High retention and safety of percutaneously implanted endovascular embolization coils as fiducial markers for image-guided stereotactic ablative radiotherapy of pulmonary tumors.
To compare the retention rates of two types of implanted fiducial markers for stereotactic ablative radiotherapy (SABR) of pulmonary tumors, smooth cylindrical gold "seed" markers ("seeds") and platinum endovascular embolization coils ("coils"), and to compare the complication rates associated with the respective implantation procedures. We retrospectively analyzed the retention of percutaneously implanted markers in 54 consecutive patients between January 2004 and June 2009. A total of 270 markers (129 seeds, 141 coils) were implanted in or around 60 pulmonary tumors over 59 procedures. Markers were implanted using a percutaneous approach under computed tomography (CT) guidance. Postimplantation and follow-up imaging studies were analyzed to score marker retention relative to the number of markers implanted. Markers remaining near the tumor were scored as retained. Markers in a distant location (e.g., pleural space) were scored as lost. CT imaging artifacts near markers were quantified on radiation therapy planning scans. Immediately after implantation, 140 of 141 coils (99.3%) were retained, compared to 110 of 129 seeds (85.3%); the difference was highly significant (p<0.0001). Of the total number of lost markers, 45% were reported lost during implantation, but 55% were lost immediately afterwards. No additional markers were lost on longer-term follow-up. Implanted lesions were peripherally located for both seeds (mean distance, 0.33 cm from pleural surface) and coils (0.34 cm) (p=0.96). Incidences of all pneumothorax (including asymptomatic) and pneumothorax requiring chest tube placement were lower in implantation of coils (23% and 3%, respectively) vs. seeds (54% and 29%, respectively; p=0.02 and 0.01). The degree of CT artifact was similar between marker types. Retention of CT-guided percutaneously implanted coils is significantly better than that of seed markers. Furthermore, implanting coils is at least as safe as implanting seeds. Using coils should permit implantation of fewer markers and require fewer repeat implantation procedures owing to lost markers.


pfs-dependent regulation of autoinducer 2 production in Salmonella enterica serovar Typhimurium.
Bacterial intercellular communication provides a mechanism for signal-dependent regulation of gene expression to promote coordinated population behavior. Salmonella enterica serovar Typhimurium produces a non-homoserine lactone autoinducer in exponential phase as detected by a Vibrio harveyi reporter assay for autoinducer 2 (AI-2) (M. G. Surette and B. L. Bassler, Proc. Natl. Acad. Sci. USA 95:7046-7050, 1998). The luxS gene product mediates the production of AI-2 (M. G. Surette, M. B. Miller, and B. L. Bassler, Proc. Natl. Acad. Sci. USA 96:1639-1644, 1999). Environmental cues such as rapid growth, the presence of preferred carbon sources, low pH, and/or high osmolarity were found to influence the production of AI-2 (M. G. Surette and B. L. Bassler, Mol. Microbiol. 31:585-595, 1999). In addition to LuxS, the pfs gene product (Pfs) is required for AI-2 production, as well as S-adenosylhomocysteine (SAH) (S. Schauder, K. Shokat, M. G. Surette, and B. L. Bassler, Mol. Microbiol. 41:463-476, 2001). In bacterial cells, Pfs exhibits both 5'-methylthioadenosine (MTA) and SAH nucleosidase functions. Pfs is involved in methionine metabolism, regulating intracellular MTA and SAH levels (elevated levels of MTA and SAH are potent inhibitors of polyamine synthetases and S-adenosylmethionine dependent methyltransferase reactions, respectively). To further investigate regulation of AI-2 production in Salmonella, we constructed pfs and luxS promoter fusions to a luxCDABE reporter in a low-copy-number vector, allowing an examination of transcription of the genes in the pathway for signal synthesis. Here we report that luxS expression is constitutive but that the transcription of pfs is tightly correlated to AI-2 production in Salmonella serovar Typhimurium 14028. Neither luxS nor pfs expression appears to be regulated by AI-2. These results suggest that AI-2 production is regulated at the level of LuxS substrate availability and not at the level of luxS expression. Our results indicate that AI-2-dependent signaling is a reflection of metabolic state of the cell and not cell density.


Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis.
Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health burden despite many therapeutic interventions. Inhaled corticosteroids (IC) may be a safe and effective therapy. To assess the safety and efficacy of IC for prevention or treatment of BPD or death in preterm infants. PubMed, the Cochrane Library, Embase, and CINAHL from their inception until November 2015 together with other relevant sources. Randomized controlled trials of ICs versus placebo for either prevention or treatment of BPD. This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Thirty-eight trials were identified, and 16 met inclusion criteria. ICs were associated with a significant reduction in death or BPD at 36 weeks' postmenstrual age (risk ratio [RR] = 0.86, 95% confidence interval [CI] 0.75 to 0.99, I2 = 0%, P = .03; 6 trials, n = 1285). BPD was significantly reduced (RR = 0.77, 95% CI 0.65 to 0.91, I2 = 0%, 7 trials, n = 1168), although there was no effect on death (RR = 0.97, 95% CI 0.42 to 2.2, I2 = 50%, 7 trials, n = 1270). No difference was found for death or BPD at 28 days' postnatal age. The use of systemic steroids was significantly reduced in treated infants (13 trials, n = 1537, RR = 0.87, 95% CI 0.76 to 0.98 I2 = 3%,). No significant differences were found in neonatal morbidities and other adverse events. Long-term follow-up data are awaited from a recent large randomized controlled trial. Very preterm infants appear to benefit from ICs with reduced risk for BPD and no effect on death, other morbidities, or adverse events. Data on long-term respiratory, growth, and developmental outcomes are eagerly awaited.


Arthroscopic Subspine Decompression Is Commonly Reported in a Heterogenous Patient Population With Concomitant Procedures: A Systematic Review.
To systematically review the evaluation, management, and surgical outcomes of arthroscopic subspine decompression in conjunction with other intra-articular hip preservation procedures. Two databases (PubMed and Embase) were searched from 2010 to 2021, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, for articles investigating arthroscopic subspine decompression using the key words: "subspine impingement", "AIIS impingement", and "extra-articular impingement." Exclusion criteria included diagnostic studies, failure to report postoperative outcomes, and case series of less than 10 hips. Studies were assessed for patient demographics, diagnostic criteria, clinical findings, concomitant procedures, outcomes, and postoperative complications. The quality of the studies was analyzed by 2 independent reviewers (A.J.C. and A.E.J.) using the Methodological Index for Non-randomized Studies (MINORS). Ten studies consisting of 438 patients (460 hips, 48.6% female) met the inclusion criteria, with average ages and follow-up ranging from 24.9 to 34.7 years and 6.0 to 44.4 months, respectively. There was 1 Level II study, 3 Level III studies, and 6 Level IV studies. The MINORS criteria yielded an average quality assessment of 13.0 (range: 7-22), with 3 methodological domains demonstrating mean scores of less than 1: unbiased assessment of the study endpoint (.25), loss of follow up less than 5% (.25), and prospective calculation of the study size (.7). The most common exam maneuver used was the subspine impingement test (9 studies). Most subspine decompressions were performed in addition to traditional femoroacetabular impingement syndrome (FAIS) procedures, with only one study (33 hips) reporting solely on isolated subspine osteoplasty. Average preoperative and postoperative modified Harris Hip Score (mHHS) values ranged from 44.93 to 75.7 and 79.5 to 98.0, respectively. Three studies noted improved hip flexion in the postoperative period. Five surgical complications were reported. Arthroscopic subspine decompression is commonly reported in a heterogenous patient population with intra-articular hip pathology. A combination of the subspine impingement test and anterior inferior iliac spine (AIIS) morphology on imaging is frequently used for diagnosis. While improved patient-reported outcomes (PROs) are consistently observed following arthroscopic decompression, conclusions are limited by study methodology and concurrent procedures performed at the time of surgery. IV, systematic review of Level II through Level IV studies.


A systematic review of delays in seeking medical attention after transient ischaemic attack.
Prompt assessment and investigation of transient ischaemic attack (TIA) followed by early initiation of secondary prevention is effective in reducing recurrent stroke. Nevertheless, many patients are slow to seek medical advice after TIA. A systematic review was undertaken to examine potential factors associated with delay in seeking medical review after TIA. The electronic databases MEDLINE, EMBASE, and Science Citation Index were searched for observational studies assessing patient delay in presentation after TIA. The search was restricted to studies published between December 1995 and September 2008. The electronic search yielded nine studies with data on presentation delay in patients with TIA; variations existed in study size, population and methodology. One study included patients with TIA only (n = 241), whereas the remaining eight studies recruited both stroke and TIA patients. Overall, TIA patients (n = 821) made up only a small proportion of the total number of patients in this analysis (n = 3,202). Length of delay varied greatly across all studies. In most studies, patients with TIA who attended an emergency department arrived there within hours. Where patients first presented to their general practitioner, 50% attended within 24 hours whereas 25% waited 2 days or more. Recognition of symptoms as stroke/TIA did not reduce the delay. The majority of delay in seeking assessment after TIA is due to a lack of response by the patient-many patients do not recognise the symptoms of stroke/TIA, and even when they do, many fail to seek emergency medical attention. The public needs educating on the importance of contacting the emergency medical services or attending an emergency department immediately after TIA.


Using Alzheimer's disease as a model for genetic risk disclosure: implications for personal genomics.
Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer's disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g. distress), along with data on participants' health behavior and insurance purchasing responses (e.g. long-term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research.


Role of cerebellar nodulus and uvula on the vestibular quick phase spatial constancy.
We investigated the orientation of quick phases (QPs) of vestibularly-induced eye movements in rabbits in response to "off-vertical" sinusoidal vestibular stimulation. We also examined the possible role of the cerebellar nodulus and ventral uvula in controlling QP spatial orientation and modification. During "off-vertical" vestibular stimulation QPs remained aligned with the earth's horizontal plane, while the slow phases (SPs) were aligned with the plane of vestibular stimulation. This suggests that QPs are coded in gravito-inertial coordinates and SPs in head coordinates. When rabbits were oscillated in the light (20 degrees peak-to-peak; 0.2 Hz) about an "off-vertical" axis for 2 h, the QPs changed their trajectory, abandoning the earth's horizontal plane to approach the plane of the stimulus. By contrast, in the absence of conjunctive optokinetic stimulation, QPs remained fixed in the earth's horizontal plane even after 2 h of "off-vertical" stimulation. The conjunctive combination of optokinetic and vestibular stimulation caused QPs to change their plane of rotation. After lesion of the nodulus-uvula the ability of rabbits to reorient QPs during conjoint vestibular-optokinetic stimulation was maintained. We conclude that the space orientation and adaptation of QPs do not require cerebellar control.


Gold(i)-BODIPY-imidazole bimetallic complexes as new potential anti-inflammatory and anticancer trackable agents.
Two new gold(i)-BODIPY-imidazole based trackable therapeutic bimetallic complexes have been synthesized and fully characterized. They display strong antiproliferative properties on several types of cancers including colon, breast, and prostate and one of them presents a significant anti-inflammatory effect. Additionally, the two compounds could be visualised in vitro by confocal microscopy in the submicromolar range.


Mechanisms of orexin 2 receptor-mediated depolarization in the rat paraventricular nucleus of the hypothalamus.
The paraventricular nucleus of the hypothalamus (PVN) contains dense orexin 2 (OX2) receptor. We examined the mechanisms of OX2 receptor-mediated excitation on electrophysiologically identified type I (putative magnocellular), low-threshold spikes (LTS)-expressing type II (putative preautonomic), and non-LTS type II (putative parvocellular neuroendocrine) neurons. In the presence of tetrodotoxin, an OX2 receptor agonist, ALOXB (30-1000 nM) depolarized 56% of type I, and 73-75% of type II neurons. In type I neurons, ALOXB-induced inward current displayed increased-conductance current-voltage (I-V) relationship and reversed polarity at -27.5 ± 4.8 mV. A Na+-Ca2+ exchanger (NCX) inhibitor, KBR-7943, attenuated ALOXB responses in the majority of type I neurons, while no attenuation was observed in nearly all type II neurons. Type II neurons exhibited three types of I-V relationships in response to ALOXB, characterized by decreased, increased, and unchanged conductance, respectively. The reversal potential of the decreased-conductance responses was near the equilibrium potential of K+ (Ek+) and became more positive in a high-K+ solution, suggesting that K+ conductance blockade is involved. In a low-Na+ solution, non-reversed I-V curves of increased-conductance responses became decreased-conductance responses and reversed polarity near Ek+, suggesting the involvement of both K+ conductance and non-selective cation conductance (NSCC). Approximately 35% of LTS-expressing type II neurons were vasopressin-immunoreactive and 71% of them responded to ALOXB. In conclusion, orexins may activate OX2 receptor on PVN neurons and cause depolarization by promoting NCX and/or NSCC in magnocellular neurons, and by decreasing K+ conductance and/or increasing NSCC in parvocellular neurons. Furthermore, the majority of vasopressinergic preautonomic neurons are under OX2 receptor regulation.


Pharmacogenetics of anticancer drug sensitivity in non-small cell lung cancer.
In mammalian cells, the process of malignant transformation is characterized by the loss or down-regulation of tumor-suppressor genes and/or the mutation or overexpression of proto-oncogenes, whose products promote dysregulated proliferation of cells and extend their life span. Deregulation in intracellular transduction pathways generates mitogenic signals that promote abnormal cell growth and the acquisition of an undifferentiated phenotype. Genetic abnormalities in cancer have been widely studied to identify those factors predictive of tumor progression, survival, and response to chemotherapeutic agents. Pharmacogenetics has been founded as a science to examine the genetic basis of interindividual variation in drug metabolism, drug targets, and transporters, which result in differences in the efficacy and safety of many therapeutic agents. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. However, these studies have yielded contradictory results because of the small number of molecular determinants of drug response examined, and in several cases this approach was revealed to be reductionistic. This limitation is now being overcome by the use of novel techniques, i.e., high-density DNA and protein arrays, which allow genome- and proteome-wide tumor profiling. Pharmacogenomics represents the natural evolution of pharmacogenetics since it addresses, on a genome-wide basis, the effect of the sum of genetic variants on drug responses of individuals. Development of pharmacogenomics as a new field has accelerated the progress in drug discovery by the identification of novel therapeutic targets by expression profiling at the genomic or proteomic levels. In addition to this, pharmacogenetics and pharmacogenomics provide an important opportunity to select patients who may benefit from the administration of specific agents that best match the genetic profile of the disease, thus allowing maximum activity.


The endothelial-enriched lncRNA LINC00607 mediates angiogenic function.
Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates, post-atherosclerotic cultured endothelial cells from patients and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1 to ultimately mediate angiogenesis.


ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells.
Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that cancer cells containing low intracellular reactive oxygen species levels (ROSLow cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties. Next, we revealed that NRF2, a master regulator of antioxidants, was able to maintain low intracellular ROS levels of CICs, even though in the absence of oxidative stress. We further characterized that NRF2 activation was required for the maintenance of CICs properties. Of ROSLow cells, NRF2 activation not only directly activates the transcription of genes encoding glycolytic enzymes but also inhibited the conversion of pyruvate to acetyl-CoA by directly activating pyruvate dehydrogenase kinase 1 (PDK1) to lead to inhibition of tricarboxylic acid (TCA) cycle; therefore, to promote Warburg effect. A positive regulatory ROS-independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) was identified to mediate the metabolic shift (Warburg effect) and stemness of CICs. Lastly, co-expression of p-PERK and p-NRF2 was significantly associated with the clinical outcome. Our data show that NRF2 acting as a central node in the maintenance of low ROS levels and stemness associated properties of the CICs, which is significantly associated with the clinical outcome, but independent from ROS stress. Future treatments by inhibiting NRF2 activation may exhibit great potential in targeting CICs.


Selective CO2 adsorption by a new metal-organic framework: synergy between open metal sites and a charged imidazolinium backbone.
Metal-organic frameworks (MOFs) are porous, tunable crystalline materials that are attracting widespread scientific attention for their potential use in post-combustion CO2 capture. In this work, we report the synthesis of a new ligand, 1,3-bis(4-carboxyphenyl)-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborate, H2Sp5-BF4, that is subsequently used for the construction of a novel MOF, Cu-Sp5-EtOH. This highly crystalline material has a charged framework that is expected to give rise to high CO2/N2 selectivity. However, the pores of the parent structure could not be accessed due to the presence of strongly coordinated ethanol molecules. After solvent exchange with methanol and subsequently heating Cu-Sp5-MeOH under vacuum, we are able to liberate the solvent providing other small molecules like CO2 access to the inside of the now porous structure, Cu-Sp5. The combination of open metal sites and framework charge leads to an exceptionally high CO2/N2 selectivity, as determined by Ideal Adsorbed Solution Theory (IAST) calculations performed on single-component adsorption isotherms. The CO2/N2 selectivity of Cu-Sp5 reaches a value of over 200 at pressures typically found in post-combustion flue gas (0.15 bar CO2/0.85 bar N2), a value that is among the highest reported to date.


Role of androgens for urethral homeostasis.
We observed that patients with hypogonadism are at higher risk to experience artificial urinary sphincter cuff erosion. Sphincter erosions have been found to be associated with urethral atrophy or compromised urethras subsequent to events limiting its blood supply. We therefore analyzed possible mechanisms how a decrease in testosterone serum levels can result decreased urethral blood flow. In a cohort of >1,200 urethroplasties, tissue specimens obtained during surgeries were analyzed for expression of androgen receptor (AR), AR-responsive TIE-2 associated with angiogenesis, and the endothelial cell marker CD31 for determination of vessel counts were analyzed immunohistochemically. A total of 11 patients were included in whom both tissue and serum testosterone levels within 2 years of the urethroplasty was available. Low serum testosterone level defined as <280 ng/dL. Image J software was used to analyze expression profiles. Mean serum testosterone level was significant lower in hypogonadal patients (179.4 ng/dL) compared to eugonadal patients (375.0 ng/dL, P=0.003). Urethral tissue of hypogonadal patients showed decreased AR expression [1.11% high power field (HPF)] compared to eugonadal patients (1.62%, P=0.016), decreased TIE-2 expression (1.84% HPF vs. 3.08%, P=0.006), and also decreased vessel counts (44.47 vessels/HPF vs. 98.33, P=0.004). There was a direct correlation of AR and TIE-2 expression levels with serum testosterone levels (rho 0.685, P=0.029, and rho 0.773, P=0.005, respectively). Of note, we did not detect a difference in age, prior radiation, coronary artery disease or hypertension among hypo- or eugonadal patient. However, higher body mass index was associated with low serum testosterone levels. Hypogonadal status is associated with decreased expression of AR and TIE-2 and also reduced vessel count in urethral tissue. We believe that the resulting decreased urethral vascularity subsequent to a hypogonadal state may be an important risk factor for complications of urethral surgery.


"Going out" of the box: Close intercultural friendships and romantic relationships spark creativity, workplace innovation, and entrepreneurship.
The present research investigates whether close intercultural relationships promote creativity, workplace innovation, and entrepreneurship-outcomes vital to individual and organizational success. We triangulate on these questions with multiple methods (longitudinal, experimental, and field studies), diverse population samples (MBA students, employees, and professional repatriates), and both laboratory and real-world measures. Using a longitudinal design over a 10-month MBA program, Study 1 found that intercultural dating predicted improved creative performance on both divergent and convergent thinking tasks. Using an experimental design, Study 2 established the causal connection between intercultural dating and creativity: Among participants who had previously had both intercultural and intracultural dating experiences, those who reflected on an intercultural dating experience displayed higher creativity compared to those who reflected on an intracultural dating experience. Importantly, cultural learning mediated this effect. Extending the first 2 studies, Study 3 revealed that the duration of past intercultural romantic relationships positively predicted the ability of current employees to generate creative names for marketing products, but the number of past intercultural romantic partners did not. In Study 4, we analyzed an original dataset of 2,226 professional repatriates from 96 countries who had previously worked in the U.S. under J-1 visas: Participants' frequency of contact with American friends since returning to their home countries positively predicted their workplace innovation and likelihood of becoming entrepreneurs. Going out with a close friend or romantic partner from a foreign culture can help people "go out" of the box and into a creative frame of mind. (PsycINFO Database Record


The quality control system.
Quality Control System: an understanding of analytical error; synthetic QC material; a set of QC rules; a process to follow if the rules signal. Quality Control (QC) Sera: reconstitution - staff trained; stability tested - post reconstitution and frozen. QC Rules: rules documented - basis of adoption; action to follow in case of failure documented; evidence of this procedure being used in place; are QC rules defined for both batch and continuous analysis - how is a 'run' defined for a continuous analytical process; means and standard deviations (SDs) of controls based on sufficient data points and reflects true state of system; evidence of staff training in the interpretation of QC rules; process documented; evidence of training of staff; evidence of regular review of Internal QC results. Patient-based QC Procedures in place: if delta check/anion gap/rerun of samples used, then a documented procedure to describe the process and evidence of it being in use; critical values - documented and evidence of use and documentation. Action on QC Rule Failure: documented process to follow with patient samples if control failure occurs; evidence that procedure has been followed in instances of control failure. External Quality Assessment (EQA) Program: Integration of Internal and External QC data.


Time to endoscopy and outcomes in upper gastrointestinal bleeding.
Upper gastrointestinal bleeding (UGIB) is a common problem associated with significant morbidity and mortality. Previous studies show that immediate endoscopies do not affect outcomes in patients; however, endoscopic interventions have evolved. The present retrospective review of endoscopies performed at a large teaching hospital assessed the timing of endoscopy with respect to the morbidity and mortality of UGIB. Diagnostic billing codes were used to assess all inpatients of gastroenterologists at the University Hospital of the London Health Sciences Centre, London, Ontario, from July 2004 to June 2006, using a centralized data recording system. Time to endoscopy (within 6 h, 6 h to 24 h and beyond 24 h) were compared for the outcomes of mortality, need for surgery and transfusion requirements. From July 2004 to June 2006, there were 502 upper endoscopies performed for the indication of suspected UGIB and 375 for overt acute nonvariceal UGIB. Approximately 10% of cases revealed variceal bleeding. When comparing endoscopy within 6 h with endoscopy at 6 h to 24 h, there were no significant differences in mortality, need for surgery (OR 3.6 and 2.8, respectively, compared with endoscopy beyond 24 h) or transfusion requirements. Even when assessing the group that received endoscopic hemostasis, time to endoscopy was not associated with better outcomes. Multivariate analysis did not demonstrate any advantages for early endoscopy (less than 6 h) compared with endoscopy within 24 h. Most patients with acute gastrointestinal bleeding can be effectively managed with endoscopy within 24 h.


Verification of endocrinological functions at a short distance between parametric speakers and the human body.
In recent years, a new type of speaker called the parametric speaker has been used to generate highly directional sound, and these speakers are now commercially available. In our previous study, we verified that the burden of the parametric speaker was lower than that of the general speaker for endocrine functions. However, nothing has yet been demonstrated about the effects of the shorter distance than 2.6 m between parametric speakers and the human body. Therefore, we investigated the distance effect on endocrinological function and subjective evaluation. Nine male subjects participated in this study. They completed three consecutive sessions: a 20-min quiet period as a baseline, a 30-min mental task period with general speakers or parametric speakers, and a 20-min recovery period. We measured salivary cortisol and chromogranin A (CgA) concentrations. Furthermore, subjects took the Kwansei-gakuin Sleepiness Scale (KSS) test before and after the task and also a sound quality evaluation test after it. Four experiments, one with a speaker condition (general speaker and parametric speaker), the other with a distance condition (0.3 m and 1.0 m), were conducted, respectively, at the same time of day on separate days. We used three-way repeated measures ANOVA (speaker factor × distance factor × time factor) to examine the effects of the parametric speaker. We found that the endocrinological functions were not significantly different between the speaker condition and the distance condition. The results also showed that the physiological burdens increased with progress in time independent of the speaker condition and distance condition.


Pool exercise for individuals with fibromyalgia.
The benefits of general aerobic exercise for individuals with fibromyalgia have been established. Recently, there have been a number of randomized controlled trials that evaluate the benefits of pool exercise for fibromyalgia. This review will integrate the results of eight pool exercise studies that have been published in the last 7 years. Pool exercise has been evaluated against sedentary control groups, land-based exercise and immersion in a warm, mineralized pool. Pool exercise has been shown to be as effective as land-based exercise and may have greater benefits with respect to mood and sleep duration. Based on follow-up studies, exercise-induced improvements in physical function, pain and mood may persist for up to 2 years. Pool exercise may be better tolerated as an initial means of exercise by individuals with arthritis in weight-bearing joints (because of water buoyancy) or by individuals who fear exercise will exacerbate their pain. Pool exercise can be an effective intervention for individuals with fibromyalgia. Future studies should reassess subjects at multiple time points to determine the time course of exercise-induced improvements and further explore the effects of pool exercise on mood and sleep quality.


Promoter-mediated diversification of transcriptional bursting dynamics following gene duplication.
During the evolution of gene families, functional diversification of proteins often follows gene duplication. However, many gene families expand while preserving protein sequence. Why do cells maintain multiple copies of the same gene? Here we have addressed this question for an actin family with 17 genes encoding an identical protein. The genes have divergent flanking regions and are scattered throughout the genome. Surprisingly, almost the entire family showed similar developmental expression profiles, with their expression also strongly coupled in single cells. Using live cell imaging, we show that differences in gene expression were apparent over shorter timescales, with family members displaying different transcriptional bursting dynamics. Strong "bursty" behaviors contrasted steady, more continuous activity, indicating different regulatory inputs to individual actin genes. To determine the sources of these different dynamic behaviors, we reciprocally exchanged the upstream regulatory regions of gene family members. This revealed that dynamic transcriptional behavior is directly instructed by upstream sequence, rather than features specific to genomic context. A residual minor contribution of genomic context modulates the gene OFF rate. Our data suggest promoter diversification following gene duplication could expand the range of stimuli that regulate the expression of essential genes. These observations contextualize the significance of transcriptional bursting.


Evidence-based interventions for cancer treatment-related mucositis: putting evidence into practice.
Mucositis is an inflammatory process that can involve the mucosal epithelial cells from the mouth to the rectum. Historically, mucositis and stomatitis were used interchangeably, but momentum has increased toward more specific terminology since the 2000s. Stomatitis refers to inflammatory diseases of the mouth, including the mucosa, dentition, periapices, and periodontium, whereas mucositis refers more globally to an inflammatory process involving the mucous membranes of the oral cavity and the gastrointestinal tract. In addition, differentiation is needed regarding mucositis involving the oral cavity and the remainder of the gastrointestinal tract that require use of a scope-type device for close examination. As a result, oral cavity mucositis has been the focus of the majority of the studies reported to date. The mucous membranes beyond the oral cavity are more challenging to view, so the mouth has been presented as revealing potential changes in the gastrointestinal tract. However, because of the variation in morphology, function of different locations, and risks associated with procedures to validate that speculation, evidence is limited. The purpose of this article is to review evidence-based interventions for mucositis, particularly in the oral cavity, and provide clinicians with guidelines for nursing interventions.


Effects of the probiotic agent Saccharomyces Boulardii on the DNA damage in acute necrotizing pancreatitis induced rats.
Pancreatitis is a mild and self-limiting disease. Although severe forms such as acute necrotizing pancreatitis (ANP) are rare it is associated with significant mortality rate reported to be 30-70%. Probiotics are viable microbial dietary supplements when introduced in sufficient quantities can have beneficial effects. The physiological effects of probiotics include suppression of bacterial infections, production of some digestive enzymes and vitamins and reconstruction of normal intestinal microflora. In the present study, the aim was to investigate the role of probiotics on the DNA damage in the peripheral lymphocytes, in the exfoliated epithelial cells and lymphocytes of the peritoneal fluids and in the pancreatic acinar cells of ANP induced rats. DNA damage was determined by COMET assay. ANP was induced by intravenous infusion of cerulein and superimposed infusion glycodeoxycholic acid into biliopancreatic duct. Saccharomyces Boulardii was used as the probiotic agent. DNA damage in pancreatic acinar cells and exfoliated epithelial cells and the lymphocytes of the peritoneal fluids was significantly higher in pancreatitis group compared to the controls and probiotic treated groups (P<0.001). No significant difference was observed in the DNA damage between the groups in the peripheral lymphocytes. In conclusion; our results support that probiotic agent Saccharomyces Boulardii can diminish bacterial infections and offer health benefits in the therapy of pancreatitis.


Pregabalin for pain in fibromyalgia in adults.
This review updates part of an earlier Cochrane review on 'Pregabalin for acute and chronic pain in adults' (Moore 2009), and considers only fibromyalgia pain.Antiepileptic drugs have been used in pain management since the 1960s. Pregabalin is an antiepileptic drug also used in management of chronic pain conditions, including fibromyalgia. Pain response with pregabalin is associated with major benefits for other symptoms, and improved quality of life and function in people with chronic painful conditions. To assess the analgesic efficacy and adverse events of pregabalin for pain in fibromyalgia in adults, compared with placebo or any active comparator. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE for randomised controlled trials from inception to May 2009 for the original review and to 16 March 2016 for this update. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. We included randomised, double-blind trials of eight weeks' duration or longer, comparing pregabalin with placebo or another active treatment for relief of pain in fibromyalgia, and reporting on the analgesic effect of pregabalin, with subjective pain assessment by the participant. Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with moderate pain relief (at least 30% pain relief over baseline or much or very much improved on Patient Global Impression of Change scale (PGIC)) or substantial pain relief (at least 50% pain relief over baseline or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and number needed to treat (NNT), using standard methods. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables. Our searches identified two new published studies with classic design, and one new published study with an enriched enrolment randomised withdrawal (EERW) design.We included eight studies. Five (3283 participants) had a classic design in which participants were randomised at the start of the study to pregabalin (150, 300, 450, or 600 mg daily) or placebo, with assessment after 8 to 13 weeks of stable treatment. No studies included active comparators. Studies had low risk of bias, except that the last observation carried forward (LOCF) imputation method used in analyses of the primary outcomes could overestimate treatment effect.Pregabalin increased the number of participants experiencing substantial benefit (at least 50% pain intensity reduction after 12 or 13 weeks' stable treatment (450 mg: RR 1.8, 95% CI 1.4 to 2.1, 1874 participants, 5 studies, high quality evidence)). Substantial benefit with pregabalin 300 to 600 mg was experienced by about 14% of participants with placebo, but about 9% more with pregabalin 300 to 600 mg (22% to 24%) (high quality evidence). Pregabalin increased the number of participants experiencing moderate benefit (at least 30% pain intensity reduction after 12 or 13 weeks' stable treatment) (450 mg: RR 1.5, 95% CI (1.3 to 1.7), 1874 participants, 5 studies, high quality evidence). Moderate benefit with pregabalin 300 to 600 mg was experienced by about 28% of participants with placebo, but about 11% more with pregabalin 300 to 600 mg (39% to 43%) (high quality evidence). A similar magnitude of effect was found using PGIC of 'very much improved' and 'much or very much improved'. NNTs for these outcomes ranged between 7 and 14 (high quality evidence).A small study (177 participants) compared nightly with twice-daily pregabalin, and concluded there was no difference in effect.Two studies (1492 participants began initial dose titration, 687 participants randomised) had an EERW design in which those with good pain relief after titration were randomised, double blind, to continuing the effective dose (300 to 600 mg pregabalin daily) or a short down-titration to placebo for 13 or 26 weeks. We calculated the outcome of maintained therapeutic response (MTR) without withdrawal, equivalent to a moderate benefit. Of those randomised, 40% had MTR with pregabalin and 20% with placebo (high quality evidence). The NNT was 5, but normalised to the starting population tested it was 12. About 10% of the initial population would have achieved the MTR outcome, similar to the result from studies of classic design. MTR had no imputation concerns.The majority (70% to 90%) of participants in all treatment groups experienced adverse events. Specific adverse events were more common with pregabalin than placebo, in particular dizziness, somnolence, weight gain, and peripheral oedema, with number needed to harm of 3.7, 7.4, 18, and 19 respectively for all doses combined (high quality evidence). Serious adverse events did not differ between active treatment groups and placebo (very low quality evidence). Withdrawals for any reason were more common with pregabalin than placebo only with the 600 mg dose in studies of classic design. Withdrawals due to adverse events were about 10% higher with pregabalin than placebo, but withdrawals due to lack of efficacy were about 6% lower (high quality evidence). Pregabalin 300 to 600 mg produces a major reduction in pain intensity over 12 to 26 weeks with tolerable adverse events for a small proportion of people (about 10% more than placebo) with moderate or severe pain due to fibromyalgia. The degree of pain relief is known to be accompanied by improvements in other symptoms, quality of life, and function. These results are similar to other effective medicines in fibromyalgia (milnacipran, duloxetine).


Trait and state interoceptive abnormalities are associated with dissociation and seizure frequency in patients with functional seizures.
Dissociative traits represent a disturbance in selfhood that may predispose to, and trigger, functional seizures (FSs). The predictive representation and control of the internal physiological state of the body (interoception) are proposed to underpin the integrity of the sense of self ("minimal selfhood"). Therefore, discrepancies between objective and subjective aspects of interoception may relate to symptom expression in patients with FSs. Here, we tested whether individual differences in trait measures of interoception relate to dissociative symptoms, and whether state interoceptive deficits predict FS occurrence. Forty-one participants with FSs and 30 controls completed questionnaire ratings of dissociation, and measures of (1) interoceptive accuracy (IA)-objective performance on heartbeat detection tasks; (2) trait interoceptive sensibility-subjective sensitivity to internal sensations (using the Porges Body Perception Questionnaire); and (3) state interoceptive sensibility-subjective trial-by-trial measures of confidence in heartbeat detection. Interoceptive trait prediction error (ITPE) was calculated from the discrepancy between IA and trait sensibility, and interoceptive state prediction error (ISPE) from the discrepancy between IA and state sensibility. Patients with FSs had significantly lower IA and greater trait interoceptive sensibility than healthy controls. ITPE was the strongest predictor of dissociation after controlling for trait anxiety and depression in a regression model. ISPE correlated significantly with FS frequency after controlling for state anxiety. Patients with FSs have disturbances in interoceptive processing that predict both dissociative traits reflecting the disrupted integrity of self-representation, and the expression of FSs. These findings provide insight into the pathophysiology of functional neurological disorder, and could lead to novel diagnostic and therapeutic approaches.


Transcriptomic responses of cancerous and noncancerous human colon cells to sulforaphane and selenium.
Diets enriched with bioactive food components trigger molecular changes in cells that may contribute to either health-promoting or adverse effects. Recent technological advances in high-throughput data generation allow for observing systems-wide molecular responses to cellular perturbations with nontoxic and dietary-relevant doses while considering the intrinsic differences between cancerous and noncancerous cells. In this chemical profile, we compared molecular responses of the colon cancer cell line HT29 and a noncancerous colon epithelial cell line (HCEC) to two widely encountered food components, sulforaphane and selenium. We conducted this comparison by generating new transcriptome data by microarray gene-expression profiling, analyzing them statistically on the single gene, network, and functional pathway levels, and integrating them with protein expression data. Sulforaphane and selenium, at doses that did not inhibit the growth of the tested cells, induced or repressed the transcription of a limited number of genes in a manner distinctly dependent on the chemical and the cell type. The genes that most strongly responded in cancer cells were observed after treatment with sulforaphane and were members of the aldo-keto reductase (AKR) superfamily. These genes were in high agreement in terms of fold change with their corresponding proteins (correlation coefficient r(2) = 0.98, p = 0.01). Conversely, selenium had little influence on the cancer cells. In contrast, in noncancerous cells, selenium induced numerous genes involved in apoptotic, angiogenic, or tumor proliferation pathways, whereas the influence of sulforaphane was very limited. These findings contribute to defining the significance of cell type in interpreting human cellular transcriptome-level responses to exposures to natural components of the diet.


Survey of clinical and pathological characteristics and outcomes of patients with prostate cancer.
The importance of implementation: Prostate cancer is the most common malignancy in men and the second leading cause of cancer death in developed countries. Therefore, further studies about the protests of disease, diagnosis and timely treatment are essential. In this study, 80 prostate cancer patients admitted to Imam Khomeini Hospital, Urmia in Iran from 2000 to 2008 were reviewed. Patients were studied according to their age, clinical protests, Gleason scoring, positive family history, smoking, type of treatment and post-treatment conditions. Questionnaires were adjusted based on the objectives and the data were extracted from the medical records of patients and the desired results were achieved. In this study, the most common age group for prostate cancer is older than 60 years (92/5%). The most common type of pathology for prostate cancer is adenocarcinoma that 93.75% of cases are included. Secondary TCC with secondary source is present in 5% and sarcoma in 1.25% of cases. 46.25% of patients with prostate cancer are smokers. The most common clinical symptoms among patients are obstructive symptoms (56.25%), and irritation of the urinary tract (52.81%). Hematuria in 26.25% and urinary incontinence in 5% of cases have been recorded. 16.3% of patients referred with metastatic symptoms. Most patients with prostate cancer have Gleason score 5-7 (40%). All patients were undergoing prostatectomy (82.5% TURP and 17.5% SPP) and 47.5% of cases were bilateral orchiectomy. The cases reviewed, 22 were followed that included 27.5% of cases. Among them, 6 people have died due prostate cancer (27.27%) that the mean age of the patients after diagnosis until death was 34.4 months. 2 others died from other causes (9.09%). The remaining 14 cases were elder patients with a mean follow-up duration of 44 months. According to the results obtained in the present study, the most common type of prostate cancer pathology is adenocarcinoma that is included 93.75% of cases. Prostate sarcoma is present at 1.25% and secondary bladder TCC at 5% of cases more over the incidence of prostate sarcoma is reported in a lower age group than adenocarcinoma, which the results obtained in a similar study in Iran in other centers. Regarding the relationship between smoking and prostate cancer it can be considered one of the important factors in this regard.


Changes in early-career family physicians' antibiotic prescribing for upper respiratory tract infection and acute bronchitis: a multicentre longitudinal study.
Inappropriate antibiotic prescription and subsequent antibacterial resistance are major threats to health worldwide. We aimed to establish whether early-career 'apprenticeship-model' experience in family practice influences antibiotic prescribing for respiratory tract infections and to also establish other associations of antibiotic prescribing changes during this early-career experience. A longitudinal analysis (2010-2014) of a cohort study of Australian GP registrars' (vocational trainees') consultations. Registrars from five regional training programs recorded data from 60 consecutive consultations, once each 6-month training Term, including the diagnoses managed and medications prescribed. The outcomes were whether an antibiotic was prescribed for the diagnoses 'upper respiratory tract infection (URTI)' and 'acute bronchitis/bronchiolitis'. Generalized linear mixed modelling was used to account for repeated measures on registrars and to include the time component: 'Term'. A total of 856 registrars recorded 108759 consultations, including 8715 'URTI' diagnoses (5.15% of diagnoses) and 2110 'acute bronchitis/bronchiolitis' diagnoses (1.25%). Antibiotics were prescribed in 16.3% [95% confidence interval (CI) 14.9-17.8] of URTI and 72.2% (95% CI 69.6-74.6) of acute bronchitis/bronchiolitis diagnoses. Moving from an earlier to later term did not significantly influence registrars' antibiotic prescribing for URTI [adjusted odds ratio (OR) 0.95; 95% CI 0.87, 1.04, P = 0.27] or acute bronchitis/bronchiolitis [OR 1.01 (95% CI 0.90-1.14), P = 0.86]. Significant associations of antibiotic prescribing for URTIs were the registrar being non-Australian educated, greater patient age, practices not privately billing patients, pathology being ordered, longer consultation duration and the registrar seeking in-consultation information or advice (including from their supervisor). Early-career experience/training failed to produce rational antibiotic prescribing for URTI and acute bronchitis/bronchiolitis. Our findings suggest that prescribing interventions could target the registrar-supervisor dyad.


Room temperature, high-efficiency, noncritical phase-matching fourth harmonic generation in partially deuterated ADP crystal.
High-efficiency frequency conversion into the deep ultraviolet in a partially deuterated ammonium dihydrogen phosphate (ADP) crystal is reported. For a 60% deuterated ADP crystal, the spontaneous Raman scattering intensity decreased by 38% compared with that of a pristine ADP crystal. At room temperature (24°C), noncritical phase-matching fourth harmonic generation of a 1053 nm laser was realized. The angular acceptance was 55.7 mrad, and the external conversion efficiency from 526 to 263 nm reached 85.3%.


Diagnosis and management of bile acid diarrhoea: a survey of UK expert opinion and practice.
Bile acid diarrhoea (BAD), which includes bile acid malabsorption, causes a variety of digestive symptoms. Diagnostic rates and management vary considerably. We conducted a survey of current practice to review expert opinion and provide guidance on diagnosis and management. An online survey was conducted of clinical members of the UK Bile Acid Related Diarrhoea Network, who had all published research on BAD (n=21). Most were National Health Service consultants who had diagnosed over 50 patients with the condition. The preferred terminology was to use BAD, with primary and secondary to classify causes. A wide range of presenting symptoms and associated conditions were recognised. SeHCAT (tauroselcholic acid) was the preferred diagnostic test, and 50% of respondents thought general practitioners should have access to this. Patients who met the Rome IV diagnostic criteria for functional diarrhoea, irritable bowel syndrome (IBS) with predominant diarrhoea or postcholecystectomy diarrhoea were usually investigated by SeHCAT, which was used sometimes in other types of IBS. Treatment with a bile acid sequestrant was offered to patients with low SeHCAT values, with expected response rates >70% in the most severe. Colestyramine was the usual sequestrant, starting between 2 g and 8 g daily; colesevelam was an alternative. In patients who had an incomplete response, increasing the dose, changing to an alternative sequestrant, use of loperamide and a low fat diet were suggested. Recommendations for follow-up and to improve the overall patient experience were made. This expert survey indicates current best practice in the diagnosis and management of BAD.


Role of secretory component, a secreted glycoprotein, in the specific uptake of IgA dimer by epithelial cells.
The binding of secretory component (SC) to epithelial cells and its role in the specific uptake of immunoglobulin A (IgA) dimer has been studied in rabbit mammary gland and liver. SC, Mr approximately 80,000, secreted by epithelial cells of the mammary gland was found associated with the cell surface of mammary cells in intact tissue. Dispersed mammary cells and plasma membrane-enriched fractions obtained from mammary glands of midpregnant rabbits bound 125I-labeled SC in a saturable time- and temperature-dependent process. The association rate followed a second order reversible reaction (k+1 approximately equal to 2.7 x 10(6) M-1 min-1 at 4 degrees C) and equilibrium was reached in about 4 h at 4 degrees C. The dissociation rate for membranes was first order (k-1 approximately equal to 1.7 x 10(-2) min-1 at 4 degrees C), whereas displacement from cells was incomplete. The apparent affinity constant was similar for membranes and cells (Ka approximately equal to 5 x 10(8) M-1) with one class of binding sites. The number of binding sites varied from one animal to another (260 to 7,000 sites/mammary cell) in relation to endogenous occupancy by SC, which was assessed by immunocytochemistry and complement-mediated cytotoxicity. Rabbit liver and heart membranes did not bind SC, and serum proteins present in rabbit milk failed to interact with mammary cells or membranes. Mammary membranes or cells and liver membranes bound 125I-labeled IgA dimer in a saturable, reversible time- and temperature-dependent process. Association and dissociation rate constants at 4 degrees C (k+1 approximately equal to 5 x 10(6) M-1 min-1 and k-1 approximately equal to 5 x 10(-3) min-1, respectively) and the apparent affinity constant (Ka approximately equal to 10(9) M-1) were similar for liver and mammary membranes; these parameters differed, however, from those reported for free SC-IgA dimer interaction. The binding capacity of membranes for IgA dimer was directly related to the amount of free SC bound to membranes. Interaction of IgA dimer with mammary or liver membranes or cells was abrogated by excess of free SC and was prevented by preincubation of membranes or cells with Fab antibody fragments directed against SC. These data indicate that the first step in the translocation process of polymeric immunoglobulins across epithelia consists of binding of SC to the surface of epithelial cells which in turn acts as a receptor for the specific uptake of IgA dimer.


Representativeness of breast cancer cases in an integrated health care delivery system.
Integrated health care delivery systems, with their comprehensive and integrated electronic medical records (EMR), are well-poised to conduct research that leverages the detailed clinical data within the EMRs. However, information regarding the representativeness of these clinical populations is limited, and thus the generalizability of research findings is uncertain. Using data from the population-based California Cancer Registry, we compared age-adjusted distributions of patient and neighborhood characteristics for three groups of breast cancer patients: 1) those diagnosed within Kaiser Permanente Northern California (KPNC), 2) non-KPNC patients from NCI-designated cancer centers, and 3) those from all other hospitals. KPNC patients represented 32 % (N = 36,109); cancer center patients represented 7 % (N = 7805); and all other hospitals represented 61 % (N = 68,330) of the total breast cancer patients from this geographic area during 1996-2009. Compared with cases from all other hospitals, KPNC had slightly fewer non-Hispanic Whites (70.6 % versus 74.4 %) but more Blacks (8.1 % versus 5.0 %), slightly more patients in the 50-69 age range and fewer in the younger and older age groups, a slightly lower proportion of in situ but higher proportion of stage I disease (41.6 % versus 38.9 %), were slightly less likely to reside in the lowest (4.2 % versus 6.5 %) and highest (36.2 % versus 39.0 %) socioeconomic status neighborhoods, and more likely to live in suburban metropolitan areas and neighborhoods with more racial/ethnic minorities. Cancer center patients differed substantially from patients from KPNC and all other hospitals on all characteristics assessed. All differences were statistically significant (p < .001). Although much of clinical research discoveries are based in academic medical centers, patients from large, integrated medical centers are likely more representative of the underlying population, providing support for the generalizability of cancer research based on electronic data from these centers.


Barriers and facilitators in the provision of post-abortion care at district level in central Uganda - a qualitative study focusing on task sharing between physicians and midwives.
Abortion is restricted in Uganda, and poor access to contraceptive methods result in unwanted pregnancies. This leaves women no other choice than unsafe abortion, thus placing a great burden on the Ugandan health system and making unsafe abortion one of the major contributors to maternal mortality and morbidity in Uganda. The existing sexual and reproductive health policy in Uganda supports the sharing of tasks in post-abortion care. This task sharing is taking place as a pragmatic response to the increased workload. This study aims to explore physicians' and midwives' perception of post-abortion care with regard to professional competences, methods, contraceptive counselling and task shifting/sharing in post-abortion care. In-depth interviews (n = 27) with health care providers of post-abortion care were conducted in seven health facilities in the Central Region of Uganda. The data were organized using thematic analysis with an inductive approach. Post-abortion care was perceived as necessary, albeit controversial and sometimes difficult to provide. Together with poor conditions post-abortion care provoked frustration especially among midwives. Task sharing was generally taking place and midwives were identified as the main providers, although they would rarely have the proper training in post-abortion care. Additionally, midwives were sometimes forced to provide services outside their defined task area, due to the absence of doctors. Different uterine evacuation skills were recognized although few providers knew of misoprostol as a method for post-abortion care. An overall need for further training in post-abortion care was identified. Task sharing is taking place, but providers lack the relevant skills for the provision of quality care. For post-abortion care to improve, task sharing needs to be scaled up and in-service training for both doctors and midwives needs to be provided. Post-abortion care should further be included in the educational curricula of nurses and midwives. Scaled-up task sharing in post-abortion care, along with misoprostol use for uterine evacuation would provide a systematic approach to improving the quality of care and accessibility of services, with the aim of reducing abortion-related mortality and morbidity in Uganda.


Well-defined regions of the Plasmodium falciparum reticulocyte binding protein homologue 4 mediate interaction with red blood cell membrane.
Two widely studied parasite protein families are considered attractive targets for developing a fully effective antimalarial vaccine: the erythrocyte binding antigen (EBA) family defining a sialic acid-dependent invasion pathway, and reticulocyte-binding homologue (RH) proteins associated with sialic acid-independent red blood cell (RBC) invasion. In this study, the micronemal invasive PfRH4 protein was finely mapped using 20-mer-long synthetic peptides spanning the entire protein length to identify protein regions that establish high affinity interactions with human RBCs. Twenty conserved, mainly alpha-helical high-activity binding peptides (HABPs) with nanomolar dissociation constants and recognizing 32, 25, 22, and 20 kDa RBC membrane molecules in a chymotrypsin and/or trypsin-sensitive manner were identified in this protein. Anti-PfRH4 rabbit sera and PfRH4 HABPs inhibited merozoite invasion in vitro, therefore suggesting the implication of these HABPs in Plasmodium falciparum invasion and supporting their inclusion in further structural and immunological studies to design potential components of a minimal subunit-based, multiantigenic, chemically synthesized antimalarial vaccine.


Complementarity between high-energy photoelectron and L-edge spectroscopy for probing the electronic structure of 5d transition metal catalysts.
We demonstrate the successful use of hard X-ray photoelectron spectroscopy (HAXPES) for selectively probing the platinum partial d-density of states (DOS) in a Pt-Cu nanoparticle catalyst which shows activity superior to pure Pt towards the oxygen-reduction reaction (ORR). The information about occupied Pt d-band states was complemented by Pt L(2)-edge X-ray absorption near-edge spectroscopy (XANES), which probes unoccupied valence states. We found a significant electronic perturbation of the Pt projected d-DOS which was narrowed and shifted to higher binding energy compared to pure platinum. The effect of this electronic structure perturbation on the chemical properties of the nanoparticle surface is discussed in terms of the d-band model. We have thereby demonstrated that the combination of L-edge spectroscopy and HAXPES allows for an experimental derivation of the valence electronic structure in an element-specific way for 5d metal catalysts.


Metabolic engineering of monoterpene biosynthesis: two-step production of (+)-trans-isopiperitenol by tobacco.
Monoterpenoid biosynthesis in tobacco was modified by introducing two subsequent enzymatic activities targeted to different cell compartments. A limonene-3-hydroxylase (lim3h) cDNA was isolated from Mentha spicata L. 'Crispa'. This cDNA was used to re-transform a transgenic Nicotiana tabacum'Petit Havana' SR1 (tobacco) line expressing three Citrus limon L. Burm. f. (lemon) monoterpene synthases producing (+)-limonene, gamma-terpinene and (-)-beta-pinene as their main products. The targeting sequences of these synthases indicate that they are probably localized in the plastids, whereas the sequence information of the P450 hydroxylase indicates targeting to the endoplasmatic reticulum. Despite the different location of the enzymes, the introduced P450 hydroxylase proved to be functional in the transgenic plants as it hydroxylated (+)-limonene, resulting in the emission of (+)-trans-isopiperitenol. Some further modifications of the (+)-trans-isopiperitenol were also detected, resulting in the additional emission of 1,3,8-p-menthatriene, 1,5,8-p-menthatriene, p-cymene and isopiperitenone.


Nuclear sequences reveal mid-range isolation of an imperilled deep-water coral population.
The mitochondrial DNA of corals and their anthozoan kin evolves slowly, with substitution rates about two orders of magnitude lower than in typical bilateral animals. This has impeded the delineation of closely related species and isolated populations in corals, compounding problems caused by high morphological plasticity. Here we characterize rates of divergence and levels of variation for three nuclear gene regions, then use these nuclear sequences as markers to test for population structure in Oculina, a taxonomically confused genus of corals. Rates of sequence divergence (obtained by comparison to Solenastrea hyades) were at least five (and sometimes over 10) times faster for the three nuclear markers than for a mitochondrial reference sequence. Nuclear sequence variation was also high within populations, although it tended to decline north of Cape Canaveral. Significant subdivision was evident among samples from 10 locations from between North Carolina and the Florida Panhandle, but neither nominal species designation nor population depth explained much of this variation. Instead, a single population from the unique deep (> 70 m) water reefs at the Oculina Banks off central Florida was a strong genetic outlier: all pairwise measures of subdivision involving this population were greater than those involving all other populations, and multilocus clustering recognized the Oculina Banks as distinct from other populations, despite its close proximity (< or = 36 km) to populations from shallower waters nearby and its location at the centre of the sampled range. Genetic isolation of the Oculina Banks population suggests that focused efforts will be needed to conserve the foundation species of these monotypic reefs and that depth may play a role in isolating marine populations and perhaps facilitating initial steps towards speciation.


Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis.
The role of the adaptive immune response, with regard to the development of autoantibodies, has been extensively studied in primary biliary cirrhosis (PBC). However, the importance of innate immunity has been noted only recently. Based on the proposed role of microorganisms in the pathogenesis of the disease, we hypothesize that patients with PBC possess a hyper-responsive innate immune system to pathogen-associated stimuli that may facilitate the loss of tolerance. To address this issue, we isolated peripheral blood monocytes from 33 patients with PBC and 26 age-matched healthy controls and stimulated such cells in vitro with defined ligands for toll-like receptor (TLR) 2 (lipoteichoic acid; LTA), TLR3 (polyIC), TLR4 (lipopolysaccharide; LPS), TLR5 (flagellin), and TLR9 (CpG-B). Supernatant fluids from the cultures were analyzed for levels of 5 different pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, IL-8, IL-12p70, and TNF-alpha. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro-inflammatory cytokines, particularly IL-1beta, IL-6, IL-8, and TNF-alpha, compared with controls. In conclusion, monocytes from patients with PBC appear more sensitive to signaling via select TLRs, resulting in secretion of selective pro-inflammatory cytokines integral to the inflammatory response that may be critical in the breakdown of self-tolerance.


Early treatment response evaluation after yttrium-90 radioembolization of liver malignancy with CT perfusion.
To evaluate computed tomography (CT) perfusion for assessment of early treatment response after transarterial radioembolization of patients with liver malignancy. Dynamic contrast-enhanced CT liver perfusion was performed before and 4 weeks after transarterial radioembolization in 40 patients (25 men and 15 women; mean age, 64 y ± 11; range, 35-80 y) with liver metastases (n = 27) or hepatocellular carcinoma (HCC) (n = 13). Arterial perfusion (AP) of tumors derived from CT perfusion and tumor diameters were measured on CT perfusion before and after transarterial radioembolization. Success of transarterial radioembolization was evaluated on morphologic follow-up imaging (median follow-up time, 4 mo) based on Response Evaluation Criteria in Solid Tumors (Version 1.1). CT perfusion parameters before and after transarterial radioembolization for different response groups were compared. Kaplan-Meier curves were plotted to illustrate overall 1-year survival rates. Liver metastases showed significant differences in AP before and after transarterial radioembolization in responders (P < .05) but not in nonresponders (P = .164). In HCC, AP values before and after transarterial radioembolization were not significantly different in responders and nonresponders (P = .180 and P = .052). Tumor diameters were not significantly different on CT perfusion before and after transarterial radioembolization in responders and nonresponders with liver metastases and HCC (P = .654, P = .968, P = .148, P = .164). In patients with significant decrease of AP in liver metastases after transarterial radioembolization, 1-year overall survival was significantly higher than in patients showing no reduction of AP. CT perfusion showed early reduction of AP in liver metastases responding to transarterial radioembolization; tumor diameter remained unchanged early after treatment. No significant early treatment response to transarterial radioembolization was found in patients with HCC. In patients with liver metastases, a decrease of AP after transarterial radioembolization was associated with a higher 1-year overall survival rate.


Early skewed distribution of total and HIV-specific CD8+ T-cell memory phenotypes during primary HIV infection is related to reduced antiviral activity and faster disease progression.
The important role of the CD8+ T-cells on HIV control is well established. However, correlates of immune protection remain elusive. Although the importance of CD8+ T-cell specificity and functionality in virus control has been underscored, further unraveling the link between CD8+ T-cell differentiation and viral control is needed. Here, an immunophenotypic analysis (in terms of memory markers and Programmed cell death 1 (PD-1) expression) of the CD8+ T-cell subset found in primary HIV infection (PHI) was performed. The aim was to seek for associations with functional properties of the CD8+ T-cell subsets, viral control and subsequent disease progression. Also, results were compared with samples from Chronics and Elite Controllers. It was found that normal maturation of total and HIV-specific CD8+ T-cells into memory subsets is skewed in PHI, but not at the dramatic level observed in Chronics. Within the HIV-specific compartment, this alteration was evidenced by an accumulation of effector memory CD8+ T (TEM) cells over fully differentiated terminal effector CD8+ T (TTE) cells. Furthermore, higher proportions of total and HIV-specific CD8+ TEM cells and higher HIV-specific TEM/(TEM+TTE) ratio correlated with markers of faster progression. Analysis of PD-1 expression on total and HIV-specific CD8+ T-cells from PHI subjects revealed not only an association with disease progression but also with skewed memory CD8+ T-cell differentiation. Most notably, significant direct correlations were obtained between the functional capacity of CD8+ T-cells to inhibit viral replication in vitro with higher proportions of fully-differentiated HIV-specific CD8+ TTE cells, both at baseline and at 12 months post-infection. Thus, a relationship between preservation of CD8+ T-cell differentiation pathway and cell functionality was established. This report presents evidence concerning the link among CD8+ T-cell function, phenotype and virus control, hence supporting the instauration of early interventions to prevent irreversible immune damage.


Nuclear morphology measurements using Fourier domain low coherence interferometry.
We present a new common path configuration Fourier domain low coherence interferometry (fLCI) optical system and demonstrate its capabilities by presenting results which determine the size of cell nuclei in a monolayer of T84 epithelial cells. The optical system uses a white light source in a modified Michelson interferometer and a spectrograph for detection of the mixed signal and reference fields. Depth resolution is obtained from the Fourier transform of the measured spectrum which provides the axial spatial cross-correlation between the signal and reference fields. The spectral dependence of scattering by the samples is determined by windowing the spectrum to measure the scattering amplitude as a function of wavenumber. We present evidence that fLCI accurately measures the longitudinal profile of cell nuclei rather than the transverse profile.


Evaluation of the relationship between platelet indices and spontaneous echo contrast in patients with mitral prosthetic heart valves.
Spontaneous echo contrast (SEC) is defined as dynamic, smoke-like echoes within the cardiac cavities with a characteristic swirling motion seen on echocardiography. Clinical studies have demonstrated that SEC is a risk factor for left atrial thrombus formation and an important indicator for potential systemic embolism. Platelet indices have been associated with the presence of SEC in patients with mitral stenosis. The aim of this study was to investigate the relationship between platelet indices and SEC in patients with prosthetic heart valves. A total of 89 patients [female: 38 (42.4%); median age: 52 years (range: 36-67 years)] with SEC formation in the left atrium, and 257 control subjects [female: 123 (47.5%); median age: 56 years (range: 45-65 years)] without SEC formation were enrolled. All of the patients were evaluated by using transthoracic and transesophageal echocardiography. Laboratory tests including complete blood count and biochemical parameters were analyzed. Patients with SEC formation had more frequent atrial fibrillation, higher left atrial diameter (LAD) and lower left ventriular ejection fraction values. Platelet indices including platelet count, platelet distribution width, mean platelet volume, and plateletcrit did not differ between the groups. Increased LAD was detected as the only independent predictor of SEC development. Platelet indices were not found to be associated with the presence of SEC formation in the left atrium among patients with mitral prosthetic valves. Therefore, the use of platelet indices alongside known echocardiographic and clinical risk factors to predict SEC development in patients with a mitral prosthesis is debatable.


Type-Specific Human Papillomavirus Distribution in Invasive Squamous Cervical Carcinomas in Tunisia and Vaccine Impact.
High risk human papillomaviruses (HPVs) are the leading cause of cervical cancer (CC) and Pap smear screening has not been successful in preventing CC in Tunisia. HPV vaccination that targets HPV16 and 18 offers a new efficient prevention tool. Identification of HPV types in CC is thus essential to determine the impact of HPV vaccine implementation. The aim of this study is to provide specific data from Tunisia. A total of 89 histological confirmed paraffin embedded samples isolated from patients with CC diagnosed between 2001 and 2011 were collected from five medical centres from Northern and Southern Tunisia. HPV DNA was detected using a nested PCR (MY09/MY11-GP5+/GP6+) and genotyping was assessed using a reverse blot line hybridisation assay that enables the detection of 32 HPV types. HPV DNA was detected in all samples. Twelve high risk types were detected; HPV16 and/or 18 were predominant, accounting together for 92.1% of all the CC cases (HPV16: 83.1%). Single infections accounted for 48.8% of the cases and were mostly linked to HPV 16 (32.6%) and less frequently to HPV 18 (2.4%). The other high risk HPV single infections were linked to HPV 35 (4.6%), 45 (4.6%), 58 (2.3%) and 59 (2.3%). Multiple infections with mixing of 2 to 4 genotypes predominately featrued HPV16 and/or 18 with HPV 35 and 45 (96.6 %) and less frequently with HPV 59, 40, 66, 73 and 58. There was no statistically significant variation in the relative distribution of HPV types with age. These results strongly indicate that prophylactic HPV vaccines can have a major impact in preventing CC in Tunisia.


Cardiac electrophysiology studies and ablations for treatment of supraventricular arrhythmias--an initial experience from Karachi.
To review the clinical experience, complications and outcome of Cardiac Electrophysiology Studies and Catheter Radiofrequency Ablation in treatment of supraventricular tachycardias in Karachi. A retrospective review of records of all patients who underwent an electrophysiological study and radiofrequency ablation at National Institute of Cardiovascular Diseases and Aga Khan University Hospital from 2005 to 2007 was performed. Patient's demographics, disease and procedural data were collected and analyzed using SPSS.V.II. We enrolled 168 patients, 150 (89%) from National Institute of Cardiovascular Diseases and 18 (11%) from Aga Khan University Hospital. Sample had 86 (51%) male participants. The mean age was 43 +/- 15 years. Indications for procedure were recurrent supraventricular tachycardias (89.9%), Wolff Parkinson White Syndrome with atrial fibrillation (5.9%), syncope (2.4%), and wide QRS tachycardia (1.8%). Final diagnosis was Wolff Parkinson White Syndrome in 80 (48%) and Atriovetricular Nodal Reentrant Tachycardia in 88 (52%). The accessory pathway in Wolff Parkinson White Syndrome was located on left side in 61% of cases and on right side in 39% of cases. Overall acute success rate for Radio Frequency ablation was 90%. Success rate for ablation of accessory pathway in Wolff Parkinson White Syndrome was 85% while that for ablation of slow pathway in AV node re-entrant tachycardia was 95%. Complications occurred in one case. Electro Physiology Studies and Radiofrequency ablation proved to be a safe and effective method for diagnosis and treatment of supraventricular tachycardias in our patients.


Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia during Gram-Negative Pneumonia-Derived Sepsis.
Platelet-dense (δ) granules are important for platelet function. Platelets contribute to host defense and vascular integrity during pneumonia and sepsis, and δ granule products, including adenosine diphosphate (ADP), can influence inflammatory responses. We therefore aimed to study the role of platelet δ granules in the host response during sepsis. Hermansky-Pudlak syndrome (Hps)3coa mice (with reduced δ granule content), mice treated with the platelet ADP receptor inhibitor clopidogrel, and appropriate control mice were infected with the human sepsis pathogen Klebsiella pneumoniae via the airways to induce pneumonia and sepsis. In order to override potential redundancy in platelet functions, we also studied Hps3coa and control mice with moderate antibody-induced thrombocytopenia (10%) prior to infection. We found that sepsis-induced thrombocytopenia tended to be less severe in Hps3coa mice, and was significantly ameliorated in Hps3coa mice with low pre-infection platelet counts. Bacterial growth was similar in Hps3coa and control mice in the presence of normal platelet counts prior to infection, but lower in the lungs of Hps3coa mice with low pre-infection platelet counts. Hps3coa mice had unaltered lung pathology and distant organ injury during pneumosepsis, irrespective of pre-infection platelet counts; lung bleeding did not differ between Hps3coa and control mice. Clopidogrel did not influence any host response parameter. These data suggest that platelet δ granules can play a detrimental role in pneumosepsis by aggravating thrombocytopenia and impairing local antibacterial defense, but that these unfavorable effects only become apparent in the presence of low platelet counts.


The genetics of depression and manic-depressive disorder.
Depressive disorders are more common in the relatives of depressed probands than in the population at large, and there is compelling evidence that the familial aggregation of bipolar disorder and severe unipolar depression is at least partly due to genetic factors. However, the evidence concerning 'non-endogenous' depression is less clear, and family environment probably plays a stronger role. Much current research is focused on two areas: firstly, the mode of inheritance of manic-depressive illness, with the use of molecular biological techniques to detect and localise major genes; and secondly, the ways in which familial predisposition and environmental insults combine to produce depressive disorder.


Local Directional Ternary Pattern for Facial Expression Recognition.
This paper presents a new face descriptor, local directional ternary pattern (LDTP), for facial expression recognition. LDTP efficiently encodes information of emotion-related features (ı.e., eyes, eyebrows, upper nose, and mouth) by using the directional information and ternary pattern in order to take advantage of the robustness of edge patterns in the edge region while overcoming weaknesses of edge-based methods in smooth regions. Our proposal, unlike existing histogram-based face description methods that divide the face into several regions and sample the codes uniformly, uses a two-level grid to construct the face descriptor while sampling expression-related information at different scales. We use a coarse grid for stable codes (highly related to non-expression), and a finer one for active codes (highly related to expression). This multi-level approach enables us to do a finer grain description of facial motions while still characterizing the coarse features of the expression. Moreover, we learn the active LDTP codes from the emotion-related facial regions. We tested our method by using person-dependent and independent cross-validation schemes to evaluate the performance. We show that our approaches improve the overall accuracy of facial expression recognition on six data sets.


Intracranial applications of digital subtraction angiography.
Digital subtraction angiography (DSA) is becoming an important method of studying the intracranial vascular structures. In patients being evaluated for cervicocerebral atherosclerosis, patency of and flow patterns in the major intracranial arteries can be determined. Quantitative as well as qualitative data on relative hemispheric contrast transit times are obtainable. Intracranial aneurysms and vascular malformations can be demonstrated by intravenous DSA, but this technique is unlikely to replace selective intraarterial catheter angiography for the definitive work-up of these conditions. In selected cases, vascular tumors of the intracranial compartment and skull base can be satisfactorily evaluated by intravenous DSA, particularly if precise and intricate anatomic detail is not required. The dural venous sinuses are optimally demonstrated by this modality. Postoperative intravenous DSA is useful for determining the results of surgical treatment of certain conditions, and is suitable for assessing the patency of surgical bypass grafts. The disadvantages of using intravenous DSA for intracranial studies include poorer spatial resolution as compared to conventional angiography, superimposition of vessels, and serious degradation of image quality by patient motion. When greater selectivity and better resolution are required, intraarterial DSA can be performed. Advantages of intraarterial DSA over conventional angiography include the availability of immediate subtraction images, the ability to use dilute concentrations of contrast agent, and lesser film cost. Intraarterial DSA shortens procedure time when therapeutic embolization is performed.


Evidence-based facilities design in health care: a study of aged care facilities in Australia.
Many facilities for people with dementia have been built with little translation of the substantial body of evidence available to inform design. Knowledge translation has been described as a four-stage process: awareness, agreement, adoption and adherence. This paper identifies where knowledge translation fails in the design of aged care facilities for people with dementia. Ten aged care facilities were audited using the Environmental Audit Tool. Senior managers and architects involved in the facility design were then interviewed to ascertain their knowledge of evidence-based principles of dementia design, their agreement with the principles and the nature of the obstacles they had encountered in their implementation. All architects claimed at least partial awareness of the design principles. Five facility managers claimed full awareness. Those facilities designed with the input of managers who were fully aware of the principles were of significantly higher design quality. There was little agreement on the significance of other obstacles. Once aged care providers are aware of the principles, they appear to find ways to implement them. If the next generation of residential aged care facilities is to be suitable for people with dementia, the facility managers must be made aware of the available design principles, architects encouraged to be more active in sharing their knowledge and ways found to improve the exchange of knowledge between the parties.


Antifungal Activity of Brazilian Propolis Microparticles against Yeasts Isolated from Vulvovaginal Candidiasis.
Propolis, a resinous compound produced by Apis mellifera L. bees, is known to possess a variety of biological activities and is applied in the therapy of various infectious diseases. The aim of this study was to evaluate the in vitro antifungal activity of propolis ethanol extract (PE) and propolis microparticles (PMs) obtained from a sample of Brazilian propolis against clinical yeast isolates of importance in the vulvovaginal candidiasis (VVC). PE was used to prepare the microparticles. Yeast isolates (n = 89), obtained from vaginal exudates of patients with VVC, were exposed to the PE and the PMs. Moreover, the main antifungal drugs used in the treatment of VVC (Fluconazole, Voriconazole, Itraconazole, Ketoconazole, Miconazole and Amphotericin B) were also tested. Minimum inhibitory concentration (MIC) was determined according to the standard broth microdilution method. Some Candida albicans isolates showed resistance or dose-dependent susceptibility for the azolic drugs and Amphotericin B. Non-C. albicans isolates showed more resistance and dose-dependent susceptibility for the azolic drugs than C. albicans. However, all of them were sensitive or dose-dependent susceptible for Amphotericin B. All yeasts were inhibited by PE and PMs, with small variation, independent of the species of yeast. The overall results provided important information for the potential application of PMs in the therapy of VVC and the possible prevention of the occurrence of new symptomatic episodes.


RUNX1 is a key target in t(4;11) leukemias that contributes to gene activation through an AF4-MLL complex interaction.
The Mixed Lineage Leukemia (MLL) protein is an important epigenetic regulator required for the maintenance of gene activation during development. MLL chromosomal translocations produce novel fusion proteins that cause aggressive leukemias in humans. Individual MLL fusion proteins have distinct leukemic phenotypes even when expressed in the same cell type, but how this distinction is delineated on a molecular level is poorly understood. Here, we highlight a unique molecular mechanism whereby the RUNX1 gene is directly activated by MLL-AF4 and the RUNX1 protein interacts with the product of the reciprocal AF4-MLL translocation. These results support a mechanism of transformation whereby two oncogenic fusion proteins cooperate by activating a target gene and then modulating the function of its downstream product.


Molecular imaging agents specific for the annulus fibrosus of the intervertebral disk.
Low back pain is a prevalent medical condition that is difficult to diagnose and treat. Current imaging methods are unable to correlate pain reliably with spinal structures, and surgical removal of painful damaged or degenerating disks is technically challenging. A contrast agent specific for the intervertebral disk could assist in the detection, diagnosis, and surgical treatment of low back pain. The styryl pyridinium (FM) fluorophores were characterized and structure-activity relationships between chemical structure and in vivo uptake were established. Two novel FM fluorophores with improved optical properties for imaging the intervertebral disks were synthesized and evaluated in mice, rats, and pigs. After a single systemic injection, eight of eight FM fluorophores provided high-contrast imaging of the trigeminal ganglia, whereas six of eight provided high-contrast imaging of the dorsal root ganglia. Unexpectedly, three of eight FM fluorophores provided high-contrast imaging of annulus fibrosus tissue of the intervertebral disks, confirmed histologically. We present the first known contrast agent specific for the intervertebral disks and identify the chemical structural motif that mediates uptake. FM fluorophores could be used for image-guided surgery to assist in the removal of intervertebral disk and lay the foundation for derivatives for magnetic resonance imaging and positron emission tomography.


Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.


Ecology, economics, and equity of the pastoral systems in the Khangchendzonga National Park, Sikkim Himalaya, India.
The Khangchendzonga National Park is a part of the eastern Himalaya global biodiversity hotspot and is located in the Sikkim state of India. Increasing livestock populations coupled with the government policy to ban grazing and its selective implementation resulted in conflict. Hence we undertook this multidisciplinary study involving consultations with traditional resource users, field surveys, and remote sensing. We found that in the greater Himalayan part, over the past 6 decades sheep have been increasingly replaced by yaks (and their crossbreeds), who descend only up to the multilayered temperate and subalpine forests during winter. These forests have been extensively manipulated by the yak herders to increase the fodder availability. In terms of economics and equity in benefit sharing, we found that a few yak herders earn high incomes by maintaining large herds while the sheep and pack animal herders earn subsistence level incomes from small herds. We propose a reduction in yak (and their female crossbreed) numbers with adequate alternative livelihood support for the herders.


The sociopolitical status of U.S. naturopathy at the dawn of the 21st century.
Naturopathic medicine in the United States had its inception around the turn of the 20th century. Subsequently, it underwent a process of relatively rapid growth until around the 1930s, followed by a period of gradual decline almost to the point of extinction due to biomedical opposition and the advent of "miracle drugs." Because its therapeutic eclecticism had preadapted it to fit into the holistic health movement that emerged in the 1970s, it was able to undergo a process of organizational rejuvenation during the last two decades of the century. Nevertheless, U.S. naturopathy as a professionalized heterodox medical system faces several dilemmas as it enters the new millennium. These include (1) the fact that it has succeeded in obtaining licensure in only two sections of the country, namely, the Far West and New England; (2) increasing competition from partially professionalized and lay naturopaths, many of whom are graduates of correspondence schools; and (3) the danger of cooptation as many biomedical practitioners adopt natural therapies.


Review: Mechanisms of anoxia tolerance in plants. II. Energy requirements for maintenance and energy distribution to essential processes.
Anoxia in plant tissues results in an energy crisis (Gibbs and Greenway 2003). How anoxia-tolerant tissues cope with such an energy crisis is relevant not only to anoxia tolerance, but also to adverse conditions in air that cause an energy crisis.To survive an energy crisis, plant cells need to reduce their energy requirements for maintenance, and also direct the limited amount of energy produced during anaerobic catabolism to the energy-consuming processes that are critical to survival.We postulate that during anoxia, reductions in ion fluxes and protein turnover achieve economies in energy consumption. Processes receiving energy from the limited supply available under anoxia include synthesis of anaerobic proteins and energy-dependent substrate transport. Energy would also be required for maintenance of membrane integrity and for regulation of cytoplasmic pH (pHcyt). We suggest that a moderate decrease in the set point of pHcyt, from approximately 7.5 to approximately 7.0 is an acclimation to the energy crisis in anoxia-tolerant tissues. This decrease in the set point of pHcyt would favour metabolism of acclimative value, such as reduction in protein synthesis and stimulation of ethanolic fermentation. During anoxia lasting several days, a proportion of the scarce energy produced may need to be spent to mitigate the acidifying effect on pHcyt arising from fluxes of undissociated organic acids across the tonoplast as a consequence of high concentrations of organic acids in the vacuole. Increases in vacuolar pH (pHvac), with concomitant decreases in the vacuolar concentrations of undissociated acids, would mitigate such an 'acid load' on the cytoplasm. We present evidence that a preferential engagement of V-PPiases, over that of V-ATPases, may direct energy flow at the tonoplast to maintain pHcyt.We conclude that the likely causes of death under anoxia are firstly, a decrease in pHcyt below 7.0. Cytoplasmic acidosis occurs in several anoxia-intolerant tissues and may contribute to their death. Such adverse decreases in pHcyt can be mitigated by the biochemical pH stat. Secondly, deterioration in membrane selectivity culminating in loss of membrane integrity would be fatal. We suggest these two causes are not mutually exclusive but may act in concert.


Atomic structure of defects and dopants in 2D layered transition metal dichalcogenides.
Layered transition metal dichalcogenides (TMDs) offer monolayer 2D systems with diverse properties that extend beyond what graphene alone can achieve. The properties of TMDs are heavily influenced by the atomic structure and in particular imperfects in the crystallinity in the form of vacancy defects, grain boundaries, cracks, impurity dopants, ripples and edge terminations. This review will cover the current knowledge of the detailed structural forms of some of the most intensively studied 2D TMDs, such as MoS2, WSe2, MoTe2, WTe2, NbSe2, PtSe2, and also covers MXenes. The review will utilize results achieved using state-of-the-art aberration corrected transmission electron microscopy, including annular dark-field scanning transmission electron microscopy (ADF-STEM) and electron energy loss spectroscopy (EELS), showing how elemental discrimination can be achieved to understand structure at a deep level. The review will also cover the impact of single atom substitutional dopants, such as Cr, V and Mn, and electron energy loss spectroscopy used to understand the local bonding configuration. It is expected that this review will provide an atomic level understanding of 2D TMDs with a connection to imperfections that can arise from chemical vapour deposition synthesis, intentional doping, rips and tears, dislocations, strain, polycrystallinity and confinement to nanoribbons.