Laparoscopic transvesical excision and reconstruction in the management of mid-urethral tape mesh erosion and stones around the bladder neck: initial experiences.
Study Type--Prevalence (prospective cohort) Level of Evidence 1b. What's known on the subject? and What does the study add? Managing foreign bodies, including mesh and stones, after anti-incontinence surgery is important because complete removal is necessary to prevent infection and recurrence of stone formation. Traditionally, surgical management of such complications has involved excision using a transurethral approach, with or without a laparoscopic transvesical procedure. The study shows that mesh complications, including exposure and adherent stones, can be successfully treated and a fast recovery can be achieved using transvesical laparoscopic excision and reconstruction. Transvesical laparoscopy is especially suitable for cases that have a restricted visual field with cystoscopy; the technique allows complete removal of mesh/stones and reconstruction with the help of an excellent visual field. • To evaluate laparoscopic transvesical excision and reconstruction for the management of vesical mesh or stones around the bladder neck as complications of anti-incontinence intervention. • To compare the techniques, outcomes and recurrence rates of laparoscopic transvesical excision and reconstruction with published results from studies using laparoscopic transvesical procedures. • We conducted a retrospective review of three patients who underwent laparoscopic transvesical excision and reconstruction for vesical mesh and stones around the bladder neck. • Patients were identified from operating records including recorded video and electronic data records. • We also conducted a literature review of the available evidence on transvesical laparoscopy for lower urinary tract complications of anti-incontinence procedures. • Between March 2005 and May 2011, three women underwent laparoscopic transvesical excision and reconstruction. All presented with storage symptoms and gross haematuria. The interval between surgery and the diagnosis of presence of a foreign body was 1-3 years. • Two women had previously undergone transobturator tape procedures and one had undergone a retropubic procedure. • Complete excision including the mucosa and muscle layer and reconstruction with intravesical sutures was achieved in all cases. • Storage symptoms were resolved within 3 days and haematuria was not observed. • None of the women had recurrent erosion at follow-up. • Laparoscopic transvesical excision and reconstruction is a technically feasible method. • This procedure offers excellent visualization of mesh materials and stones, especially in cases of location near the anterior bladder neck. • In selected patients, laparoscopic transvesical excision and reconstruction is an acceptable technique for first-line treatment of complications of anti-incontinence procedures.


Identifying modifiable and nonmodifiable cost drivers of ambulatory rotator cuff repair: a machine learning analysis.
Implementing novel tools that identify contributors to the cost of orthopedic procedures can help hospitals maximize efficiency, minimize waste, improve surgical decision-making, and practice value-based care. The purpose of this study was to develop and internally validate a machine learning algorithm to identify key drivers of total charges after ambulatory arthroscopic rotator cuff repair and compare its performance with a state-of-the-art statistical learning model. A retrospective review of the New York State Ambulatory Surgery and Services Database was performed to identify patients who underwent elective outpatient rotator cuff repair (RCR) from 2015 to 2016. Initial models were constructed using patient characteristics (age, gender, insurance status, patient income, Elixhauser Comorbidity Index) as well as intraoperative variables (concomitant procedures and services, operative time). These were subsequently entered into 5 separate machine learning algorithms and a generalized additive model using natural splines. Global variable importance and partial dependence curves were constructed to identify the greatest contributors to cost. A total of 33,976 patients undergoing ambulatory RCR were included. Median total charges after ambulatory RCR were $16,017 (interquartile range: $11,009-$22,510). The ensemble model outperformed the generalized additive model and demonstrated the best performance on internal validation (root mean squared error: $7112, 95% confidence interval: 7036-7188; logarithmic root mean squared error: 0.354, 95% confidence interval: 0.336-0.373, R2: 0.53), and identified major drivers of total charges after RCR as increasing operating room time, patient income level, number of anchors used, use of local infiltration anesthesia/peripheral nerve blocks, non-White race/ethnicity, and concurrent distal clavicle excision. The model was integrated into a web-based open-access application capable of providing individual predictions and explanations on a case-by-case basis. This study developed an ensemble supervised machine learning algorithm that outperformed a sophisticated statistical learning model in predicting total charges after ambulatory RCR. Important contributors to total charges included operating room time, duration of care, number of anchors used, type of anesthesia, concomitant distal clavicle excision, community characteristics, and patient demographic factors. Generation of a patient-specific payment schedule based on the Agency for Healthcare Research and Quality risk of mortality highlighted the financial risk assumed by physicians in flat episodic reimbursement schedules given variable patient comorbidities and the importance of an accurate prediction algorithm to appropriately reward high-value care at low costs.


The field of psychiatric contention in the UK, 1960-2000.
In this paper I discuss the question of how we should understand the concept of "social movements", particularly as applied to health related movements. My argument is that movements should be understood as "fields of contention". This concept, as I develop it, emphasizes two key aspects of social movement mobilization. Firstly, departing from traditional models of movements, which tend to view them as unified "things", it draws our attention to the numerous groups and agents who interact within the internal space of a "movement" and to the relations, alliances and conflicts between those various groups/agents as they unfold through time. Secondly, it draws our attention to the embedding of social movement struggles within multiple differentiated contexts of struggle, each of which affords different opportunities for struggle but each of which makes different demands upon activists if struggle is to prove effective. The model of fields of contention is explored within the paper using empirical data on a variety of "social movement organizations" (SMOs) which have formed around the mental health system in the UK over the last forty years.


Reduction of the uptake by a macrophagic cell line of nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate).
Amphiphilic and fluorescent covalently labelled core-shell nanoparticles based on poly(methyl methacrylate) (PMMA), were prepared by random copolymerisation of N-Vinyl carbazole (NVC) with MMA, initiated on polysaccharidic radicals, yielding diblock copolymers of either dextran-P(MMA-NVC) (Nanodex* particles), or heparin-P(MMA-NVC) (Nanohep* particles). Nanoparticles made from random copolymers of P(MMA-NVC) (PMMA*) were used as controls. The interactions between particles and a J774A1 murine macrophage-like cell line were quantified by direct measurement of the cell-associated fluorescence. The association with the cells occurred within 30 min. Nanodex* and Nanohep* showed considerably less association than the control PMMA* particles. Some of the particle uptake could be attributed to phagocytosis, but more than 50% of the cell-associated fluorescence persisted at low temperature or in the presence of cytochalasin B. The results suggest that both the adsorption and the internalisation processes can be inhibited by the presence of the polysaccharide chains. In conclusion, these results confirm that nanoparticles prepared with heparin or dextran chains on their surface, probably in a brush-like configuration, show "stealth" properties in vitro as had previously been observed in vivo. If this biomimetic approach can also be applied to biodegradable polymers, these systems would provide at least an alternative to PEG-modified particles as long-circulating drug carriers systems or imaging agents.


Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome.
The cellular-stress response can mediate cellular protection through expression of heat-shock protein (Hsp) 70, which can interfere with the process of apoptotic cell death. Stress-induced apoptosis proceeds through a defined biochemical process that involves cytochrome c, Apaf-1 and caspase proteases. Here we show, using a cell-free system, that Hsp70 prevents cytochrome c/dATP-mediated caspase activation, but allows the formation of Apaf-1 oligomers. Hsp70 binds to Apaf-1 but not to procaspase-9, and prevents recruitment of caspases to the apoptosome complex. Hsp70 therefore suppresses apoptosis by directly associating with Apaf-1 and blocking the assembly of a functional apoptosome.


Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains.
Dopamine regulates reward, cognition, and locomotor functions. By mediating rapid reuptake of extracellular dopamine, the dopamine transporter is critical for spatiotemporal control of dopaminergic neurotransmission. Here, we use super-resolution imaging to show that the dopamine transporter is dynamically sequestrated into cholesterol-dependent nanodomains in the plasma membrane of presynaptic varicosities and neuronal projections of dopaminergic neurons. Stochastic optical reconstruction microscopy reveals irregular dopamine transporter nanodomains (∼70 nm mean diameter) that were highly sensitive to cholesterol depletion. Live photoactivated localization microscopy shows a similar dopamine transporter membrane organization in live heterologous cells. In neurons, dual-color dSTORM shows that tyrosine hydroxylase and vesicular monoamine transporter-2 are distinctively localized adjacent to, but not overlapping with, the dopamine transporter nanodomains. The molecular organization of the dopamine transporter in nanodomains is reversibly reduced by short-term activation of NMDA-type ionotropic glutamate receptors, implicating dopamine transporter nanodomain distribution as a potential mechanism to modulate dopaminergic neurotransmission in response to excitatory input.The dopamine transporter (DAT) has a crucial role in the regulation of neurotransmission. Here, the authors use super-resolution imaging to show that DAT clusters into cholesterol-dependent membrane regions that are reversibly regulated by ionotropic glutamate receptors activation.


[Serum lysozyme concentrations in patients with morbus Crohn before and after bowel resection (author's transl)].
Serum lysozyme (muramidase) concentrations were determined in five patients with Morbus Crohn before and after resection of inflammated bowel areas. The serum lysozyme activity which was elevated before surgical treatment in all patients fell to normal values after bowel resection within a few hours. Our findings suggest, that the elevated serum lysozyme reflects an increased lysozyme production in the inflammated bowel tissue.


Discrimination of an amphetamine-pentobarbitone mixture by rats in an AND-OR paradigm.
Rats were trained to discriminate a mixture of amphetamine plus pentobarbitone from either drug separately in a two-bar procedure with food reinforcement. Discrimination was 86% accurate after 48 sessions, and no dose of amphetamine or pentobarbitone alone produced mixture-appropriate responding. Some mixtures increased response rates whereas the same doses of each drug separately had little effect. The same rats were then trained to discriminate a mixture from saline. There was a continuing lack of discriminative response to amphetamine and only a partial response to pentobarbitone, and under these conditions mixtures did not increase overall response rates. Thus, the way rats are trained, and their previous history, can determine the characteristics of the cue obtained.


Improving our estimates: assessing misclassification of abortion accessibility in the United States.
Quantify the misclassification of abortion accessibility resulting from calculations based on block groups, census tracts, ZCTAs, or counties versus census blocks. We included 850 facilities from the 2018 ANSIRH Facility Database and Planned Parenthood website. Accessibility was the proportions of 18-44 year-old women living within a 30-, 60-, and 90-minute drive from an abortion-providing facility. We calculated accessibility using five different geographic units: census blocks, block groups, census tracts, ZCTAs, and counties. We estimated the potential magnitude of abortion accessibility misclassification resulting by calculating the difference between accessibility calculated using each geographic unit, respectively, for each drive time as compared to census blocks. In this analysis, counties, the largest geographic unit considered, underestimated national abortion accessibility compared with census blocks by up to 24.21 percentage points; while block group-, census tract, or ZCTA-based national estimates of abortion accessibility in the US resulted in small underestimates relative to estimates constructed using census blocks. Studies of population accessibility should use the smallest feasible geographic unit of analysis. While this study focused on abortion accessibility, our findings likely apply to other health services, particularly those with distributions like abortion care.


Genomic and Phenotypic Biomarkers for Precision Medicine Guidance in Advanced Prostate Cancer.
Prostate cancer (PCa) is the second most diagnosed malignant neoplasm and is one of the leading causes of cancer-related death in men worldwide. Despite significant advances in screening and treatment of PCa, given the heterogeneity of this disease, optimal personalized therapeutic strategies remain limited. However, emerging predictive and prognostic biomarkers based on individual patient profiles in combination with computer-assisted diagnostics have the potential to guide precision medicine, where patients may benefit from therapeutic approaches optimally suited to their disease. Also, the integration of genotypic and phenotypic diagnostic methods is supporting better informed treatment decisions. Focusing on advanced PCa, this review discusses polygenic risk scores for screening of PCa and common genomic aberrations in androgen receptor (AR), PTEN-PI3K-AKT, and DNA damage response (DDR) pathways, considering clinical implications for diagnosis, prognosis, and treatment prediction. Furthermore, we evaluate liquid biopsy, protein biomarkers such as serum testosterone levels, SLFN11 expression, total alkaline phosphatase (tALP), neutrophil-to-lymphocyte ratio (NLR), tissue biopsy, and advanced imaging tools, summarizing current phenotypic biomarkers and envisaging more effective utilization of diagnostic and prognostic biomarkers in advanced PCa. We conclude that prognostic and treatment predictive biomarker discovery can improve the management of patients, especially in metastatic stages of advanced PCa. This will result in decreased mortality and enhanced quality of life and help design a personalized treatment regimen.


Levels of T lymphocytes, but not specific antibodies, reflect clinical presentation in human herpes simplex keratitis.
Total erythrocyte Rosette-forming cells (ERFC) have been found to be decreased in 44 patients with recurrent ocular herpes but normal in 26 patients with the primary form of the disease. Active ERFC have been found to be decreased in 27 patients with herpetic keratouveitis and normal in 43 patients with superficial herpetic keratitis. Antibodies to herpes simplex virus could not be used to distinguish the various clinical presentations of the disease.


Evaluations of clinical tobacco cessation interventions in Arab populations: A systematic review.
Tobacco smoking is prevalent among Arab smokers. Interventions to support smoking cessation may differ in effectiveness in this population from Western populations usually studied. This review assessed evidence of effectiveness of clinical smoking interventions in Arab smokers. A systematic search for comparative trials evaluating tobacco cessation interventions in Arab populations was conducted in the MEDLINE, EMBASE, PyschINFO, CINHAL and Web of Science databases. Behavioural, pharmacological and combined interventions were included. Reference lists of included studies were hand searched. The outcome measure was self- reported tobacco abstinence at the final follow-up, with biochemical verification where available. Assessment of evidence for effectiveness was undertaken using Bayes Factors. A total of 659 titles and abstracts were identified. Five studies met the inclusion criteria. Four of these were randomized controlled trials and one was a non-randomized comparative trial. Differences between study features precluded meaningful aggregation for a meta-analysis. The four randomized trials all yielded Bayes Factors <1, suggesting no effect of the intervention compared with the control condition. The non-randomized trial, conducted in tuberculosis clinics in Sudan, yielded an extremely high Bayes Factor (>1000), supporting the hypothesis of effectiveness; however, the study was judged to have a high risk of bias. As yet, there is no convincing direct evidence that clinical smoking cessation interventions, which are found to be effective in Western populations, are also effective for Arab smokers. There is an urgent need for high quality randomized trials evaluating interventions in this population.


Combined spinal and general anesthesia attenuate tumor promoting effects of surgery. An experimental animal study.
Radical prostatectomy, a standard management approach for localized Prostate Cancer (PC), may cause a stress response associated with immune modulating effects. Regional anesthesia was hypothesized to reduce the immune effects of surgery by minimizing the neuroendocrine surgical stress response, thus mitigating tumor cells dissemination. Our primary objective was to investigate whether the use of spinal blocks attenuates PC tumor cells dissemination on an animal model. We also assessed the number of circulating NK cells and the amount of inflammatory and anti-inflammatory cytokines. A subcutaneous tumor model, with PC-3M cell line transfected with a luciferase-producing gene (PC-3M-luc-C6) was used. After proper tumor establishment and before tumors became metastatic, animals were submitted to tumor excision surgeries under general or combined (general and spinal) anesthesia. A control group was only anesthetized with general anesthesia. The subcutaneous tumor model with PC-3M-luc-C6 cells was effective in causing distant metastasis after 35 days. The number of circulating tumor cells increased in animals that underwent surgery under general anesthesia alone compared to the group submitted to combined anesthesia. Interleukin 6 levels were different in all groups, with increase in the general anesthesia group. Our results suggest that combination of spinal and general anesthesia may attenuate the suppression of innate tumor immunity and it might be related to a reduction in the neuroendocrine response to surgery. Animal Ethics Committee 1332/2019.


Proposed management of childhood tuberculosis in low-incidence countries.
The incidence of childhood tuberculosis continues to decline in central Europe, but due to migration from high incidence countries paediatricians will still be confronted with it. The management of childhood tuberculosis in low-incidence, high-income countries differs from most high-incidence countries. The primary measures for preventing the transmission of tuberculosis to children are the detection of adult source cases, detection of latent TB infection (LTBI) in children by history, tuberculin skin testing and, if necessary and recommended, interferon-gamma release assays. Children with LTBI should receive preventive therapy. The inclusion of tuberculosis in the differential diagnosis of unclear pulmonary and extrapulmonary disease remains important, and tuberculosis has to be managed according to international standards.


A comparison between real-time intraoperative voice dictation and the operative report in laparoscopic cholecystectomy: a multicenter prospective observational study.
The current operative report often inadequately reflects events occurring during laparoscopic cholecystectomy (LC). The addition of intraoperative video recording to the operative report has already proven to add important information. It was hypothesized that real-time intraoperative voice dictation (RIVD) can provide an equal or more complete overview of the operative procedure compared to the narrative operative report (NR) produced postoperatively. SONAR is a multicenter prospective observational trial, conducted at four surgical centers in the Netherlands. Elective LCs of patients aged 18 years and older were included. Participating surgeons were requested to dictate the essential steps of LC during surgery. RIVDs and NRs were reviewed according to the stepwise LC guideline of the Dutch Society for Surgery. The cumulative adequacy rates for RIVDs were compared with those of the postoperatively written NR. 79 of 90 cases were eligible for inclusion and available for further analysis. RIVD resulted in a significantly higher adequacy rate compared to NR for the circumferential dissection of the cystic duct and artery (NR 32.5% vs. RIVD 61.0%, P = 0.016). NR had higher adequacy rates in reporting the transection of the cystic duct (NR 100% vs. RIVD 77.9%, P = < 0.001) and the removal of the gallbladder from the liver bed (NR 98.7% vs. RIVD 68.8%, P < 0.001). The total adequacy was not significantly different between the two reporting methods (NR 78.0% vs. RIVD 76.4%, P = 1.00). Overall, the adequacy of RIVD is comparable to the postoperatively written NR in reporting surgical steps in LC. However, the most essential surgical step, the circumferential dissection of the cystic duct and artery, was reported more adequately in RIVD.


Individual risk preference as a predictor of health behaviour: evidence from the use of condoms against HIV/AIDS in Ghana.
It is evident that public health education interventions to promote the use of condoms against HIV infections in Ghana have yielded modest results. However, existing studies in the field of sexual and reproductive health in Ghana have failed to account for differences in risk preferences of individuals. This study fills the gap by investigating how individuals' risk preferences predict their behaviour toward using condoms against HIV in Ghana. Conceptually, the study followed the Grossman health capital theoretical model for risk preference and health behaviour nexus. Data were obtained from the most recent Ghana Living Standards Survey Round 7 (GLSS 7), conducted in 2017. Using data from GLSS 7, a probit regression model was estimated to show how the risk preferences of individuals that did not abstain from sex predicted their use of condoms against HIV. To ensure robustness, two scenarios of declared risk preferences were used to predict the use of condom behaviour against HIV. Probit regression estimation shows that the risk preferences of individuals that did not abstain from sex significantly predicted their use of condoms against HIV in Ghana. Even though the study found that the predicted probability of using a condom reduces among risk-averse individuals that do not abstain from sex, not using a condom against HIV was found to be worse among risk lovers. The study provides empirical evidence that public health education against HIV/AIDS in Ghana cannot continue to ignore the risk preference of individuals. The results of this study have immediate implications, first for a comprehensive and continuous measurement of risk preferences among Ghanaians in major household surveys going forward. At the moment, the latest round of the GLSS is just about the only household survey in Ghana that has attempted to collect some data on individual time and risk preferences using only hypothetical monetary rewards. Second is the immediate consideration of individual risk preferences in public health education campaigns against HIV/AIDS in Ghana.


Philosophy on steroids: why the anti-doping position could use a little enhancement.
There is currently much concern over the use of pharmaceuticals and other biomedical techniques to enhance athletic performance--a practice we might refer to as doping. Many justifications of anti-doping efforts claim that doping involves a serious moral transgression. In this article, I review a number of arguments in support of that claim, but show that they are not conclusive, suggesting that we do not have good reasons for thinking that doping is wrong.


Decoding the mechanism of hypertension through multiomics profiling.
Hypertension, characterised by a constant high blood pressure, is the primary risk factor for multiple cardiovascular events and a major cause of death in adults. Excitingly, innovations in high-throughput technologies have enabled the global exploration of the whole genome (genomics), revealing dysregulated genes that are linked to hypertension. Moreover, post-genomic biomarkers, from the emerging fields of transcriptomics, proteomics, glycomics and lipidomics, have provided new insights into the molecular underpinnings of hypertension. In this paper, we review the pathophysiology of hypertension, and highlight the multi-omics approaches for hypertension prediction and diagnosis.


Resolution of blood eosinophilia and limited mouth opening after short-term follow-up in a pediatric Langerhans cell histiocytosis case.
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia that often affects children, presenting a broad clinical spectrum. Here, we report a 13-year-old male Salvadorian patient who was referred presenting a nodular swelling at the mandibular angle region, mildly symptomatic, few weeks ago, which relevantly was associated with limited mouth opening. Intraoral examination was unremarkable. Imaginological exams revealed an osteolytic lesion affecting the vestibular cortex at the right mandibular angle. The blood test results were normal, except for eosinophilia (21%; absolute eosinophil count 4 × 109/L). After an incisional biopsy, microscopical and immunohistochemical analyses were consistent with LCH diagnosis, which corresponded to a single system-single site category. After a few weeks, the mandibular movements were re-established, and complete resolution of blood eosinophilia was observed. LCH with blood eosinophilia is rarely reported. To our knowledge, 3 cases have been previously published.


Correlation between bone mineral density and sarcopenia in US adults: a population-based study.
In the aging process of the body, in addition to changes in fat and muscle content, there is also bone loss, implying the possibility of a strong muscle-bone-lipid link. In this study, we initially investigated the relationship between lumbar BMD and low muscle mass and the relationship between "muscle-bone-lipid." The datasets from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 were used in a cross-sectional investigation. BMD and appendicular skeletal muscle (ASM) were measured by dual-energy X-ray absorptiometry (DXA), and appendicular skeletal muscle was adjusted by body mass index (BMI) as a marker of sarcopenia. Weighted multivariate regression and logistic regression analysis were used to explore the independent relationship between lumbar BMD and sarcopenia. Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationship. In 8386 participants with ages 20-59 years, there was a negative association between lumbar BMD and sarcopenia. In the fully adjusted model, the risk of developing sarcopenia decreased by 93% for each 1-unit increase in lumbar BMD (OR = 0.07, 95%CI 0.03-0.20). The risk of sarcopenia was 58% lower in participants in the highest quartile of lumbar BMD than in those in the lowest quartile (OR = 0.42, 95%CI 0.27-0.64). This negative association was more pronounced in the population of women with BMI ≥ 25. Our findings suggest that lumbar BMD is negatively associated with sarcopenia in US adults. The dynamic balance between "muscle-bone-lipid" is likely to be related to the pathogenesis of bone loss.


Analysis of relevant proteins from bone graft harvested using the reamer irrigator and aspirator system (RIA) versus iliac crest (IC) bone graft and RIA waste water.
Femoral reaming using a Reamer Irrigator Aspirator (RIA) can produce greater than three liters of waste water per procedure, which contains cells and proteins that could promote bone healing. This purpose of this study was to determine the protein profile of RIA waste water and compare protein synthesis by cells harvested via RIA versus iliac crest (IC) bone graft. Bone graft was collected from 30 patients-15 using RIA from the femur and 15 harvested from the iliac crest. Waste water collected during the RIA procedure was analyzed in 12 patients. Cells from each graft were cultured in monolayer using growth media for 14days and inductive media for the next 14days. Media samples were collected on days 14, 21, and 28. Proteins for analysis were chosen based on their potential in bone healing, pro-inflammatory, and anti-inflammatory processes. Proteins present in RIA waste water indicate the potential for clinical use of this filtrate as an adjunct for enhancing bone production, healing, and remodeling. Similarly, cells cultured from RIA bone graft harvests compared favorably to those from iliac crest bone grafts with respect to their potential to aid in bone healing. RIA waste water has potential to serve as an autogenic and allogenic enhancer for bone healing. Continued development of processing protocols for viable commercial use of the waste water and pre-clinical studies designed to evaluate RIA waste water products for bone healing are ongoing.


Haemophilus influenzae strains possess variations in the global transcriptional profile in response to oxygen levels and this influences sensitivity to environmental stresses.
An alcohol dehydrogenase, AdhC, is required for Haemophilus influenzae Rd KW20 growth with high oxygen. AdhC protects against both exogenous and metabolically generated, endogenous reactive aldehydes. However, adhC in the strain 86-028NP is a pseudogene. Unlike the Rd KW20 adhC mutant, 86-028NP does grow with high oxygen. This suggests the differences between Rd KW20 and 86-028NP include broader pathways, such as for the maintenance of redox and metabolism that avoids the toxicity related to oxygen. We hypothesized that these differences affect their resistance to relevant toxic chemicals, including reactive aldehydes. Across a range of oxygen concentrations, despite the growth profiles of Rd KW20 and 86-028NP being similar, there was a significant variation in their sensitivity to reactive aldehydes. 86-028NP is more sensitive to methylglyoxal, formaldehyde and glycolaldehyde under high oxygen than low oxygen as well as compared to Rd KW20. Also, as oxygen levels changed the whole genome gene expression profiles of Rd KW20 and 86-028NP revealed distinctions in their transcriptomes (the iron, FNR and ArcAB regulons). These were indicative of a difference in their intracellular redox properties and we show it is this that underpins their survival against reactive aldehydes.


The mechanism of the aminoacylation of transfer ribonucleic acid. The kinetics and stoichiometry of the lysis of aminoacyl-tRNA.
It is often stated that the aminoacylation of transfer RNA proceeds in discrete steps: (formula: see article). If this is a complete description of the reaction, the reverse overall formation of ATP should not be more rapid than the formation of Enz . (AA approximately AMP). We show for four different amino acid:tRNA ligases that lysis of AA-tRNA (with PPi and AMP) to ATP is faster than lysis of AA-tRNA (with AMP only) to Enz . (AA approximately AMP). This requires that the transition state proceeds from a quaternary complex of PPi, AMP, AA-tRNA and Enz. From the law of microscopic reversibility, this requires that in the forward reaction the AA-tRNA bond be formed before PPi leaves the enzyme complex. Therefore, the forward reaction passes through the quaternary complex Enz . ATP . AA . tRNA. (In view of recent evidence of the specific requirement of two cations, the complex is accurately described as senary).


Effective NH2-grafting on attapulgite surfaces for adsorption of reactive dyes.
The amine moiety has an important function in many applications, including, adsorption, catalysis, electrochemistry, chromatography, and nanocomposite materials. We developed an effective adsorbent for aqueous reactive dye removal by modifying attapulgite with an amino-terminated organosilicon (3-aminopropyltriethoxysilane, APTES). Surface properties of the APTES-modified attapulgite were characterized by the Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and nitrogen adsorption-desorption. We evaluated the impact of solvent, APTES concentration, water volume, reaction time, and temperature on the surface modification. NH(2)-attapulgite was used to remove reactive dyes in aqueous solution and showed very high adsorption rates of 99.32%, 99.67%, and 96.42% for Reactive Red 3BS, Reactive Blue KE-R and Reactive Black GR, respectively. These powerful dye removal effects were attributed to strong electrostatic interactions between reactive dyes and the grafted NH(2) groups.


Antibiotic-associated Stevens-Johnson syndrome.
Overview of: Lee EY, Knox C, Phillips EJ. Worldwide prevalence of antibiotic-associated Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol 2023;159:384-392.


Different crosslinking as a strategy to improve films produced from external mesocarp of pequi (Caryocar brasiliense).
The pequi (Caryocar brasiliense) external mesocarp is rich in phenolic compounds and pectin and demonstrates the potential to produce active and biodegradable films. Thus, the present study aimed to produce films with pequi mesocarp as a polymer matrix and evaluate the influence of crosslinking agents (calcium chloride and citric acid) on the film's properties. The films obtained from pequi mesocarp (MF), showed in general, complete biodegradation in 33 days, good antioxidant capacity, and inhibition against S. aureus (24.7 mm) and E. coli (23.0 mm). The crosslinking agents reduced solubility by up to 35% and increased the elongation of the films by up to 3.5-fold. Calcium chloride promoted a higher reduction in solubility, and both agents increase the antioxidant and antimicrobial activities, compared to MF. Citric acid proved to be the best agent to modify the properties of pequi mesocarp films. In addition to the crosslinking action, it presented plasticizing effect.


Selective induction of pancreatic ductular tumors by single doses of N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters.
The selectivity of response by the Syrian hamster pancreas to the neoplastic effect of N-nitrosobis(2-oxopropyl)amine (BOP) was demonstrated by single subcutaneous injections of the compound. Only occasional tumors were induced simultaneously with those of the pancreas in the biliary ducts, kidneys and lungs of a few hamsters. In the pancreas, the ductules, especially those of an intrainsular location, were the cells primarily affected. The responded to doses as low as 1/40 of the LD50, whereas ductal lesions were found only in some hamsters treated with doses above 1/5 of the LD50. Hence it is concluded that hamster ductular cells are the most responsive to the carcinogenic action of BOP.


Regulation of Geminin and Cdt1 expression by E2F transcription factors.
Geminin and Cdt1 play an essential role in the initiation of DNA replication, by regulating the chromatin loading of the MCM complex. In this study, we showed that the transcription of human Geminin and Cdt1, as well as that of MCM7, is activated by transcription factors E2F1-4, but not by factors E2F5-7. Analysis of various Geminin and Cdt1 promoter constructs showed that an E2F-responsive sequence in the vicinity of the transcription initiation site is necessary for the transcriptional activation. The promoter activity for human Geminin was activated by the E7, but not E6, oncogene of human papillomavirus type 16. While E2F1-induced activation of human Cdt1 gene transcription was suppressed by pRb, but not by p107 or p130, its E2F4-induced activation was suppressed by pRb, p107, and p130. Furthermore, the promoter activities of human Geminin and Cdt1 were demonstrated to be growth-dependent. Taken together, the results demonstrate that Geminin and Cdt1 constitute targets for various members of the E2F family of transcription factors, and that expression of Geminin and Cdt1 is perhaps mediated by the activation of a pRb/E2F pathway.


Factors Predicting Lung Contusions in Critically Ill Trauma Children: A Multivariate Analysis of 330 Cases.
The aim of the study was to identify factors predicting lung contusion in trauma children. Retrospective study conducted for a period of 8 years (January 01, 2005-December 31, 2012) in a medical surgical intensive care unit. All trauma patients younger than 15 years were included. Two groups were compared: those with lung contusions (C+ group) and those without lung contusions (C- group). We included 330 patients. The mean (SD) age was 7.6 (4.3) years. Chest injury was diagnosed in 70 patients (21.2%). All our patients needed mechanical ventilation. Lung contusions were diagnosed in 43 patients (13% of all patients and 61.4% of patients with chest trauma). In multivariate analysis, independent factors predicting lung contusion were road traffic accident (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.2-8.6; P = 0.019), increased Pediatric Risk of Mortality (PRISM) score (OR, 1.1; 95% CI, 1.1-1.2; P = 0.017), hepatic contusion (OR, 4.8; 95% CI, 1.3-17.1; P = 0.017), and pelvic ring fracture (OR, 3.5; 95% CI, 1.1-10.5; P = 0.026). Death occurred in 46 patients (13.9%). Intensive care unit mortality was significantly higher in the C+ group (OR, 2.5; 95% CI, 1.2-5.4; P = 0.021). However, mortality was not different between the 2 groups after adjusting for PRISM score (OR, 1.2; 95% CI, 0.5-2.9; P = 0.752) or after adjusting for Injury Severity Score (OR, 0.7; 95% CI, 0.3-2.1; P = 0.565). Lung contusion is common in critically ill children with chest trauma. The diagnosis should be considered in patients with road traffic accident, increased PRISM score, hepatic contusion, and pelvic ring fracture.


Ca2+-ATPase inhibitor induces IL-4 and MCP-1 production in RBL-2H3 cells.
The effects of a Ca2(+)-ATPase inhibitor, cyclopiazonic acid (CPA), and two hydroquinone-antioxidants, 2,5-di-(tert-butyl)-1,4-hydroquinone (DTBHQ) and 2,5-di-(tert-amyl)-1,4-hydroquinone (DTAHQ) on the release of IL-4 and MCP-1 from RBL-2H3 cells were investigated. CPA, DTBHQ and DTAHQ, all of which induce intracellular free Ca2+ concentration ([Ca2+]i) increase, induced IL-4 and MCP-1 release in a dose-dependent manner. The release of TNF-alpha required both a Ca2(+)-ATPase inhibitor and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the Ca2(+)-ATPase inhibitors induced IL-4 and MCP-1 production without TPA. The release of IL-4 and MCP-1 reached a maximum at 9 and 6 h, respectively. IL-4 and MCP-I release was inhibited by treatment with the immunosuppressant FK-506 and actinomycin D. Therefore, in our system IL-4 and MCP-1 release involves Ca2(+)-dependent and FK-506-sensitive signaling pathways. This is the first report about Th-2 type cytokine and chemokine production in RBL-2H3 cells.


Investigation and threshold of optimum blood concentration of voriconazole: a descriptive statistical meta-analysis.
Voriconazole (VRCZ) reportedly possesses a broad spectrum of antifungal activity against Aspergillus spp. and Candida spp., and the blood concentration of VRCZ is correlated with both the efficacy and the adverse effects of this drug. Monitoring of the blood concentration target level of VRCZ has not yet been widely adopted in the medical field, and no evidence concerning this target level has been reported. Accordingly, we used a meta-analysis to investigate the optimal blood concentration of VRCZ. Using data from 12 reports, we found that the success rate for fungal infection treatment increased significantly at VRCZ levels greater than 1.0 μg/ml when a graded cutoff value within the range of 1.0-3.0 μg/ml was used as the VRCZ trough blood concentration [odds ratio (OR) 7.23, 95% confidence interval (CI) 2.84-18.37, P < 0.0001]. Concerning the safety evaluation, the incidence of adverse neurological effects increased significantly at a cutoff value of 4.0 μg/ml when a graded cutoff value within the range of 3.0-6.0 μg/ml was used (OR 2.23, 95% CI 1.12-4.46, P = 0.02). However, in all 12 literature sources, an increasing incidence of liver dysfunction was reported at higher blood concentrations, and no accurate cutoff values were obtained. Consequently, a VRCZ trough blood concentration more than 1.0 μg/ml from the perspective of efficacy and less than 4.0 μg/ml from the perspective of safety is recommended.


Small-angle x-ray scattering investigation of the solution structure of troponin C.
X-ray crystallographic studies of troponin C (Herzberg, O., and James, M.N.G. (1985) Nature 313, 653-659; Sundaralingam, M., Bergstrom, R., Strasburg, G., Rao, S.T., and Roychowdhury, P. (1985a) Science 227, 945-948) have revealed a novel protein structure consisting of two globular domains, each containing two Ca2+-binding sites, connected via a nine-turn alpha-helix, three turns of which are fully exposed to solvent. Since the crystals were grown at pH approximately 5, it is of interest to determine whether this structure is applicable to the protein in solution under physiological conditions. We have used small-angle x-ray scattering to examine the solution structure of troponin C at pH 6.8 and the effect of Ca2+ on the structure. The scattering data are consistent with an elongated structure in solution with a radius of gyration of approximately 23.0 A, which is quite comparable to that computed for the crystal structure. The experimental scattering profile and the scattering profile computed from the crystal structure coordinates do, however, exhibit differences at the 40-A level. A weak Ca2+-facilitated dimerization of troponin C was observed. The data rule out large Ca2+-induced structural changes, indicating rather that the molecule with Ca2+ bound is only slightly more compact than the Ca2+-free molecule.


Implantable Cardioverter Defibrillators for Primary Prevention of Mortality in Patients With Nonischemic Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials.
Implantable cardioverter defibrillators (ICDs) improve survival in patients with heart failure due to ischemic cardiomyopathy, but their benefit in nonischemic cardiomyopathy (NICM) has been recently questioned. We performed a meta-analysis of randomized clinical trials to examine the effect of ICDs on total mortality and arrhythmic death in patients with NICM. We also examined the impact of age and cardiac resynchronization therapy (CRT) on the relative effect of ICD compared to control. We searched the MEDLINE and EMBASE databases for randomized trials evaluating the effect of ICD versus control in patients with NICM. Hazard ratios (HR) with 95% confidence interval (CI) were calculated using a random effects model. Six trials involving 2,967 patients were included (ICD, n = 1,553; control, n = 1,414). Based on the pooled estimate across the six studies, the use of ICD was associated with a significant reduction in total mortality (HR = 0.78, 95% CI 0.66-0.92; P = 0.003), as well as arrhythmic death (HR = 0.46, 95% CI 0.29-0.71; P = 0.0005) compared to control. ICD decreased total mortality in younger patients compared to control (HR = 0.63, 95% CI 0.46-0.86; P = 0.004), but not in older patients (HR = 0.97, 95% CI 0.56-1.68; P = 0.92). In patients with CRT, ICD reduced total mortality compared to control (HR = 0.78, 95% CI 0.65-0.95; P = 0.02), but not in patients with CRT (HR = 0.71, 95% CI 0.40-1.26). ICDs decrease total mortality and arrhythmic deaths in patients with NICM. The benefit of ICD appears to be dependent on age and concomitant use of CRT.


Sleep deprivation affects gait control.
Different levels of sleep restriction affect human performance in multiple aspects. However, it is unclear how sleep deprivation affects gait control. We applied a paced gait paradigm that included subliminal rhythm changes to analyze the effects of different sleep restriction levels (acute, chronic and control) on performance. Acute sleep deprivation (one night) group exhibited impaired performance in the sensorimotor synchronization gait protocol, such as a decrease in the Period Error between the footfalls and the auditory stimulus as well as missing more frequently the auditory cues. The group with chronic sleep restriction also underperformed when compared to the control group with a tendency to a late footfall with respect to the RAC sound. Our results suggest that partial or total sleep deprivation leads to a decrease in the performance in the sensorimotor control of gait. The superior performance of the chronic sleep group when compared to the acute group suggests that there is a compensatory mechanism that helps to improve motor performance.


Chronic trans-astaxanthin treatment exerts antihyperalgesic effect and corrects co-morbid depressive like behaviors in mice with chronic pain.
Patients suffering from chronic neuropathic pain are at high risk of co-morbid depression, which burdens healthcare. Trans-astaxanthin has been shown in our previous studies to exert antidepressant-like effect. This work aimed to investigate the effects of trans-astaxanthin on pain-related depressive-like behaviors in mice and explored the mechanism(s). Chronic constriction injury (CCI) model was used in this research. Chronic pain was evaluated by thermal hyperalgesia in Hargreaves test and mechanical allodynia in von Frey test, depressive-like behaviors were evaluated by immobility time in forced swim test and tail suspension test. Chronic trans-astaxanthin treatment ameliorated mechanical allodynia and thermal hyperalgesia, as well as decreasing immobility time in forced swim test and tail suspension test in CCI mice, and these actions were abolished by co-treatment with P-Chlorophenylalanine (PCPA). Subsequent study indicated that indoleamine 2,3-dioxygenase (IDO) expression increased after CCI surgery in hippocampus and spinal cord, accompanied by increase of kynurenine (KYN)/tryptophan (TRY) ratio, decrease of serotonin (5-HT)/TRY ratio and decrease of 5-HT/5-HIAA ratio. The above results affected by CCI surgery were reversed by trans-astaxanthin treatment. Moreover, trans-astaxanthin at 80mg/kg was demonstrated to effectively antagonize IL-1β, IL-6 and TNF-α expression in hippocampus and spinal cord of CCI mice. Taken together, chronic trans-astaxanthin administration exerts therapeutic effects on thermal hyperalgesia and co-morbid depressive-like behaviors in CCI mice. These effects of trans-astaxanthin involves the serotonergic system, and also may be owing to its potent anti-inflammatory property.


Caring for Climbers.
Caring for climbers can be a challenge and requires familiarity with the distinctive mechanisms of common climbing injuries. Injuries such as climber's finger, climber's elbow, extensor hood syndrome, lateral collateral ligamentous injuries from climbing overload, and posttraumatic osteochondritis dissecans, among others, cannot be diagnosed if the practitioner does not have a specialized knowledge of the sport and the mechanisms of trauma and overuse that can occur. Understanding these injuries will increase the provider's breadth of knowledge and will bridge trust with patients who climb.


Pre-oxygenation using high-flow nasal oxygen in parturients undergoing caesarean section in general anaesthesia: A prospective, multi-centre, pilot study.
Parturients undergoing caesarean section in general anaesthesia have an increased risk of desaturating during anaesthesia induction. Pre- and peri-oxygenation with high-flow nasal oxygen prolong the safe apnoea time but data on parturients undergoing caesarean section under general anaesthesia are limited. This pilot study aimed to investigate the clinical effects and frequency of desaturation in parturients undergoing caesarean section in general anaesthesia pre- and peri-oxygenated with high-flow nasal oxygen and compare this to traditional pre-oxygenation using a facemask. In this prospective, non-randomised, multi-centre study we included pregnant women with a gestational age ≥30 weeks undergoing caesarean section under general anaesthesia. All parturients were asked to participate in the intervention group consisting of pre-oxygenation using high-flow nasal oxygen. Parturients declining participation were pre-oxygenated with a traditional facemask. Primary outcome was the proportion of parturients desaturating below 93% from start of pre-oxygenation until 1 min after tracheal intubation. Secondary outcomes investigated end-tidal oxygen concentrations after tracheal intubation and the proportion of parturients with signs of regurgitation. A total of 34 parturients were included, 25 pre- and peri-oxygenated with high-flow nasal oxygen and 9 pre-oxygenated with facemask. No difference in patient or airway characteristics could be seen except for a higher BMI in the high-flow nasal oxygen group (31.4 kg m-2 [4.7] vs. 27.7 kg m-2 [3.1]; p = .034). No woman in any of the two groups desaturated below 93%. The lowest peripheral oxygen saturation observed, in any parturient, was 97%. There was no difference detected in end-tidal oxygen concentration after tracheal intubation, 87% (6) in the high-flow nasal oxygen group vs 80% (15) in the facemask group (p = .308). No signs of regurgitation, in any parturient, were seen. Pre- and peri-oxygenation with high-flow nasal oxygen maintain adequate oxygen saturation levels during induction of anaesthesia also in parturients. Regurgitation of gastric content did not occur in any parturient and no other safety concerns were observed in this pilot study.


History of the roles of nurses caring for persons with mental retardation.
A historic examination of the major responsibilities of nurses in providing care to individuals with mental retardation indicates that the responsibilities have remained relatively constant, whereas the roles have shifted and expanded over time from nursing assistant activities to advanced practice roles. Regardless of the setting, nurses have been involved in primary and secondary prevention, case finding, health care management of the individual with mental retardation and their family across the life span, instruction about this care to other nurses, and referral. This specialty nursing practice has a long history. In recent years, the role of nurses in interdisciplinary care has waned with the continual trend of institutional closings and movement of the clients to small community group homes. As individuals with mental retardation achieve greater participation in their communities, the roles and responsibilities of nurses who specialize in the care of persons with mental retardation will also change, but much effort is needed today to enforce nursing's contribution in this field to the other disciplines involved in the care of these individuals and to society. The recent Surgeon General's report [57], Closing the Gap: A National Blueprint for Improving the Health of Individuals with Mental Retardation (2001), could serve as such a springboard for renewal of nursing action in this field.


Relative biological effectiveness in a proton spread-out Bragg peak formed by pencil beam scanning mode.
In recent years, there is an increased interest in using scanning modes in proton therapy, due to the more conformal dose distributions, thanks to the spot-weighted dose delivery. The dose rate in each spot is however much higher than the dose rate when using passive irradiation modes, which could affect the cell response. The purpose of this work was to investigate how the relative biological effectiveness changes along the spread-out Bragg peak created by protons delivered by the pencil beam scanning mode. Cell survival and micronuclei formation were investigated in four positions along the spread-out Bragg peak for various doses. Monte Carlo simulations were used to estimate the dose-averaged linear energy transfer values in the irradiation positions. The cell survival was found to decrease the deeper the sample was placed in the spread-out Bragg peak, which corresponds to the higher linear energy transfer values found using Monte Carlo simulations. The micronuclei frequencies indicate more complex cell injuries at that distal position compared to the proximal part of the spread-out Bragg peak. The relative biological effectiveness determined in this study varies significantly and systematically from 1.1, which is recommended value by the International Commission on Radiation Units, in all the studied positions. In the distal position of spread-out Bragg peak the relative biological effectiveness values were found to be 2.05 ± 0.44, 1.85 ± 0.42, 1.53 ± 0.38 for survival levels 90, 50 and 10%, respectively.


Charge-reversal nanoemulsions: A systematic investigation of phosphorylated PEG-based surfactants.
Surfactants bearing monophosphate esters with PEG of increasing chain length and different lipophilic tail structures were investigated to improve the effectiveness of enzyme triggered charge-converting nanoemulsions. The surfactants PEG-8-stearate, PEG-22-tocopheryl succinate (TPGS), PEG-3-oleate, PEG-9-oleate and PEG-9-lauryl ether were phosphorylated and incorporated in a self-emulsifying drug delivery system (SEDDS) exhibiting a defined PEG corona. To provide a positive zeta potential increasing amounts of the cationic surfactant benzalkonium chloride (BA) were incorporated. The effect of these PEG monophosphate esters (P-PEG-surfactants) was evaluated based on enzyme induced phosphate release and change in zeta potential. Significant enzyme induced charge conversion was observed for all P-PEG-surfactants, showing shifts from Δ3 mV to Δ31 mV. Surfactants comprising the shortest and longest PEG chain showed similar amplitudes (P-PEG-3-oleate: Δ11.9 mV; P-PEG-22-TPGS Δ10.2 mV), whereas P-PEG-8-stearate, P-PEG-9-oleate and P-PEG-9-lauryl ether bearing similarly long PEG chains but different lipophilic tail structures resulted in pronounced differences in amplitudes of Δ10.3 mV, Δ14.5 mV and Δ18.1 mV, respectively. Furthermore, an indirect correlation between the lipophilicity of P-PEG-surfactants and the obtained charge-reversing effect was observed. With the exception of P-PEG-lauryl ether, this charge-reversal effect decreased with increasing BA concentrations. In conclusion, the enzyme induced amplitude of charge conversion of P-PEG-surfactants depends to a high extent on their lipophilic tail structure. Based on this knowledge potent charge-reversal nanoemulsions can be designed.


The possible involvement of adenylate cyclase inhibition in the field potential suppression through alpha-2 adrenergic receptors in the bed nucleus of the stria terminalis.
Catecholamines, such as norepinephrine (NE), cause a field potential suppression through alpha-2 adrenergic receptors in thin sections of the bed nucleus of the stria terminalis. Phosphodiesterase inhibitors or cyclic AMP (cAMP) analogues attenuate the NE-induced suppression. These results suggest that the NE-induced suppression is mediated by adenylate cyclase inhibition and a resultant decrease of intracellular cAMP content.


Comparative water use and nitrogen relationships in a mistletoe and its host.
The impact of the xylem-tapping mistletoe Phoradendron juniperinum on the nitrogen and water relations of its host Juniperus osteosperma was investigated under natural field conditions. Leaf conductance, leaf water potential, and leaf Kjeldahl nitrogen contents were followed through the growing season on mistletoes, infected junipers (separating infected from uninfected stems) and uninfected junipers. Infected trees experienced lower leaf water potentials than uninfected trees and also had lower leaf conductances and lower leaf nitrogen contents. Infected juniper stems had higher conductances than uninfected stems. Mistletoes had higher leaf nitrogen contents than their hosts and much of this nitrogen appeared as arginine, a potential nitrogen storage compound. Photosynthetic rates (per unit leaf area) were significantly higher in junipers than in the mistletoe, and higher in the uninfected than infected junipers. Water use efficiencies as estimated by carbon isotope ratios were significantly lower in mistletoes than in their hosts. Increased mistletoe infestation appeared to increase absolute water use efficiency of both host and mistletoe.


Nitrogen isotopes indicate vehicle emissions and biomass burning dominate ambient ammonia across Colorado's Front Range urban corridor.
Urban ammonia (NH3) emissions contribute to poor local air quality and can be transported to rural landscapes, impacting sensitive ecosystems. The Colorado Front Range urban corridor encompasses the Denver Metropolitan Area, rural farmland/rangeland and montane forest between the city and the Rocky Mountains. Reactive nitrogen emissions from the corridor are partly responsible for increased N deposition to the wildland-urban interface (WUI) in this region. To determine the significance of individual NH3 sources to WUI ecosystems, we measured the concentration and isotopic composition (δ15N-NH3) of ambient NH3(g) from April to October 2018 across a five-site urban to rural gradient in the corridor. The urban sites had higher NH3 concentrations and δ15N-NH3 values than the rural/suburban sites. Based on isotope mixing models, NH3 emission source contributions for all sites were fertilizer (12 ± 5.7%), livestock waste (18 ± 12%), vehicles (37 ± 23%), and biomass burning (34 ± 20%). Vehicle contributions were consistent across all months with an average of 35% and summer months showed a peak in biomass burning contributions (40%). As wildfires are projected to increase due to climate change, we stress a need for constraints on the isotopic signature of NH3 emitted from wildfires. Vehicle emissions contributed the greatest amount of NH3 (40%) at the urban sites while rural/suburban sites had higher agricultural contributions (41%). Had 2018 not had an anomalously high wildfire season, 46% and 60% of the NH3 would have been attributed to vehicle emissions at the WUI site and urban sites, respectively. NH3 emissions have historically been ascribed to agricultural activities but these findings illustrate the universal significance of vehicle emissions and the potential for sustained wildfire activity to be a primary contributor to NH3. Air quality (e.g., particulate matter) and nitrogen deposition reduction plans may benefit by including management practices that address vehicle NH3 emissions.


Interferon-gamma release assays can effectively screen migrants for the tuberculosis infection, but urgent, active cases need clinical recognition.
Increasing numbers of migrants to Sweden are screened for tuberculosis (TB), and a rational approach to screening is required. We evaluated positive tuberculin skin tests (TSTs) and interferon-gamma release assays (IGRAs) on paediatric migrants in relation to the TB incidence in the corresponding foreign-born populations in Stockholm. This study examined the characteristics of migrants under the age of 18 who were referred to a paediatric TB clinic at Karolinska University Hospital from 2008 to 2014 by primary care centres in Stockholm County. We saw 943 TST-positive children with a median age of 14 years at the TB clinic and performed IGRAs on 557. IGRA positivity ranged from 64% in migrants from Somalia to 20% in those from the former Soviet Union and eastern Europe, with an estimated population level prevalence of 18.8% and 4.2%, respectively. These were significantly correlated to TB incidence in foreign-born Stockholm children. We diagnosed active TB in 20 screened migrants, and advanced, symptomatic TB was diagnosed in 10 recently arrived migrants without screening. IGRAs showed higher specificity than TST in identifying tuberculosis. TB screening should focus on migrants from high-incidence countries, but this may be inadequate to detect advanced TB cases.


Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence. Results of the second study of the International Society of Paediatric Oncology: MMT84.
The second International Society of Paediatric Oncology (SIOP) study for rhabdomyosarcoma (MMT84) had several goals. The two principal aims were: (1) to improve the survival of children with rhabdomyosarcoma; and (2) to reduce the late effects from therapy by restricting the indications for surgery and/or radiotherapy after good response to initial chemotherapy. A further aim was to investigate the role of high-dose chemotherapy in young patients with parameningeal primary tumours. 186 previously untreated eligible patients entered the study. Patients with completely resected primary tumour received three courses of IVA (ifosfamide, vincristine and actinomycin D). Patients with incompletely resected tumour received six to 10 courses of IVA according to stage. Patients achieving complete remission with chemotherapy alone did not usually receive radiotherapy or undergo extensive surgery, but patients remaining in partial remission received local therapy with surgery and/or radiotherapy. Only patients over 5 years of age with parameningeal disease and patients over 12 years with tumours at any site were given systematic irradiation. Complete remission was achieved in 91% (170/186) of all patients. With a median follow-up of 8 years, the 5-year overall survival was 68% (+/- 3% standard error of the mean (SEM) and the 5-year event-free survival 53% (+/- 4% SEM). These results show an improvement over previous SIOP study (RMS75) in which survival was 52% and event-free survival was 47%. Among the 54 patients who exhibited isolated local relapse, 35% (19/54) survived in further remission longer than 2 years after retreatment, including local therapy (surgery +/- radiotherapy). Analysis of the overall burden of therapy received by all surviving children (including primary treatment and treatment for relapse if required) showed that 24% (28/116) were treated by limited surgery followed by three courses of IVA, 29% (34/116) were treated by chemotherapy alone (after initial biopsy) and 13% (15/116) received chemotherapy plus conservative local treatment (limited surgery or radiotherapy for residual disease). Only 34% (39/116) received intensive local therapy defined as radical wide field radiotherapy or radical surgery or both. Compared with the results obtained in the previous SIOP study, treatment in MMT84 was based on response to initial chemotherapy and, despite an overall reduction of the use of local therapy, significantly improved survival for patients with non-metastatic disease. This trial, also for the first time, provides evidence that retreatment after local relapse can achieve long-term second remissions.


Application of endoscopic endonasal approach in skull base surgeries: summary of 1886 cases in a single center for 10 consecutive years.
Endonasal endoscopic skull base surgery has undergone rapid technological developments and is now widely performed, but its strengths and weaknesses deserve further investigation and deliberation. This study was performed to investigate the surgical indications, complications, and technical advantages and disadvantages of endonasal endoscopic skull base surgery. The clinical data of 1886 endoscopic endonasal skull base surgeries performed in our ward at Beijing Tiantan Hospital from June 2006 to June 2016 were retrospectively analyzed. One thousand ninety-three (73.4%, 1490) pituitary adenomas, 54 (24.9%, 217) chordomas, 28 (80.0%, 35) craniopharyngiomas, and 15 (83.3%, 18) meningiomas underwent total resection. Two patients died postoperatively, both having pituitary adenomas. Other postoperative complications included olfactory disorders (n = 226, 11.9%), postoperative cerebrospinal fluid leakage (n = 78, 4.1%), hypopituitarism (n = 74, 3.9%), diabetes insipidus (n = 64, 3.4%), intracranial infection (n = 36, 1.9%), epistaxis (n = 24, 1.3%), vascular injury (n = 8, 0.4%), optic nerve injury (n = 8, 0.4%), and oculomotor movement impairment (n = 4, 0.2%). In total, 1517 (80.4%) patients were followed up for 6 to 126 months (average, 42.5 months) postoperatively. A total of 196 (13.2%) pituitary adenomas and 13 (37.1%) craniopharyngiomas recurred but no meningiomas recurred. Chordomas recurred in 97 (44.7%) patients, in whom 5-year survival rate was 65%. Endoscopic surgery is an innovative surgical technique and the first choice for most midline extradural lesions such as chordomas, and an excellent choice for pituitary adenomas. It probably will be a good technique for many kinds of craniopharyngiomas and a common technique for most of skull base meningiomas, so the surgical indications of these cases should be chosen carefully to make good use of its respective advantages.


Pyrrole-2,5-dione analogs as a promising antioxidant agents: microwave-assisted synthesis, bio-evaluation, SAR analysis and DFT studies/interpretation.
A new series of pyrrole analogs were developed via the microwave irradiation synthesis. Consequently, got a high yield of the products. As pyrroles are familiar for showing various biological properties, all obtained compounds were screened for their antioxidant properties, most of the compounds showing significant activity. In fact, the motifs 5e, 5g, 5h and 5m showed outstanding antioxidant properties. Further, to enlighten the biologically energetic behavior underlying the antioxidant activity, compounds DFT studies were performed. Noteworthy results have been attained and the structure activity relationship (SAR) was discussed with the support of this results. It was found that highly biological active compounds exhibited a low HOMO-LUMO energy gap (Eg) and the high Eg value compounds show very low/negligible or inactive antioxidant activities. In other cases, compounds containing high HOMO energy levels also provide high antioxidant activity. The thought-provoking point of our results is that theoretical descriptors of the HOMO-LUMO energy gap and the highest occupied molecular orbital energy are important descriptors in the bioorganic research to support the biological experiments.


Tissue factor activity on microvesicles from cancer patients.
The expression of active tissue factor (TF) on the surface of microvesicles (MVs) is essential for the activation of the coagulation system and transduction of the signaling pathways in cancer cells. In its use as a biomarker for cancer-associated venous thromboembolism (VTE), TF has shown high expression variability. As a contribution to this discussion, we present a study investigating plasma samples from patients with various progressive tumors at high risk for VTE. Based on our previous study uncovering microvesicles (MVs), the larger ectosome-like extracellular vesicles (EV), as the major source of TF activity in EV preparations, we now determined TF activity on enriched MVs isolated from plasma of cancer patients and compared it with that on MVs from healthy individuals. We found considerably higher amounts of MVs as well as higher levels of MV-bound TF activities in the plasma of cancer patients. We also show that preparations from plasma of cancer patients have the potency to induce ERK phosphorylation in a human tumor cell line through proteinase-activated receptor two (PAR2) activation. We suggest that MVs instead of whole EV preparations, and TF activity rather than its antigenic quantification should be used in clinical studies for identifying patients with progressive tumors at high risk for VTE.


An artificial mitochondrial tail signal/anchor sequence confirms a requirement for moderate hydrophobicity for targeting.
Tail-anchored proteins are a group of membrane proteins oriented with their amino terminus in the cytoplasm and their carboxy terminus embedded in intracellular membranes. This group includes the apoptosis-mediating proteins of the Bcl-2 family as well as the vesicle targeting proteins of the SNARE group, among others. A stretch of hydrophobic amino acids at the extreme carboxy terminus of these proteins serves both as a membrane anchor and as a targeting signal. Tail-anchored proteins are differentially targeted to either the endoplasmic reticulum or the mitochondrial outer membrane and the mechanism which accomplishes this selective targeting is poorly understood. Here we define important characteristics of the signal/anchor region which directs proteins to the mitochondrial outer membrane. We have created an artificial sequence consisting of a stretch of 16 leucines bounded by positively charged amino acids. Using this template we demonstrate that moderate hydrophobicity distinguishes the mitochondrial tail-anchor sequence from that of the endoplasmic reticulum tail-anchor sequence. A change as small as introduction of a single polar residue into a sequence that otherwise targets to the endoplasmic reticulum can substantially switch targeting to the mitochondrial outer membrane. Further we show that a mitochondrially targeted tail-anchor has a higher propensity for the formation of alpha-helical structure than a sequence directing tail-anchored proteins to the endoplasmic reticulum.


Does postprandial storage of triglycerides in endothelial cells contribute to the endothelial dysfunction associated with insulin resistance and fatty diets?
Insulin resistance syndrome is associated with endothelial dysfunction characterized by decreased nitric oxide bioactivity and subnormal endothelium-dependent vasodilation. Excessive exposure to free fatty acids (FFAs) is thought to mediate this dysfunction, at least in part, since free fatty acid overexposure, both in vivo and in vitro, decreases the capacity of endothelial cells to generate bioactive nitric oxide. Yet this endothelial dysfunction tends to correlate, not with fasting FFA levels, but with poor insulin suppressibility of FFA flux postprandially. I propose that triglycerides are synthesized and stored in endothelial cells during the postprandial period, when FFAs and insulin are jointly elevated, and that this triglyceride pool serves as a source of FFA overexposure postabsorptively--thus accounting for the endothelial dysfunction associated with insulin resistance syndrome and the role of excessive postprandial FFA flux in its induction. Since a substantial proportion of postprandial FFA flux derives, not from adipocytes, but from the fat provided by meals, these considerations may help to rationalize the documented clinical utility of very-low-fat diets for management of coronary disease.


Long-term prognosis of patients with cardiac syndrome X: a review.
Follow-up studies of patients with cardiac syndrome X (CSX) generally report good prognosis. However, some recent studies report an adverse outcome for women. Structured literature search and meta-analysis for studies regarding prognosis of cardiac syndrome X patients. We identified 85 studies, ultimately selecting 16 for inclusion. Meta-analysis yielded a pooled major cardiac event percentage of 1.5% per 5 years and a pooled vascular event percentage of 4.8% per 5 years (n = 16 studies, n = 1694 patients). Fourteen studies reported upon the recurrence rate of angina pectoris: the pooled percentage of angina recurrence was 55% (n = 1336 patients). The present review of recent archival literature demonstrates an overall major cardiac event rate of 1.5% per 5 years. Although this is an excellent prognosis for CSX patients, the quality of life is impaired because of the high recurrence rate of angina pectoris (55%).


Cardiovascular responses to the change from the left lateral to the upright position in pregnant hypertensives.
To evaluate by non-invasive means, the autonomically mediated changes in heart rate and blood pressure in response to postural change in pregnancy. Ninety-one patients were studied, of whom 17 were non-pregnant controls, 21 were normotensive parturients, 22 had non-proteinuric hypertension, and 31 were pre-eclamptics. In all patients the heart rate and blood pressure response to the change from the left lateral to the erect position was measured non-invasively, during the third trimester in the pregnant groups. The change from the left lateral to the erect position induced significantly greater mean changes (increases) in systolic blood pressure in the normotensive pregnant (PC) women than all other groups (P<0.05). Pre-eclamptic patients (PE) exhibited significantly less of an increase in systolic blood pressure than the non-proteinuric hypertensive (H) group. Both the H and PC groups showed significantly greater increases in diastolic pressure than the non-pregnant (NP) group. PE patients had a significantly smaller increase in diastolic pressure than the H group. There were no significant differences between heart rate changes when comparing the PC, NP and H groups. The PE group exhibited a significantly greater increase in heart rate on adopting the erect position than all other groups. Pre-eclamptics exhibit smaller changes in blood pressure than normotensive pregnant patients and non-proteinuric hypertensives on standing, while producing an exaggerated heart rate response, indicating altered autonomic compensatory mechanisms in these patients.


The localization of bypass tracts in the Wolff-Parkinson-White syndrome from the surface electrocardiogram.
The bypass tracts of the WFW syndrome may be situated anywhere along the AV ring. Accurate localization of such tracts has in the past been largely effected by electrophysiologic studies, particularly epicardial mapping. During recent years, however, criteria for localization of the bypass tracts from the conventional 12-lead ECG have become increasingly apparent. The preceding presentation constitutes a review and state of the art governing these rapidly developing diagnostic principles.


The amyloid-beta peptide binds to cyclin B1 and increases human cyclin-dependent kinase-1 activity.
The pathological features of Alzheimer's disease include deposition of amyloid-beta (Abeta) containing plaques and increases in the expression of cyclin-dependent kinase (CDK) enzymes. Chemical inhibition of CDKs prevents the neurotoxicity of the Abeta peptide. The activity of these kinases requires the binding of a cyclin component to the catalytic enzyme component. This study characterizes direct interactions between Abeta and cyclin B1. Abeta fragments containing the cytotoxic 31-35 region could inhibit biotinylated Abeta binding to cyclin B1. The same cytotoxic Abeta fragments all increased CDK-1 phosphorylation of known substrates in a cell free system. The CDK-1 inhibitor olomoucine prevented the cytotoxicity of Abeta 31-35 containing peptides in differentiated human teratocarcinoma cell line, Ntera 2/cl-D1 (NT-2) neurons. These direct interactions between cyclin B1 and Abeta provide potential mechanisms for the cytotoxicity of the Abeta peptide.


Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation.
The authors describe the clinical, histopathologic, and ultrastructural findings in two eyes obtained at autopsy from a 21-year-old woman with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome). The eyes were obtained immediately after death. The right eye was fixed in 10% neutral-buffered formalin and processed for standard histologic examination. The left eye was fixed in a neutral-buffered 2.5% glutaraldehyde solution and processed for transmission electron microscopic examination. The authors compared the histologic and ultrastructural findings with the clinical features recorded photographically. The main clinical ophthalmologic features were bilateral ptosis, chronic external ophthalmoplegia, diffuse choroidal atrophy, atypical pigmentary retinopathy with macular involvement, and patchy atrophy of the iris stroma. Molecular genetic analysis detected a tRNA Leu (UUR) point mutation at position 3243 of mitochondrial DNA (MELAS genotype). Results of histologic and ultrastructural examination showed ragged-red fibers in the rectus muscles, degeneration of photoreceptor outer segments in the macula, hyperpigmentation and atrophy of the retinal pigment epithelium of the macula, atrophy of the iris stroma, early posterior subcapsular cataract, and optic atrophy. The retinal pigment epithelium, inner segments of the photoreceptors, smooth muscle cells of the choroidal and retinal vessels, the dilator and sphincter muscle of the iris, cornea, lens epithelium, and ciliary epithelium all contained many, often enlarged, structurally abnormal mitochondria with occasional paracrystalline inclusions and circular cristae. The MELAS-associated mitochondrial DNA nucleotide 3243 point mutation can cause a spectrum of ocular signs and symptoms that may be dependent on the patient's age and the amount of mutant mitochondrial DNA in the tissue. MELAS syndrome should be considered in the differential diagnosis of bilateral ptosis, external ophthalmoplegia, and atypical pigmentary retinopathy with macular involvement.


Tyrophagus putrescentiae: an allergenically important mite.
The incidence of positive skin tests to the mite Tyrophagus putrescentiae was measured and compared with skin reactions to Dermatophagoides pteronyssinus and other allergens in Australian and New Guinean populations, and mite counts were determined in Sydney and New Guinea houses. Positive reactions to T. putrescentiae were as frequent as those for D. pteronyssinus in asthmatics in Sydney and were the commonest positive reactions in the normal New Guinea population. T. putrescentiae-specific serum IgE levels were determined and some IgG cross-reactions of D. pteronyssinus and T. putrescentiae antigens were demonstrated. It is suggested that T. putrescentiae is an important source of allergen and should be considered whenever D. pteronyssinus is thought to be a problem. A convenient method for culturing and isolating T. putrescentiae is described.


Sensitizing effects of leukotriene B4 on intradental primary afferents.
Previous studies have established that leukotriene B4 (LTB4) sensitizes cutaneous nociceptors. In this study the effects of LTB4 on spontaneous and stimulus-evoked nerve activity from primary afferents innervating the dentin of canines in adult cats were examined. LTB4 treatment (25 micrograms/ml) significantly enhanced stimulus-evoked intradental nerve activity (INA) for at least 20 min after the removal of the compound from the recording preparation. Teeth treated with LTB4 demonstrated enhanced spontaneous nerve activity following the removal of hypertonic saline used to evoked INA. These findings provide additional evidence that LTB4 is able to sensitize nociceptors and may be a long-lasting hyperalgesic factor which may contribute to pain of pulpal origin.


Cloning and molecular modeling of duodenase with respect to evolution of substrate specificity within mammalian serine proteases that have lost a conserved active-site disulfide bond.
Mammalian serine proteases such as the chromosome 14 (Homo sapiens, Mus musculus) located granzymes, chymases, cathepsin G, and related enzymes including duodenase collectively represent a special group within the chymotrypsin family which we refer to here as "granases". Enzymes of this group have lost the ancient active-site disulfide bond Cys191-Cys220 (bovine chymotrypsinogen A numbering) which is strongly conserved in classic serine proteases such as pancreatic, blood coagulation, and fibrinolysis proteases and others (granzymes A, M, K and leukocyte elastases). We sequenced the cDNA encoding bovine (Bos taurus) duodenase, a granase with unusual dual trypsin-like and chymotrypsin-like specificity. The sequence revealed a 17-residue signal peptide and two-residue (GlyLys) activation peptide typical for granases. Production of the mature enzyme is apparently accompanied by further proteolytic processing of the C-terminal pentapeptide extension of duodenase. Similar C-terminal processing is known for another dual-specific granase, human cathepsin G. Using phylogenetic analysis based on 39 granases we retraced the evolution of residues 189 and 226 crucial for serine protease primary specificity. The analysis revealed that while there is no obvious link between mutability of residue 189 and the appearance of novel catalytic properties in granases, the mutability of residue 226 evidently gives rise to different specificity subgroups within this enzyme group. The architecture of the extended substrate-binding site of granases and structural basis of duodenase dual specificity based on molecular dynamic method are discussed. We conclude that the marked selectivity of granases that is crucial to their role as regulatory proteases has evolved through the fine-tuning of specificity at three levels--primary, secondary, and conformational.


Value of a confidential COVID-19 helpline for nursing home staff.
We hosted a confidential helpline to address concerns about COVID-19 prevention among staff in 12 nursing homes in Orange County, California. We fielded 301 inquiries from April 2021-April 2022, most commonly involving questions about vaccines (40%), nursing home COVID-19 prevention (28%), SARS-CoV-2 variants (18%), symptom reporting (10%), and home and community COVID-19 prevention (5%). During COVID-19 surges, staff dominantly expressed fear, anger, and exhaustion. During nadirs, sentiment shifted towards optimism and acceptance.


Outcomes of cold snare piecemeal EMR for nonampullary small-bowel adenomas larger than 1 cm: a retrospective study.
Nonampullary small-bowel adenomas ≥10 mm are typically resected using cautery-based polypectomy, which is associated with significant adverse events. Studies have demonstrated the safety and efficacy of piecemeal cold snare EMR for removing large colon polyps. Our aim was to assess the safety and efficacy of cold snare EMR for removal of large adenomas in the small bowel. A retrospective study of patients who underwent lift and piecemeal cold snare EMR of small-bowel adenomas ≥1 cm between January 2014 and March 2019 was conducted at a tertiary care medical center. Polyp characteristics at the time of index and surveillance endoscopy were collected. Primary outcomes were residual or recurrent adenoma (RRA) seen on surveillance endoscopy, polyp eradication rate, and number of endoscopic procedures required for eradication. Adverse events including immediate and delayed bleeding, perforation, stricture, pancreatitis, and postpolypectomy syndrome were assessed. Of 43 patients who underwent piecemeal cold snare EMR, 39 had follow-up endoscopy. Polyps ranged in size from 10 to 70 mm (mean, 26.5 mm). RRA was found in 18 patients (46%), with increased polyp size correlating with higher recurrence (P < .001). Polyp eradication was observed in 35 patients (89%), requiring a median of 2 (range, 1-6) endoscopic procedures. Only 1 patient (2.3%) had immediate postprocedural bleeding. No cases of perforation or postpolypectomy syndrome were seen. Piecemeal cold snare EMR may be a feasible, safe, and efficacious technique for small-bowel polyps >10 mm. Prospective, randomized studies are needed to assess how outcomes compare with traditional cautery-based polypectomy.


Pyrogenic carbon-promoted haloacetic acid decarboxylation to trihalomethanes in drinking water.
Drinking water disinfection by chlorination or chloramination can result in the formation of disinfection byproducts (DBPs) such as haloacetic acids (HAAs) and trihalomethanes (THMs). Pyrogenic carbonaceous matter (PCM), such as activated carbon (AC), is commonly used as an ostensibly inert adsorbent to remove HAAs from water. HAA degradation has been mainly attributed to biological factors. This study, for the first time, revealed that abiotic HAA degradation in the presence of PCM could be important under water treatment conditions. Specifically, we observed complete destruction of Br3AA, a model HAA, in the presence of powder AC at pH 7 within 30 min. To understand the role of PCM and the reaction mechanism, we performed a systematic study using a suite of HAAs and various PCM types. We found that PCM significantly accelerated the transformation of three HAAs (Br3AA, BrCl2AA, Br2ClAA) at pH 7. Product characterization indicated an approximately 1:1 HAA molar transformation into their respective THMs following a decarboxylation pathway with PCM. The Br3AA activation energy (Ea) was measured by kinetic experiments at 15-45 °C with and without a model PCM, wherein a significant decrease in Ea from 25.7 ± 3.2 to 13.6 ± 2.2 kcal•mol-1 was observed. We further demonstrated that oxygenated functional groups on PCM (e.g., -COOH) can accelerate HAA decarboxylation using synthesized polymers to resemble PCM. Density functional theory simulations were performed to determine the enthalpy of activation (ΔH‡) for Br3AA decarboxylation with H3O+ and formic acid (HCOOH). The presence of HCOOH significantly lowered the overall ΔH‡ value for Br3AA decarboxylation, supporting the hypothesis that -COOH catalyzes the C-C bond breaking in Br3AA. Overall, our study demonstrated the importance of a previously overlooked abiotic reaction pathway, where HAAs can be quickly converted to THMs with PCM under water treatment relevant conditions. These findings have substantial implications for DBP mitigation in water quality control, particularly for potable water reuse or pre-chlorinated water that allow direct contact between HAAs and AC during filtration as well as PAC fines traveling with finished water in water distribution systems. As such, the volatilization and relative low toxicity of volatile THMs may be considered as a detoxification process to mitigate adverse DBP effects in drinking water, thereby lowering potential health risks to consumers.


Testing the underlying processes leading to learned distractor rejection: Learned oculomotor avoidance.
Target templates stored in visual memory guide visual attention toward behaviorally relevant target objects. Visual attention also is guided away from nontarget distractors by longer-term learning, a phenomenon termed "learned distractor rejection." Template guidance and learned distractor rejection can occur simultaneously to further increase search efficiency. However, the underlying processes guiding learned distractor rejection are unknown. In two visual search experiments employing eye-tracking, we tested between two plausible processes: proactive versus reactive attentional control. Participants searched through two-color, spatially unsegregated displays. Participants could guide attention by both target templates and consistent nontarget distractors. We observed fewer distractor fixations (including the first eye movement) and shorter distractor dwell times. The data supported a single mechanism of learned distractor rejection, whereby observers adopted a learned, proactive attentional control setting to avoid distraction whenever possible. Further, when distraction occurred, observers rapidly recovered. We term this proactive mechanism "learned oculomotor avoidance." The current study informs theories of visual attention by demonstrating the underlying processes leading to learned distractor suppression during strong target guidance.


De novo design of caseinolytic protein proteases inhibitors based on pharmacophore and 2D molecular fingerprints.
Caseinolytic protein proteases (ClpP) are large oligomeric protein complexes that contribute to cell homeostasis as well as virulence regulation in bacteria. Inhibitors of ClpP can significantly attenuate the capability to produce virulence factors of the bacteria. In this work, we developed a workflow to expand the chemical space of potential ClpP inhibitors based on a set of β-lactones. In our workflow, an artificial pharmacophore model was generated based on HipHop and HYPOGEN method. A de novo compound library based on molecular fingerprints was constructed and virtually screened by the pharmacophore model. The results were further investigated by molecular docking study. The workflow successfully achieved potential ClpP inhibitors. It could be applied to design more novel potential ClpP inhibitors and provide theoretical basis for the further optimization of the hit compounds.


CD44-mediated tumor homing of hyaluronic acid nanogels for hypoxia-activated photodynamic therapy against tumor.
In this study, unique hypoxia-activated hyaluronic acid nanogels (HANGs) were reported for CD44-targeted delivery of photosensitizers (chlorin e6, Ce6) for diagnostic imaging and photodynamic therapy (PDT) of cancers. Through the use of a hypoxia-responsive cross-linker (AZO-CDI), the HANGs were prepared by chemically cross-linking primary amine groups-functionalized hyaluronic acid (HA). Under normoxic condition, fluorescence of Ce6 conjugated on the HANGs was highly quenched, and level of reactive oxygen species (ROS) generated from the HANGs was rather low after laser irradiation. However, under hypoxic condition, the HANGs underwent rapid disassociation, and fluorescence of Ce6 conjugated on the HANGs was recovered, triggering high-level singlet oxygen generation after laser irradiation. Due to the presence of HA, the HANGs showed much higher cellular uptake by CD44-positive cancer cells (A549 cells) than that by CD44-negative cancer cells (HepG2 cells). In addition, the HANGs could generate higher level of ROS in A549 cells because of improved cancer cell uptake. This excellent tumor-targeting and singlet oxygen-generating ability of the HANGs was favorable to hypoxia-activated PDT of CD44-positive cancers with significant inhibition of tumor growth within the whole treatment period. Taken together, the HANGs are safe and effective tools in treating CD44-positive cancers.


Responses of salivary glands to intake of soft diet.
Modernization has made individuals prefer processed and cooked foods (soft food), but this eating habit may have negative effects on the oral cavity. However, laboratory animals fed with soft diet are commonly used in an attempt to clarify this issue, and various oral tissues, including the salivary glands have been examined. In this review, we summarize the findings of previous studies concerning the responses of salivary glands to daily intake of soft diet. The weight of the parotid glands decreased in rodents fed with soft diet (liquid or powder). In atrophic parotid glands, acinar cell shrinkage is histologically observed and the DNA content is reduced, showing that the atrophy is caused by a decrease in the size and number of acinar cells. Immunohistochemical examinations showed that the decrease in the acinar cell number was induced by suppression of acinar cell proliferation and acceleration of apoptosis. The atrophic parotid glands recovered following a change from soft to pellet diet. Other salivary glands, such as the submandibular, sublingual, and palatine glands, responded only slightly to the soft diet feeding. Accumulated research data showed that a soft diet negatively affects the parotid glands much more than other salivary glands and that atrophic parotid glands are able to recover by switching to a hard diet. Therefore, it should be emphasized that good eating habits are important for not only digestion but also the health of oral tissues, including the salivary glands.


The complete mitochondrial genome of the Columbia lance nematode, Hoplolaimus columbus, a major agricultural pathogen in North America.
The plant-parasitic nematode Hoplolaimus columbus is a pathogen that uses a wide range of hosts and causes substantial yield loss in agricultural fields in North America. This study describes, for the first time, the complete mitochondrial genome of H. columbus from South Carolina, USA. The mitogenome of H. columbus was assembled from Illumina 300 bp pair-end reads. It was annotated and compared to other published mitogenomes of plant-parasitic nematodes in the superfamily Tylenchoidea. The phylogenetic relationships between H. columbus and other 6 genera of plant-parasitic nematodes were examined using protein-coding genes (PCGs). The mitogenome of H. columbus is a circular AT-rich DNA molecule 25,228 bp in length. The annotation result comprises 12 PCGs, 2 ribosomal RNA genes, and 19 transfer RNA genes. No atp8 gene was found in the mitogenome of H. columbus but long non-coding regions were observed in agreement to that reported for other plant-parasitic nematodes. The mitogenomic phylogeny of plant-parasitic nematodes in the superfamily Tylenchoidea agreed with previous molecular phylogenies. Mitochondrial gene synteny in H. columbus was unique but similar to that reported for other closely related species. The mitogenome of H. columbus is unique within the superfamily Tylenchoidea but exhibits similarities in both gene content and synteny to other closely related nematodes. Among others, this new resource will facilitate population genomic studies in lance nematodes from North America and beyond.


Single-port and four-port laparoscopic cholecystectomy: difference in outcomes.
Patients prefer minimally invasive procedures with fast recovery, minimal pain and good cosmesis. Single-port cholecystectomy may decrease the need for narcotic pain medication and thus shorten recovery. Outcome-based evidence for this procedure is still being assembled. Single-port cholecystectomy patients were matched based on age and gender with control patients undergoing four-port cholecystectomy during the same time. The primary endpoint was in hospital use of narcotic pain medication, measured by morphine equivalents. Secondary endpoints were operative time and length of stay. Statistical analysis was done by Student's t-test. Fifty patients (36 women, 14 men) underwent single port cholecystectomy between 11/2009-7/2012 and 50 patients underwent traditional cholecystectomy during the same time period. All patients were matched within 10 years of age. Morbidity was 4% for the single port group, 0% for the traditional cholecystectomy. There were no conversions to open cholecystectomy. The single-port group required a median of 29.0 mg (range, 8.7-180 mg) morphine equivalents of pain medication and the control group required a median of 33.2 mg (range, 0-185.7 mg) morphine equivalents (P=0.04). Single port cholecystectomy operative times were longer (median, 85 vs. 77 minutes, P=0.03). In this small study, there is a statistically significant difference in narcotic use during the initial hospital stay was measured between the two groups. After the initial ten cases, the operative time for single-port cholecystectomy approximated the standard four-port cholecystectomy. Prospective randomized controlled trials are necessary to investigate differences in outcomes between the two approaches.


Elevated levels of activin A in heart failure: potential role in myocardial remodeling.
Although modulation of inflammatory processes has been suggested as a new treatment modality in heart failure (HF), our knowledge about abnormalities in the cytokine network during HF is still limited. On the basis of a previous cDNA array study examining peripheral blood mononuclear cells from HF patients, we hypothesized a role for activin A, a member of the transforming growth factor (TGF)-beta superfamily, in the pathogenesis of HF. This study had 4 main and novel findings. First, serum levels of activin A were significantly elevated in patients with HF (n=86) compared with healthy control subjects (n=20), with increasing levels according to disease severity as assessed by clinical, hemodynamic, and neurohormonal parameters. Second, compared with control subjects, HF patients, as determined by real-time quantitative reverse transcriptase polymer chain reaction, also had markedly increased gene expression of the activin A subunit activin betaA in T cells but not in monocytes. Third, in a rat model of HF, we demonstrated a concerted induction of the gene expression of activin betaA and activin receptors IA, IB, IIA, and IIB after myocardial infarction. Immunohistochemical analysis localized activin A solely to cardiomyocytes. Finally, activin A markedly increased gene expression of mediators involved in infarction healing and myocardial remodeling (ie, atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta1, and monocyte chemoattractant protein-1) in neonatal rat cardiomyocytes. Together with our demonstration of activin A-induced gene expression in neonatal cardiomyocytes of mediators related to myocardial remodeling, the expression pattern of activin A during clinical and experimental HF suggests an involvement of this cytokine in the pathogenesis of HF.


Nature and mechanism of the in vivo oligomerization of nucleoid protein H-NS.
Two types of two-hybrid systems demonstrate that the transcriptional repressor, nucleoid-associated protein H-NS (histone-like, nucleoid structuring protein) forms dimers and tetramers in vivo, the latter being the active form of the protein. The H-NS 'protein oligomerization' domain (N-domain) is unable to oligomerize in the absence of the intradomain linker while the 'DNA-binding' C-domain clearly displays a protein-protein interaction capacity, which contributes to H-NS tetramerization and which is lost following Pro115 mutation. Linker deletion or substitution with KorB linker abolishes H-NS oligomerization. A model describing H-NS dimerization and tetramerization based on all available data and suggesting the existence in the tetramer of a bundle of four alpha-helices, each contributed by an H-NS monomer, is presented.