[Mouth diseases and dental materials: potential for study with cytofluorometry].
The potential dental materials have of inducing mouth diseases is well known, and various methods have been developed to investigate this phenomenon. Among these there are histological studies of the pulp and periodontium exposed to dental materials, both in vivo and in vitro in humans and animals. Other studies are based on the clinical observation of the effects induced by dental materials. Aim of the paper is to evaluate the use of flow cytometry to analyse crevicular fluid to study its content in terms of inflammatory cells and inflammation mediators. Samples of crevicular fluid were collected by aspiration using a bevelled needle mounted on a 5 ml syringe from patients without periodontitis and with periodontitis and multiple heterogeneous dental restorations. This method was adopted since it allows to place the cells of the fluid in suspension. Part of the fluid was analysed by cytology and part by flow cytometry. In the patients without periodontal disease cytological examination revealed the presence of desquamated epithelial cells and colonies of cocci, rods and spirochaetae. In the patients with periodontal disease the same examination revealed, besides the above, the presence of inflammatory cells. Flow cytometry confirmed the findings of cytological examination, thus proving to be an effective method for studying crevicular fluid. This method allows to identify specific inflammatory cells or mediators of inflammation in crevicular fluid and may therefore prove to be very useful in the study of alterations induced by some dental materials at the level of the gingival sulcus.


The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats.
Cerebral ischemia reperfusion (IR) injury is a process in which oxidative and apoptotic mechanisms play a part. Neuroprotective agents to be found could work out well for the efficient and safe minimization of cerebral IR injury. Crocin is a strong antioxidant agent; however the influence of this agent on the experimental cerebral ischemia model has not been studied extensively and thus it is not well-known. The objective of our study was to investigate the antioxidant, antiapoptotic and protective effects of crocin on the global cerebral IR induced by four-vessel occlusion. A total of 30 adult female Sprague-Dawley rats were equally and randomly separated into three groups as follows: sham, IR and IR+crocin (40mg/kg/day orally for 10days). 24h after electrocauterization of bilateral vertebral arteries, bilateral common carotid arteries were occluded for 30min and reperfused for 30min. Oxidative stress parameters (TAS, TOS, OSI), haematoxylin and eosin staining, caspase-3 and hypoxia-inducible factor-1 alpha (HIF-1α) expressions and TUNEL methods were investigated. There was a significant difference between the IR and sham groups by means of OSI level, histopathological scoring, caspase-3, HIF-1α and TUNEL-positive cell parameters. We have also observed that pre-treatment with crocin reduced these parameter levels back to the baseline. The data obtained from the present study suggest that crocin may exert antiapoptotic, antioxidant and protective effects in IR-mediated brain injury induced by four-vessel occlusion. To the best of our knowledge, this would be the first study to be conducted in this field.


Capsaicin activated currents in rat dorsal root ganglion cells.
Capsaicin is a pungent-tasting compound produced by plants in the Capsium family that activates a subset of primary afferent neurons associated with pain and thermoreception. Previous studies from dorsal root ganglion (DRGs) neurons suggest that many of capsaicin's physiological responses are a consequence of its activating a cation-selective current. To further characterize the responses to capsaicin whole-cell patch-clamp measurements were performed on rat DRGs to which 0.1-10 microM capsaicin was continuously applied. The capsaicin-activated currents exhibited marked variability in their thresholds, amplitude (to 15 nA), rates of desensitization, and the number of distinct maxima in the evoked current. Similar responses were found in rat trigeminal ganglion cells. The heterogeneity in the magnitude of the currents evoked by 0.1 microM capsaicin likely reflects different types of capsaicin-sensitive neurons; a result consistent with in vitro extracellular recordings from capsaicin-sensitive sensory afferents (Seno and Dray 1993).


Atrial Fibrillation and Risk of ST-Segment-Elevation Versus Non-ST-Segment-Elevation Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study.
It has recently been reported that atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with the type of MI (ST-segment-elevation MI [STEMI] versus non-ST-segment-elevation MI [NSTEMI]) might shed light on the potential mechanisms. We examined the association between AF and incident MI in 14 462 participants (mean age, 54 years; 56% women; 26% blacks) from the Atherosclerosis Risk in Communities (ARIC) study who were free of coronary heart disease at baseline (1987-1989) with follow-up through December 31, 2010. AF cases were identified from study visit ECGs and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow-up of 21.6 years, 1374 MI events occurred (829 NSTEMIs, 249 STEMIs, 296 unclassifiable MIs). In a multivariable-adjusted model, AF (n=1545) as a time-varying variable was associated with a 63% increased risk of MI (hazard ratio,1.63; 95% confidence interval, 1.32-2.02). However, AF was associated with NSTEMI (hazard ratio, 1.80; 95% confidence interval, 1.39-2.31) but not STEMI (hazard ratio, 0.49; 95% confidence interval, 0.18-1.34; P for hazard ratio comparison=0.004). Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men (P for interaction <0.01 for both). AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI.


Discussing end-of-life issues in nursing homes: a nationwide study in France.
discussing end-of-life issues with nursing home residents and their relatives is needed to ensure patient-centred care near the end of life. this study aimed to estimate the frequency of nursing home physicians discussing end-of-life issues with residents and their relatives and to investigate how discussing end-of-life issues was associated with care outcomes in the last month of life. post-mortem cohort study in a nationwide, representative sample of 78 nursing home facilities in France. Residents who died from non-sudden causes between 1 October 2013 and 31 May 2014 in these facilities were included (n = 674). end-of-life issues were discussed with at most 21.7% of the residents who died during the study period. In one-third of the situations (32.8%), no discussion about end-of-life-related topics ever occurred, either with the resident or with the relatives. Older people with severe dementia were less likely to have discussed more than three of the six end-of-life topics we investigated, compared with residents without dementia (OR = 0.17, 95% CI = 0.08-0.22). In the last month of life, discussing more than three end-of-life issues with the residents or their relatives was significantly associated with reduced odds of dying in a hospital facility (adjusted OR = 0.51, 95% CI = 0.33-0.79) and with a higher likelihood of withdrawing potentially futile life-prolonging treatments (adjusted OR = 2.37, 95% CI = 1.72-3.29). during the last months of life, discussions about end-of-life issues occurred with only a minority of nursing home decedents, although these discussions may improve end-of-life care outcomes.


[Pathogenesis and methods evaluation of liver fibrosis in HIV/HCV co-infection].
The paper presents the pathogenetic base of liver fibrosis in HIV/HCV co-infection. The factors influencing on fibrosis progression, dependent on progressive immunosuppression and the effects of antiretroviral drugs are discussed in details. Current diagnostic possibilities, including the role of histopathologic evaluation of liver tissue and non-invasive methods--serum fibrosis markers and elastometry--are presented.


Expression of Ets-1 proto-oncoprotein in gastrointestinal stromal tumors, leiomyomas and schwannomas.
Gastrointestinal stromal tumors (GISTs) are rare. GISTs differ from other mesenchymal tumors of the gastrointestinal tract (e.g. leiomyomas and schwannomas). The purpose of this study was to investigate the role of Ets-1 in the growth and differentiation of GISTs. Twenty-eight GISTs, nine leiomyomas and six schwannomas were examined by immunohistochemical staining method for Ets-1 in this study. Specimens were selected from surgical pathology archival tissues at Nagasaki University Hospital. Ets-1 protein was expressed in the cytoplasm of cells in all of these tumors. Immunohistochemical staining revealed that 27 GISTs (96.4%), six leiomyomas (66.7%), and five schwannomas (83.3%) were positive for Ets-1. Ets-1 expression was statistically different between GISTs and leiomyomas (P<0.005). However, there was no correlation between Ets-1 expression and clinical risk categories. Ets-1 plays an important role in the growth and differentiation of GISTs, leiomyomas and schwannomas.


Comparison of three serological tests in gonococcal infection.
Three serological tests used in the diagnosis of gonococcal infection were compared with cultural techniques in 857 females attending the Prenatal and Gynaecology Clinics at the Winnipeg General Hospital. The tests evaluated were the microflocculation technique (MFT), the indirect fluorescent-antibody technique (IFAT), and the complement-fixation technique (CFT). One hundred six patients had positive cultures for Neisseria gonorrhoeae. In this population, the MFT was reactive in 80 patients (75.4%), the IFAT was reactive in 74 (69.8%), and the CFT was reactive in 33 (31.1%). In the 751 patients with negative cultures, the MFT was positive in 11.4%, the IFAT was positive in 17.4%, and the CFT was positive in 10.5%. Sera from 9 of 10 patients with gonococcal arthritis were positive with the MFT.


Establishment of porcine and human expanded potential stem cells.
We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.


Prediction in the Aging Brain: Merging Cognitive, Neurological, and Evolutionary Perspectives.
Although the aging brain is typically characterized by declines in a variety of cognitive functions, there has been growing attention to cognitive functions that may stabilize or improve with age. We integrate evidence from behavioral, computational, and neurological domains under the hypothesis that over the life span the brain becomes more effective at predicting (i.e., utilizing knowledge) compared to learning. Moving beyond mere description of the empirical literature-with the aim of arriving at a deeper understanding of cognitive aging-we provide potential explanations for a learning-to-prediction shift based on evolutionary models and principles of senescence and plasticity. The proposed explanations explore whether the occurrence of a learning-to-prediction shift can be explained by (changes in) the fitness effects of learning and prediction over the life span. Prediction may optimize (a) the allocation of limited resources across the life span, and/or (b) late-life knowledge transfer (social learning). Alternatively, late-life prediction may reflect a slower decline in prediction compared to learning. By discussing these hypotheses, we aim to provide a foundation for an integrative neurocognitive-evolutionary perspective on aging and to stimulate further theoretical and empirical work.


Reduced response of the hypothalamo-pituitary-adrenal axis to alpha1-agonist stimulation during lactation.
To determine whether altered noradrenergic activation of the hypothalamo-pituitary-adrenal (HPA) axis contributes to the attenuated neuroendocrine response to stress observed during lactation, the effect of intracerebroventricular injection of the alpha1-agonist methoxamine (100 microg) was compared between virgin and lactating rats. Virgin rats showed significant increases in plasma corticosterone after methoxamine, reaching 317 +/- 44 ng/ml at 10 min and remaining significantly elevated for more than 120 min, but lactating rats showed no significant increase in corticosterone levels. Furthermore, methoxamine induced an increase in paraventricular nucleus (PVN) CRF messenger RNA expression in virgin, but not lactating, animals. Both groups of rats exhibited comparable elevations in plasma PRL after methoxamine treatment. Arginine vasopressin messenger RNA expression within the parvocellular PVN was greater in the lactating animals than in the virgin controls, but methoxamine injection was without further effect. Studies performed on ovariectomized virgin rats and ovariectomized rats receiving estradiol or progesterone replacement failed to reproduce the attenuated HPA responses seen after methoxamine treatment, although methoxamine-induced PRL levels were greatly increased by estradiol, probably arising from an effect on hormone synthesis. In vitro electrophysiological recordings of PVN neurons in hypothalamic slices from proestrous virgin and lactating rats showed that 45-52% of neurons in both groups exhibited excitatory responses to 10(-4) M methoxamine, but there was a differential response to 10(-5) M methoxamine, with PVN neurons from lactating animals failing to show a response. These data show a selective down-regulation of alpha1-mediated activation of the HPA axis in lactating animals. This may contribute to the attenuated stress-induced activation of the HPA axis during lactation.


Comparing multifocal pupillographic objective perimetry (mfPOP) and multifocal visual evoked potentials (mfVEP) in retinal diseases.
Multifocal pupillographic objective perimetry (mfPOP) shows regions of slight hypersensitivity away from retinal regions damaged by diabetes or age-related macular degeneration (AMD). This study examines if such results also appear in multifocal visual evoked potentials (mfVEPs) recorded on the same day in the same patients. The pupil control system receives input from the extra-striate cortex, so we also examined evidence for such input. We recruited subjects with early type 2 diabetes (T2D) with no retinopathy, and patients with unilateral exudative AMD. Population average responses of the diabetes patients, and the normal fellow eyes of AMD patients, showed multiple regions of significant hypersensitivity (p < 0.05) on both mfPOP and mfVEPs. For mfVEPs the occipital electrodes showed fewer hypersensitive regions than the surrounding electrodes. More advanced AMD showed regions of suppression becoming centrally concentrated in the exudative AMD areas. Thus, mfVEP electrodes biased towards extra-striate cortical responses (surround electrodes) appeared to show similar hypersensitive visual field locations to mfPOP in early stage diabetic and AMD damage. Our findings suggest that hypersensitive regions may be a potential biomarker for future development of AMD or non-proliferative diabetic retinopathy, and may be more informative than visual acuity which remains largely undisturbed during early disease.


[Technical success rate, peri-interventional complications and radiation exposure of the transarterial embolization for leiomyomas of the uterus].
To analyze the technical success rate, incidence and type of peri-interventional complications, and radiation exposure of uterine artery embolization (UAE) in symptomatic leiomyomas of the uterus. This prospective study includes 75 patients consecutively treated with UAE from October 2000 through August 2002, with all interventions performed by the same radiologist. Technical success rate, interventional material, and incidence and type of peri-interventional complications (length of hospitalization) were recorded and categorized according to the definitions of the Society of Interventional Radiology (SIR). Fluoroscopy time (FT), dose-area product (DAP), and effective dose (ED) were determined for each intervention and the influence of the radiologist's experience on the radiation exposure analyzed. UAE was technically successful in 97.3 % of the cases. Peri-interventional complications occurred in 14.7 %. Four complications (5.3 %) were classified as major class C according to the SIR (post-embolization syndrome requiring prolonged drug treatment and hospitalization [n = 3] perforation of the uterine artery [n = 1]). None of the complications led to discontinuation of the intervention, subsequent surgical intervention, or permanent sequelae. FT decreased significantly (p < 0.05) until the 35th intervention. The median FT decreased from 18.8 min (13.4 - 28 min [25th to 75th percentile]) to 11.8 min (9.7 - 13.3 min [25th to 75th percentile]). The DAP decreased by 25.3 % to a median of 8.547 (6.527 - 11.590 cGy*cm (2) [25th to 75th percentile]). The median ED was 31.5 mSv from the 36th intervention onward. UAE has a high technical success rate with a low rate of peri-interventional complications. The study showed a statistically significant learning effect with a decrease in radiation exposure for the first 35 interventions. The effective dose of UAE is comparable to that of 1 to 2 small bowel enema.


Efficacy of Artificial Chordal Reconstruction for Idiopathic Severe Mitral Regurgitation Due To Chordal Rupture in Infancy.
Early surgical intervention is required for sudden onset, severe mitral regurgitation (MR) due to chordal rupture in infants with normal development younger than 1 year. The condition has been recognized as idiopathic. However, the surgical options in children are limited because of their size and somatic growth. We sought to examine the efficacy of mitral valve plasty by artificial chordal reconstruction for these infants in mid-to-long term. From August 2005 through June 2012, 8 consecutive patients aged 1-7 months underwent mitral valve plasty by chordal reconstruction using expanded polytetrafluoroethylene sutures for MR, owing to leaflet prolapse. The geometric parameters of the diameter of the mitral annulus (D1), the long axis of the left ventricular (LV) chamber (D2), and the length of the papillary muscle including the reconstructed chordae (D3) were measured, as well as MR grade (0-4) and LV end-diastolic dimension, at each time point. The parameters were compared with those in the control group that included Kawasaki disease patients without cardiac lesions and healthy children (n = 51). Mean follow-up period was 5.8 (2.8-9.6) years. Freedom from reoperation was 100%. MR grades were 3.9 ± 0.4 preoperatively, 2.4 ± 0.9 at discharge, and 1.4 ± 0.6 at the latest. Postoperative MR was improved within 1 year in 5 of 6 patients who had grade 2 or higher regurgitation. LV end-diastolic dimensions were 109% (% of normal), 113%, and 107% at discharge, 3, and 5 years, respectively. Geometric configuration indicated by the D1/D2 ratio did not significantly change with time. The length of the papillary muscle including reconstructed chordae (D3) strongly correlated with body surface area (r(2) = 0.65), which seemed to be equivalent to that in the control group. In conclusion, postoperative mitral valve function and geometry was preserved. This procedure with a low morbidity should be an option for pediatric patients with acute severe MR.


Matching the emitting wavelength from a very-small-aperture laser to the resonant property of a nanometric C-aperture.
An experimental method is proposed to increase the output power from a C-aperture very-small-aperture laser (VSAL). This method is based on the resonant property of a C aperture and the tunability of the emitting wavelength from a VSAL. The drive current of the VSAL is altered to tune the emitting wavelength. The experimental results indicate that, when the emitting wavelength matches the resonant wavelength of the C aperture fabricated on the VSAL, the output power is enhanced 7.2 times. So a strong output power from a C-aperture VSAL can be obtained with small power consumption. This study may be useful to the design and application of a VSAL.


Incidence and Risk Factors for Intensive Care Unit-related Post-traumatic Stress Disorder in Veterans and Civilians.
The incidence and risk factors of post-traumatic stress disorder (PTSD) related to the intensive care unit (ICU) experience have not been reported in a mixed veteran and civilian cohort. To describe the incidence and risk factors for ICU-related PTSD in veterans and civilians. This is a prospective, observational, multicenter cohort enrolling adult survivors of critical illness after respiratory failure and/or shock from three Veterans Affairs and one civilian hospital. After classifying those with/without preexisting PTSD (i.e., PTSD before hospitalization), we then assessed all subjects for ICU-related PTSD at 3 and 12 months post hospitalization. Of 255 survivors, 181 and 160 subjects were assessed for ICU-related PTSD at 3- and 12-month follow-up, respectively. A high probability of ICU-related PTSD was found in up to 10% of patients at either follow-up time point, whether assessed by PTSD Checklist Event-Specific Version (score ≥ 50) or item mapping using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). In the multivariable regression, preexisting PTSD was independently associated with ICU-related PTSD at both 3 and 12 months (P < 0.001), as was preexisting depression (P < 0.03), but veteran status was not a consistent independent risk factor for ICU-related PTSD (3-month P = 0.01, 12-month P = 0.48). This study found around 1 in 10 ICU survivors experienced ICU-related PTSD (i.e., PTSD anchored to their critical illness) in the year after hospitalization. Preexisting PTSD and depression were strongly associated with ICU-related PTSD.


Loss of locus coeruleus noradrenergic neurons alters the inflammatory response to LPS in substantia nigra but does not affect nigral cell loss.
In Parkinson's disease (PD), destruction of noradrenergic neurons in the locus coeruleus (LC) may precede damage to nigral cells and subsequently exaggerate dopaminergic cell loss. We examine if destruction of the locus coeruleus with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) alters dopaminergic cell loss in substantia nigra (SN) initiated by lipopolysaccharide (LPS) in the rat through an effect on glial cell activation. In rats, a single intraperitoneal dose of DSP-4 administered 8 days previously, caused a marked loss of tyrosine hydroxylase positive neurons in LC but no change in dopaminergic cell number in SN. Unilateral nigral LPS administration resulted in marked dopaminergic cell death with reactive microgliosis associated with enhanced p47 phox in OX-6 and OX-42 positive microglia. There was proliferation of inducible nitric oxide synthase (iNOS)-positive cells, formation of 3-nitrotyrosine (3-NT) and proliferation of astrocytes that expressed glial cell line-derived neurotrophic factor (GDNF). Following combined DSP-4 treatment and subsequent administration of LPS, unexpectedly, no further loss of tyrosine hydroxylase (TH)-immunoreactivity (-ir) occurred in the SN compared to the effects of LPS alone. However, there was a marked alteration in the morphology of microglial cell and a reduction of 3-NT- and iNOS-ir was evident. Expression of p47 phox was downregulated in microglia but up-regulated in TH-ir neurons. No further change in GFAP-ir was observed compared to that produced by DSP-4 alone or LPS alone, but the expression of GDNF was markedly reduced. This study suggests that in contrast to previous reports, prior LC damage does not influence subsequent nigral dopaminergic cell degeneration induced by LPS. Rather it appears to attenuate the microglial response thought to contribute to disease progression in PD.


Ultrastructural localization of the 150/130 Kd antigens in sexual and asexual blood stages of Plasmodium falciparum-infected human erythrocytes.
The subcellular localization of the 150/130 Kd antigen in Plasmodium falciparum-infected erythrocytes was determined by electron microscopy using monoclonal antibody 9B11 and immuno-gold labeling. We now find that this antigen may be associated with the membrane of newly-infected human erythrocytes and the cytoplasm of ring stage parasites. During differentiation of the parasite to the trophozoite stage, the antigens are no longer detectable on the erythrocyte membrane, while gold particles become more numerous within the parasite and in the erythrocyte cytoplasm adjacent to the parasite. As the parasites develop into schizonts, more antigen appears within the parasites, and some of it appears in the erythrocyte cytoplasm. At the segmented schizont stage, many intraparasitic gold particles are associated with rhoptries and micronemes of developing merozoites. Likewise, gold particles are associated with elements of the rhoptry-microneme complex in free merozoites. No gold particles are detected on the surface of merozoites. These antigens are found most abundantly in erythrocytes infected with gametocytes, revealing a localization pattern similar to that of mature trophozoite-infected erythrocytes. These subcellular localization patterns are similar to those described for the ring-infected erythrocyte surface antigen.


Effect of the addition of chemotherapy to radiotherapy on cognitive function in patients with low-grade glioma: secondary analysis of RTOG 98-02.
The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival. A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini-Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5. Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms. The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.


Acceptability and feasibility of CyberSenga: an Internet-based HIV-prevention program for adolescents in Mbarara, Uganda.
Capitalizing on emerging data suggesting that HIV-preventive behaviors can be positively affected by Internet-based programs, we developed and tested CyberSenga, an Internet-based, comprehensive sexuality education program for adolescents in Mbarara, Uganda. Three hundred and sixty-six secondary school students were randomly assigned to either the five-lesson program (+ booster) or a treatment-as-usual control. At three-month follow-up, intervention participants provided feedback on the program acceptability. Six focus groups with intervention participants were additionally conducted after the final follow-up at 6 months. Data support a hypothesis of feasibility: despite schedule interruptions, 95% of intervention participants completed all the five modules; only 17% deviated from the once-a-week intended delivery schedule. Internet service was uninterrupted during the field period and, in general, the technology performed to specifications. The intervention also appears to be acceptable: 94% of intervention youth somewhat or strongly agreed that they learned a lot and 93% said they were somewhat or very likely to recommend the program. Although more than two in three youth somewhat or strongly agreed that the program talked too much about sex (70%) and condoms (75%), 89% somewhat or strongly disagreed that "I do not think kids like me should do the CyberSenga program." Feedback from focus group participants further suggested that the content was generally acceptable and did not contradict local norms in most cases. In fact, despite concerns from some local stakeholders to the contrary, information about condoms did not appear to be confusing or contradictory for youth who were abstinent. Nonetheless, some of the sexual topics seemed to be unfamiliar or uncomfortable for some participants - particularly brief references to oral and anal sex. Together, both qualitative and quantitative data suggest that the program is a feasible and acceptable way of delivering HIV preventive information to both sexually experienced and inexperienced adolescents in Mbarara, Uganda.


Radiobiological Assessment of Targeted Radionuclide Therapy with [177Lu]Lu-PSMA-I&T in 2D vs. 3D Cell Culture Models.
In vitro therapeutic efficacy studies are commonly conducted in cell monolayers. However, three-dimensional (3D) tumor spheroids are known to better represent in vivo tumors. This study used [177Lu]Lu-PSMA-I&T, an already clinically applied radiopharmaceutical for targeted radionuclide therapy against metastatic castrate-resistant prostate cancer, to demonstrate the differences in the radiobiological response between 2D and 3D cell culture models of the prostate cancer cell lines PC-3 (PSMA negative) and LNCaP (PSMA positive). After assessing the target expression in both models via Western Blot, cell viability, reproductive ability, and growth inhibition were assessed. To investigate the geometric effects on dosimetry for the 2D vs. 3D models, Monte Carlo simulations were performed. Our results showed that PSMA expression in LNCaP spheroids was highly preserved, and target specificity was shown in both models. In monolayers of LNCaP, no short-term (48 h after treatment), but only long-term (14 days after treatment) radiobiological effects were evident, showing decreased viability and reproductive ability with the increasing activity. Further, LNCaP spheroid growth was inhibited with the increasing activity. Overall, treatment efficacy was higher in LNCaP spheroids compared to monolayers, which can be explained by the difference in the resulting dose, among others.


In Vitro Effects of Chronic Spirolide Treatment on Human Neuronal Stem Cell Differentiation and Cholinergic System Development.
Spirolides (SPX) are marine toxins, produced by dinoflagellates that act as potent antagonists of nicotinic acetylcholine receptors. These compounds are not toxic for humans, and since there are no reports of human intoxications caused by this group of toxins they are not yet currently regulated in Europe. Currently 13-desmethyl spirolide C, 13,19-didesmethyl spirolide C, and 20-methyl spirolide G are commercially available as reference materials. Previous work in our laboratory has demonstrated that after 4 days of treatment of primary mice cortical neurons with 13-desmethyl spirolide C, the compound ameliorated the glutamate induced toxicity and increased acetylcholine levels and the expression of the acetylcholine synthesizing enzyme being useful both in vitro and in vivo to decrease the brain pathology associated with Alzheimer's disease. In this work, we aimed to extend the study of the neuronal effects of spirolides in human neuronal cells. To this end, human neuronal progenitor cells CTX0E16 were employed to evaluate the in vitro effect of spirolides on neuronal development. The results presented here indicate that long-term exposure (30 days) of human neuronal stem cells to SPX compounds, at concentrations up to 50 nM, ameliorated the MPP+-induced neurotoxicity and increased the expression of neuritic and dendritic markers, the levels of the choline acetyltransferase enzyme and the protein levels of the α7 subunit of nicotinic acetylcholine receptors. These effects are presumably due to the previously described interaction of these compounds with nicotinic receptors containing both α7 and α4 subunits. All together, these data emphasize the idea that SPX could be attractive lead molecules against neurodegenerative disorders.


Navigated tissue characterization during skin cancer surgery.
Basal cell carcinoma (BCC) is the most commonly diagnosed skin cancer and is treated by surgical resection. Incomplete tumor removal requires surgical revision, leading to significant healthcare costs and impaired cosmesis. We investigated the clinical feasibility of a surgical navigation system for BCC surgery, based on molecular tissue characterization using rapid evaporative ionization mass spectrometry (REIMS). REIMS enables direct tissue characterization by analysis of cell-specific molecules present within surgical smoke, produced during electrocautery tissue resection. A tissue characterization model was built by acquiring REIMS spectra of BCC, healthy skin and fat from ex vivo skin cancer specimens. This model was used for tissue characterization during navigated skin cancer surgery. Navigation was enabled by optical tracking and real-time visualization of the cautery relative to a contoured resection volume. The surgical smoke was aspirated into a mass spectrometer and directly analyzed with REIMS. Classified BCC was annotated at the real-time position of the cautery. Feasibility of the navigation system, and tissue classification accuracy for ex vivo and intraoperative surgery were evaluated. Fifty-four fresh excision specimens were used to build the ex vivo model of BCC, normal skin and fat, with 92% accuracy. While 3 surgeries were successfully navigated without breach of sterility, the intraoperative performance of the ex vivo model was low (< 50%). Hypotheses are: (1) the model was trained on heterogeneous mass spectra that did not originate from a single tissue type, (2) during surgery mixed tissue types were resected and thus presented to the model, and (3) the mass spectra were not validated by pathology. REIMS-navigated skin cancer surgery has the potential to detect and localize remaining tumor intraoperatively. Future work will be focused on improving our model by using a precise pencil cautery tip for burning localized tissue types, and having pathology-validated mass spectra.


Protection of chickens from infectious laryngotracheitis with a recombinant fowlpox virus expressing glycoprotein B of infectious laryngotracheitis virus.
Infectious laryngotracheitis (ILT) is an economically important disease of chickens caused by a type I gallid herpesvirus, infectious laryngotracheitis virus (ILTV). The vaccines currently available are modified live viruses, which are effective in preventing disease outbreaks. However, they have often been associated with a variety of adverse effects including spread of vaccine virus to non-vaccinates, inadequate attenuation, production of latently infected carriers, and increased virulence as a result of in vivo passage. In this study, a recombinant fowlpox virus expressing glycoprotein B (gB) of ILTV (rFPV-ILTVgB) was constructed. Protection of specific pathogen free (SPF) and commercial chickens from ILT with the rFPV-ILTVgB and commercial ILTV vaccine (Nobilis ILT) were compared after challenge with a lethal dose of virulent ILTV.Both the rFPV-ILTVgB- and the Nobilis ILT-vaccinated SPF chickens were completely protected from death, while 90% of the unvaccinated chickens died after challenge. The immunized commercial chickens were also 100% protected with rFPV-ILTVgB, compared with 85% protected with Nobilis ILT. The protective efficacy was also measured by the antibody response to ILTV gB, isolation of challenge virus and polymerase chain reaction amplification of the ILTV thymidine kinase gene after challenge. The results showed that rFPV-ILTVgB could be a potential safe vaccine to replace current modified live vaccines for preventing ILT.


Effect of co-aggregation on the pathogenicity of oral bacteria.
The pathogenicity of oral bacteria was studied by measuring the development of subcutaneous abscesses in mice after infection with Actinomyces viscosus and Streptococcus mitis either singly or as co-aggregated pairs. Heat-treated cells were also tested. The pathogenicity of the co-aggregates was examined in various viable and heat-treated combinations of the two bacterial species. More abscesses were formed by A. viscosus than S. mitis at all the bacterial concentrations tested. Also, abscess formation by co-aggregates of the two strains produced a higher percentage of abscess formation than those caused by infection with pure suspensions of A. viscosus or S. mitis. Co-aggregated cells were more resistant to phagocytosis and killing by neutrophils in vitro and in vivo. Furthermore, A. viscosus in co-aggregates were resistant to killing after engulfment by neutrophils. These results suggest that oral bacteria that are able to co-aggregate may resist phagocytosis, and this ability may be linked with pathogenicity.


Homicide Rates of Transgender Individuals in the United States: 2010-2014.
To estimate homicide rates of transgender US residents and relative risks (RRs) of homicide with respect to cisgender comparators intersected with age, gender, and race/ethnicity. I estimated homicide rates for transgender residents and transfeminine, Black, Latin@, and young (aged 15-34 years) subpopulations during the period 2010 to 2014 using Transgender Day of Remembrance and National Coalition of Anti-Violence Programs transgender homicide data. I used estimated transgender prevalences to estimate RRs using cisgender comparators. I performed a sensitivity analysis to situate all results within assumptions about underreporting of transgender homicides and assumptions about the prevalence of transgender residents. The overall homicide rate of transgender individuals was likely to be less than that of cisgender individuals, with 8 of 12 RR estimates below 1.0. However, the homicide rates of young transfeminine Black and Latina residents were almost certainly higher than were those of cisfeminine comparators, with all RR estimates above 1.0 for Blacks and all above 1.0 for Latinas. Antiviolence public health programs should identify young and Black or Latina transfeminine women as an especially vulnerable population.


Chondroblastic Variant of Osteosarcoma of Mandible: Report of a Rare Case.
Osteosarcoma (OS), a common malignant tumour of the long bones, is rarely seen in the craniofacial region (5-8%). Though it's aetiology is unknown, previous radiotherapy, Pagets disease, Retinoblastoma and benign bone lesions such as fibrous dysplasia are considered as predisposing factors. It is seen commonly in adults between the third and fourth decades of life, in the Gnathic location mandible. We report a rare case of chondroblastic variant of OS of the right mandible, in a 35-year-old male, who underwent right segmental mandibulectomy with fibular graft reconstruction and is having disease free survival one and half years post surgery. Craniofacial OSs, are considered a separate category in view of their low histologic grade, less frequent metastases and better prognosis. Hence the diagnosis of this variant is important. This case is reported because of its rarity and typical histopathological features.


Intracranial tuberculomas at the Kenyatta National Hospital, Nairobi.
To study the frequency, mode of presentation and outcome following treatment of intracranial tuberculomas. A retrospective study. Kenyatta National Hospital, from January 1985 to December 1995. Thirty patients with intracranial tuberculomas. The male:female ratio was 1:1.1. Sixty per cent of the patients were below the age of thirty years. Twenty per cent of the patients had concomitant extracranial tuberculosis of which fifty per cent was pulmonary. The average duration of symptoms at the time of diagnosis was seven months. Headache was the commonest symptom and occurred in 70% of the patients. Seizures were seen in 37% of the patients. Nine patients had a Mantoux test done and five were positive. Twelve patients underwent serological screening for the human immunodeficiency virus (HIV) and only one was positive. Common features seen in computerised tomography (CT) scan of the head were isodense and hyperdense mass lesion with ring enhancement in 38% of the cases, associated brain oedema and mass effect. Calcification and cystic changes were rare as were hypodense changes. All the patients received anti-tuberculosis therapy. Thirty three per cent of the patients made a full recovery, one patient became debilitated, two patients died while undergoing treatment, seven patients recovered with persistent neurological deficits and eight patients were lost to follow up. Intracranial tuberculomas constituted a large proportion of intracranial tumours at the Kenyatta National Hospital during the period under study.


Smoking in preeclamptic women is associated with higher birthweight for gestational age and lower soluble fms-like tyrosine kinase-1 levels: a nested case control study.
Smoking paradoxically increases the risk of small-for-gestational-age (SGA) birth but protects against preeclampsia. Some studies have reported a "U-shaped" distribution of fetal growth in preeclamptic pregnancies, but reasons for this are unknown. We investigated whether cigarette smoking interacts with preeclampsia to affect fetal growth, and compared levels of soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating anti-angiogenic protein, in preeclamptic smokers and non-smokers. From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia (cases) and 443 controls. Smoking exposure was assessed by self-report and maternal hair nicotine levels. Fetal growth was assessed as z-score of birthweight for gestational age (BWGA). sFlt-1 was measured in plasma samples collected at the 24-26-week visit. In linear regression, smoking and preeclampsia were each associated with lower BWGA z-scores (β = -0.29; p = 0.008, and β = -0.67; p < 0.0001), but positive interaction was observed between smoking and preeclampsia (β = +0.86; p = 0.0008) such that smoking decreased z-score by -0.29 in controls but increased it by +0.57 in preeclampsia cases. Results were robust to substituting log hair nicotine for self-reported smoking and after adjustment for confounding variables. Mean sFlt-1 levels were lower in cases with hair nicotine levels above vs. below the median (660.4 pg/ml vs. 903.5 pg/ml; p = 0.0054). Maternal smoking seems to protect against preeclampsia-associated fetal growth restriction and may account, at least partly, for the U-shaped pattern of fetal growth described in preeclamptic pregnancies. Smoking may exert this effect by reducing levels of the anti-angiogenic protein sFlt-1.


. . . On foster care International Society of Psychiatric-Mental Health Nurses.
Mental health problems are particularly widespread for foster children. There are approximately 700,000 youth in foster care and nonfamily settings in the United States. The mean entry age is 3 years. The average stay is 2 years. Experts estimate that between 30% and 85% of youngsters in out-of-home care have significant emotional disturbances. Foster care children represent 5% of Medicaid enrollees but use approximately 40% of Medicaid funds. A substantial number of these children have psychological problems so serious that they require residential placement. Adolescents living with foster parents or in group homes have about four times the rate of serious psychiatric disorders than those living with their own families (2009a). Despite this level of need, less than one-third of children in the child protective system are receiving mental health services (2009a). Child psychiatric nurse advocates from the Association of Child and Adolescent Psychiatric Nurses Division of the International Society of Psychiatric-Mental Health Nurses compiled this position statement for adoption by the Board of Directors as the Association's formal statement on the plight of children and adolescents in foster care. Areas that need to be addressed include (a) lack of consistent and comprehensive service planning; (b) communications across agencies and with the youth, their foster parents, and key stakeholders; (c) use of evidence-based interventions to prevent and reduce the incidence of disability; (d) education of child welfare case workers about mental and emotional therapeutic management; and (e) education of foster parents and youth about mental health issues and appropriate treatments.


[Food preferences of 10- to 14-year-old boys and girls].
To assess their food preferences a list of 114 foods and 14 beverages was submitted to a sample of 696 boys and 537 girls aged 10 to 14 years. For each item subjects had to rare by means of a five-point facial scale how much they liked or disliked it. Items with highest preference ratings were foods like pizza, ice cream, spaghetti, French fries, hamburgers, pudding, corn flakes, potato chips and popcorn, but also included the most common types of fruit. Disliked to a high degree were liver, canned or steamed fish, raw sauerkraut and red cabbage. In food groups derived by factor analysis, fast food, candy and salty snacks (along with fruit) showed highest mean liking, while vegetables (particularly cooked) ranked at the bottom of the scale. In boys significantly stronger preferences were found for food groups such as fast food, meats, cold cuts and fish, whereas girls had a (slightly) higher preference for fruit, vegetables and cheese. Neither children's age nor relative weight were related to their food preferences to a significant degree. Similarly, groups defined by father's educational level did not show important differences in their food preferences.


Retrograde transport of fluoro-gold in corticospinal and rubrospinal neurons 10 and 20 weeks after T-9 spinal cord transection.
Retrograde labeling with horseradish peroxidase is greatly diminished in corticospinal and rubrospinal neurons axotomized by complete T-9 spinal cord transection. We found, 10 or 20 weeks after a complete T-9 cord transection, that the number of corticospinal and rubrospinal neurons retrogradely labeled after Fluoro-Gold insertion into a new transection at T-1 did not differ from that of controls. While transection alters uptake, transport, and/or intracellular metabolism of some transportable substances, it does not affect the ability of the neurons to be retrogradely labeled with Fluoro-Gold.


Improved detection of aberrant splicing with FRASER 2.0 and the intron Jaccard index.
Detection of aberrantly spliced genes is an important step in RNA-seq-based rare-disease diagnostics. We recently developed FRASER, a denoising autoencoder-based method that outperformed alternative methods of detecting aberrant splicing. However, because FRASER's three splice metrics are partially redundant and tend to be sensitive to sequencing depth, we introduce here a more robust intron-excision metric, the intron Jaccard index, that combines the alternative donor, alternative acceptor, and intron-retention signal into a single value. Moreover, we optimized model parameters and filter cutoffs by using candidate rare-splice-disrupting variants as independent evidence. On 16,213 GTEx samples, our improved algorithm, FRASER 2.0, called typically 10 times fewer splicing outliers while increasing the proportion of candidate rare-splice-disrupting variants by 10-fold and substantially decreasing the effect of sequencing depth on the number of reported outliers. To lower the multiple-testing correction burden, we introduce an option to select the genes to be tested for each sample instead of a transcriptome-wide approach. This option can be particularly useful when prior information, such as candidate variants or genes, is available. Application on 303 rare-disease samples confirmed the relative reduction in the number of outlier calls for a slight loss of sensitivity; FRASER 2.0 recovered 22 out of 26 previously identified pathogenic splicing cases with default cutoffs and 24 when multiple-testing correction was limited to OMIM genes containing rare variants. Altogether, these methodological improvements contribute to more effective RNA-seq-based rare diagnostics by drastically reducing the amount of splicing outlier calls per sample at minimal loss of sensitivity.


Outcome of cartilage at 12years of follow-up after anterior cruciate ligament reconstruction.
In cases of chronic anterior laxity, reconstruction of the anterior cruciate ligament (ACL) can slow the development of osteoarthritis. This study was conducted to determine the overall prevalence of osteoarthritis and to identify the risk factors after ACL reconstruction. Meniscus tears, time from injury to surgery, body mass index (BMI), residual laxity, and cartilage lesions influence the progression towards osteoarthritis. This multicenter, retrospective study on the outcome of cruciate ligaments at 12 years of follow-up was conducted within the 2014 SOFCOT Symposium. The cohort included 675 arthroscopic reconstructions of the ACL from January 2002 to December 2003. The clinical evaluation included the objective and subjective IKDC score. Osteoarthritis was analyzed on 589 knee X-rays according to the IKDC classification. The predictive factors of osteoarthritis development studied were age, gender, BMI, time from injury to surgery, activity level, medial or lateral meniscectomy, type of graft, medial or lateral chondropathy, tunnel positioning, and residual laxity. Univariate and multivariate analyses with logistic regression were performed. The mean follow-up was 11.9±0.8 years. The subjective IKDC score was 83.7±13. At 12 years, the rate of moderate to severe osteoarthritis l (IKDCC or D) was 19% (16% medial tibiofemoral osteoarthritis, 4% lateral tibiofemoral osteoarthritis, and 2% patellofemoral osteoarthritis). The prognostic factors were age at surgery greater than 34 years (P<0.05), cartilage lesions at surgery (P<0.05), medial or lateral meniscectomy (P<0.05), and residual laxity (P<0.05). This large-scale study identified risk factors for osteoarthritis that should improve the information provided to patients on long-term progression after ACL reconstruction. Retrospective cohort study, level IV.


ASCENDING AORTIC ANEURYSM RESECTION EIGHT MONTHS AFTER TRIPLE CORONARY ARTERY BYPASS: CASE REPORT.
This report involves the surgical treatment of a patient who underwent saphenous vein triple coronary artery bypass and subsequently developed an ascending aortic aneurysm and aortic insufficiency. Although the implantation of vascular structures into synthetic grafts is commonplace, this case is unique in that it involves the successful implantation of an aortic island containing the origin of the coronary arteries.


Personal characteristics associated with handwashing behaviour among Japanese university students studying abroad: Prospective observational studies.
Hand hygiene is recommended to travellers to prevent common travel-related illnesses such as diarrhoea and respiratory infection. For effective hygiene promotion interventions, we aimed to identify the personal characteristics associated with handwashing behaviour. Prospective observational studies consisting of pre- and post-travel surveys were conducted among Japanese university students studying abroad between 2016 and 2018 (n = 825; 6-38 travel days). Associations of age, sex, study major, and overseas travel experience with handwashing behaviour (5-point scale) were evaluated using ordinal logistic regression models, with adjustment for destination, travel duration, and psychological factors (risk perception of diarrhoea and concern about hygiene). Among the participants in our analysis (n = 629), 28.0 % washed their hands before every meal while abroad. The male sex and no overseas travel experience were associated with decreased frequency of infrequent handwashing, even after adjusting for all potential confounding factors, whereas the study major was not associated. The adjusted odds ratios (95 % confidence intervals) were 0.74 (0.56-0.99) for men vs. women and 0.69 (0.52-0.93) for no overseas travel experience vs. overseas travel experience but not to the current destination. The lack of overseas travel experience correlated with handwashing frequency in both men and women. In addition to the travel destination, the male sex and no overseas travel experience should be highlighted in pretravel hand hygiene interventions.


Longitudinal observation of treatment patterns and outcomes for patients with fibromyalgia: 12-month findings from the reflections study.
To describe 12-month treatment patterns and outcomes for patients starting a new medication for fibromyalgia in routine clinical practice. Data from 1,700 patients were collected at baseline and 1, 3, 6, and 12 months. Repeated measures and Poisson regression models controlling for demographic, clinical, and baseline outcomes were used to assess changes in health outcomes (Brief Pain Inventory severity and interference, Sheehan Disability Scale, Fibromyalgia Impact Questionnaire), satisfaction, and economic factors for patients who initiated on pregabalin (214, 12.6%), duloxetine (264, 15.5%), milnacipran (134, 7.9%), or tricyclic antidepressants (66, 3.9%). Sensitivity analyses were run using propensity-matched cohorts. Patients started on 145 unique drugs for fibromyalgia, and over 75% of patients took two or more medications concurrently for fibromyalgia at each time point assessed. Overall, patients showed improvement on the four health outcomes, with few differences across medication cohorts. At baseline, patients reported annual averages of 20.3 visits for outpatient care, 27.7 missed days of work, and 32.6 days of care by an unpaid caregiver. The duloxetine and milnacipran (vs pregabalin or tricyclic antidepressant) cohorts had fewer outpatient visits during the 12-month study. Patients reported satisfaction with overall treatment and their fibromyalgia medication (46.0% and 42.8%, respectively). In this real-world setting, patients with fibromyalgia reported modest improvements, high resource, and medication use, and were satisfied with the care they received. Cohort differences were difficult to discern because of the high rates of drug discontinuation and concomitant medication use over the 12-month study period.


Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection.
The rate of disease progression among persons infected with human immunodeficiency virus type 1 (HIV-1) varies widely, and the relative prognostic value of markers of disease activity has not been defined. To compare clinical, serologic, cellular, and virologic markers for their ability to predict progression to the acquired immunodeficiency syndrome (AIDS) and death during a 10-year period. Prospective, multicenter cohort study. Four university-based clinical centers participating in the Multicenter AIDS Cohort Study. 1604 men infected with HIV-1. The markers compared were oral candidiasis (thrush) or fever; serum neopterin levels; serum beta 2-microglobulin levels; number and percentage of CD3+, CD4+, and CD8+ lymphocytes; and plasma viral load, which was measured as the concentration of HIV-1 RNA found using a sensitive branched-DNA signal-amplification assay. Plasma viral load was the single best predictor of progression to AIDS and death, followed (in order of predictive strength) by CD4+ lymphocyte count and serum neopterin levels, serum beta 2-microglobulin levels, and thrush or fever. Plasma viral load discriminated risk at all levels of CD4+ lymphocyte counts and predicted their subsequent rate of decline. Five risk categories were defined by plasma HIV-1 RNA concentrations: 500 copies/mL or less, 501 to 3000 copies/mL, 3001 to 10000 copies/mL, 10001 to 30000 copies/mL, and more than 30000 copies/mL. Highly significant (P < 0.001) differences in the percentages of participants who progressed to AIDS within 6 years were seen in the five risk categories: 5.4%, 16.6%, 31.7%, 55.2%, and 80.0%, respectively. Highly significant (P < 0.001) differences in the percentages of participants who died of AIDS within 6 years were also seen in the five risk categories: 0.9%, 6.3%, 18.1%, 34.9%, and 69.5%, respectively. A regression tree incorporating both HIV-1 RNA measurements and CD4+ lymphocyte counts provided better discrimination of outcome than did either marker alone; use of both variables defined categories of risk for AIDS within 6 years that ranged from less than 2% to 98%. Plasma viral load strongly predicts the rate of decrease in CD4+ lymphocyte count and progression to AIDS and death, but the prognosis of HIV-infected persons is more accurately defined by combined measurement of plasma HIV-1 RNA and CD4+ lymphocytes.


Extraordinary Magnetic Response of an Anisotropic 2D Antiferromagnet via Site Dilution.
A prominent characteristic of 2D magnetic systems is the enhanced spin fluctuations, which reduce the ordering temperature. We report that a magnetic field of only 1000th of the Heisenberg superexchange interaction can induce a crossover, which for practical purposes is the effective ordering transition, at temperatures about 6 times the Néel transition in a site-diluted two-dimensional anisotropic quantum antiferromagnet. Such a strong magnetic response is enabled because the system directly enters the antiferromagnetically ordered state from the isotropic disordered state, skipping the intermediate anisotropic stage. The underlying mechanism is achieved on a pseudospin-half square lattice realized in the [(SrIrO3)1/(SrTiO3)2] superlattice thin film that is designed to linearly couple the staggered magnetization to external magnetic fields by virtue of the rotational symmetry-preserving Dzyaloshinskii-Moriya interaction. Our model analysis shows that the skipping of the anisotropic regime despite finite anisotropy is due to the enhanced isotropic fluctuations under moderate dilution.


Microbial risk assessment framework for exposure to amended sludge projects.
Although the U.S. Environmental Protection Agency has a long history of using risk-based approaches for regulatory purposes, pollutant limits for pathogens in biosolids are not currently based on quantitative risk assessments. We developed and demonstrated a risk-based methodology for assessing the risk to human health from exposure to pathogens via biosolids. Four models were developed, incorporating direct ingestion, groundwater, and aerosol exposure pathways. Three sources of environmental data were used to estimate risk: pathogen monitoring of sludge, efficacy of sludge treatment, and pathogen monitoring of biosolids. Risk estimates were obtainable even for Class A biosolids, where posttreatment monitoring data are below detectable levels, demonstrating that risk assessments for biosolids exposure are practical. Model analyses suggest that: a) a two-digester design decreases the probability of risks >10(-4) compared with one-digester designs, b) risks associated with exposures to groundwater and aerosol pathways were, in general, lower than exposures to the direct ingestion pathway, and c) secondary transmission can be an important factor in risk estimation. The risk-based approach presented here provides a tool to a) help biosolids producers interpret the results of biosolids monitoring data in terms of its health implications, b) help treatment plant engineers evaluate the risk-based benefits of operational changes to existing or projected treatment processes, and c) help environmental managers evaluate potential capital improvements and/or land application site placement issues. Regulation of pathogens can now be based on human health risk in a manner parallel to other water-related risks.


Structure and dynamics of the membrane-bound form of Pf1 coat protein: implications of structural rearrangement for virus assembly.
The three-dimensional structure of the membrane-bound form of the major coat protein of Pf1 bacteriophage was determined in phospholipid bilayers using orientation restraints derived from both solid-state and solution NMR experiments. In contrast to previous structures determined solely in detergent micelles, the structure in bilayers contains information about the spatial arrangement of the protein within the membrane, and thus provides insights to the bacteriophage assembly process from membrane-inserted to bacteriophage-associated protein. Comparisons between the membrane-bound form of the coat protein and the previously determined structural form found in filamentous bacteriophage particles demonstrate that it undergoes a significant structural rearrangement during the membrane-mediated virus assembly process. The rotation of the transmembrane helix (Q16-A46) around its long axis changes dramatically (by 160 degrees) to obtain the proper alignment for packing in the virus particles. Furthermore, the N-terminal amphipathic helix (V2-G17) tilts away from the membrane surface and becomes parallel with the transmembrane helix to form one nearly continuous long helix. The spectra obtained in glass-aligned planar lipid bilayers, magnetically aligned lipid bilayers (bicelles), and isotropic lipid bicelles reflect the effects of backbone motions and enable the backbone dynamics of the N-terminal helix to be characterized. Only resonances from the mobile N-terminal helix and the C-terminus (A46) are observed in the solution NMR spectra of the protein in isotropic q > 1 bicelles, whereas only resonances from the immobile transmembrane helix are observed in the solid-state (1)H/(15)N-separated local field spectra in magnetically aligned bicelles. The N-terminal helix and the hinge that connects it to the transmembrane helix are significantly more dynamic than the rest of the protein, thus facilitating structural rearrangement during bacteriophage assembly.


Preference transitivity and symbolic representation in capuchin monkeys (Cebus apella).
Can non-human animals comprehend and employ symbols? The most convincing empirical evidence comes from language-trained apes, but little is known about this ability in monkeys. Tokens can be regarded as symbols since they are inherently non-valuable objects that acquire an arbitrarily assigned value upon exchange with an experimenter. Recent evidence suggested that capuchin monkeys, which diverged from the human lineage 35 million years ago, can estimate, represent and combine token quantities. A fundamental and open question is whether monkeys can reason about symbols in ways similar to how they reason about real objects. Here we examined this broad question in the context of economic choice behavior. Specifically, we assessed whether, in a symbolic context, capuchins' preferences satisfy transitivity--a fundamental trait of rational decision-making. Given three options A, B and C, transitivity holds true if A > or = B, B > or = C and A > or = C (where > or = indicates preference). In this study, we trained monkeys to exchange three types of tokens for three different foods. We then compared choices monkeys made between different types of tokens with choices monkeys made between the foods. Qualitatively, capuchins' preferences revealed by the way of tokens were similar to those measured with the actual foods. In particular, when choosing between tokens, monkeys displayed strict economic preferences and their choices satisfied transitivity. Quantitatively, however, values measured by the way of tokens differed systematically from those measured with the actual foods. In particular, for any pair of foods, the relative value of the preferred food increased when monkeys chose between the corresponding tokens. These results indicate that indeed capuchins are capable of treating tokens as symbols. However, as they do so, capuchins experience the cognitive burdens imposed by symbolic representation.


Microarray-based survey of repetitive genomic sequences in Vicia spp.
A modified DNA microarray-based technique was devised for preliminary screening of short fragment genomic DNA libraries from three Vicia species (V. melanops, V. narbonensis, and V. sativa) to isolate representative highly abundant DNA sequences that show different distribution patterns among related legume species. The microarrays were sequentially hybridized with labeled genomic DNAs of thirteen Vicia and seven other Fabaceae species and scored for hybridization signals of individual clones. The clones were then assigned to one of the following groups characterized by hybridization to: (1) all tested species, (2) most of the Vicia and Pisum species, (3) only a few Vicia species, and (4) preferentially a single Vicia species. Several clones from each group, 65 in total, were sequenced. All Group I clones were identified as rDNA genes or fragments of chloroplast genome, whereas the majority of Group II clones showed significant homologies to retroelement sequences. Clones in Groups III and IV contained novel dispersed repeats with copy numbers 10(2)-10(6)/1C and two genus-specific tandem repeats. One of these belongs to the VicTR-B repeat family, and the other clone (S12) contains an amplified portion of the rDNA intergenic spacer. In situ hybridization using V. sativa metaphase chromosomes revealed the presence of the S12 sequences not only within rDNA genes, but also at several additional loci. The newly identified repeats, as well as the retroelement-like sequences, were characterized with respect to their abundance within individual genomes. Correlations between the repeat distributions and the current taxonomic classification of these species are discussed.


A failure to find socially mediated taste aversion learning in Norway rats (R. norvegicus).
Observer rats interacted with conspecific demonstrators immediately after demonstrators ate a novel diet and were made ill by LiCl injection. Following their interaction with demonstrators, observers were tested for aversion to their ill demonstrator's diet. Previous research has shown that (a) an observer can extract information from a demonstrator sufficient to permit identification of the demonstrator's diet (Galef & Wigmore, 1983) and (b) a rat ill from LiCl toxicosis is an adequate unconditioned stimulus in a taste aversion learning paradigm (Lavin, Freise, & Coombes, 1980). Further, two of the present experiments demonstrated that cues emitted by a rat, reflecting the particular diet it has eaten, are an adequate conditional stimulus in a toxicosis-induced aversion learning situation. Observer avoidance of a diet previously ingested by an ill demonstrator was, however, not demonstrated. The implications of the failure to find socially mediated aversion learning are discussed.


Sexually transmitted diseases: an epidemic in adolescent girls?
The prevalence of sexually transmitted disease (STD) in adolescent girls aged 15-19 attending a department of genitourinary medicine was compared for the years 1972 and 1982. Data were obtained from the confidential register using the coding of the clinic returns to the Department of Health (form SBH 60). There were 1373 patients in 1972 and 1799 in 1982, 6.4% and 7% respectively of the total female clinic population. The prevalence of syphilis, gonorrhoea, and infection with Trichomonas vaginalis, herpes simplex virus, and warts was almost unchanged. Other conditions, which are not classified as STD, were largely responsible for the increase in new attendances, the prevalence of these conditions having nearly doubled over the ten year period. Thus an epidemic of STD has not been shown in this adolescent female population over the past decade.


Sex and Racial Disparities in the Treatment and Outcomes of Muscle-invasive Bladder Cancer.
To identify racial and sex disparities in the treatment and outcomes of muscle-invasive bladder cancer (MIBC) using a nationwide oncology outcomes database. Using the National Cancer Database, we identified patients with muscle invasive bladder cancer from 2004 to 2014. Treatments analyzed included no treatment, cystectomy, neoadjuvant chemotherapy plus cystectomy ("optimal treatment"), cystectomy plus adjuvant chemotherapy, and chemoradiation. Propensity matching compared mortality outcomes between sexes. Logistic models evaluated predictors of receiving optimal treatment, as well as mortality. Forty seven thousand two hundred and twenty nine patients were identified. Most patients were male (73.4%) and underwent cystectomy alone (69.0%). Propensity score matching demonstrated increased 90-day mortality in women vs men (13.0% vs 11.6%, P = .009), despite adjusting for differences in treatments between sexes. Logistic regression models showed no difference in receipt of optimal treatment between sexes (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.83-1.22) although black patients were less likely to receive optimal treatment (OR 0.15, 95% CI 0.05-0.48). Logistic regression models confirmed increased 90-day mortality in female (OR 1.17, CI 1.08-1.27, P < .001) and black (OR 1.29, CI 1.11-1.50, P = .001) patients. Females had a lower overall survival on Cox regression analysis (Hazard Ratio 0.92, 95% CI 0.87-0.97). While there do not appear to be significant treatment disparities between sexes, women experience higher 90-day mortality and lower overall survival. Black patients are less likely to receive optimal treatment and have a higher risk of 90-day mortality. Additional research is needed to determine the variables leading to worse outcomes in females and identify impediments to black patients receiving optimal treatment.


The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis.
An isoleucine>methionine mutation at position 148 in the PNPLA3 gene (p.I148M, rs738409) has recently been identified as a susceptibility factor for liver damage in steatohepatitis. Here, we studied whether the PNPLA3 rs738409 polymorphism also affects predisposition to hepatocellular carcinoma (HCC). We compared distributions of PNPLA3 genotypes in 80 and 81 Caucasian patients with alcoholic and hepatitis C virus (HCV)-associated HCC to 80 and 81 age- and sex-matched patients with alcohol-related and HCV-related cirrhosis without HCC, respectively. PNPLA3 genotypes in 190 healthy individuals from the same population served as reference. Potential confounders obesity, diabetes, HCV genotype and HBV co-infection were controlled by univariate and multivariate logistic regression with forward variable selection. PNPLA3 genotypes were in Hardy-Weinberg equilibrium for all study groups. The frequency of the 148M allele was significantly (p<0.001) increased in alcoholic cirrhosis with (53.7%) and without HCC (36.2%) but was not different between healthy controls (22.9%) and patients with cirrhosis (25.3%; p = 0.545) and HCC (30.2%; p = 0.071) due to hepatitis C. HCC risk was highest in 148M/M homozygous patients with alcoholic liver disease (odds ratio (OR) 16.8 versus healthy controls; 95% confidence interval (CI) 6.68-42.43, p<0.001). Finally, multivariate regression confirmed 148M/M homozygosity (OR 2.8; 95%-CI: 1.24-6.42; p = 0.013) as HCC risk factor in alcoholic cirrhosis. In HCV-related cirrhosis only HCV genotype 1 was confirmed as a HCC risk factor (OR 4.2; 95%-CI: 1.50-11.52; p = 0.006). The PNPLA3 148M variant is a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects are negligible in patients with cirrhosis due to HCV. This polymorphism provides an useful tool to identify individuals with particularly high HCC risk in patients with alcoholic liver disease that should be taken into account in future HCC prevention studies.


Characteristics of interneurons in the ocellar system of the honeybee.
Intracellular recording and staining has revealed new aspects of the anatomy and physiology of ocellar interneurons in the honeybee (Apis mellifera). Homologous large first-order interneurons (L-neurons) from different individuals vary in structure as well as in their response to light. Even the response patterns of one type of L-neuron may present a continuum from graded responses to spiking responses. The response depends on the state of the L-neuron and cannot be correlated with particular morphological types. Graded responses are unimodal and can be elicited exclusively by stationary illumination of the ocelli, whereas spiking L-neurons can also respond to stimuli of other sensory modalities. Recordings from the same type of multimodal spiking L-neuron in different individuals demonstrate considerable variation in responses to different modalities. The existence of two response patterns in the same cell that can encode different information may be of general importance with respect to the processing of information in the brain. There appears to be a variety of different pathways enabling interaction of ocellar and compound eye signals either by direct contact between ocellar and optic lobe neurons or by convergence of the two pathways to a common descending or local interneuron. Two examples are discussed: an ocellar small first-order interneuron (S-neuron) that project directly to the optic lobes and a local interneuron that is situated in the posterior midbrain close to situated in the posterior midbrain close to ocellar terminals and optic lobe outputs and that responds to stimulation of both visual systems.(ABSTRACT TRUNCATED AT 250 WORDS)


Preschoolers' sleep behaviour: associations with parental hardiness, sleep-related cognitions and bedtime interactions.
Childhood sleep problems which are prevalent in Western societies are associated with a wide range of emotional, cognitive and behavioural disturbances. Growing evidence suggests that parents play a pivotal role in children's sleep behaviour and that a parenting style which promotes self-regulation is beneficial. This study tested a unique model that included parental hardiness, sleep-related cognitions, bedtime interactions and child sleep behaviour. Parents (N = 110) with a child attending preschool (mean age = 3.81 years, SD = .84) responded to a survey assessing their level of hardiness, sleep-related cognitions, bedtime interactions and their child's sleep behaviour and temperament. Secondary caregivers completed a survey assessing child sleep and temperament, and teachers/childcare workers also reported on child temperament. In line with previous research, 37% of children in this community sample met criteria for a sleep problem. Regression analyses and structural equation modelling confirmed that low parental hardiness, problematic sleep-related cognitions and a greater number of parental interactions at bedtime significantly predicted child sleep problems, after considering child temperament. This study's theoretically driven model not only offers an explanation for what contributes to and maintains sleep problems in childhood but also suggests new areas for research. Importantly, the model can also be readily translated into clinical interventions to develop and enhance effective authoritative parenting.


Three-dimensional vertebral motions produced by mechanical force spinal manipulation.
The aim of this study was to quantify and compare the 3-dimensional intersegmental motion responses produced by 3 commonly used chiropractic adjusting instruments. Six adolescent Merino sheep were examined at the Institute for Medical and Veterinary Science, Adelaide, Australia. In all animals, triaxial accelerometers were attached to intraosseous pins rigidly fixed to the L1 and L2 spinous processes under fluoroscopic guidance. Three handheld mechanical force chiropractic adjusting instruments (Chiropractic Adjusting Tool [CAT], Activator Adjusting Instrument IV [Activator IV], and the Impulse Adjusting Instrument [Impulse]) were used to randomly apply posteroanterior (PA) spinal manipulative thrusts to the spinous process of T12. Three force settings (low, medium, and high) and a fourth setting (Activator IV only) were applied in a randomized repeated measures design. Acceleration responses in adjacent segments (L1 and L2) were recorded at 5 kHz. The multiaxial intersegmental (L1-L2) acceleration and displacement response at each force setting was computed and compared among the 3 devices using a repeated measures analysis of variance (alpha = .05). For all devices, intersegmental motion responses were greatest for axial, followed by PA and medial-lateral (ML) measurement axes for the data examined. Displacements ranged from 0.11 mm (ML axis, Activator IV low setting) to 1.76 mm (PA axis, Impulse high setting). Compared with the mechanical (spring) adjusting instruments (CAT, Activator IV), the electromechanical Impulse produced the most linear increase in both force and intersegmental motion response and resulted in the greatest acceleration and displacement responses (high setting). Significantly larger magnitude intersegmental motion responses were observed for Activator IV vs CAT at the medium and high settings (P < .05). Significantly larger-magnitude PA intersegmental acceleration and displacement responses were consistently observed for Impulse compared with Activator IV and CAT for the high force setting (P < .05). Larger-magnitude, 3D intersegmental displacement and acceleration responses were observed for spinal manipulative thrusts delivered with Impulse at most force settings and always at the high force setting. Our results indicate that the force-time characteristics of impulsive-type adjusting instruments significantly affects spinal motion and suggests that instruments can and should be tuned to provide optimal force delivery.


The inhibitory effect of Isoliquiritigenin on the proliferation of human arterial smooth muscle cell.
Isoliquiritigenin (ISL) has various biological activities including as antioxidant and an inhibitor of PI3K/AKT signaling pathway. However, both oxidative stress and activated PI3K/AKT signaling contribute to the aberrant proliferation of vascular smooth muscle cells (VSMCs). This study is aimed to explore the effect of ISL on the proliferation of human arterial smooth muscle cells (HASMCs) and to investigate the underlying mechanisms. BrdU incorporation, cell cycle and reactive oxygen species (ROS) in normal or ISL treated HASMCs were analyzed by flow cytometry. Cell viablity was measured by CCK-8. Protein expression levels were examined by Western blot, and superoxide dismutase (SOD) activity was detected by using commercial kit. We observed that ISL could inhibit the proliferation of HASMCs in a dose and time dependent manner. Cell cycle of ISL treated HASMCs arrested mainly in G1/S phase and accompanied with elevated expression of p27 and decreased expression of CyclinD1 and CyclinE. In addition, ISL could down-regulated the expression of p-PI3K and p-AKT, alleviated oxidative stress and enhanced the SOD activity in HASMCs. Furthermore, H2O2 treatment partly improved cell viability and up regulated p-PI3K and p-AKT in HASMCs. Therefore, we concluded that ISL inhibited the proliferation of HASMCs via attenuating oxidative stress and suppressing PI3K/AKT signaling pathway. The inhibitory effect of ISL on PI3K/AKT signaling pathway, at least partly, was mediated by ROS.


All-trans-retinoic acid inhibits chondrogenesis of rat embryo hindlimb bud mesenchymal cells by downregulating p53 expression.
Despite the well-established role of all-trans-retinoic acid (ATRA) in congenital clubfoot (CCF)-like deformities in in vivo models, the essential cellular and molecular targets and the signaling mechanisms for ATRA-induced CCF-like deformities remain to be elucidated. Recent studies have demonstrated that p53 and p21, expressed in the hindlimb bud mesenchyme, regulate cellular proliferation and differentiation, contributing to a significant proportion of embryonic CCF-like abnormalities. The objective of the present study was to investigate the mechanisms for ATRA-induced CCF, by assessing ATRA-regulated chondrogenesis in rat embryo hindlimb bud mesenchymal cells (rEHBMCs) in vitro. The experimental study was based on varying concentrations of ATRA exposure on embryonic day 12.5 rEHBMCs in vitro. The present study demonstrated that ATRA inhibited the proliferation of cells by stimulating apoptotic cell death of rEHBMCs. It was also observed that ATRA induced a dose-dependent reduction of cartilage nodules compared with the control group. Reverse transcription-polymerase chain reaction and western blotting assays revealed that the mRNA and protein expression of cartilage-specific molecules, including aggrecan, Sox9 and collagen, type II, α 1 (Col2a1), were downregulated by ATRA in a dose-dependent manner; the mRNA levels of p53 and p21 were dose-dependently upregulated from 16 to 20 h of incubation with ATRA, but dose-dependently downregulated from 24 to 48 h. Of note, p53 and p21 were regulated at the translational level in parallel with the transcription with rEHBMCs treated with ATRA. Furthermore, the immunofluorescent microscopy assays indicated that proteins of p53 and p21 were predominantly expressed in the cartilage nodules. The present study demonstrated that ATRA decreases the chondrogenesis of rEHBMCs by inhibiting cartilage-specific molecules, including aggrecan, Sox9 and Col2al, via regulating the expression of p53 and p21.


Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset.
New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.


Quantification and Tissue Localization of Selenium in Rice (Oryza sativa L., Poaceae) Grains: A Perspective of Agronomic Biofortification.
In worldwide production, rice is the second-most-grown crop. It is considered a staple food for many populations and, if naturally enriched in Se, has a huge potential to reduce nutrient deficiencies in foodstuff for human consumption. This study aimed to develop an agronomic itinerary for Se biofortification of Oryza sativa L. (Poaceae) and assess potential physicochemical deviations. Trials were implemented in rice paddy field with known soil and water characteristics and two genotypes resulting from genetic breeding (OP1505 and OP1509) were selected for evaluation. Plants were sprayed at booting, anthesis and milky grain phases with two different foliar fertilizers (sodium selenate and sodium selenite) at different concentrations (25, 50, 75 and 100 g Se·ha-1). After grain harvesting, the application of selenate showed 4.9-7.1 fold increases, whereas selenite increased 5.9-8.4-fold in OP1509 and OP1505, respectively. In brown grain, it was found that in the highest treatment selenate or selenite triggered much higher Se accumulation in OP1505 relatively to OP1509, and that no relevant variation was found with selenate or selenite spraying in each genotype. Total protein increased exponentially in OP1505 genotype when selenite was applied, and higher dosage of Se also increased grain weight and total protein content. It was concluded that, through agronomic biofortification, rice grain can be enriched with Se without impairing its quality, thus highlighting its value in general for the industry and consumers with special needs.


Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia.
Comprehensive data were reported to the International Bone Marrow Transplant Registry by 24 worldwide teams regarding 144 patients with severe aplastic anemia who were treated with HLA-identical, allogeneic bone marrow transplantation between 1975 and 1978. One hundred fourteen patients received one transplant and 30 received two. Sustained engraftment of donor marrow occurred on the first transplant attempt in 76% of the patients whose engraftment status could be evaluated. Moderate, severe, or lethal graft-vs-host disease (GVHD) occurred in 52% of the engrafted patients. The one-year survival rate for all patients was 44% (64/144). Among the one-year survivors, the primary disease was apparently cured in 90% and improved in 10%. Thus far, four patients died one to five years after transplant. Of the 60 patients currently alive, ten have chronic GVHD and the remainder are in good health. Multivariate analyses of the data disclosed a number of pretransplant factors associated with engraftment, GVHD, and one-year survival. The most important finding was that the use of male donors was preferable to female donors because of a higher rate of engraftment, less severe GVHD, and a higher one-year survival rate.


Immunotherapy for non-muscle-invasive bladder cancer: from the origins of BCG to novel therapies.
Supplies of intravesical Bacillus Calmette-Guérin (BCG), the first-line treatment for most intermediate- and high-risk non-muscle-invasive bladder cancers (NMIBC), have proven unreliable over the past decade. This review considers the evolution of BCG immunotherapy for NMIBC: from the discovery of the antitumour side effects of tuberculosis and subsequently the BCG vaccine, to recent advances in novel immunotherapeutic agents. We summarize the evidence for alternative options to standard intravesical BCG therapy regimens and describe the potential for immune response manipulating drugs in the treatment of NMIBC. These new agents, including immune checkpoint inhibitors, toll-like receptor agonists and recombinant viral vectors, may provide better options in the management of NMIBC in the future.


Juvenile and adult congenital heart disease: time-resolved 3D contrast-enhanced MR angiography.
To assess the incremental diagnostic value of time-resolved three-dimensional (3D) magnetic resonance (MR) angiography over single-phase 3D MR angiography and cine MR imaging in juvenile and adult patients with congenital heart disease (CHD). The study was HIPAA compliant and was approved by the institutional review board. Written informed consent was obtained from each patient. Eighty-one consecutive patients (46 male and 35 female patients; mean age, 31.1 years +/- 13.5 [standard deviation]) with CHD were examined with a 1.5-T MR imaging unit. The imaging protocol comprised time-resolved MR angiography (repetition time msec/echo time msec, 2.01/0.81) after injection of 0.03 mmol gadodiamide per kilogram of body weight at 4 mL/sec and single-phase high-spatial-resolution MR angiography (2.87/0.97) after injection of 0.15 mmol/kg gadodiamide at 1.5 mL/sec. After review of the time-resolved and conventional MR angiographic data sets, each of two independent observers listed the additional clinical information gained from time-resolved MR angiographic data. A Wilcoxon signed rank test was used to test for statistical differences between the image quality ratings of the two observers. Time-resolved and single-phase high-spatial-resolution MR angiography yielded diagnostic image data in all patients. Observers 1 and 2 found functional information in time-resolved MR angiographic series in 52 and 51 patients, respectively, that was not seen at high-spatial-resolution MR angiography. Intra- and extracardiac shunts, respectively, were exclusively depicted by time-resolved MR angiography for observer 1 in 18 and two patients and for observer 2 in 15 and two patients. However, both observers reported higher confidence in the assessment of such smaller vascular structures as supraaortic vessels (in 12 patients for observer 1 and 11 patients for observer 2) and major aortopulmonary collateral arteries (in eight patients for observer 1 and 10 patients for observer 2) at high-spatial-resolution MR angiography. No significant difference was evident in image quality scoring between the two observers (P = .32 for time-resolved and P = .47 for conventional MR angiography). Compared with conventional MR angiography, time-resolved MR angiography yields clinically relevant information in a substantial number of patients; hence, the two techniques should be regarded as complementary.


A symmetry interaction approach to [M2L2]4+ metallocycles and their self-catenation.
Dinuclear [M2L2]n+ (M = Pd2+ or Pt2+) metallo-rectangles have a rich history, particularly in molecular recognition, including self-catenation events. These structures are mostly generated via a ligand-directed approach with cis-capped M2+ corners. We report here a symmetry interaction approach using 3 : 1 complementary denticity, giving a new route to [M2L2]4+ rectangles and their self-catenation.


Non-invasive biomonitoring of organic pollutants using feather samples in feral pigeons (Columba livia domestica).
A large portion of organic pollutants (OPs) represent a potential hazard to humans and living beings due to their toxic properties. For several years, birds have been used as biomonitor species of environmental pollution. Polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated biphenyl ethers (PBDEs), organophosphate pesticides (OPPs), polycyclic aromatic hydrocarbons (PAHs) and pyrethroids (PYRs) were assessed in body feather samples of 71 feral pigeons (Columba livia domestica) collected from Asturias and Galicia (NW Spain). The percentage of detection for all chemical groups were above 90% in studied birds. The general pattern was dominated by PAHs (mean value ± standard deviation (SD) 32 ± 15 ng/g) followed by OCPs (3.8 ± 1.1 ng/g), PYRs (3.4 ± 3.8 ng/g), PCBs (1.6 ± 1.0 ng/g), OPPs (1.3 ± 0.70 ng/g) and PBDEs (0.80 ± 0.30 ng/g). Significant differences were observed between age, location and gender suggesting different sources of exposure and accumulation pathways.


Combined use of extensively porous coated femoral components with onlay cortical strut allografts in revision of Vancouver B2 and B3 periprosthetic femoral fractures.
Periprosthetic femoral fractures following total hip arthroplasty are getting more prevalent. The aim of this study was to evaluate the clinical results of combined use of uncemented extensively porous coated femoral components with onlay cortical strut allografts in revision of Vancouver type B2 and B3 periprosthetic femoral fractures. Thirteen hips after total hip arthroplasty in 13 patients who suffered a Vancouver B2 or B3 periprosthetic fracture were treated with an uncemented extensively porous coated femoral component combined with onlay cortical strut allografts. Each patient was assigned a Harris hip score, and a visual analog scale (VAS) score for pain and satisfaction. Radiographs were examined for component stability, fracture site and allograft-host union and allograft reconstruction. At an average of 5.3-year follow-up, no patient required repeat revision. The average Harris hip score was (71.8 +/- 6.3) points, the pain VAS score was (16.6 +/- 4.3) points, and the patient satisfaction VAS score was (81.5 +/- 5.7) points. Radiographic examination showed no detectable loosening of the prostheses, and 12 cases were presented fixation by osseointegration and the other one was stable fibrous ingrown fixation. All fractures united for (5.2 +/- 1.4) months in average. And all onlay strut allografts united to host bone for about (11.5 +/- 2.6) months. Combined use of uncemented, long stemmed, extensively porous coated implant with cortical onlay strut allografts can achieve good clinic results and high rate of union for both fracture site and allograft-host bone junction. This technique could be used routinely to augment fixation and healing of Vancouver B2 and B3 periprosthetic fractures.


A glycated whey protein isolate-epigallocatechin gallate nanocomplex enhances the stability of emulsion delivery of β-carotene during simulated digestion.
A glycated whey protein isolate-epigallocatechin gallate (EGCG) nanocomplex-stabilized emulsion was used to encapsulate β-carotene. This study evaluated the stability of the emulsion in different environments and assessed its protective effect on β-carotene. The active compound-loaded emulsion was subjected to in vitro simulated digestion. The results show that the glycated whey protein isolate-EGCG nanocomplex-stabilized emulsion has greater storage, salt ion, and thermal stability than the whey protein isolate-EGCG nanocomplex. Moreover, the emulsion exerts a considerable inhibitory effect on the degradation of the active compounds. However, the strong hydrolysis of the protein by pancreatin prevents the emulsion from surviving in the intestinal fluid, and the speed and degree of lipolysis is faster and more intense than that of naked medium-chain triglyceride (MCT). This study provides useful information for the application of natural hydrophobic active ingredients to water-soluble edible protein emulsion systems in food and drug delivery.


A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice.
Previously we found that the amino-terminal region of the NS1 protein of influenza A virus plays a key role in preventing the induction of beta interferon (IFN-beta) in virus-infected cells. This region is characterized by its ability to bind to different RNA species, including double-stranded RNA (dsRNA), a known potent inducer of IFNs. In order to investigate whether the NS1 RNA-binding activity is required for its IFN antagonist properties, we have generated a recombinant influenza A virus which expresses a mutant NS1 protein defective in dsRNA binding. For this purpose, we substituted alanines for two basic amino acids within NS1 (R38 and K41) that were previously found to be required for RNA binding. Cells infected with the resulting recombinant virus showed increased IFN-beta production, demonstrating that these two amino acids play a critical role in the inhibition of IFN production by the NS1 protein during viral infection. In addition, this virus grew to lower titers than wild-type virus in MDCK cells, and it was attenuated in mice. Interestingly, passaging in MDCK cells resulted in the selection of a mutant virus containing a third mutation at amino acid residue 42 of the NS1 protein (S42G). This mutation did not result in a gain in dsRNA-binding activity by the NS1 protein, as measured by an in vitro assay. Nevertheless, the NS1 R38AK41AS42G mutant virus was able to replicate in MDCK cells to titers close to those of wild-type virus. This mutant virus had intermediate virulence in mice, between those of the wild-type and parental NS1 R38AK41A viruses. These results suggest not only that the IFN antagonist properties of the NS1 protein depend on its ability to bind dsRNA but also that they can be modulated by amino acid residues not involved in RNA binding.