Risk factors of congenital hypothyroidism using propensity score: a matched case-control study.
The aim of this study was to investigate the relationship between congenital hypothyroidism and several variables using two different adjustment methods. This matched case-control study was conducted in Hamadan Province, the west of Iran, in 2012 enrolling neonates born between 2005 and 2011 and covered by screening program for congenital hypothyroidism. The neonates with TSH titer more than 10 mU/l or T4 titer less than 6.4 μg/dl were considered as cases. Each case was individually matched for birth place and year with four neonates with normal TSH and T4 titers as controls. The data were analyzed using two different approaches including propensity score and multiple conditional logistic regression model. Of 1313 enrolled neonates, 277 (159 girls) were cases and 1036 (531 girls) were controls. The most important prognostic factors which had significant effect on congenital hypothyroidism included twin, birth season, maturity, jaundice at birth, birth weight, age at pregnancy, maternal anemia and goiter, gestational age, delivery type, father's education and smoking status, and consanguinity. The associations reported by logistic regression were stronger that of than propensity score analysis in most items, although the differences were not statistically significant. We addressed the effect of numerous potential risk factors on congenital hypothyroiditis and the impact of these factors on the disease occurrence. However, future prospective studies are needed to test these findings and hypothesis and to investigate the true effect of these potential risk factors on congenital hypothyroiditis.


Role of Acoustic Streaming in Formation of Unsteady Flow in Billet Sump during Ultrasonic DC Casting of Aluminum Alloys.
The present work investigated melt flow pattern and temperature distribution in the sump of aluminum billets produced in a hot-top equipped direct chilling (DC) caster conventionally and with ultrasonic irradiation. The main emphasis was placed on clarifying the effects of acoustic streaming and hot-top unit type. Acoustic streaming characteristics were investigated first by using the earlier developed numerical model and water model experiments. Then, the acoustic streaming model was applied to develop a numerical code capable of simulating unsteady flow phenomena in the sump during the DC casting process. The results revealed that the introduction of ultrasonic vibrations into the melt in the hot-top unit had little or no effect on the temperature distribution and sump profile, but had a considerable effect on the melt flow pattern in the sump. Our results showed that ultrasound irradiation makes the flow velocity faster and produces a lot of relatively small eddies in the sump bulk and near the mushy zone. The latter causes frequently repeated thinning of the mushy zone layer. The numerical predictions were verified against measurements performed on a pilot DC caster producing 203 mm billets of Al-17%Si alloy. The verification revealed approximately the same sump depth and shape as those in the numerical simulations, and confirms the frequent and large fluctuations of the melt temperature during ultrasound irradiation. However, the measured temperature distribution in the sump significantly differed from that predicted numerically. This suggests that the present mathematical model should be further improved, particularly in terms of more accurate descriptions of boundary conditions and mushy zone characteristics.


Diagnosing comorbid psychiatric disorders in substance abusers: validity of the Spanish versions of the Psychiatric Research Interview for Substance and Mental Disorders and the Structured Clinical Interview for DSM-IV.
The authors' goal was to assess the validity of DSM-IV diagnoses obtained with the Spanish versions of the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) and the Structured Clinical Interview for DSM-IV (SCID) compared with the longitudinal, expert, all data (LEAD) procedure in a group of substance abusers. A total of 105 substance abusers recruited at a drug abuse treatment center in Barcelona, Spain, were assessed. The PRISM and SCID were administered blindly by independent research interviewers. LEAD diagnoses were made by two senior psychiatrists who were blind to PRISM and SCID diagnoses. The kappa statistic was used to measure concordance between the LEAD procedure and the PRISM and SCID. Affective and anxiety disorders were diagnosed more frequently by the PRISM and SCID than by the LEAD procedure. Use of the PRISM resulted in more diagnoses of substance-induced depression, and use of the SCID resulted in more diagnoses of primary major depression than the LEAD procedure. Kappas between the LEAD procedure and the PRISM in current major depression, past substance-induced depression, and borderline personality disorder were better than those obtained between the LEAD procedure and the SCID. The concordance among the three methods for diagnoses of current dependence disorders was good or excellent for alcohol, anxiolytic, cocaine, and heroin dependence and fair for cannabis dependence. Abuse diagnoses showed poor concordance. Using the LEAD procedure as a "gold standard," the authors conclude that the Spanish version of the PRISM seems to be a better instrument than the Spanish version of the SCID for diagnosing major depression and borderline personality disorders in substance abusers.


[The treatment of cleft lip, cleft palate and other dysmorphisms: the ideal technic and therapeutic reality].
Good results in any surgical or orthodontic procedure require expert technique, well adapted to the problem and scrupulously executed. A technique that would achieve the best results can be described as "ideal" and can serve as a theoretical model for all similar cases. But, in dealing with apparently similar problems: cleft lips and palates, Class II or Class III cases... in reality, we are treating individual patients, none quite the same as any other. These differences derive from the varying characteristics of individual patients and from the varying and unpredictable responses of their tissues, and from their varying capacities to accommodate to and withstand insults, suffering, and the sensory-motor effects of their deformities and of the treatment they undergo, and, finally, from their variable readiness to submit to and to pay for treatment with their time and with their money. Any therapeutic technique must take into account these realities which sometimes oblige us to modify an ideal technique so that it will fit the specialized needs of a patient, an accommodation that can be defined as "therapeutic realism". When we ignore this reality, we risk the paradox of providing patients with technically ideal results that they find unsatisfactory or discover that what we thought was a technically mediocre outcome has delighted our patient: ultimately, it is the patient's judgment that determines the "therapeutic result" and is, in effect, the Final Evaluation of the technical result.


Does a higher income have positive health effects? Using the earned income tax credit to explore the income-health gradient.
The existence of a positive relationship between income and morbidity has been well documented in the literature. But it is unclear whether the relationship is positive because increased income allows individuals to purchase more health inputs that improve their health, because healthy individuals are more productive and thus can earn higher wages in the labor market, or because a third factor is improving health and increasing income. This article explores whether increases in income improve the health of the low-income population. Because health status may affect income, this article uses an "instrumental variable" strategy that considers income variations over seventeen years of changes in the generosity of state and federal Earned Income Tax Credits (EITC, a measure that should be exogenous to health status). I measured health status using both the self-reported health status and the functional limitations indicated on the Survey of Income and Program Participation (SIPP), as well as the self-reported health status indicated on the March Current Population Survey (CPS). I found only limited support for the theory that the relationship between income and morbidity is derived from shifts in income. Although I did observe a correlation between income and self-reported health, I found no evidence that increases in income significantly improve self-reported health statuses. In addition, while increases in income appear to reduce the prevalence of hearing limitations when using corrective measures, these increases did not have a significant effect on most of the other functional limitations considered here. These findings suggest that the ability to improve short-term health outcomes through public transfer payments may be limited. However, the lifetime effects on the health of people with higher incomes would still be a valuable avenue for future research.


Structures of bilirubin conjugates synthesized in vitro from bilirubin and uridine diphosphate glucuronic acid, uridine diphosphate glucose or uridine diphosphate xylose by preparations from rat liver.
1. In incubation mixtures containing digitonin-activated or untreated preparations from rat liver, albumin-solubilized bilirubin as the acceptor substrate and (a) UDP-glucuronic acid, (b) UDP-glucose or (c) UDP-xylose as the sugar donor, formation of the following ester glycosides was demonstrated: with (a), bilirubin beta-d-monoglucuronoside, with (b), bilirubin beta-d-monoglucoside and with (c), bilirubin monoxyloside or mixtures of the mono-and di-xyloside. 2. With UDP-glucuronic acid prolonged incubation and variation of the composition of the incubation mixtures yielded equimolar amounts of azodipyrrole (I) and azodipyrrole beta-d-monoglucuronoside (II) after treatment of the incubation mixtures with the diazonium salt of ethyl anthranilate. The azo-derivatives were identified by t.l.c. by reference to known compounds and by the following chemical tests. After ammonolysis the conjugated azo-derivative (II) yielded d-glucuronic acid and the carboxylic acid amide of azodipyrrole, indicating transfer of a glucuronic acid residue to the carboxylic acid groups of bilirubin. The beta-d-configuration of the sugar moiety and binding at C-1 were demonstrated by enzymic hydrolysis tests. 3. Analogous evidence established the structure of the reaction product obtained with UDP-glucose as the sugar donor, as bilirubin beta-d-monoglucoside. 4. With UDP-xylose as the sugar donor xylosyl transfer to the carboxylic acid groups of bilirubin with attachment at C-1 was demonstrated in an analogous way. A beta-d-configuration is considered very likely, but requires confirmation. 5. Monoxyloside formation was predominant at pH7.4, whereas at decreasing pH values increasing fractions of the substrate were converted into the dixyloside. Prolonged incubation, low concentrations of bilirubin and high concentrations of UDP-xylose favoured diconjugate formation. The available evidence supports the synthesis sequence: bilirubin --> bilirubin monoxyloside --> bilirubin dixyloside.


Caloric, but not macronutrient, compensation by humans for required-eating occasions with meals and snack varying in fat and carbohydrate.
Six subjects participated in a residential study assessing the effects of covert macronutrient and energy manipulations during three required-eating occasions (breakfast, lunch, and afternoon snack) on total macronutrient and energy intakes. Overall, energy content of the occasions varied between approximately 3000 and approximately 7000 kJ (approximately 700 and approximately 1700 kcal) with the majority of the differential derived from either fat or carbohydrate (CHO). Each condition (high, medium, and low fat; high, medium, and low CHO; and no required eating) was examined for 2 d. Subjects compensated for the energy content of the required occasions such that only under the low-CHO condition (11,297 +/- 3314 kJ) was total daily energy intake lower than that observed in the absence of required occasions (13,297 +/- 1356 kJ). Only total energy intake under the high-fat condition (12,326 +/- 2548 kJ) was significantly different from its matched CHO condition (high-CHO condition: 14,665 +/- 2686 kJ). In contrast to the clear evidence for caloric compensation, there were no differential effects of condition on macronutrient intake, ie, there was no macronutrient compensation.


Possible production of high-energy gamma rays from proton acceleration in the extragalactic radio source markarian 501
The active galaxy Markarian 501 was discovered with air-Cerenkov telescopes at photon energies of 10 tera-electron volts. Such high energies may indicate that the gamma rays from Markarian 501 are due to the acceleration of protons rather than electrons. Furthermore, the observed absence of gamma ray attenuation due to electron-positron pair production in collisions with cosmic infrared photons implies a limit of 2 to 4 nanowatts per square meter per steradian for the energy flux of an extragalactic infrared radiation background at a wavelength of 25 micrometers. This limit provides important clues about the epoch of galaxy formation.


In Vivo Targeting of Clostridioides difficile Using Phage-Delivered CRISPR-Cas3 Antimicrobials.
Clostridioides difficile is an important nosocomial pathogen that causes approximately 500,000 cases of C. difficile infection (CDI) and 29,000 deaths annually in the United States. Antibiotic use is a major risk factor for CDI because broad-spectrum antimicrobials disrupt the indigenous gut microbiota, decreasing colonization resistance against C. difficile Vancomycin is the standard of care for the treatment of CDI, likely contributing to the high recurrence rates due to the continued disruption of the gut microbiota. Thus, there is an urgent need for the development of novel therapeutics that can prevent and treat CDI and precisely target the pathogen without disrupting the gut microbiota. Here, we show that the endogenous type I-B CRISPR-Cas system in C. difficile can be repurposed as an antimicrobial agent by the expression of a self-targeting CRISPR that redirects endogenous CRISPR-Cas3 activity against the bacterial chromosome. We demonstrate that a recombinant bacteriophage expressing bacterial genome-targeting CRISPR RNAs is significantly more effective than its wild-type parent bacteriophage at killing C. difficile both in vitro and in a mouse model of CDI. We also report that conversion of the phage from temperate to obligately lytic is feasible and contributes to the therapeutic suitability of intrinsic C. difficile phages, despite the specific challenges encountered in the disease phenotypes of phage-treated animals. Our findings suggest that phage-delivered programmable CRISPR therapeutics have the potential to leverage the specificity and apparent safety of phage therapies and improve their potency and reliability for eradicating specific bacterial species within complex communities, offering a novel mechanism to treat pathogenic and/or multidrug-resistant organisms.IMPORTANCEClostridioides difficile is a bacterial pathogen responsible for significant morbidity and mortality across the globe. Current therapies based on broad-spectrum antibiotics have some clinical success, but approximately 30% of patients have relapses, presumably due to the continued perturbation to the gut microbiota. Here, we show that phages can be engineered with type I CRISPR-Cas systems and modified to reduce lysogeny and to enable the specific and efficient targeting and killing of C. difficilein vitro and in vivo. Additional genetic engineering to disrupt phage modulation of toxin expression by lysogeny or other mechanisms would be required to advance a CRISPR-enhanced phage antimicrobial for C. difficile toward clinical application. These findings provide evidence into how phage can be combined with CRISPR-based targeting to develop novel therapies and modulate microbiomes associated with health and disease.


Comparative analysis of individuals with and without chiropractic coverage: patient characteristics, utilization, and costs.
Back pain accounts for more than $100 billion in annual US health care costs and is the second leading cause of physician visits and hospitalizations. This study ascertains the effect of systematic access to chiropractic care on the overall and neuromusculoskeletal-specific consumption of health care resources within a large managed-care system. A 4-year retrospective claims data analysis comparing more than 700 000 health plan members with an additional chiropractic coverage benefit and 1 million members of the same health plan without the chiropractic benefit. Members with chiropractic insurance coverage, compared with those without coverage, had lower annual total health care expenditures ($1463 vs $1671 per member per year, P<.001). Having chiropractic coverage was associated with a 1.6% decrease (P = .001) in total annual health care costs at the health plan level. Back pain patients with chiropractic coverage, compared with those without coverage, had lower utilization (per 1000 episodes) of plain radiographs (17.5 vs 22.7, P<.001), low back surgery (3.3 vs 4.8, P<.001), hospitalizations (9.3 vs 15.6, P<.001), and magnetic resonance imaging (43.2 vs 68.9, P<.001). Patients with chiropractic coverage, compared with those without coverage, also had lower average back pain episode-related costs ($289 vs $399, P<.001). Access to managed chiropractic care may reduce overall health care expenditures through several effects, including (1) positive risk selection; (2) substitution of chiropractic for traditional medical care, particularly for spine conditions; (3) more conservative, less invasive treatment profiles; and (4) lower health service costs associated with managed chiropractic care. Systematic access to managed chiropractic care not only may prove to be clinically beneficial but also may reduce overall health care costs.


Examination of the interior of sand fly (Diptera: Psychodidae) abdomen reveals novel cuticular structures involved in pheromone release: Discovering the manifold.
The males of many species of New World Phlebotomines produce volatile terpenoid chemicals, shown in Lutzomyia longipalpis s.l. to be sex/aggregation pheromones. Pheromone is produced by secretory cells which surround a cuticular reservoir which collects the pheromone and passes it through a cuticular duct to the surface of the insect. The pheromone then passes through specialised cuticular structures on the abdominal surface prior to evaporation. The shape and distribution of the specialised structures are highly diverse and differ according to species. In this study we used SEM to examine the interior cuticular pheromone collection and transport structures of 3 members of the Lu. longipalpis s.l. species complex and Migonemyia migonei. We found a new structure which we have called the manifold which appears to be a substantial extension of the interior tergal cuticle connected in-line with the cuticular duct and reservoir. The manifold of the Campo Grande member of the complex is longer and wider than the Jacobina member whereas the manifold of the Sobral member was shorter than both other members of the complex. Overall, the secretory apparatus of the Sobral member was smaller than the other two. The manifold of M. migonei was very different to those found in Lu. longipalpis s.l. and was positioned in a pit-like structure within the tergal cuticle. The secretory reservoir was connected by a short duct to the manifold. Differences in the size and shape of the manifold may be related to the chemical structure of the pheromone and may have taxonomic value. Examination of the interior cuticle by SEM may help to locate the secretory apparatus of vector species where pheromonal activity has been inferred from behavioural studies but the external secretory structures or pheromones have not yet been found.


How, why and under what circumstances does a quality improvement collaborative build knowledge and skills in clinicians working with people with dementia? A realist informed process evaluation.
In increasingly constrained health and aged care services, strategies are needed to improve quality and translate evidence into practice. In dementia care, recent failures in quality and safety have led the WHO to prioritise the translation of known evidence into practice. While quality improvement collaboratives have been widely used in healthcare, there are few examples in dementia care.We describe a recent quality improvement collaborative to improve dementia care across Australia and assess the implementation outcomes of acceptability and feasibility of this strategy to translate known evidence into practice. A realist-informed process evaluation was used to analyse how, why and under what circumstances a quality improvement collaborative built knowledge and skills in clinicians working in dementia care.This realist-informed process evaluation developed, tested and refined the programme theory of a quality improvement collaborative. Data were collected pre-intervention and post-intervention using surveys and interviews with participants (n=28). A combined inductive and deductive data analysis process integrated three frameworks to examine the context and mechanisms of knowledge and skill building in participant clinicians.A refined program theory showed how and why clinicians built knowledge and skills in quality improvement in dementia care. Six mechanisms were identified: motivation, accountability, identity, collective learning, credibility and reflective practice. These mechanisms, in combination, operated to overcome constraints, role boundaries and pessimism about improved practice in dementia care.A quality improvement collaborative designed for clinicians in different contexts and roles was acceptable and feasible in building knowledge, skills and confidence of clinicians to improve dementia care. Supportive reflective practice and a credible, flexible and collaborative process optimised quality improvement knowledge and skills in clinicians working with people with dementia.Trial registration numberACTRN12618000268246.


Nucleotide sequences of tobacco chloroplast genes for elongator tRNAMet and tRNAVal (UAC): the tRNAVal (UAC) gene contains a long intron.
The nucleotide sequences of tobacco chloroplast genes for elongator tRNAMet and tRNAVal (UAC) have been determined. The tRNAVal gene contains a 571 base pairs intron located in the anticodon loop. The tRNAVal gene is transcribed as a 750 bases precursor RNA molecule. Both tRNAs deduced from the DNA sequences show 97% sequence homologies with those of spinach chloroplasts.


CD39 identifies a specific CD8 + T cell population in lung adenocarcinoma-related metastatic pleural effusion.
Malignant pleural effusion (MPE), which is a complex microenvironment that contains numerous immune and tumour signals, is common in lung cancer. Gene alterations, such as driver gene mutations, are believed to affect the components of tumour immunity in the microenvironment (TIME) of non-small-cell lung cancer. In this study, we have shown that pleural CD39 + CD8 + T cells are selectively elevated in lung adenocarcinoma (LUAD) with wild-type epidermal growth factor receptor (EGFRwt) compared to those with newly diagnosed mutant EGFR (EGFRmu). Furthermore, these CD39 + CD8 + T cells are more prevalent in MPE with acquired resistance to EGFR-tyrosine kinase inhibitors (AR-EGFR-TKIs). Our analysis reveals that pleural CD39 + CD8 + T cells exhibit an exhausted phenotype while still retaining cytolytic function. Additionally, they have a higher T cell receptor (TCR) repertoire clonality compared to CD39-CD8 + T cells, which is a unique characteristic of LUAD-related MPE. Further investigation has shown that TCR-Vβ clonality tends to be more enhanced in pleural CD39 + CD8 + T cells from MPE with AR-EGFR-TKIs. In summary, we have identified a subset of CD8 + T cells expressing CD39 in MPE, which may potentially be tumour-reactive CD8 + T cells. This study provides new insights into the dynamic immune composition of the EGFRmu tumour microenvironment.


Synthesis and biological evaluation of 8-hydroxy-2,7-naphthyridin-2-ium salts as novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
By analogy with the natural product chelerythrine, which has been identified as an inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), we prepared a small series of 8-hydroxy-2,7-naphthyridin-2-ium salts. Spectroscopic analyses allowed us to elucidate the zwitterionic nature of 2,7-naphthyridin-1(7H)-ones, the neutral state of 8-hydroxy-2,7-naphthyridin-2-ium salts. Among the tested compounds, we identified dual inhibitors of AChE and BChE as well as an inhibitor showing a preferential inhibition of AChE over BChE. By in vitro characterization in combination with docking studies, we were able to identify structural features that influence the biological activity of 8-hydroxy-2,7-naphthyridin-2-ium salts.


Reduced virulence of a Listeria monocytogenes phospholipase-deficient mutant obtained by transposon insertion into the zinc metalloprotease gene.
A phospholipase-deficient mutant, termed JL762, was obtained from a virulent strain of Listeria monocytogenes by screening a bank of 5,000 Tn1545 transposon-induced mutants on 2.5% egg yolk brain heart infusion agar. As previously shown (J. Mengaud, C. Geoffroy, and P. Cossart, Infect. Immun. 59:1043-1049, 1991), the transposon insertion took place inside the gene mpl, which encodes a zinc metalloprotease. By Western blot (immunoblot) analysis, we showed that loss of phospholipase activity was associated with loss of a 29-kDa zinc-dependent phosphatidylcholine-phospholipase C (PC-PLC) in culture supernatant of JL762 and of EGD-SmR incubated with ion chelator. As the parental strain, JL762 still produced in supernatants approximately 33-kDa proteins antigenically closely related to the 29-kDa PC-PLC. These results strongly suggest that the zinc metalloprotease of L. monocytogenes might play a role in the maturation of the 29-kDa PC-PLC. Although the uptake and the intracellular growth of bacteria were not affected in vitro, we found that the virulence of mutant JL762 was strongly impaired in the mouse.


[Immunocytochemical detection of creatine kinase isoenzymes (CK BB) in human cerebral cortex].
The localization of creatine phosphokinase-BB (CPK-BB) in the neocortex of persons without mental pathology, who died of cardiovascular diseases (n-15) was investigated immunocytochemically. It has been found that there are several differences in the visualization of CPK-BB in neurons and astrocytes under various conditions of autopsy material treatment. The data obtained may attest to the existence of the immunochemically different forms of CPK-BB in the human brain. The appropriate conditions were defined for satisfactory visualization of CPK-BB on material of pathomorphologic collections.


Increased neuronal nitric oxide synthase activity in retinal neurons in early diabetic retinopathy.
There are increased levels of nitric oxide (NO) in diabetic retinas. The purpose of this study was to determine the extent that neuronal nitric oxide synthase (nNOS) contributes to the increased levels of retinal NO in early diabetic retinopathy by examining the expression and activity of nNOS in retinal neurons after 5 weeks of diabetes. Changes in NO levels were measured using NO imaging of retinal neurons in mice with streptozotocin-induced diabetes for five weeks. NO imaging was compared to nNOS localization using immunocytochemistry, and nNOS message and protein levels were measured using quantitative real-time PCR and western blots. There was a close anatomic correlation between the localization of the increased NO production and the nNOS immunoreactivity in the retinal plexiform layers of diabetic retinas. There was no change in nNOS message, but nNOS protein was decreased and its subcellular localization was altered. Treatment with insulin or aminoguanidine partially ameliorated the increase in NO in diabetic retinas. These results suggest that increased nNOS activity is responsible for the majority of increased NO in retinal neurons in early diabetic retinopathy. This supports a role for increased nNOS activity in the early neuronal dysfunction in the diabetic retina.


Real-Time Analysis of Animal Feeding Behavior With a Low-Calculation-Power CPU.
Our goal was to develop an automated system to determine whether animals have learned and changed their behavior in real-time using a low calculation-power central processing unit (CPU). The bottleneck of real-time analysis is the speed of image recognition. For fast image recognition, 99.5% of the image was excluded from image recognition by distinguishing between the subject and the background. We achieved this by applying a binarization and connected-component labeling technique. This task is important for developing a fully automated learning apparatus. The use of such an automated system can improve the efficiency and accuracy of biological studies. The pond snail Lymnaea stagnails can be classically conditioned to avoid food that naturally elicits feeding behavior, and to consolidate this aversion into long-term memory. Determining memory status in the snail requires real-time analysis of the number of bites the snail makes in response to food presentation. The main algorithm for counting bites comprises two parts: extracting the mouth images from the recorded video and measuring the bite rate corresponding to the memory status. Reinforcement-supervised learning and image recognition were used to extract the mouth images. A change in the size of the mouth area was used as the cue for counting the number of bites. The accuracy of the final judgment of whether or not the snail had learned was the same as that determined by human observation. This method to improve the processing speed of image recognition has the potential for broad application beyond biological fields.


Acetabular reconstruction with impaction bone grafting and cemented polyethylene socket in total hip revision arthroplasty.
Bone deficiency in revision total hip arthroplasty is a challenge to the surgeon. One option for restoration of the bone stock is impaction bone grafting and use of a cemented socket. The aim of this study was to evaluate the mid-term clinical outcome of impaction bone grafting and cemented socket revisions. A total of 59 patients (60 hips) underwent revision arthroplasty with impaction bone grafting and application of a cemented socket on the acetabular side in the Turku University Hospital from 1999 to 2004. The study end-point was re-revision for any reason. The cumulative percentages for survival were followed and estimated with Kaplan-Meier curves. Associations between occurrence of re-revision and potential risk factors were analyzed with logistic regression. Results were quantified by odd ratios and 95% confidence intervals. The mean age of the patients was 69 years (33% male). A total of 3% of the patients had a class I Paprosky acetabular defect, 38% had class II, and 55% had class III. The overall survival rate was 73%. The mean follow-up time was 7 years. The most common reason for re-revision was aseptic loosening of the acetabular component (13 patients, 81% of re-revisions). Cox's regression analysis did not identify any risk factors for re-revision. Our results were inferior compared to some previous studies. Impaction bone grafting of acetabular defects in revision total hip arthroplasty may not always provide a reliable bone stock in long-term.


Adapting and testing a brief intervention to reduce maternal anxiety during pregnancy (ACORN): study protocol for a randomised controlled trial.
National guidelines in the UK, United States of America, Canada, and Australia have recently stressed the importance of identifying and treating antenatal anxiety and depression. However, there is little research into the most effective and acceptable ways of helping women manage their symptoms of anxiety and stress during pregnancy. Research indicates the necessity to consider the unique needs and concerns of perinatal populations to ensure treatment engagement, highlighting the need to develop specialised treatments which could be integrated within routine antenatal healthcare services. This trial aims to develop a brief intervention for antenatal anxiety, with a focus on embedding the delivery of the treatment within routine antenatal care. This study is a two-phase feasibility trial. In phase 1 we will develop and pilot a brief intervention for antenatal anxiety, blended with group support, to be led by midwives. This intervention will draw on cognitive behavioural principles and wider learning from existing interventions that have been used to reduce anxiety in expectant mothers. The intervention will then be tested in a pilot randomised controlled trial in phase 2. The following outcomes will be assessed: (1) number of participants meeting eligibility criteria, (2) number of participants consenting to the study, (3) number of participants randomised, (4) number of sessions completed by those in the intervention arm, and (5) number of participants completing the post-intervention outcome measures. Secondary outcomes comprise: detailed feedback on acceptability, which will guide further development of the intervention; and outcome data on symptoms of maternal and paternal anxiety and depression, maternal quality of life, quality of couple relationship, mother-child bonding, infant temperament and infant sleep. The study will provide important data to inform the design of a future full-scale randomised controlled trial of a brief intervention for anxiety during pregnancy. This will include information on its acceptability and feasibility regarding implementation within current antenatal services, which will inform whether ultimately this provision could be rolled out widely in healthcare settings. Current Controlled Trials ISRCTN95282830 . Registered on 29 October 2014.


The combined effects of limited nutrition and high-frequency loading on intervertebral discs with endplates.
Whole ovine caudal intervertebral discs were cultured under simulated-physiologic or high-frequency loading and either sufficient or limited nutrition for 7 days. To study the effect of high-frequency loading under sufficient or limited glucose conditions and to investigate the additive effects of load and nutrition on cell survival, gene expression, and cell activity after 7 days of culture. Limited nutrition and certain mechanical stimuli are generally believed to be etiologic factors for disc degeneration. Although these effects and their interactions have been demonstrated in cell culture, no investigations have been reported in entire discs. Discs were maintained in a whole organ culture bioreactor system under simulated-physiologic (0.2 Hz) or high-frequency (10 Hz) loading, in media with either limited (2 g/L) or sufficient (4.5 g/L) glucose concentration. After 7 days, cell viability, relative gene expression, newly synthesized chondroitin sulfate content, glycosaminoglycan synthesis rate, and disc morphology were assessed after culture and compared with fresh tissue. Culture under either limited glucose or high-frequency loading conditions led to a significant drop in cell viability. Combined treatment with limited glucose and high-frequency loading resulted in an additive increase in cell death in both the anulus fibrosus and nucleus pulposus and in an increase in MMP13 gene expression. Supporting in vivo studies and cell culture experiments, high-frequency loading simulating vibration conditions shows detrimental effects on intervertebral disc cells in whole organ culture. The effect on cell viability was exacerbated by limited nutrition culture. However, neither frequency nor limited glucose affected cell metabolism, measured by glycosaminoglycan synthesis rate. Longer culture periods may be required to detect changes at the extracellular matrix level.


Cdc42-dependent activation of NADPH oxidase is involved in ethanol-induced neuronal oxidative stress.
It has been suggested that excessive reactive oxygen species (ROS) and oxidative stress play an important role in ethanol-induced damage to both the developing and mature central nervous system (CNS). The mechanisms underlying ethanol-induced neuronal ROS, however, remain unclear. In this study, we investigated the role of NADPH oxidase (NOX) in ethanol-induced ROS generation. We demonstrated that ethanol activated NOX and inhibition of NOX reduced ethanol-promoted ROS generation. Ethanol significantly increased the expression of p47(phox) and p67(phox), the essential subunits for NOX activation in cultured neuronal cells and the cerebral cortex of infant mice. Ethanol caused serine phosphorylation and membrane translocation of p47(phox) and p67(phox), which were prerequisites for NOX assembly and activation. Knocking down p47(phox) with the small interfering RNA was sufficient to attenuate ethanol-induced ROS production and ameliorate ethanol-mediated oxidative damage, which is indicated by a decrease in protein oxidation and lipid peroxidation. Ethanol activated cell division cycle 42 (Cdc42) and overexpression of a dominant negative (DN) Cdc42 abrogate ethanol-induced NOX activation and ROS generation. These results suggest that Cdc42-dependent NOX activation mediates ethanol-induced oxidative damages to neurons.


Understanding the binding properties of an unusual metal-binding protein--a study of bacterial frataxin.
Deficiency of the small mitochondrial protein frataxin causes Friedreich's ataxia, a severe neurodegenerative pathology. Frataxin, which has been highly conserved throughout evolution, is thought to be involved in, among other processes, Fe-S cluster formation. Independent evidence shows that it binds iron directly, although with very distinct features and low affinity. Here, we have carried out an extensive study of the binding properties of CyaY, the bacterial ortholog of frataxin, to different divalent and trivalent cations, using NMR and X-ray crystallography. We demonstrate that the protein has low cation specificity and contains multiple binding sites able to chelate divalent and trivalent metals with low affinity. Binding does not involve cavities or pockets, but exposed glutamates and aspartates, which are residues that are unusual for iron chelation when not assisted by histidines and/or cysteines. We have related how such an ability to bind cations on a relatively large area through an electrostatic mechanism could be a valuable asset for protein function.


Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients.
Fentanyl is widely used for analgesia, sedation, and anesthesia both in adult and pediatric populations. Yet, only few pharmacokinetic studies of fentanyl in pediatrics exist as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling is a mechanistic approach to explore drug pharmacokinetics and allows extrapolation from adult to pediatric populations based on age-related physiological differences. The aim of this study was to develop a PBPK model of fentanyl and norfentanyl for both adult and pediatric populations. The adult PBPK model was established in PK-Sim® using data from 16 clinical studies and was scaled to several pediatric subpopulations. ~93% of the predicted AUClast values in adults and ~88% in pediatrics were within 2-fold of the corresponding value observed. The adult PBPK model predicted a fraction of fentanyl dose metabolized to norfentanyl of ~33% and a fraction excreted in urine of ~7%. In addition, the pediatric PBPK model was used to simulate differences in peak plasma concentrations after bolus injections and short infusions. The novel PBPK models could be helpful to further investigate fentanyl pharmacokinetics in both adult and pediatric populations.


A Cost-Consequence Analysis of Different Screening Procedures in Alzheimer's Disease: Results from the MOPEAD Project.
For care planning and support, under-detection and late diagnosis of Alzheimer's disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation. To make a cost-consequence analysis of MOPEAD. Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population. Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was €3,115 with the web-approach, €2,722 with the Open-House, €1,530 in primary care, and €1,190 by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists.There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP. In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.


Improving quality through clinical registries in urology.
In this review, we highlight the use of clinical registries for quality improvement and research purposes in urology. We focus on national and regional clinical database registries, such as the National Surgical Quality Improvement Programme, the Cancer of the Prostate Strategic Urologic Research Endeavor, the Michigan Urological Surgery Improvement collaborative and the American Urological Association Quality Registry programme. It is widely known that claims-based and institutional databases are limited in their capacity to provide granular, real-time data for quality improvement purposes. As a result, clinical registries have emerged as an attractive alternative given their ability to capture large amounts of data across networks of health records. Another added benefit of Federally Qualified Clinical Data Registries (QCDRs) is the ability to meet emerging Medicare quality reporting standards, such as Physician Quality Reporting System and Meaningful Use. Despite the enthusiasm for QCDRs in the field of urology, however, myriad challenges remain in their implementation and widespread adoption including integration of existing health-information technology infrastructure, the accurate measurement of quality measures and the availability of clinically relevant quality measures in subspecialty practices. Quality measurement and improvement have become important aspects of modern clinical practice. Advances in health information technology have ushered in new tools, such as clinical registries, which simultaneously improve the quality of scientific research and clinical care while assisting eligible professionals in meeting federally mandated reporting requirements.


Behavioral Role of the Reciprocal Inhibition between a Pair of Mauthner Cells during Fast Escapes in Zebrafish.
During many behaviors in vertebrates, the CNS generates asymmetric activities between the left and right sides to produce asymmetric body movements. For asymmetrical activations of the CNS, reciprocal inhibition between the left and right sides is believed to play a key role. However, the complexity of the CNS makes it difficult to identify the reciprocal inhibition circuits at the level of individual cells and the contribution of each neuron to the asymmetric activity. Using larval zebrafish, we examined this issue by investigating reciprocal inhibition circuits between a pair of Mauthner (M) cells, giant reticulospinal neurons that trigger fast escapes. Previous studies have shown that a class of excitatory neurons, called cranial relay neurons, is involved in the reciprocal inhibition pathway between the M cells. Using transgenic fish, in which two of the cranial relay neurons (Ta1 and Ta2) expressed GFP, we showed that Ta1 and Ta2 constitute major parts of the pathway. In larvae in which Ta1/Ta2 were laser-ablated, the amplitude of the reciprocal IPSPs dropped to less than one-third. Calcium imaging and electrophysiological recording showed that the occurrence probability of bilateral M-cell activation upon sound/vibration stimuli was greatly increased in the Ta1/Ta2-ablated larvae. Behavioral experiments revealed that the Ta1/Ta2 ablation resulted in shallower body bends during sound/vibration-evoked escapes, which is consistent with the observation that increased occurrence of bilateral M-cell activation impaired escape performance. Our study revealed major components of the reciprocal inhibition circuits in the M cell system and the behavioral importance of the circuits.SIGNIFICANCE STATEMENT Reciprocal inhibition between the left and right side of the CNS is considered imperative for producing asymmetric movements in animals. It has been difficult, however, to identify the circuits at the individual cell level and their role in behavior. Here, we address this problem by examining the reciprocal inhibition circuits of the hindbrain Mauthner (M) cell system in larval zebrafish. We determined that two paired interneurons play a critical role in the reciprocal inhibition between the paired M cells and that the reciprocal inhibition prevents bilateral firing of the M cells and is thus necessary for the full body bend during M cell-initiated escape. Further, we discussed the cooperation of multiple reciprocal inhibitions working in the hindbrain and spinal cord to ensure high-performance escapes.


Subregion districting analysis for municipal solid waste collection privatization.
Privatization of municipal solid waste (MSW) collection can improve service quality and reduce cost. To reduce the risk of an incapable company serving an entire collection area and to establish a competitive market, a large collection area should be divided into two or more subregions, with each subregion served by a different company. The MSW subregion districting is generally done manually, based on the planner's intuition. Major drawbacks of a manual approach include the creation of a districting plan with poor road network integrity for which it is difficult to design an efficient collection route. The other drawbacks are difficulty in finding the optimal districting plan and the lack of a way to consistently measure the differences among subregions to avoid unfair competition. To determine an MSW collection subregion districting plan, this study presents a mixed-integer optimization model that incorporates factors such as compactness, road network integrity, collection cost, and regional proximity. Two cases are presented to demonstrate the applicability of the proposed model. In both cases, districting plans with good road network integrity and regional proximity have been generated successfully.


Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
UV-sensitive syndrome (UVsS) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. UVsS cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage. It was suggested that UVsS does not belong to any complementation groups of known photosensitive disorders such as xeroderma pigmentosum and Cockayne syndrome (CS). To identify the gene responsible for UVsS, we performed a microcell-mediated chromosome transfer based on the functional complementation of UV hypersensitivity. We found that one of the UVsS cell lines, UVs1KO, acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for CS group B (CSB), which involves neurological abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, we sequenced the CSB gene from UVs1KO and detected a homozygous null mutation. Our results indicate that previous complementation analysis of UVs1KO was erroneous. This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities. On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a UVsS cell line obtained from an unrelated patient, indicating genetic heterogeneity in UVsS. Possible explanations for the discrepancy in the genotype-phenotype relationship in UVs1KO are presented.


Statistical regularization in linearized microwave imaging through MRF-based MAP estimation: hyperparameter estimation and image computation.
The application of a Markov random fields (MRF) based maximum a posteriori (MAP) estimation method for microwave imaging is presented in this paper. The adopted MRF family is the so-called Gaussian-MRF (GMRF), whose energy function is quadratic. In order to implement the MAP estimation, first, the MRF hyperparameters are estimated by means of the expectation-maximization (EM) algorithm, extended in this case to complex and nonhomogeneous images. Then, it is implemented by minimizing a cost function whose gradient is fully analytically evaluated. Thanks to the quadratic nature of the energy function of the MRF, well posedness and efficiency of the proposed method can be simultaneously guaranteed. Numerical results, also performed on real data, show the good performance of the method, also when compared with conventional techniques like Tikhonov regularization.


A lightweight speech recognition method with target-swap knowledge distillation for Mandarin air traffic control communications.
Miscommunications between air traffic controllers (ATCOs) and pilots in air traffic control (ATC) may lead to catastrophic aviation accidents. Thanks to advances in speech and language processing, automatic speech recognition (ASR) is an appealing approach to prevent misunderstandings. To allow ATCOs and pilots sufficient time to respond instantly and effectively, the ASR systems for ATC must have both superior recognition performance and low transcription latency. However, most existing ASR works for ATC are primarily concerned with recognition performance while paying little attention to recognition speed, which motivates the research in this article. To address this issue, this article introduces knowledge distillation into the ASR for Mandarin ATC communications to enhance the generalization performance of the light model. Specifically, we propose a simple yet effective lightweight strategy, named Target-Swap Knowledge Distillation (TSKD), which swaps the logit output of the teacher and student models for the target class. It can mitigate the potential overconfidence of the teacher model regarding the target class and enable the student model to concentrate on the distillation of knowledge from non-target classes. Extensive experiments are conducted to demonstrate the effectiveness of the proposed TSKD in homogeneous and heterogeneous architectures. The experimental results reveal that the generated lightweight ASR model achieves a balance between recognition accuracy and transcription latency.


Electrophysiological differentiation of alpha-receptors on arteriolar smooth muscle.
The effects of clonidine (a prototype of an alpha 2-agonist) and phenylephrine (a prototype of an alpha 1-agonist) on intracellularly recorded electrical activity and vessel size of feline submucosal arterioles were compared. Phenylephrine constricts the vessels and causes a depolarization and the initiation of oscillations of the membrane potential. These oscillations occasionally give rise to spike potentials. In contrast, clonidine produces no significant depolarization of the resting potential in spite of the simultaneous initiation of contraction. Neurally induced depolarizations (excitatory junction potentials) are not blocked and are sometimes augmented by the nonselective alpha-blocker phentolamine even though the depolarization induced by norepinephrine is blocked by phentolamine. Excitatory junction potentials are antagonized by the alpha 1-blocker prazosin. The contraction caused by clonidine is blocked to a greater degree by yohimbine (a relatively selective alpha 2-blocker) than by prazosin. The contraction caused by phenylephrine is blocked to a greater degree by prazosin than by yohimbine. These data indicate that phenylephrine and clonidine act by different mechanisms and, taken together with previous studies, suggest that alpha 1- and alpha 2-stimulation utilize different excitation-contraction coupling mechanisms.


Developmental- and Tissue-Specific Expression of NbCMT3-2 Encoding a Chromomethylase in Nicotiana benthamiana.
The chromomethylase (CMT) protein family is unique to plants and controls non-CpG methylation. Here, we investigated the developmental expression of CMT3-2 in Nicotiana benthamiana (NbCMT3-2) and its significance by analyzing plants with silenced NbCMT3-2 and leaf tissues transiently expressing the N-terminal polypeptide. Alignment of the NbCMT3-2 amino acid sequence with that of other plant CMT3s showed a specific N-terminal extension required for nuclear localization. Transient expression of the N-terminal polypeptide in N. benthamiana resulted in chlorotic lesions. NbCMT3-2 was expressed mainly in proliferating tissues such as the shoot apex and developing leaves. We generated transgenic N. benthamiana harboring a fusion reporter construct linking the NbCMT3-2 promoter region and the β-glucuronidase (GUS) reporter (pNbCMT3-2::GUS) to analyze the tissue-specific expression of NbCMT3-2. NbCMT3-2 was expressed in the shoot and root apical meristem and leaf primordia in young seedlings and highly expressed in developing leaves and ovary as well as lateral buds in mature plants. Virus-induced gene silencing used to knock down the expression of NbCMT3 or NbCMT3-2 or both led to partial loss of genomic DNA methylation. Plants with suppressed NbCMT3 expression grew and developed normally, whereas leaves with NbCMT3-2 knockdown showed mild curling as compared with controls. Silencing NbCMT3/3-2 severely interfered with leaf development and directly or indirectly affected the expression of genes involved in jasmonate homeostasis. The differential roles of NbCMT3 and NbCMT3-2 were investigated and compared. We reveal the expression patterns of NbCMT3-2 in proliferating tissues. NbCMT3-2 may play an essential role in leaf development by modulating jasmonate pathways.


Acute renal failure in children: etiology, treatment and outcome.
Children with acute renal failure (ARF) may be treated in pediatric renal or intensive care (PICU) units where there is an increasing use of continuous renal replacement therapies such as hemofiltration (HF). Over three years, we prospectively recorded details of all patients with ARF treated both within our regional pediatric renal unit, in two local neonatal intensive care units (NICUs), and one PICU, which are all supported by our institution. Our study included eighty-three ARF patients (43% male) with a median age of 5.7 years (range 1 day - 19.8 years); 41% of patients were < 2 years, 20% 2-5 years, 13% 5-10 years and 26% > 10 years of age. A total of 37 patients (45%) were treated in the renal unit versus 46 (55%) patients in NICU/PICU. The initial treatment modality was conservative in 33%, peritoneal dialysis (PD) in 23%, hemodialysis (HD) in 15%, HF in 28%, and isolated plasmafiltration in one percent of the patients. About 16% of the patients required more than one treatment modality. Outcome data at three months showed normal renal function in 49%, deaths in 20%, dialysis dependent disease in 14%, chronic renal failure (GFR < 60ml/min/1.73m2) in eight percent, and proteinuria and/or hypertension in seven percent of the patients. Only one (3%) death occurred in 37 patients treated in the renal unit compared to 16 deaths in 46 patients (35%) treated in the NICU/PICU. Our findings further confirm the low mortality rate with isolated renal failure and the substantial mortality and renal workload in intensive care areas where renal failure is often part of multi-organ failure. Further prospective studies will be required to analyze the impact of early hemofiltration in such patients.


Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet?
Spurred on by ever-evolving developments in analytical methodology, the microbiome, and the gut microbiome in particular, has become the hot topic in biomedical research. Ingenious experiments in animal models have revealed the extent to which the gut microbiota sustains health and how its disruption might contribute to disease pathogenesis. Not surprisingly, associations between the microbiota and disease states in humans have been the subject of considerable interest and many links proposed. However, with rare exceptions, the incrimination of an altered microbiota in disease pathogenesis seems premature at this time given our incomplete understanding of the composition of the gut microbiota in health and the effect of many confounding factors in the interpretation of supposedly abnormal microbial signatures. Future studies must account for these variables and the bidirectionality of host-microorganism interactions in health and disease. In this Perspectives, the status of microbiota signatures in the clinical arena (for facilitating diagnosis or refining prognosis) will be critically assessed and guidance toward future progress provided.


Sound radiation from impact-driven raked piles.
Sound emissions from impact pile driving of raked piles present a significant azimuthal dependence in the radiated sound field due to the non-axisymmetric orientation of the pile. In this work the sound radiation from raked piles is modeled using a finite element method (FEM) model of the pile and near-field region. The near-field model of the sound field is then used as input into a normal mode model to predict the sound radiation in the far-field. The azimuthal dependence of the radiated sound field is shown to be accurately predicted using an equivalent axisymmetric FEM model of the pile configuration, thus negating the need to construct a fully three-dimensional model (3D) of the raked pile. This is achieved by matching the radiated field from the equivalent axisymmetric pile model to a vertical array of phased point sources, and then horizontally offsetting the source locations to match the incline of the raked pile. The resulting sound field closely matches the numerical predictions from a fully 3D FEM model of the raked pile. The results of numerical modeling are compared to corresponding acoustic measurements taken on the North West shelf of Western Australia.


Incidental mastoid opacification on computed tomography in the pediatric population.
Incidental mastoid opacification (IMO) is a common radiologic finding and source of referral to otolaryngologists. Our objectives were to: 1) determine the rate of IMO in our pediatric population; 2) identify those with clinical mastoiditis; and 3) identify factors necessitating an otolaryngology consultation. This was a retrospective chart review at an academic, tertiary, pediatric hospital in an urban setting. Pediatric patients with the keyword 'mastoid' on a computed tomography (CT) scan report were reviewed. The effect of age, gender, season and the use of contrast media on the rate of IMO was also analyzed. Chi-square analysis was used to compare the significance of categorical frequencies. The rate of IMO in our cohort was 14.2% (164/1157). In children <8 years of age, the IMO rate was 22.0% compared to 5.6% in children 8-17 years of age (p < .001). The IMO rate in male children was 16.6% compared to 11.0% in female children (p = .007). There was no statistically significant higher rate of IMO during winter (15.1%) compared to summer (9.0%) and in CT scans with contrast (16.0%) compared to without contrast (14.0%). Our department of otolaryngology was formally consulted in 3% (5/164) of IMO cases. None of those patients had clinical mastoiditis. This is the largest study identifying IMO on CT and in children to date. Although the overall rate of IMO in the pediatric population is 14.2%, it is rarely clinically significant.


Isokinetic knee joint evaluation in track and field events.
The purpose of this study was to evaluate maximal torque of the knee flexors and extensors, flexor/extensor ratios, and maximal torque differences between the 2 lower extremities in young track and field athletes. Forty male track and field athletes 13-17 years old and 20 male nonathletes of the same age participated in the study. Athletes were divided into 4 groups according to their age and event (12 runners and 10 jumpers 13-15 years old, 12 runners and 6 jumpers 16-17 years old) and nonathletes into 2 groups of the same age. Maximal torque evaluation of knee flexors and extensors was performed on an isokinetic dynamometer at 60°·s(-1). At the age of 16-17 years, jumpers exhibited higher strength values at extension than did runners and nonathletes, whereas at the age of 13-15 years, no significant differences were found between events. Younger athletes were weaker than older athletes at flexion. Runners and jumpers were stronger than nonathletes in all relative peak torque parameters. Nonathletes exhibited a higher flexor/extensor ratio compared with runners and jumpers. Strength imbalance in athletes was found between the 2 lower extremities in knee flexors and extensors and also at flexor/extensor ratio of the same extremity. Young track and field athletes exhibit strength imbalances that could reduce their athletic performance, and specific strength training for the weak extremity may be needed.


[Conservative, laparoscopic and medical treatment of ectopic pregnancy].
Ectopic pregnancy is that in which implantation of fertilized zygote occurs out of the uterine cavity mucosa (fallopian tube ampulla, isthmus, interstice, cervix, ovary or abdomen). Patients with ectopic pregnancy history have bad forecast on subsequent fertility. To describe conservative, laparoscopic and medical treatment to ectopic pregnancy (estimation of results). Revision of 65 files of ectopic pregnancy with salpingocentesis, lineal salpingostomy and methotrexate terapy. Salpingocentesis and lineal salpingostomy prove tube permeability in 81.4 to 90% of cases. The number of intrauterine pregnancies has a 60 to 67% of variation. Presently we take care four intrauterine pregnancies, two with each surgical procedure. It is important to asses prophylactic administration of methotrexate to avoid ectopic pregnancy. This drug was prescribed in six successful cases with a unique dosage of 25 mg. Determination of HCG and gynecologic ultrasonography facilitate ectopic pregnancy diagnosis.


Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease.
Citrullinated proteins are the products of a posttranslational process in which arginine residues undergo modification into citrulline residues when catalyzed by peptidylarginine deiminases (PADs) in a calcium ion-dependent manner. In our previous report, PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of protein citrullination in human neuronal degeneration, we examined whether citrullinated proteins are produced during Alzheimer's disease (AD). By Western blot analysis with antimodified citrulline antibody, citrullinated proteins of varied molecular weights were detected in hippocampal tissues from patients with AD but not normal humans. Two of the citrullinated proteins were identified as vimentin and glial fibrillary acidic protein (GFAP) by using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. Interestingly, PAD2 was detected in hippocampal extracts from AD and normal brains, but the amount of PAD2 in the AD tissue was markedly greater. Histochemical analysis revealed citrullinated proteins throughout the hippocampus, especially in the dentate gyrus and stratum radiatum of CA1 and CA2 areas. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also ubiquitous throughout both the AD and the normal hippocampal areas. PAD2 enrichment coincided well with citrullinated protein positivity. Double immunofluorescence staining revealed that citrullinated protein- and PAD2-positive cells also coincided with GFAP-positive cells, but not all GFAP-positive cells were positive for PAD2. As with GFAP, which is an astrocyte-specific marker protein, PAD2 is distributed mainly in astrocytes. These collective results, the abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 in hippocampi of patients with AD, strongly suggest that PAD has an important role in the onset and progression of AD and that citrullinated proteins may become a useful marker for human neurodegenerative diseases.


Upregulation of CX3CR1 expression in circulating T cells of systemic lupus erythematosus patients as a reflection of autoimmune status through characterization of cytotoxic capacity.
This study investigated CX3CR1 expression in human peripheral blood T lymphocytes and their subsets, exploring changes in SLE patients and its diagnostic potential. Peripheral blood samples from 31 healthy controls and 50 SLE patients were collected. RNA-Seq data from SLE patient PBMCs were used to analyze CX3CR1 expression in T cells. Flow cytometry determined CX3CR1-expressing T lymphocyte subset proportions in SLE patients and healthy controls. Subset composition and presence of GZMB, GPR56, and perforin in CX3CR1+ T lymphocytes were analyzed. T cell-clinical indicator correlations were assessed. ROC curves explored CX3CR1's diagnostic potential for SLE. CX3CR1+CD8+ T cells exhibited higher GPR56, perforin, and GZMB expression than other T cell subsets. The proportion of CX3CR1+ was higher in TEMRA and lower in Tn and TCM. PMA activation reduced CX3CR1+ T cell proportions. Both RNA-Seq and flow cytometry revealed elevated CX3CR1+ T cell proportions in SLE patients. Significantly lower perforin+ and GPR56+ proportions were observed in CX3CR1+CD8+ T cells in SLE patients. CX3CR1+ T cells correlated with clinical indicators. CX3CR1+ T cells display cytotoxic features, with heightened expression in CD8+ T cells, particularly in adult SLE patients. Increased CX3CR1 expression in SLE patient T cells suggests its potential as an adjunctive diagnostic marker for SLE.


BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE.
Benign prostatic hyperplasia (BPH) represents a significant burden in ageing men due to frequently associated lower urinary tract symptoms (LUTS), which may impair quality of life. BPH is also a progressive disease, mainly characterized by a deterioration of LUTS over time, and in some patients by the occurrence of serious outcomes such as acute urinary retention (AUR) and need for BPH-related surgery. The goals of therapy for BPH are not only to improve bothersome LUTS but also to identify those patients at risk of unfavourable outcomes, to optimize their management. In selected patients, combination of an alpha(1)-blocker and a 5alpha-reductase inhibitor is the most effective form of BPH medical therapy to reduce the risk of clinical progression and relieve LUTS. Monotherapy also significantly reduces the risk of BPH clinical progression, mainly through a reduction of LUTS deterioration for alpha(1)-blockers while 5alpha-reductase inhibitors also reduce the risk of AUR and need for BPH-related surgery. Enlarged prostate and high serum prostate-specific antigen levels have been consistently found to be good clinical predictors of AUR and BPH-related surgery in longitudinal population-based studies and placebo arms of controlled studies. High post-void residual urine (PVR) is also associated with an increased risk of LUTS deterioration and should thus be reconsidered in practice as a predictor of BPH progression. Conversely, baseline LUTS severity and low peak flow rate, initially identified as predictors of unfavourable outcomes in community setting, behave paradoxically in controlled trials, probably as a consequence of strict inclusion criteria and subsequent regression to the mean and glass ceiling effects. Lastly, there is increasing evidence that dynamic variables, such as LUTS and PVR worsening, and lack of symptomatic improvement with alpha(1)-blockers are important predictors of future LUTS/BPH-related events, allowing better identification and management of patients at risk of BPH progression.


Antineoplastic agents. 551. Isolation and structures of bauhiniastatins 1-4 from Bauhinia purpurea.
Bioassay-guided (P388 lymphocytic leukemia cell line) separation of extracts prepared from the leaves, stems, and pods of Bauhinia purpurea, and, in parallel, its roots, led to the isolation of four new dibenz[b,f]oxepins (2a, 3-5) named bauhiniastatins 1-4, as well as the known and related pacharin (1) as cancer cell growth inhibitors. The occurrence of oxepin derivatives in nature is quite rare. Bauhiniastatins 1-4 were found to exhibit significant growth inhibition against a minipanel of human cancer cell lines, and bauhiniastatin 1 (2a) was also found to inhibit the P388 cancer cell line. Structures for these new cancer cell growth inhibitors were established by spectroscopic techniques that included HRMS and 2D NMR.


NFIA controls telencephalic progenitor cell differentiation through repression of the Notch effector Hes1.
The balance between self-renewal and differentiation of neural progenitor cells is an absolute requirement for the correct formation of the nervous system. Much is known about both the pathways involved in progenitor cell self-renewal, such as Notch signaling, and the expression of genes that initiate progenitor differentiation. However, whether these fundamental processes are mechanistically linked, and specifically how repression of progenitor self-renewal pathways occurs, is poorly understood. Nuclear factor I A (Nfia), a gene known to regulate spinal cord and neocortical development, has recently been implicated as acting downstream of Notch to initiate the expression of astrocyte-specific genes within the cortex. Here we demonstrate that, in addition to activating the expression of astrocyte-specific genes, Nfia also downregulates the activity of the Notch signaling pathway via repression of the key Notch effector Hes1. These data provide a significant conceptual advance in our understanding of neural progenitor differentiation, revealing that a single transcription factor can control both the activation of differentiation genes and the repression of the self-renewal genes, thereby acting as a pivotal regulator of the balance between progenitor and differentiated cell states.


Determination of the protein and free amino acid content in a sample using o-phthalaldehyde and N-acetyl-L-cysteine.
A spectrophotometric method is proposed for determining the protein content in a sample after total acid hydrolysis. In the procedure, free amino acids are caused to react with o-phthalaldehyde and N-acetyl-L-cysteine at pH 9.5, using isoleucine as the reference compound. Correction factors are used to take into account the differences between the molar absorptivities of the amino acid isoindoles and the recoveries of the amino acids after the hydrolysis treatment. The limit of detection was in the range 40-50 micrograms of protein, and the recoveries were usually 101 +/- 3% with a coefficient of variation lower than 4%. The free amino acid content in a partially hydrolysed protein was also determined.


Treat chronic hepatitis C virus infection in decompensated cirrhosis - pre- or post-liver transplantation? the ironic conundrum in the era of effective and well-tolerated therapy.
The management of hepatitis C virus (HCV) infection in patients with decompensated cirrhosis has evolved dramatically over the past few years mainly due to the availability of all-oral antiviral regimens. The currently approved all-oral direct-acting antivirals (DAA) containing sofosbuvir, ledipasvir, daclatasvir and ribavirin, in various combinations, have shown to be safe and effective in patients with decompensated cirrhosis with sustained virological response (SVR) rates nearly comparable to those with well-compensated liver disease. Unique issues yet remain such as the challenges with renal insufficiency, tolerability of ribavirin and risk of further hepatic decompensation with a protease inhibitor-based regimen. While most patients who achieve SVR have demonstrated improvement in hepatic synthetic function over the short course of follow, the long-term beneficial effects are unknown. Further, the baseline predictors of improvement in hepatic function have not been well delineated and thus have left us in a quandary as to what we might expect with successful therapy and thus we are at a loss to well educate our patients. The major concern, in potential liver transplant candidates, is of unintended 'harm' by achieving SVR but without improvement in hepatic function to an extent where the patients might function well. As HCV therapies are as effective in liver transplant recipients, there is a growing sentiment in some of the transplant quarters that those with decompensated liver disease and awaiting liver transplant be treated for HCV after liver transplant. This strategy would thus eliminate any concern of leaving a patient in 'no person's' land by treating HCV successfully pretransplant but not to the point of functional normalcy, while also would maintain the risk of HCC. Yet a contrarian view would be that not all patients have access to liver transplantation (LT), cannot bear the cost, have comorbidities or contraindications to LT. While the debate continues, it is essential that we develop robust predictors of improvement in liver function so that we can carefully select our patients for therapy in the context of liver transplantation.


Steric Manipulation as a Mechanism for Tuning the Reduction and Oxidation Potentials of Phenothiazines.
Synthetic chemists customarily tune the redox characteristics of π-conjugated molecules by introducing electron-donating or electron-withdrawing substituents onto the molecular core, or by modifying the length of the π-conjugated pathway. Any steric effects of such efforts on molecular geometry typically affect both the neutral and charged (oxidized or reduced) states indiscriminately. However, in electroactive systems that undergo significant conformational changes upon oxidation or reduction, we can leverage the steric and inductive effects of substitution to attain considerable control over individual redox potentials. Here, we make use of density functional theory to elucidate the interplay between electronic and geometric effects of peripheral substitution on the model system of phenothiazine. For instance, we introduce substituents at positions ortho to the nitrogen atom (positions 1 and 9) to induce steric strain in the radical-cation state without significant effect on the neutral molecule, thereby augmenting the overall ionization potential. Notably, this steric effect persists for electron-donating substituents; the resulting ionization potentials therefore deviate from outcomes foretold by Hammett constants. Moreover, the same procedure has limited effect on electron affinities because of differences in phenothiazines' relaxation process upon reduction compared to oxidation. Our results promote molecular design guidelines for manipulating redox potentials in classes of electroactive compounds that experience dramatic changes in geometry upon ionization.


Resolution of indeterminate MRI with CEUS in patients at high risk for hepatocellular carcinoma.
To show the contribution of CEUS to characterization of indeterminate MRI observations in high-risk patients for hepatocellular carcinoma (HCC). From July to December 2015, 42 consecutive patients referred to CEUS with indeterminate MRI scans comprise our study cohort. There are 50 indeterminate nodule-like observations and 10 arterial phase hyperenhancing foci, suggesting pseudolesions/arterio-portal shunts. MRI and CEUS lesions are classified according to their enhancement features in all phases and Liver Imaging and Reporting Data System (LI-RADS) in a blind read format. Clinical pathologic correlation and 24 months follow-up are performed. A majority, 37/50 (74%), of indeterminate nodule-like observations have arterial phase enhancement without washout on MRI. CEUS further characterizes enhancement and shows washout in 14/37 (38%). In total, CEUS diagnoses 16 malignant lesions in 14 patients including 14 HCC and 2 ICC. 12/16 (75%) malignant lesions are confirmed by biopsy or follow-up. Ultrasound identification of a nodule differentiates real nodules from pseudolesions. Of the ten suspected arterial-portal shunts on MRI, two show a real nodule on ultrasound, confirmed as an HCC and a regenerative nodule. 15/42 (36%) patients have LI-RADS escalated from LR-3 or 4 on MRI to LR-4 or 5 on CEUS. Overall, the sensitivity of CEUS is (13/16) 81.3% and specificity is (37/37) 100% for malignant diagnosis. Grayscale ultrasound detects true nodules. Dynamic CEUS detects and characterizes washout, correctly predicting HCC. CEUS is complimentary to MRI and can serve as a problem-solving tool when MRI is indeterminate.


Glycosylation Network Analysis Toolbox: a MATLAB-based environment for systems glycobiology.
Systems glycobiology studies the interaction of various pathways that regulate glycan biosynthesis and function. Software tools for the construction and analysis of such pathways are not yet available. We present GNAT, a platform-independent, user-extensible MATLAB-based toolbox that provides an integrated computational environment to construct, manipulate and simulate glycans and their networks. It enables integration of XML-based glycan structure data into SBML (Systems Biology Markup Language) files that describe glycosylation reaction networks. Curation and manipulation of networks is facilitated using class definitions and glycomics database query tools. High quality visualization of networks and their steady-state and dynamic simulation are also supported. The software package including source code, help documentation and demonstrations are available at http://sourceforge.net/projects/gnatmatlab/files/.


Looking forward to student-athlete mental health: Racial/ethnic trends from 2010 to 2015.
This study examined trends in functionally impairing depression, significant anxiety, suicidal ideation, and suicide attempts among college student-athletes across time, racial/ethnic group, and student-athlete standing. The sample consisted of 39,840 White, Black, Hispanic/Latinx, Asian/Pacific Islander, Native American, and Multiracial students who reported participating in "varsity" level college athletics in the past 12 months during the Spring 2010-2015 administrations of the American College of Health Association National College Health Assessment II. Chi-square and difference in proportion tests compared mental health rates across time, racial/ethnic groups, and student-athlete status (student-athlete versus non-athlete). Findings suggested a lack of differences in mental health rates between 2010 and 2015, with the exception of a higher rate of anxiety for White student-athletes in 2015. Racial/ethnic comparisons pointed to relatively consistent heightened risks for depression and suicide concerns among Asian/Pacific Islander and Multiracial student-athletes compared to White student-athletes. Student-athlete status appeared most consistently to benefit White student-athletes, whereas there was evidence of potential liability of student-athlete status for Asian/Pacific Islander student-athletes. Results make the case for adopting a racially/ethnically aware cultural lens when conceptualizing mental health risk and resilience among student-athletes.


The role of cluster energy nonaccommodation in atmospheric sulfuric acid nucleation.
We discuss the possible role of energy nonaccommodation (monomer-cluster collisions that do not result in stable product formation due to liberated excess energy) in atmospheric nucleation processes involving sulfuric acid. Qualitative estimates of the role of nonaccommodation are computed using quantum Rice-Ramsberger-Kassel theory together with quantum chemically calculated vibrational frequencies and anharmonic coupling constants for small sulfuric acid-containing clusters. We find that energy nonaccommodation effects may, at most, decrease the net formation rate of sulfuric acid dimers by up to a factor of 10 with respect to the hard-sphere collision rate. A decrease in energy nonaccommodation due to an increasing number of internal degrees of freedom may kinetically slightly favor the participation of amines rather than ammonia as stabilizing agents in sulfuric acid nucleation, though the kinetic enhancement factor is likely to be less than three. However, hydration of the clusters (which always occurs in ambient conditions) is likely to increase the energy accommodation factor, reducing the role that energy nonaccommodation plays in atmospheric nucleation.


Image variability and face matching.
This study investigates whether variability in perceived trait judgements disrupts our ability to match unfamiliar faces. In this preregistered study, 174 participants completed a face matching task where they were asked to indicate whether two ambient face images belonged to the same person or different people (17,748 total data points). Participants completed 51 match trials consisting of images of the same person that differed substantially on one trait (either trustworthiness, dominance or attractiveness) with minimal differences in the alternate traits. Participants also completed 51 mismatch trials which contained two photos of similar-looking individuals. We hypothesised that participants would make more errors on match trials when images differed in terms of attractiveness ratings than when they differed on trustworthiness or dominance. Contrary to expectations, images that differed in terms of attractiveness were matched most accurately, and there was no relationship between the extent of differences in attractiveness ratings and accuracy. There was some evidence that differences in perceived dominance and, to a lesser extent, trustworthiness were associated with lower face matching performance. However, these relationships were not significant when alternate traits were accounted for. The findings of our study suggest that face matching performance is largely robust against variation in trait judgements.


Polymorphisms in Gap Junction Proteins and their Role in Predisposition of Acute Myocardial Infarction in Egyptians.
Connexin (Cx) proteins are the building blocks of gap junctions. Among these, Cx37 and Cx40 are expressed on vascular system and reported to have cardioprotective role. Linking polymorphisms in genes coding for Cx and coronary artery disease (CAD) risk showed conflicting results in different populations. None has been studied before in Egyptians. Therefore, the aims of this study were to investigate the influence of Cx37 C1019T and Cx40 A71G polymorphisms on the predisposition of acute myocardial infarction (AMI) in Egyptians, to study linkage disequilibrium (LD) and combined effects of single nucleotide polymorphisms (SNPs) and to correlate the genotypes with sVCAM-1 serum levels. Total of 201 Egyptian subjects were recruited for the study. They were divided into 104 AMI patients and 97 healthy controls. Genotypes for each participant were determined using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum sVCAM-1was measured by ELISA. Allele frequencies for both Cx37 and Cx40 were not significantly different between AMI and Controls (p=0.93 and p=0.26 respectively). Moreover, studying the dominant and recessive models concluded that none of the genotypes was a risk factor. Both SNPs were not in LD (R2=0.0027). Serum analysis showed higher levels of sVCAM-1 in AMI patients (p<0.0001). sVCAM-1 levels were not significantly different among SNPs (Cx37; p=0.244 and Cx40; p=0.266). This study shows that Cx37 C1019T and Cx40 A71G polymorphisms are not associated with cardioprotective role in Egyptians. Moreover, both SNPs are inherited separately and none of the genotypes were associated with higher sVCAM-1 levels.


Targeting mTORC1-mediated metabolic addiction overcomes fludarabine resistance in malignant B cells.
MTOR complex-1(mTORC1) activation occurs frequently in cancers, yet clinical efficacy of rapalogs is limited because of the associated activation of upstream survival pathways. An alternative approach is to inhibit downstream of mTORC1; therefore, acquired resistance to fludarabine (Flu), a purine analogue and antimetabolite chemotherapy, active agent for chronic lymphocytic leukemia (CLL) was investigated. Elevated phospho-p70S6K, also known as RPS6KB1 (ribosomal protein S6 kinase, 70kDa, polypeptide 1) (T389), an mTORC1 activation marker, predicted Flu resistance in a panel of B-cell lines, isogenic Flu-resistant (FluR) derivatives, and primary human CLL cells. Consistent with the anabolic role of mTORC1, FluR cells had higher rates of glycolysis and oxidative phosphorylation than Flu-sensitive (FluS) cells. Rapalogs (everolimus and rapamycin) induced moderate cell death in FluR and primary CLL cells, and everolimus significantly inhibited glycolysis and oxidative phosphorylation in FluR cells. Strikingly, the higher oxidative phosphorylation in FluR cells was not coupled to higher ATP synthesis. Instead, it contributed primarily to an essential, dihydroorotate dehydrogenase catalyzed, step in de novo pyrimidine biosynthesis. mTORC1 promotes pyrimidine biosynthesis by p70S6 kinase-mediated phosphorylation of CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; Ser1859) and favors S-phase cell-cycle progression. We found increased phospho-CAD (S1859) and higher S-phase population in FluR cells. Pharmacological inhibition of de novo pyrimidine biosynthesis using N-phosphonacetyl-l-aspartate and leflunomide, RNAi-mediated knockdown of p70S6K, and inhibition of mitochondrial respiration were selectively cytotoxic to FluR, but not FluS, cells. These results reveal a novel link between mTORC1-mediated metabolic reprogramming and Flu resistance identifying mitochondrial respiration and de novo pyrimidine biosynthesis as potential therapeutic targets. This study provides the first evidence for mTORC1/p70S6K-dependent regulation of pyrimidine biosynthesis in a relevant disease setting.


Effects of heat removal through the hand on metabolism and performance during cycling exercise in the heat.
This two-part study tested the hypotheses that the use of a new cooling device, purported to extract heat from the body core through the palm of the hand, would (a) attenuate core temperature rise during submaximal exercise in the heat, thereby suppressing exercise-associated metabolic changes, and (b) facilitate a higher sustained workload, thus shortening the completion time of a time-trial performance test. In Study 1, 8 male triathletes (age 27.9 +/- 2.0 yrs, mass 77.2 +/- 3.1 kg, VO2peak 59.0 +/- 4.1 ml x min(-1) x kg(-1)) cycled for 1 hr at the same absolute workload (approximately 60% VO2peak) in a heated room (31.9 +/- 0.1 degrees C, 24 +/- 1% humidity) on two occasions counterbalanced for cooling (C) or noncooling (NC). In Study 2, 8 similar subjects (age 26.9 +/- 2.0 yrs, mass 75.2 +/- 3.7 kg, VO2peak 54.1 +/- 3.1 ml x min(-1) x kg(-1)) performed two 30-km cycling time-trial performance tests under the same conditions (C(T), NC(T)). In Study 1, cooling attenuated the rise in tympanic temperature (T(TY)) (1.2 +/- 0.2 vs. 1.8 +/- 0.2 degrees C; p < 0.01) and lowered mean oxygen consumption (VO2, 2.4 +/- 0.1 vs. 2.7 +/- 0.1 L x min(-1); p < 0.05) and blood lactate (1.7 +/- 0.2 vs. 2.2 +/- 0.2 mmol x L(-1); p < 0.01) during exercise. There were no significant differences in respiratory exchange ratio (RER), blood glucose, heart rate (HR), face temperature (T(F)), or back temperature (T(B)) between NC and C. In Study 2, time to complete 30 km was 6 +/- 1% less with cooling than without cooling (60.9 +/- 2.0 vs. 64.9 +/- 2.6 min; p < 0.01). During the last 20% of C(T), subjects sustained a workload that was 14 +/- 5% (p = 0.06) higher than NC(T) at the same T(TY) and HR. Heat extraction through the hand during cycle ergometer exercise in the heat can (a) lower T(TY), lactate concentration, and VO2 during a submaximal set-workload test and (b) reduce the time it takes to complete a 30-km time-trial test.


Role of lung-marginated monocytes in an in vivo mouse model of ventilator-induced lung injury.
Recruited leukocytes play an important role in ventilator-induced lung injury, although studies have focused predominantly on neutrophils. Inflammatory subset Gr-1(high) monocytes are recruited to sites of inflammation and have been implicated in acute lung injury induced by systemic endotoxin. To investigate the recruitment and role of Gr-1(high) monocytes in an in vivo mouse model of ventilator-induced lung injury. Anesthetized mice were ventilated with low or high stretch. Flow cytometry was used to quantify monocyte subset margination to the lungs, and to assess their in situ cellular activation in response to mechanical stretch. To investigate monocyte involvement in lung injury progression, a two-hit model was used, with a subclinical dose of lipopolysaccharide (intraperitoneal) given 2 hours prior to high-stretch ventilation. In some animals, monocytes were depleted using intravenous clodronate liposomes. Development of lung injury was assessed in ventilated animals by peak inspiratory pressure and respiratory system mechanics. High-stretch ventilation induced significant pulmonary margination of Gr-1(high) but not Gr-1(low) monocytes compared with nonventilated mice. These monocytes displayed increased activation status, with higher CD11b (vs. nonventilated mice) and lower L-selectin expression (vs. low-stretch ventilation). Lipopolysaccharide challenge led to enhanced lung margination of Gr-1(high) monocytes and neutrophils, and sensitized the lungs to high stretch-induced pulmonary edema. Clodronate-liposome pretreatment depleted lung monocytes (but not neutrophils) and significantly attenuated lung injury. High-stretch mechanical ventilation promotes pulmonary margination of activated Gr-1(high) monocytes, which play a role in the progression of ventilator-induced lung injury.


Local health and social care responses to implementing the national cold weather plan.
The Cold Weather Plan (CWP) for England was launched by the Department of Health in 2011 to prevent avoidable harm to health by cold weather by enabling individuals to prepare and respond appropriately. This study sought the views of local decision makers involved in the implementation of the CWP in the winter of 2012/13 to establish the effects of the CWP on local planning. It was part of a multi-component independent evaluation of the CWP. Ten LA areas were purposively sampled which varied in level of deprivation and urbanism. Fifty-two semi-structured interviews were held with health and social care managers involved in local planning between November 2012 and May 2013. Thematic analysis revealed that the CWP was considered a useful framework to formalize working arrangements between agencies though local leadership varied across localities. There were difficulties in engaging general practitioners, differences in defining vulnerable individuals and a lack of performance monitoring mechanisms. The CWP was welcomed by local health and social care managers, and improved proactive winter preparedness. Areas for improvement include better integration with general practice, and targeting resources at socially isolated individuals in cold homes with specific interventions aimed at reducing social isolation and building community resilience.


Antigenicity and Immunogenicity of HIV-1 Envelope Trimers Complexed to a Small-Molecule Viral Entry Inhibitor.
Small-molecule viral entry inhibitors, such as BMS-626529 (BMS-529), allosterically block CD4 binding to HIV-1 envelope (Env) and inhibit CD4-induced structural changes in Env trimers. Here, we show that the binding of BMS-529 to clade C soluble chimeric gp140 SOSIP (ch.SOSIP) and membrane-bound trimers with intact transmembrane domain (gp150) prevented trimer conformational transitions and enhanced their immunogenicity. When complexed to BMS-529, ch.SOSIP trimers retained their binding to broadly neutralizing antibodies (bNAbs) and to their unmutated common ancestor (UCA) antibodies, while exposure of CD4-induced (CD4i) non-bNAb epitopes was inhibited. BMS-529-complexed gp150 trimers in detergent micelles, which were isolated from CHO cells, bound to bNAbs, including UCA and intermediates of the CD4 binding site (bs) CH103 bNAb lineage, and showed limited exposure of CD4i epitopes and a glycosylation pattern with a preponderance of high-mannose glycans. In rabbits, BMS-529-complexed V3 glycan-targeting ch.SOSIP immunogen induced in the majority of immunized animals higher neutralization titers against both autologous and select high mannose-bearing heterologous tier 2 pseudoviruses than those immunized with the noncomplexed ch.SOSIP. In rhesus macaques, BMS-529 complexed to CD4 bs-targeting ch.SOSIP immunogen induced stronger neutralization against tier 2 pseudoviruses bearing high-mannose glycans than noncomplexed ch.SOSIP trimer immunogen. When immunized with gp150 complexed to BMS-529, rhesus macaques showed neutralization against tier 2 pseudoviruses with targeted glycan deletion and high-mannose glycan enrichment. These results demonstrated that stabilization of Env trimer conformation with BMS-529 improved the immunogenicity of select chimeric SOSIP trimers and elicited tier 2 neutralizing antibodies of higher potency than noncomplexed trimers.IMPORTANCE Soluble forms of HIV-1 envelope trimers exhibit conformational heterogeneity and undergo CD4-induced (CD4i) exposure of epitopes of non-neutralizing antibodies that can potentially hinder induction of broad neutralizing antibody responses. These limitations have been mitigated through recent structure-guided approaches and include trimer-stabilizing mutations that resist trimer conformational transition and exposure of CD4i epitopes. The use of small-molecule viral inhibitors that allosterically block CD4 binding represents an alternative strategy for stabilizing Env trimer in the pre-CD4-triggered state of both soluble and membrane-bound trimers. In this study, we report that the viral entry inhibitor BMS-626529 restricts trimer conformational transition and improves the immunogenicity of select Env trimer immunogens.


Dibutyl phthalate impairs neural progenitor cell proliferation and hippocampal neurogenesis.
Dibutyl phthalate (DBP) is commonly used plasticizer and a known endocrine disruptor that can cause birth defects and developmental disorders. Although several studies have reported that DBP has neurotoxic effects on neurite outgrowth and on learning and memory, its neurotoxic effects on neural progenitor cells (NPCs) have not been investigated. The present study was undertaken to determine the effects of DBP on NPCs and hippocampal neurogenesis. At high concentration DBP (500 μM) retarded NPC proliferation without affecting cell viability by arresting the cell cycle at G1 but did not cause cell death. DNA damage was observed by examining p53 expression and by γH2AX staining. DBP-treated cells had elevated ROS levels and exhibited mitochondrial dysfunction, which can cause DNA damage. Adult hippocampal neurogenesis was investigated using BrdU immunohistochemistry in young C57BL/6 mice intraperitoneally administrated with vehicle or DBP (10 or 50 mg/kg) for 2 weeks. DBP administered mice were found to have significantly fewer newly generated neurons in hippocampi, and the Morris water maze test revealed that DBP (50 mg/kg) impaired spatial learning and memory. Taken together, these findings suggest that DBP has harmful effects on NPCs and hippocampal neurogenesis and that DBP exposure could lead to learning and memory dysfunctions.


Revisiting Truth or Triviality: The External Validity of Research in the Psychological Laboratory.
Anderson, Lindsay, and Bushman (1999) compared effect sizes from laboratory and field studies of 38 research topics compiled in 21 meta-analyses and concluded that psychological laboratories produced externally valid results. A replication and extension of Anderson et al. (1999) using 217 lab-field comparisons from 82 meta-analyses found that the external validity of laboratory research differed considerably by psychological subfield, research topic, and effect size. Laboratory results from industrial-organizational psychology most reliably predicted field results, effects found in social psychology laboratories most frequently changed signs in the field (from positive to negative or vice versa), and large laboratory effects were more reliably replicated in the field than medium and small laboratory effects.