treatment improved nasal polyp size and nasal obstruction compared with placebo, with no new safety indications, in patients with recurrent, refractory severe chronic rhinosinusitis with nasal polyps. These findings suggest that mepolizumab provides an effective add-on treatment option to standard of care in this population. GlaxoSmithKline.


The Impact of Teachers' Modifications of an Evidenced-Based HIV Prevention Intervention on Program Outcomes.
The degree to which evidence-based program outcomes are affected by modifications is a significant concern in the implementation of interventions. The ongoing national implementation of an evidence-based HIV prevention program targeting grade 6 students in The Bahamas [Focus on Youth in The Caribbean (FOYC)] offers an opportunity to explore factors associated with teachers' modification of FOYC lessons and to examine the impact of types and degrees of modifications on student outcomes. Data were collected in 2012 from 155 teachers and 3646 students in 77 government elementary schools. Results indicate that teachers taught 16 of 30 core activities, 24.5 of 46 total activities and 4.7 of 8 sessions. Over one-half of the teachers made modifications to FOYC core activities; one-fourth of the teachers modified 25 % or more core activities that they taught (heavily modified FOYC). Omitting core activities was the most common content modification, followed by lengthening FOYC lessons with reading, writing assignments or role-play games, and shortening core activities or adding educational videos. Mixed-effects modeling revealed that omitting core activities had negative impacts on all four student outcomes. Shortening core activities and adding videos into lessons had negative impacts on HIV/AIDS knowledge and/or intention to use condom protection. Heavy modifications (>1/4 core activities) were associated with diminished program effectiveness. Heavy modifications and omitting or shortening core activities were negatively related to teachers' level of implementation. We conclude that poorer student outcomes were associated with heavy modifications.


Preservation of the arterial vascularisation after hepatic artery pseudoaneurysm following orthotopic liver transplantation: long-term results.
Hepatic artery pseudoaneurysm (HAP) is a serious complication of orthotopic liver transplantation (OLT). The aim of this study was to determine risk factors for HAP and the best management of this complication. Between 1990 and 2005, 787 OLT were performed at our center. Patients who developed HAP were identified from our prospective database and risk factors of HAP were identified. Management of HAP was analyzed retrospectively. There were 16 OLT (2.5%) complicated by HAP [median delay =13 days; range: 4-100 days]. Presentation was massive bleeding with shock (n=13), pain (n=2), or transient gastrointestinal bleeding (n=1). Bacteriological culture of HAP wall or ascites fluid was positive in 13 (81%) patients. Bilio-enteric anastomosis and biliary leak were identified as risk factors for HAP (p=0.011 and 0.002, respectively), whereas indication for OLT, surgical technique (full-graft OLT versus other techniques), and re-LT were not. Mortality rate after HAP rupture was 53% (7/13), but no deaths occurred in the 3 patients treated before rupture. Treatment included: excision and immediate revascularization [n=7; early mortality =2 (28%), long-term graft survival =4 (57%)], hepatic artery ligation [n=5; early mortality =3 (80%);, long-term graft survival with good liver function =0], and endovascular treatment [n=2; early mortality =0, long-term survival with good liver function =2]. HAP post-OLT carries a high mortality rate when detected after rupture, but recognition before rupture usually allows a successful outcome. Reconstruction with bilio-enteric anastomosis and postoperative biliary leak increase the risk for HAP. In these settings, CT with contrast injection should be performed to screen for HAP when there is any suspicion. Graft revascularization should be attempted whenever possible.


Employees' attitudes towards welfare technology in substance abuse treatment in Finland.
The significance of welfare and health technology has been highlighted in recent years. However, employees' attitudes towards welfare technology in substance abuse treatment have received little attention. This article examines employees' readiness to introduce welfare technology in substance abuse treatment and their attitudes towards its use. The theoretical framework of this study is based on Ajzen's (1991, 2001) theory of planned behaviour, and the ongoing discussion about the adoption of new technology in healthcare. The research data (N = 129) were collected in the form of an electronic questionnaire in Finland in 2015. The results are consistent with the theory of planned behaviour and previous studies on the acceptance of information systems in healthcare. Employees' readiness to introduce new welfare technology applications and devices in substance abuse treatment is influenced by their personal appreciation of welfare technology, the expectations of their colleagues and supervisors, as well as their own perceptions of their capacity to learn to use the applications. The study found some links between demographic factors and cognitions related to welfare technology. In particular, employees with a healthcare background are more inclined to adopt the technology than other employees in substance abuse treatment. In addition, a person's age has a negative relationship with their perceived technology management. However, age has no significant connection with attitudes and no direct independent effect on the readiness to introduce a new welfare technology. Lastly, the results show that previous positive experiences of welfare technology make it easier to introduce new technologies.


Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation.
Diabetic retinopathy (DR) is associated with microglial activation and increased levels of inflammatory cytokines. Genistein, a tyrosine kinase inhibitor, has been shown to possess anti-inflammatory potential that so far untested in animal models of diabetes. The aims of this study are to evaluate the efficacy of genistein for alleviation of diabetes-induced retinal inflammation and also to gain insight into the molecular mechanisms involved therein by analyzing the effect of genistein on concomitant microglia activation in the diabetic retina and in isolated cells. Streptozotocin (STZ)-induced diabetic Sprague Dawley rats were used. After diabetes was established for two weeks a single intravitreal injection of genistein or vehicle was performed. Forty-eight hours later, rats were killed, their retinal and vitreal samples were processed for Quantitative Real Time-PCR (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA) analyses, respectively. For the in vitro study, isolated microglial cells from retinas of newborn rats were used. mRNA as well as protein levels for tumor necrosis factor α (TNF-α), a robust marker of inflammation, were increased in the retina early in the course of diabetes. Moreover, diabetes resulted in elevation of ionized calcium binding adaptor molecule-1 (Iba1) mRNA, known to be upregulated in activated microglia. These effects of diabetes in retina were all reduced by intervention treatment with genistein. Using an in vitro bioassay, we demonstrated the release of TNF-α from microglia activated by glycated albumin, a risk factor for diabetic disorders. This inflammatory signal involves the activation of tyrosine kinase and its subsequent events, ERK and P38 MAPKs. Genistein represses the release of TNF-α and significantly inhibits ERK and P38 phosphorylation in activated microglial cells by acting as a tyrosine kinase inhibitor. These findings show genistein to be effective in dampening diabetes-induced retinal inflammation by interfering with inflammatory signaling (ERK and P38 MAPKs) that occurs in activated microglia. This beneficial effect of genistein may represent a new intervention therapy to modulate early pathological pathways long before the occurrence of vision loss among diabetics.


Transforming X-ray detection with hybrid photon counting detectors.
Hybrid photon counting (HPC) detectors have radically transformed basic research at synchrotron light sources since 2006. They excel at X-ray diffraction applications in the energy range from 2 to 100 keV. The main reasons for their superiority are the direct detection of individual photons and the accurate determination of scattering and diffraction intensities over an extremely high dynamic range. The detectors were first adopted in macromolecular crystallography where they revolutionized data collection. They were soon also used for small-angle scattering, coherent scattering, powder X-ray diffraction, spectroscopy and increasingly high-energy applications. Here, we will briefly survey the history of HPC detectors, explain their technology and then show in detail how improved detection has transformed a wide range of experimental techniques. We will end with an outlook to the future, which will probably see HPC technology find even broader use, for example, in electron microscopy and medical applications. This article is part of the theme issue 'Fifty years of synchrotron science: achievements and opportunities'.


A 31 year old woman with essential hypertension grade III and branch retinal vein occlusion with homozygous C677T MTHFR hyperhomocysteinemia and high Lp(a) levels.
We report a 31-year old woman with essential hypertension grade III and history of branch retinal vein occlusion in the setting of hyperhomocysteinemia due to homozygous MTHFR gene mutation and elevated Lp(a). The patient was treated successfully with antihypertensive treatment, acetylsalicylic acid and multivitamin complex supplementation.


Basal body movements as a mechanism for mitochondrial genome segregation in the trypanosome cell cycle.
The mitochondrial genome of Trypanosoma brucei is organized in the form of a complex catenated network of circular DNA molecules. This mass of DNA, known as the kinetoplast, is present at a unique site in the single mitochondrion, and is replicated in a discrete, periodic S phase of the cell cycle. The single-copy nature of the kinetoplast suggests that there is a mechanism ensuring segregation fidelity of replicated copies to each daughter cell. Historically, speculation regarding the nature of this mechanism has often attributed significance to the close association between the kinetoplast and the flagellum basal body. We provide here direct evidence that this mitochondrial DNA complex is indeed linked to the basal body, and segregation of the kinetoplast DNA is dependent on a microtubule-mediated separation of the new and old flagellar basal bodies during the cell cycle. This unique system may represent the remnants of an evolutionarily archaic mechanism for genome segregation.


Prognostic factors of status epilepticus in children.
We retrospectively reviewed the medical records of 189 children who were admitted to the Pediatric Neurology Department at Yonsei University College of Medicine with status epilepticus (SE) between April, 1994 and April, 2003. The children were followed up for a mean duration of 17 months. We analyzed the clinical findings and the relationships between neurologic sequelae, recurrence, age of onset, presumptive causes, types of seizure, seizure duration and the presence of fever. Mean age at SE onset was 37 months. Incidences by seizure type classification were generalized convulsive SE in 73.5%, and non-convulsive SE in 26.5%. The incidences of presumptive causes of SE were idiopathic 40.7%, epilepsy 29.1%, remote 16.4% and acute symptomatic in 13.3%. Among all the patients, febrile episodes occurred in 35.4%, especially in patients under 3 year old, and 38.4% of these were associated with febrile illness regardless of presumptive cause. Neurologic sequelae occurred in 33% and the mortality rate was 3%. Neurologic sequelae were lower in patients that presented with an idiopathic etiology and higher in generalized convulsive SE patients. The recurrence of SE was higher in patients with a remote symptomatic epileptic etiology, and generalized convulsive SE showed higher rates of recurrence. Based on this retrospective study, the neurologic outcomes and recurrence of SE were found to be strongly associated with etiology and seizure type. Age, seizure duration and the presence of febrile illness were found to have no effect on outcome.


The moderating effects of race on return visits to the psychiatric emergency room.
Racial differences in variables that predict return to the psychiatric emergency room were examined. A random sample of 319 clients was obtained from the logs of a psychiatric emergency room of a state-operated, acute care psychiatric hospital. The dependent variable was a return visit to the psychiatric emergency room within 18 months of the index visit. Separate logistic regression equations were calculated for African Americans (N = 163) and Caucasians (N = 156) to estimate the moderating effects of race. Four variables predicted return to the emergency room for both African Americans and Caucasians: previous visits to the psychiatric emergency room, previous psychiatric hospitalizations, current receipt of outpatient treatment, and nonreceipt of aftercare following the index visit to the emergency room. Three unique predictors were found for African Americans: never having been married, not living in stable housing, and not being admitted at the index visit. Generally, repeat visitors from both racial groups tended to be chronic users of psychiatric services who may be using the psychiatric emergency room for routine psychiatric care. However, race was also an important moderator variable; several risk factors predicted a return visit only for African Americans.


Genotyping of Candida albicans using length fragment and high-resolution melting analyses together with minisequencing of a polymorphic microsatellite locus.
Microsatellite length polymorphism (MLP) typing is a PCR-based method used for genotyping of the diploid yeast Candida albicans. However, MLP is subject to homoplasia which can hamper the accuracy of the results. We combined fragment length analysis, high-resolution DNA melting (HRM) analysis, and SNaPshot minisequencing after a single amplification of the CDC3 locus to study 95 epidemiologically independent C. albicans isolates. HRM analysis for a given electrophoretic group led to a maximum of three different curves due to the presence of a SNP upstream of the tandem repeat which could be characterized using the SNaPshot assay. The combination of the three methods had a discriminatory index of 0.88 in complete congruence with previous MLP typing (Mantel test R=0.99, P<10(-)(4)). HRM is a useful tool of adding resolving power to MLP genotyping in identifying SNPs.


Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude.
TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.


A modified extensile exposure for the treatment of complex or malunited acetabular fractures.
A modification of the extended iliofemoral incision of Letournel and Judet facilitates the operative exposure of T-type, complex transverse, and both-column acetabular fractures and malunions. The modification includes the utilization of a T-shaped skin incision with large flaps, and osteotomies of the iliac crest, greater trochanter, and anterior superior iliac spine. The iliotibial band is transected and the abductor muscle mass is rotated posteriorly, hinged on the superior gluteal neurovascular bundle. Twenty patients had open reduction and internal fixation of a complex acetabular fracture using this surgical approach. Excellent surgical exposure allowed good or excellent reduction of the acetabulum in all patients. No flap necrosis developed, and all fractures healed. One non-union of a trochanteric osteotomy needed revision. This approach provides increased exposure of the posterior column and visualization of the entire surface of the joint and it allows fixation of the fracture from both sides of the iliac wing. The T-shaped skin incision allows utilization of a standard posterior approach with conversion to the extensile exposure if necessary. Options for late reconstruction are not compromised. Lagscrew fixation of the osteotomies allows aggressive rehabilitation of the joint.