Chemical genetics identifies small-molecule modulators of neuritogenesis involving neuregulin-1/ErbB4 signaling.
Genetic findings have suggested that neuregulin-1 (Nrg1) and its receptor v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) may play a role in neuropsychiatric diseases. However, the downstream signaling events and relevant phenotypic consequences of altered Nrg1 signaling in the nervous system remain poorly understood. To identify small molecules for probing Nrg1-ErbB4 signaling, a PC12-cell model was developed and used to perform a live-cell, image-based screen of the effects of small molecules on Nrg1-induced neuritogenesis. By comparing the resulting phenotypic data to that of a similar screening performed with nerve growth factor (NGF), this multidimensional screen identified compounds that directly inhibit Nrg1-ErbB4 signaling, such as the 4-anilino-quinazoline Iressa (gefitinib), as well as compounds that potentiate Nrg1-ErbB4 signaling, such as the indolocarbazole K-252a. These findings provide new insights into the regulation of Nrg1-ErbB4 signaling events and demonstrate the feasibility of using such a multidimensional, chemical-genetic approach for discovering probes of pathways implicated in neuropsychiatric diseases.


The spacing effect: Improving electrocardiogram interpretation.
Accurate electrocardiogram (ECG) interpretation is critical for safe patient care, making this skill a necessary competency for medical school graduation. Improved long-term memory retention with repeated exposure to material is one of the most evidenced-based components of adult learning science. This curricular innovation aimed to determine if implementing spaced repetition and retrieval practice using ECG quizzes during the principal clinical year would improve ECG interpretation skills among medical students enrolled in a Longitudinal Integrated Clerkship (LIC). The curricular innovation applied the spacing effect and retrieval practice. Cognitive science demonstrates enhanced long-term retention through repeated interval exposure to learned material. Studies of spaced retrieval indicate that memory retention is enhanced through tests involving effortful recall. LIC students in an intervention group were exposed to the spacing effect with periodic ECG quizzes throughout their clinical clerkship year. The results of the 17-item post-test for 140 students were analysed: LIC intervention, N = 54; block control, N = 62; and LIC control, N = 24. The ANOVA test was significant (p < 0.001). Games-Howell post hoc testing showed that the mean score in the LIC intervention group was significantly higher compared with the LIC control group (p < 0.001) and the block control group (p < 0.001). There was no significant difference between the LIC control and block control groups (p = 0.59). Spaced repetition of material through ECG quizzes improved ECG interpretation skills on an ECG post-test and mitigates the forgetting curve, maintaining student competency in ECG interpretation.


Challenges in Participant Engagement and Retention Using Mobile Health Apps: Literature Review.
Mobile health (mHealth) apps are revolutionizing the way clinicians and researchers monitor and manage the health of their participants. However, many studies using mHealth apps are hampered by substantial participant dropout or attrition, which may impact the representativeness of the sample and the effectiveness of the study. Therefore, it is imperative for researchers to understand what makes participants stay with mHealth apps or studies using mHealth apps. This study aimed to review the current peer-reviewed research literature to identify the notable factors and strategies used in adult participant engagement and retention. We conducted a systematic search of PubMed, MEDLINE, and PsycINFO databases for mHealth studies that evaluated and assessed issues or strategies to improve the engagement and retention of adults from 2015 to 2020. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Notable themes were identified and narratively compared among different studies. A binomial regression model was generated to examine the factors affecting retention. Of the 389 identified studies, 62 (15.9%) were included in this review. Overall, most studies were partially successful in maintaining participant engagement. Factors related to particular elements of the app (eg, feedback, appropriate reminders, and in-app support from peers or coaches) and research strategies (eg, compensation and niche samples) that promote retention were identified. Factors that obstructed retention were also identified (eg, lack of support features, technical difficulties, and usefulness of the app). The regression model results showed that a participant is more likely to drop out than to be retained. Retaining participants is an omnipresent challenge in mHealth studies. The insights from this review can help inform future studies about the factors and strategies to improve participant retention.


A framework and a measurement instrument for sustainability of work practices in long-term care.
In health care, many organizations are working on quality improvement and/or innovation of their care practices. Although the effectiveness of improvement processes has been studied extensively, little attention has been given to sustainability of the changed work practices after implementation. The objective of this study is to develop a theoretical framework and measurement instrument for sustainability. To this end sustainability is conceptualized with two dimensions: routinization and institutionalization. The exploratory methodological design consisted of three phases: a) framework development; b) instrument development; and c) field testing in former improvement teams in a quality improvement program for health care (N teams = 63, N individual = 112). Data were collected not until at least one year had passed after implementation.Underlying constructs and their interrelations were explored using Structural Equation Modeling and Principal Component Analyses. Internal consistency was computed with Cronbach's alpha coefficient. A long and a short version of the instrument are proposed. The χ2- difference test of the -2 Log Likelihood estimates demonstrated that the hierarchical two factor model with routinization and institutionalization as separate constructs showed a better fit than the one factor model (p < .01). Secondly, construct validity of the instrument was strong as indicated by the high factor loadings of the items. Finally, the internal consistency of the subscales was good. The theoretical framework offers a valuable starting point for the analysis of sustainability on the level of actual changed work practices. Even though the two dimensions routinization and institutionalization are related, they are clearly distinguishable and each has distinct value in the discussion of sustainability. Finally, the subscales conformed to psychometric properties defined in literature. The instrument can be used in the evaluation of improvement projects.


PML is a ROS sensor activating p53 upon oxidative stress.
Promyelocytic leukemia (PML) nuclear bodies (NBs) recruit partner proteins, including p53 and its regulators, thereby controlling their abundance or function. Investigating arsenic sensitivity of acute promyelocytic leukemia, we proposed that PML oxidation promotes NB biogenesis. However, physiological links between PML and oxidative stress response in vivo remain unexplored. Here, we identify PML as a reactive oxygen species (ROS) sensor. Pml-/- cells accumulate ROS, whereas PML expression decreases ROS levels. Unexpectedly, Pml-/- embryos survive acute glutathione depletion. Moreover, Pml-/- animals are resistant to acetaminophen hepatotoxicity or fasting-induced steatosis. Molecularly, Pml-/- animals fail to properly activate oxidative stress-responsive p53 targets, whereas the NRF2 response is amplified and accelerated. Finally, in an oxidative stress-prone background, Pml-/- animals display a longevity phenotype, likely reflecting decreased basal p53 activation. Thus, similar to p53, PML exerts basal antioxidant properties but also drives oxidative stress-induced changes in cell survival/proliferation or metabolism in vivo. Through NB biogenesis, PML therefore couples ROS sensing to p53 responses, shedding a new light on the role of PML in senescence or stem cell biology.


Current ESRD burden and its future trend in Beijing, China.
To report the trend of incidence, prevalence, and mortality of end-stage renal disease (ESRD) patients on maintenance hemodialysis (MHD) in Beijing, China from 2007 to 2013. Patient-level data was collected from Beijing hemodialysis (HD) facilities by the Beijing Hemodialysis Quality Control and Improvement Center (BJHDQCIC). Rates for incidence, prevalence, and mortality were calculated. The incidence rate declined from 136.3 per million population (pmp) in 2009 to 94.4 pmp in 2013. From 2010, the leading cause of incident ESRD has changed from chronic glomerulonephritis to diabetes mellitus. The prevalence rate showed an increasing trend and reached 579 pmp at the end of 2013. Chronic glomerulonephritis was still the leading cause of ESRD in prevalent MHD patients. The annual mortality rate showed a declining trend and reached 6.4% in 2013. In Beijing, there is a declining incidence rate, increasing prevalence rate, and declining mortality for MHD patients.


Family history and age at the onset of upper urinary tract calculi.
The aim of this study was to evaluate the effect of family history on the age of urinary calculus formation and its relation with characteristics of the calculi and patients. In a cross-sectional study in Tabriz, a total of 210 patients with upper urinary tract calculi were evaluated. Their demographics and clinical characteristics and detailed information on their family history were recorded. Of the patients, 28.6% had a positive family history for urinary calculi. Siblings were the majority of the affected family members (71.1%). The rate of a positive family history was slightly higher in women than in men (30.0% versus 28.1%; P = .20). The mean age at the disease onset of the men with and without a positive family history was 37.2 years versus 39.3 years, respectively (P = .20). Such a difference was not detected in the female patients, either (P = .63). In general, the calculi were more detected on the left renal unit, but more prevalent on the right side in patients with a positive family history (P = .008). No relation was found between the number and size of the calculi and the family history. About one-third of the patients with urinary calculi had a positive family history too. Men with affected family members are slightly more susceptible to the disease at younger ages. There might be differences in the side of the calculi and family members with a history of disease that warrants further studies.


Role of inducers in detection of blaPDC-mediated oxyimino-cephalosporin resistance in Pseudomonas aeruginosa.
Pseudomonas aeruginosa possessing chromosomally inducible blaPDCalong with other intrinsic mechanism causes infection with high mortality rate. It is difficult to detect inducible AmpC enzymes in this organism and is usually overlooked by routine testing that may lead to therapeutic failure. Therefore, three different inducers were evaluated in the present study to assess their ability of induction of blaPDCin P. aeruginosa. A total of 189 consecutive Pseudomonas isolates recovered from different clinical specimens (November 2011-April 2013) were selected for the study. Isolates were screened with cefoxitin for AmpC β-lactamases and confirmed by modified three-dimensional extract test (M3DET). Inductions were checked using three inducers, namely, clavulanic acid, cefoxitin and imipenem along with ceftazidime. Molecular screening of AmpC β-lactamase genes was performed by PCR assay. Antimicrobial susceptibility and minimum inhibitory concentrations (MICs) were determined, and repetitive extragenic palindromic-PCR of all blaPDCharbouring isolates was performed. Inducible phenotype was observed in 42 (24.3%) of 97 (56%) isolates confirmed by M3DET. Among these, 22 isolates harboured chromosomal blaPDCgene, and cocarriage of both chromosomal and plasmid-mediated blaAmpC genes was observed in seven isolates. Cefoxitin-ceftazidime-based test gave good sensitivity and specificity for detecting inducible AmpC enzymes. Isolates harbouring blaPDCshowed high MIC against all tested cephalosporins and monobactam. DNA fingerprinting of these isolates showed 22 different clones of P. aeruginosa. P. aeruginosa harbouring inducible (chromosomal) and plasmid-mediated AmpC β-lactamase is a matter of concern as it may limit therapeutic option. Using cefoxitin-ceftazidime-based test is simple and may be used for detecting inducible AmpC β-lactamase amongst P. aeruginosa.


Investigation of carbon buildup in simulations of multi-impact bombardment of Si with 20 keV C60 projectiles.
Beams of single C(+) ions are used for the incorporation of Si in the synthesis of thin films of SiC, which have a wide range of technological applications. We present a theoretical investigation of the use of C60 cluster beams to produce thin films of SiC on a Si substrate, which demonstrates that there are potential advantages to using C60(+) cluster ion beams over C(+) single ion beams. Molecular dynamics simulations of the multi-impact bombardment of Si with 20 keV normal incident C60 projectiles are performed to study the buildup of carbon and the formation of a region of Si-C mixing up to a fluence of 1.6 impacts/nm(2) (900 impacts). The active region of the Si solid is defined as the portion of target that contains almost all of the C atoms and the height ranges from 3 nm to more than 7 nm below the average surface height. The C fraction in the active region is calculated as a function of fluence, and a simple model is developed to describe the dependence of the C fraction on fluence. An analytic function from this model is fit to the data from the molecular dynamics simulations and extrapolated to predict the fluence necessary to achieve equilibrium conditions in which the C fraction is constant with fluence. The fraction of C atoms at equilibrium is predicted to be 0.19, and the fluence necessary to achieve 90% of this asymptotic maximum value is equal to 4.0 impacts/nm(2).


A prospective study of muscular strength and all-cause mortality in men with hypertension.
This study sought to assess the impact of muscular strength on mortality in men with hypertension. Muscular strength is inversely associated with mortality in healthy men, but this association has not been examined in men with hypertension. We followed 1,506 hypertensive men age 40 years and older enrolled in the Aerobics Center Longitudinal Study from 1980 to 2003. Participants received an extensive medical examination at baseline. Muscular strength was quantified by combining 1 repetition maximum (1-RM) measures for leg and bench press and cardiorespiratory fitness assessed by maximum exercise test on a treadmill. During an average follow-up of 18.3 years, 183 deaths occurred. Age-adjusted death rates per 10,000 person-years across incremental thirds of muscular strength were 81.8, 65.5, and 52.0 (p < 0.05 for linear trend). Multivariable Cox regression hazard ratios were 1.0 (reference), 0.81 (95% confidence interval [CI]: 0.57 to 1.14), and 0.59 (95% CI: 0.40 to 0.86) across incremental thirds of muscular strength. After further adjustment for cardiorespiratory fitness, those participants in the upper third of muscular strength still had a lower risk of death (hazard ratio [HR]: 0.66; 95% CI: 0.45 to 0.98). In the muscular strength and CRF combined analysis, men simultaneously in the upper third of muscular strength and high fitness group had the lowest mortality risk among all combination groups (HR: 0.49; 95% CI: 0.30 to 0.82), with men in the lower third of muscular strength and low fitness group as reference. High levels of muscular strength appear to protect hypertensive men against all-cause mortality, and this is in addition to the benefit provided by cardiorespiratory fitness.


Detecting unstable plaques in humans using cardiac CT: Can it guide treatments?
Advances in imaging technology have driven the rapid expansion in the use of CT in the assessment of coronary atherosclerotic plaque. Based on a rapidly growing evidence base, current guidelines recommend coronary CT angiography as the first-line diagnostic test for patients presenting with stable chest pain. There is a growing need to refine current methods for diagnosis and risk stratification to improve the individualisation of preventative therapies. Imaging assessments of high-risk plaque with CT can be used to differentiate stable from unstable patterns of coronary atherosclerosis and potentially to improve patient risk stratification. This review will focus on coronary imaging with CT with a specific focus on the detection of coronary atherosclerosis, high-risk plaque features, and the implications for patient management.


Factors Associated With the Actual Behavior and Intention of Rating Physicians on Physician Rating Websites: Cross-Sectional Study.
Although online physician rating information is popular among Chinese health consumers, the limited number of reviews greatly hampers the effective usage of this information. To date, little has been discussed on the variables that influence online physician rating from the users' perspective. This study aims to investigate the factors associated with the actual behavior and intention of generating online physician rating information in urban China. A web-based cross-sectional survey was conducted, and the valid responses of 1371 Chinese health consumers were recorded. Using a pilot interview, we analyzed the effects of demographics, health variables, cognitive variables, and technology-related variables on online physician rating information generation. Binary multivariate logistic regression, multiple linear regression, one-way analysis of variance analyses, and independent samples t test were performed to analyze the rating behavior and the intentions of the health consumers. The survey instrument was designed based on the existing literature and the pilot interview. In this survey, 56.7% (778/1371) of the responders used online physician rating information, and 20.9% (287/1371) of the responders rated the physicians on the physician rating website at least once (posters). The actual physician rating behavior was mainly predicted by health-related factors and was significantly associated with seeking web-based physician information (odds ratio [OR] 5.548, 95% CI 3.072-10.017; P<.001), usage of web-based physician service (OR 2.771, 95% CI 1.979-3.879; P<.001), health information-seeking ability (OR 1.138, 95% CI 0.993-1.304; P=.04), serious disease development (OR 2.699, 95% CI 1.889-3.856; P<.001), good medical experience (OR 2.149, 95% CI 1.473-3.135; P<.001), altruism (OR 0.612, 95% CI 0.483-0.774; P<.001), self-efficacy (OR 1.453, 95% CI 1.182-1.787; P<.001), and trust in online physician rating information (OR 1.315, 95% CI 1.089-1.586; P=.004). Some factors influencing the intentions of the posters and nonposters rating the physicians were different, and the rating intention was mainly determined by cognitive and health-related factors. For posters, seeking web-based physician information (β=.486; P=.007), using web-based medical service (β=.420; P=.002), ability to seek health information (β=.193; P=.002), rating habits (β=.105; P=.02), altruism (β=.414; P<.001), self-efficacy (β=.102; P=.06), trust (β=.351; P<.001), and perceived ease of use (β=.275; P<.001) served as significant predictors of the rating intention. For nonposters, ability to seek health information (β=.077; P=.003), chronic disease development (β=.092; P=.06), bad medical experience (β=.047; P=.02), rating habits (β=.085; P<.001), altruism (β=.411; P<.001), self-efficacy (β=.171; P<.001), trust (β=.252; P<.001), and perceived usefulness of rating physicians (β=.109; P<.001) were significantly associated with the rating intention. We showed that different factors affected the physician rating behavior and rating intention. Health-related variables influenced the physician rating behavior, while cognitive variables were critical in the rating intentions. We have proposed some practical implications for physician rating websites and physicians to promote online physician rating information generation.


[Advantages of computerized management in a gastrointestinal endoscopy unit].
Computerized management of the activity of a gastrointestinal endoscopy unit in a hospital requires technological resources that include an intrahospital network, a computerized endoscopy program, a computerized appointments program and electronic medical records. The endoscopy unit should define the portfolio of services it provides and establish the time required to perform each procedure, probably using distinct criteria for outpatient and inpatient requests. Computerized management should establish forms designed to receive, accept and schedule requests, and should transfer all the contents of the request to the endoscopy program. The endoscopy program makes and stores reports and images. Integration among the programs allows these contents to be transferred to the electronic medical record. Measures to guarantee the confidentiality and safety of the medical information in each center should be implemented in accordance with its policy on access to medical information.


Species richness patterns along environmental gradients in island land molluscan fauna.
The relationship between species richness and environmental variables may change depending on habitat structure, dispersal ability, species mixing, and community adaptation to the environment. It is crucial to know how these factors regulate the environment-diversity relationship. The land molluscan fauna of the Ogasawara Islands in the West Pacific is an excellent model system to address this question because of the high species endemicity (> 90%), small area, and simple habitat structure of the islands. I examined relationships among indigenous species composition, richness, and habitat condition, and especially productivity and forest moisture on the island of Anijima. Two major communities of snails could be distinguished by detrended correspondence analysis (DCA): one group dominated in a moist habitat with high productivity, and the other group dominated in a dry habitat with low productivity. However, species richness became highest at the intermediate condition between the habitats in which the two snail communities were dominant, so that species richness showed a hump-shaped relationship with moisture and productivity. In contrast, the species richness of the snail community in the moist habitat showed a monotonically positive correlation, and that in the dry habitat showed a monotonically negative correlation with moisture and productivity. Thus, the greater species richness in intermediate moisture and productivity resulted from the ecotone effect or community overlap at the transitional areas, where faunas with different ecologies can meet in a single site. These findings suggest that hump-shaped productivity-diversity relationships in land Mollusca would reflect the ecotone effect as a result of the mixing of species adapted to either fertile habitats or sterile habitats.


Endogenous adenosine inhibits evoked substance P release from perifused networks of myenteric ganglia.
Isolated myenteric ganglion networks were prepared from guinea pig ileum and were used in a perifusion protocol to examine the effects of interstitial adenosine on evoked release of substance P-like immunoreactivity (SPLI). The release of SPLI evoked by elevated extracellular K+ concentration was increased in the presence of tetrodotoxin (TTX), indicating tonic inhibition of SPLI release and revealing net inhibitory interganglionic transmission. Perifusion in the presence of the adenosine A1 receptor-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine enhanced evoked SPLI release, which was further enhanced in the additional presence of TTX, indicating that adenosine contributes some, but not all, of the overall inhibitory tone within the networks. In addition to neural release of adenosine per se, an additional source was investigated. Perifusion in the presence of alpha, beta-methylene-ADP plus guanosine 5'-monophosphate, which inhibits ecto-adenosinetriphosphatase (ATPase) activity, enhanced SPLI release, indicating that hydrolysis of released ATP contributes to the total interstitial nucleoside concentration and thereby to the overall inhibitory tone. It is concluded that endogenous adenosine, some of which arises from ATP metabolism, is an important contributor to the overall inhibitory tone present in myenteric ganglion networks.


Towards an explicit account of implicit learning.
The human brain supports acquisition mechanisms that can extract structural regularities implicitly from experience without the induction of an explicit model. Reber defined the process by which an individual comes to respond appropriately to the statistical structure of the input ensemble as implicit learning. He argued that the capacity to generalize to new input is based on the acquisition of abstract representations that reflect underlying structural regularities in the acquisition input. We focus this review of the implicit learning literature on studies published during 2004 and 2005. We will not review studies of repetition priming ('implicit memory'). Instead we focus on two commonly used experimental paradigms: the serial reaction time task and artificial grammar learning. Previous comprehensive reviews can be found in Seger's 1994 article and the Handbook of Implicit Learning. Emerging themes include the interaction between implicit and explicit processes, the role of the medial temporal lobe, developmental aspects of implicit learning, age-dependence, the role of sleep and consolidation. The attempts to characterize the interaction between implicit and explicit learning are promising although not well understood. The same can be said about the role of sleep and consolidation. Despite the fact that lesion studies have relatively consistently suggested that the medial temporal lobe memory system is not necessary for implicit learning, a number of functional magnetic resonance studies have reported medial temporal lobe activation in implicit learning. This issue merits further research. Finally, the clinical relevance of implicit learning remains to be determined.


[Collagenolytic enzymes of pathogenic microorganisms].
The review summarizes characteristics of pathogenic microbial collagenolytic enzymes. Th collagenases usually represent the main factors of virulence; they provide microbe penetration int host tissues and supply microorganisms with nutritients. The study of these enzymes is of great valu for scientific, medical and biochemical purposes.


Dong Quai (angelica sinensis) in the treatment of hot flashes for men on androgen deprivation therapy: results of a randomized double-blind placebo controlled trial.
To determine whether Dong Quai, a Chinese herbal compound purported to be efficacious in treating menopausal vasomotor symptoms, has a therapeutic benefit in treating hot flashes among prostate cancer patients receiving androgen deprivation therapy. A randomized double-blind placebo controlled trial was conducted involving 22 men receiving luteinizing hormone-releasing hormone agonist therapy for prostate cancer with bothersome hot flashes. After recording a baseline log of the frequency, duration and severity of daily hot flashes, patients were randomly assigned in a 1:1 ratio to receive daily placebo or Dong Quai for 3 months. Vasomotor and adverse events were recorded daily. Blood work including serum prostate-specific antigen (PSA), international normalized ratio of prothrombin time and partial thromoboplastin time were recorded at baseline and at the termination of the study. Seventeen of the 22 patients enrolled completed the trial. Baseline vasomotor duration and severity were equivalent between the groups, however the number of hot flashes were significantly more in the Dong Quai group (p = 0.02). With respect to the change in number of hot flashes per day, there was a slight decrease in the mean number among the Dong Quai group which was insignificant. The absolute change and average percentage change in perceived hot flash severity was similar in both groups. There was no significant decrease in the duration of the hot flashes between the 2 groups. Disease progression based on either PSA increase or change in digital rectal exam was not observed in any patient. In this small pilot study, there were no significant differences in the severity, frequency or duration of hot flashes among men receiving placebo or Dong Quai.


Predictive value of General Movements Assessment for developmental delay at 18 months in children with complex congenital heart disease.
Infants with complex congenital heart disease are at increased risk of impaired fetal brain growth, brain injury, and developmental impairments. The General Movement Assessment (GMA) is a valid and reliable tool to predict cerebral palsy (CP), especially in preterm infants. Predictive properties of the GMA in infants with complex congenital heart disease (CCHD) are unknown. To evaluate predictive properties of the GMA to predict developmental outcomes, including cerebral palsy (CP), at 18-months corrected age (CA) in children with CCHD undergoing heart surgery in the first month of life. A prospective cohort of 56 infants with CCHD (35 males, 21 females) was assessed with GMA at writhing age (0-6 weeks CA) and fidgety age (7-17 weeks CA) and the Bayley Scales of Infant Development at 18 months. GMA focused on markedly reduced GM-variation and complexity (definitely abnormal (DA) GM-complexity) and fidgety movements. Predictive values of GMA for specific cognitive, language and motor delay (composite scores <85th percentile) and general developmental delay (delay in all domains) were calculated at 18 months. At fidgety age, all infants had fidgety movements and no child was diagnosed with CP. DA GM-complexity at fidgety age predicted general developmental delay at 18 months (71 % sensitivity, 90 % specificity), but predicted specific developmental delay less robustly. DA GM-complexity at writhing age did not predict developmental delay, nor did it improve prediction based on DA GM-complexity at fidgety age. In infants with CCHD and fidgety movements, DA GM-complexity at fidgety age predicted general developmental delay.


No Pass Laws Here! Internal Border Controls and the Global 'Hostile Environment'.
This article explores internal border controls in 1980s Britain, examining how they were conceptualised and resisted by a group of activists, the No Pass Laws Here! Group. Drawing on archival research conducted at the Hull History Centre and the Institute of Race Relations and focusing analysis on the Group's public-facing information leaflets and bulletins, this article explores how internal border controls created differentiated access to employment and the welfare state, targeting migrant and racialised residents and citizens. The No Pass Laws Here! Group's framing and analysis, in particular their use of pass laws as a frame through which to apprehend the spread of internal border controls, this article argues, allows us to draw out the continuities between policies developed to maintain colonial rule and those present in the metropole.


Circulating miR-660-5p is associated with no-reflow phenomenon in patients with ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.
This study aims to investigate the association of circulating miR-660-5p with no-reflow phenomenon (NRP) in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Consecutive patients diagnosed with anterior STEMI within 12 h of pain onset were included; in these patients, coronary angiography confirmed that the left anterior descending artery was infarcted. Angiographic NRP was defined as a final thrombolysis in myocardial infarction (TIMI) flow 2 or 3 with a myocardial blush grade (MBG) <2. High miR-660-5p was defined as a value in the third tertile. The relationship of circulating miR-660-5p with NRP was assessed using Spearman correlation analysis and multiple logistic regression analysis. Fifty-two eligible patients were finally included in this study (mean age: 56±12.4 years, >65 years: 53.8%, male: 76.9%, and mean Body Mass Index: 26.3±3.5). The incidence of NRP was 38.5%. Circulating miR-660-5p was significantly related to the mean platelet volume (MPV). The patients were grouped into tertiles by miR-660-5p levels (Q1: <7.18, Q2: 7.18-11.31, Q3: >11.31). Those in the high microRNA-660-5p group had nearly a 6-fold higher risk of NRP than those in the low microRNA-660-5p group [odds ratio (OR) = 5.68, 95% confidence interval (CI) 1.40-23.07, p=0.015]. When analyzed by tertiles, relative odds of NRP were consistently increasing (OR1 for Q2 vs. Q1: 1.25, 95% CI: 0.27-5.73, p=0.770; OR2 for Q3 vs. Q1: 5.96, 95% CI: 1.33-26.66, p=0.02), despite multivariable adjustment. Receiver operating characteristic curve analysis demonstrated that the microRNA-660-5p level of 10.17 was the best cut-off level to predict the incidence of the NRP in patients undergoing PPCI with an area under the ROC curve (AUC) of 0.768 (95% CI: 0.636-0.890). Circulating miR-660-5p was significantly associated with NRP, and it may be a useful biomarker to predict the incidence of NRP in patients with STEMI undergoing PPCI.


Modified SVPWM technique for CMV reduction in asymmetrical dual three phase induction machine drive.
Due to its advantages, the asymmetrical dual three-phase induction motor drive is a strong choice in high-power applications. However, the common-mode voltage produced by the voltage source inverters affects the winding insulation and damages the bearings. Common-mode voltage is also responsible for electromagnetic interference and leakage currents. This paper, therefore, analyses the common-mode voltage produced by the inverter supplying a dual three-phase induction motor drive and proposes a novel modified space vector decomposition-based Space Vector Pulse Width Modulation (SVPWM) technique for common mode reduction. The vector space decomposition-based space vector modulation technique offers excellent flexibility as it reduces the common-mode voltage (CMV) by exploiting the additional degree of freedom in a dual three-phase system. The common-mode voltage (CMV) can be reduced to one-sixth of the DC link voltage compared to the highest CMV, i.e. half of the DC-link voltage produced in conventional space vector modulation. The proposed method is also validated experimentally to demonstrate the effectiveness of the proposed scheme in terms of the amplitude of CMV, pulsations, and total harmonic distortion(THD) in current.


Na+/H+ and Na+/NH+4 activities of zebrafish NHE3b expressed in Xenopus oocytes.
Zebrafish Na(+)/H(+) exchanger 3b (zNHE3b) is highly expressed in the apical membrane of ionocytes where Na(+) is absorbed from ion-poor fresh water against a concentration gradient. Much in vivo data indicated that zNHE3b is involved in Na(+) absorption but not leakage. However, zNHE3b-mediated Na(+) absorption has not been thermodynamically explained, and zNHE3b activity has not been measured. To address this issue, we overexpressed zNHE3b in Xenopus oocytes and characterized its activity by electrophysiology. Exposure of zNHE3b oocytes to Na(+)-free media resulted in significant decrease in intracellular pH (pH(i)) and intracellular Na(+) activity (aNa(i)). aNa(i) increased significantly when the cytoplasm was acidified by media containing CO₂-HCO₃(-) or butyrate. Activity of zNHE3b was inhibited by amiloride or 5-ethylisopropyl amiloride (EIPA). Although the activity was accompanied by a large hyperpolarization of ∼50 mV, voltage-clamp experiments showed that Na(+)/H(+) exchange activity of zNHE3b is electroneutral. Exposure of zNHE3b oocytes to medium containing NH₃/NH₄(+) resulted in significant decreases in pH(i) and aNa(i) and significant increase in intracellular NH₄(+) activity, indicating that zNHE3b mediates the Na(+)/NH₄(+) exchange. In low-Na(+) (0.5 mM) media, zNHE3b oocytes maintained aNa(i) of 1.3 mM, and Na(+)-influx was observed when pHi was decreased by media containing CO₂-HCO₃(-) or butyrate. These results provide thermodynamic evidence that zNHE3b mediates Na(+) absorption from ion-poor fresh water by its Na(+)/H(+) and Na(+)/NH₄(+) exchange activities.


"A priori" Dietary Patterns and Cognitive Function in the SUN Project.
To study and compare associations of 5 dietary patterns - Mediterranean dietary pattern (MDP), Dietary Approaches to Stop Hypertension (DASH), Mediterranean-DASH Intervention for Neurodegenerative delay (MIND), Alternative Healthy Eating Index (AHEI-2010), and a pro-vegetarian diet (PVD) - with cognitive function. A subgroup of 806 participants from the "Seguimiento Universidad de Navarra"(SUN) cohort of university graduates, >55 years old, was interviewed with the validated Spanish Telephone Interview for Cognitive Status (STICS-m) at baseline and after 2 and 6 years. For recruitment to the SUN cohort, participants completed a validated food-frequency questionnaire to calculate dietary adherence scores. These scores were used as independent variables in linear regression models (a model for each dietary pattern) to assess their association with the 6-year change in STICS-m as the dependent variable. Linear mixed models were also fitted to compare trajectories of STICS-m scores. All models were adjusted for relevant confounding factors. Adjusted differences showed advantages in the 6-year change in STICS-m score of 0.25 (95% CI 0.04-0.45) for an increase of 1-SD (9 points) in the AHEI-2010 and of 0.27 (95% CI 0.05-0.48) for an increase of 1-SD (1.5 points) in the MIND diet. The MDP, DASH, and PVD scores yielded positive differences in their point estimates for an increase in 1-SD, but results were not statistically significant. The MIND diet appeared to modify changes in cognitive function over time. Our results showed a beneficial association between the MIND diet and cognitive function and suggested a benefit for the AHEI-2010 pattern. Results for the MDP, DASH, and PVD were inconclusive.


Systemic prokinetic pharmacologic treatment for postoperative adynamic ileus following abdominal surgery in adults.
Postoperative adynamic bowel atony interferes with recovery following abdominal surgery. Prokinetic pharmacologic drugs are widely used to accelerate postoperative recovery. To evaluate the benefits and harms of systemic acting prokinetic drugs to treat postoperative adynamic ileus in patients undergoing abdominal surgery. Trials were identified by computerised searches of the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the Cochrane Colorectal Cancer Group specialised register. The reference lists of included trials and review articles were tracked and authors contacted. Randomised controlled parallel-group trials (RCT) comparing the effect of systemically acting prokinetic drugs against placebo or no intervention. Four reviewers independently extracted the data and assessed trial quality. Trial authors were contacted for additional information if needed. Thirty-nine RCTs met the inclusion criteria contributing a total of 4615 participants. Most trials enrolled a small number of patients and showed moderate to poor (reporting of) methodological quality, in particular regarding allocation concealment and intention-to-treat analysis. Fifteen systemic acting prokinetic drugs were investigated and ten comparisons could be summarized. Six RCTs support the effect of Alvimopan, a novel peripheral mu receptor antagonist. However, the trials do not meet reporting guidelines and the drug is still in an investigational stage. Erythromycin showed homogenous and consistent absence of effect across all included trials and outcomes. The evidence is insufficient to recommend the use of cholecystokinin-like drugs, cisapride, dopamine-antagonists, propranolol or vasopressin. Effects are either inconsistent across outcomes, or trials are too small and often of poor methodological quality. Cisapride has been withdrawn from the market due to adverse cardiac events in many countries. Intravenous lidocaine and neostigmine might show a potential effect, but more evidence on clinically relevant outcomes is needed. Heterogeneity among included trials was seen in 10 comparisons. No major adverse drug effects were evident. Alvimopan may prove to be beneficial but proper judgement needs adherence to reporting standards. Further trials are needed on intravenous lidocaine and neostigmine. The remaining drugs can not be recommended due to lack of evidence or absence of effect.


In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection.
To examine the role of germinal centers (GCs) in the generation and selection of high affinity antibody-forming cells (AFCs), we have analyzed the average affinity of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific AFCs and serum antibodies both during and after the GC phase of the immune response. In addition, the genetics of NP-binding AFCs were followed to monitor the generation and selection of high affinity AFCs at the clonal level. NP-binding AFCs gradually accumulate in bone marrow (BM) after immunization and BM becomes the predominant locale of specific AFCs in the late primary response. Although the average affinity of NP-specific BM AFCs rapidly increased while GCs were present (GC phase), the affinity of both BM AFCs and serum antibodies continued to increase even after GCs waned (post-GC phase). Affinity maturation in the post-GC phase was also reflected in a shift in the distribution of somatic mutations as well as in the CDR3 sequences of BM AFC antibody heavy chain genes. Disruption of GCs by injection of antibody specific for CD154 (CD40 ligand) decreased the average affinity of subsequent BM AFCs, suggesting that GCs generate the precursors of high affinity BM AFCs; inhibition of CD154-dependent cellular interactions after the GC reaction was complete had no effect on high affinity BM AFCs. Interestingly, limited affinity maturation in the BM AFC compartment still occurs during the late primary response even after treatment with anti-CD154 antibody. Thus, GCs are necessary for the generation of high affinity AFC precursors but are not the only sites for the affinity-driven clonal selection responsible for the maturation of humoral immune responses.


Treatment options for refractory depression.
A significant proportion of patients with depressive disorders do not experience a full response with antidepressant treatment. Fortunately, most eventually remit, even though the time to response may be significantly delayed in many patients. A variety of options exist to deal with these difficult clinical situations. Established strategies include switching to an antidepressant of an alternative class (e.g., tricyclic to a monoamine oxidase inhibitor [MAOI] or selective serotonin reuptake inhibitor [SSRI]), electroconvulsive therapy (ECT), and augmentation with lithium or thyroid hormone. Promising alternatives include combined serotonin and norepinephrine enhancement strategies (e.g., SSRI plus serotonin norepinephrine reuptake inhibitor [NSRI] or higher doses of venlafaxine or fluoxetine), steroid suppression therapy, augmentation with atypical antipsychotics, and psychotherapy.


[Early functional and structural changes in the nerve tissue following contact with chymopapain].
Using magnetic resonance imaging, conventional histology, and spinal evoked potentials, the authors studied the short-term effects of chymopapain on nerve tissue in the lumbar vertebral canal region in rats. Chymopapain in different concentrations was injected into the subarachnoid space in 31 rats. As early as 20 minutes later latency changes in the evoked potentials were observed; the histologic examinations after two hours showed bleeding, swelling of the myelin, and vascular changes. Magnetic resonance imaging of the lumbar spine, performed after six hours, showed a markedly stronger signal, indicative of an intraspinal edema, as compared to the control group. The authors' studies are clear proof that changes in nerve tissue following contact with chymopapain occur considerably faster than hitherto assumed in the literature.


Breast cancer genes: looking for BRACA's lost brother.
Breast cancer, specifically mammary carcinoma, is the most common cause of death from cancer in women worldwide, with a lifetime risk of one in nine, and its prevalence is increasing. It represents around 30% of all cancer in females and approximately 40,000 deaths in the United States per year. Important advances have been made in detection and treatment, but a significant number of breast cancers are still detected late. This summary of its epidemiology and history, the molecular aspects of detection and the main implicated genes emphasizes the etiology and heterogeneity of the disease. It is still not clear whether the remaining cases of breast cancer negative to BRCA are due to mutations in another high penetrance gene or to unknown factors yet to be discovered.


[Psychiatric institutions and communities: a study of the demand for mental health care in the State of São Paulo, Brazil]
Psychiatric hospitals have been accused of being both ineffective institutions and the main parties responsible for the chronic status of the mentally ill. However, there is a lack of research on the influence of mental health care facilities on either the communities in which they are located or the nearby out-patient services. Their presence may be a cause for increased psychiatric demand. This study investigates a possible association between the existence of such hospitals in given communities and an increase in hospitalization and demand for primary care services. The author compares the demand and client profile of out-patient services in similar communities, both with and without psychiatric hospitals Some evidence was found that in communities with such hospitals there is an increase in both hospital admittance and consultations in mental health care.


The preparation of large-scale synchronous cultures of the trypanosomatid, Crithidia fasciculata,by cell-size selection: changes in respiration and adenylate charge through the cell-cycle.
Large-scale synchronous cultures of Crithidia fasciculata were prepared by a sedimentation-velocity-size-election method using a non-somotic gradient in a zonal rotor. Synchrony indices of up to 0-68 were obtained (average length of cell-cycle, 5-1h). Dry weight, protein and RNA increased continuously so as to double in one cell-cycle. Rates of oxygen uptake/ml culture increased overall so as to double over a cell-cycle, but rose to maxima at five periods in the cell-cycle. KCN gave a similar degree of inhibition throughout, and so did not alter the periodicity or amplitude of the oscillations. Total adenylates doubled over a cycle, and complex changes in pool sizes of ATP, ADP and AMP were temporally interrelated and were correlated with changes of oxygen uptake rates rather than with changes in biosynthetic requirements. Adenylate charge varied between 0-47 and 0-66 Discontinuous respiratory activity of mitochondria through the cell-cycle and possible mechanisms for its control are discussed with reference to previous data.


Hyperosmotic medium partially restores the growth defect and the impaired production of sterigmatocystin of an Aspergillus nidulans ΔpmtC mutant in a HogA-independent manner.
The protein O-mannosyltransferase catalyzes O-mannosylation in the endoplasmic reticulum by transferring mannose to the seryl or threonyl residues of substrate proteins. We previously reported a deletion mutant of O-mannosyltransferase C (ΔpmtC) in Aspergillus nidulans with impaired vegetative growth and sterigmatocystin (ST) production. In this study, we investigated whether osmotic conditions contribute to the developmental processes and ST biosynthesis of the ΔpmtC deletion mutant. We found that hyphal growth and ST production partially improved in the presence of NaCl, KCl or sorbitol as osmotic stabilizers. Conidiation of the ΔpmtC deletion mutant was not restored under osmotic stress conditions when the hogA gene was deleted. The hogA gene encodes a protein required for the cellular response to osmotic pressure. However, the yield of ST and the vegetative growth of the ΔhogA ΔpmtC double deletant was restored by high osmolarity in a HogA-independent manner.


Effect of glucose supplement timing on protein metabolism after resistance training.
We determined the effect of the timing of glucose supplementation on fractional muscle protein synthetic rate (FSR), urinary urea excretion, and whole body and myofibrillar protein degradation after resistance exercise. Eight healthy men performed unilateral knee extensor exercise (8 sets/approximately 10 repetitions/approximately 85% of 1 single maximal repetition). They received a carbohydrate (CHO) supplement (1 g/kg) or placebo (Pl) immediately (t = 0 h) and 1 h (t = +1 h) postexercise. FSR was determined for exercised (Ex) and control (Con) limbs by incremental L-[1-13C]leucine enrichment into the vastus lateralis over approximately 10 h postexercise. Insulin was greater (P < 0.01) at 0.5, 0.75, 1.25, 1.5, 1.75, and 2 h, and glucose was greater (P < 0.05) at 0.5 and 0.75 h for CHO compared with Pl condition. FSR was 36.1% greater in the CHO/Ex leg than in the CHO/Con leg (P = not significant) and 6.3% greater in the Pl/Ex leg than in the Pl/Con leg (P = not significant). 3-Methylhistidine excretion was lower in the CHO (110.43 +/- 3.62 mumol/g creatinine) than P1 condition (120.14 +/- 5.82, P < 0.05) as was urinary urea nitrogen (8.60 +/- 0.66 vs. 12.28 +/- 1.84 g/g creatinine, P < 0.05). This suggests that CHO supplementation (1 g/kg) immediately and 1 h after resistance exercise can decrease myofibrillar protein breakdown and urinary urea excretion, resulting in a more positive body protein balance.


Nasal reconstruction in heminasal deficiency (proboscis lateralis): two case reports, with airway reconstruction in one case.
Proboscis lateralis is a very rare congenital malformation with heminasal hypoplasia or aplasia. The affected side is represented by a trunk (proboscis) which can be positioned from the upper eyelid down to the alar base. We present two cases of proboscis lateralis, one in which we reconstructed an airway. The first case is a 16-year-old male patient who presented with heminasal aplasia. Immediately after birth, a proboscis lateralis was resected from the right upper eyelid as primary treatment elsewhere. We reconstructed the nose using costal cartilage as framework. A paramedian forehead flap was transposed to give the patient a nose with adult dimensions. We made no attempt to reconstruct an airway in this case as unilateral nasal breathing appeared adequate. The second case is a 14-year-old male patient who presented with heminasal aplasia on his right side, where a nodule-like appendix was existent with a fistula underneath. A computed tomographic scan revealed an existing hypoplastic posterior nasal airway and a complete ventilated sinus system. The fact that there was an existing posterior airway encouraged us to construct an anterior airway to create an airflow passage. Costal cartilage was taken for framework reconstruction and nasal skin was completely replaced by a paramedian forehead flap. The reconstructed airflow passage was stable.


The Hopkins Rehabilitation Engagement Rating Scale - Reablement Version (HRERS-RV): Development and psychometric properties.
Patient or user engagement with health and social care interventions is receiving increased attention and interest within practice settings and research. An English evaluation of three reablement services wished to include a measure of user-engagement so as to explore its association with outcomes. As no measure of reablement engagement existed, an existing measure designed for use with physical rehabilitation patients (the Hopkins Rehabilitation Engagement Rating Scale) was adapted and its psychometric properties were tested. The adapted version was completed by reablement staff at the time an individual (n = 129) was discharged from one of the three reablement services. Outcomes data (Barthel Index, Nottingham Extended Activities of Daily Living Scale, General Health Questionnaire-12) collected by the evaluation study at baseline (that is, at entry into reablement), discharge and 6 months postdischarge was used for some psychometric testing. Internal consistency and construct, predictive and discriminant validity were investigated. The adapted scale measured a single construct and had good internal consistency. Tests of predictive and discriminant validity were positive. Findings from a separate, small-scale (n = 31) test-retest study offer an early indication that this is acceptable. There was, however, evidence of a ceiling effect and we consider ways this may be ameliorated. The Hopkins Rehabilitation Engagement Rating Scale - Reablement Version offers a means by which user engagement in reablement can be measured using a staff-completed instrument. The association between engagement and reablement outcomes, revealed when testing for predictive validity, supports the argument for greater attention and investment in research on user engagement in reablement. More broadly, researching engagement within the context of an intervention often delivered by multiple practitioners offers the opportunity to further understand this concept which, in the past, has particularly focused on interventions delivered by a single practitioner. In addition, future work should include developing a companion measure completed by service users.


Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma.
Although the typical clinical manifestations of multiple myeloma (MM) are summarized by the CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone lesions), a significant proportion of patients with MM present with a variety of other clinical manifestations. We conducted a study evaluating the presenting symptoms that led to the diagnosis of MM. We conducted a retrospective review of 170 consecutive patients with MM seen at the Penn State Hershey Cancer Institute. Among patients with symptomatic MM, 74% presented with CRAB symptoms, 20% presented with non-CRAB manifestations, and 6% had both clinical features. Ten categories of non-CRAB manifestations were found, in order of decreasing frequency: neuropathy (because of spinal cord compression, nerve root compression, or peripheral neuropathy), extramedullary involvement, hyperviscosity syndrome, concomitant amyloidosis (eg, nephrotic syndrome or cardiopathy), hemorrhage/coagulopathy, systemic symptoms (eg, fever or weight loss), primary plasma cell leukemia, infections, cryoglobulinemia, and secondary gout. Kaplan-Meier estimates of survival in patients with non-CRAB manifestations did not show a significant difference from the survival of patients presenting with CRAB symptoms. Presenting symptoms of MM may be grouped in a total of 14 categories, 4 for the CRAB and 10 for the less common non-CRAB features. Grouped together, non-CRAB manifestations do not appear to confer a negative effect on the prognosis of patients with MM.


Free Fatty Acids and Methyl Jasmonate Trigger Defense Reactions in Laminaria digitata.
Arachidonic acid, linolenic acid and methyl jasmonate (MeJA) were found to be strong triggers of an oxidative burst in the kelp Laminaria digitata. These findings constitute the first report of an oxidative burst in an algal system induced by free fatty acids. The source of reactive oxygen species can be at least partially inhibited by diphenylene iodonium (DPI). Treatment with arachidonic acid increases the levels of a number of free fatty acids [including myristic (C14:0), linoleic (C18:2), linolenic (C18:3) and eicosapentaeneoic (C20:5) acids] and hydroxylated derivatives [such as 15-hydroxyeicosatetraenoic acid (15-HETE), 13-hydroxyoctadecatrienoic acid (13-HOTE) and 15-hydroxyeicosapentaenoic acid (15-HEPE)]. Similar to a previous report of the function of an alginate oligosaccharide-triggered oxidative burst in the establishment of resistance in L. digitata against infection by its brown algal endophyte Laminariocolax tomentosoides, C20:4- and MeJA-induced oxidative bursts seem to be involved in establishing the same protection in L. digitata. Altogether, this study supports the notion that lipid oxidation signaling plays a key role in defense induction in marine brown algae.


Changes in the expression of fibroblast growth factor receptors mark distinct stages of chondrogenesis in vitro and during chick limb skeletal patterning.
Members of the fibroblast growth factor (FGF) family of growth factors are key regulators of limb skeletal patterning and growth. Abnormal expression of FGFs or mutations in their receptors (fgfrs) result in skeletal disorders. Here we show that changes in the expression of fgfrs are intrinsic properties of differentiating cartilage. In mesenchymal micromass cultures differentiating into cartilage, as in ovo, fgfr 1 mRNA was found predominantly in undifferentiated, proliferating mesenchyme, fgfr 2 in precartilage cell aggregates, and fgfr 3 in differentiating cartilage nodules. Thus, our data suggest that switches in the expression of fgfr 1, 2, and 3 mRNAs are associated with phases of cartilage patterning both in vitro and in ovo, and mark distinct stages in the development of the limb skeleton.


Criteria for item selection for a preference-based measure for use in economic evaluation.
Preference-based measures allow patients to report their level of health, and the responses are then scored using preference weights from a representative general population sample for use in cost utility analysis. The development process of new preference-based measures should ensure that valid items are selected to reflect the constructs of interest included in the measure and that are suitable for use in preference-elicitation exercises. Existing criteria on patient-reported outcome measures (PROMs) development were reviewed, and additional considerations were taken into account in order to generate criteria to support development of new preference-based measures. Criteria covering 22 different aspects related to item selection for preference-based measures are presented. These include criteria related to how items are phrased to ensure accurate completion, the coverage of items in terms of range of domains as well as focus on current outcomes and whether items are suitable for valuation. The criteria are aimed at supporting the development of new preference-based measures with discussion to ensure that even where there is conflict between criteria, issues have been considered at the item selection stage. This would minimize problems at valuation stage by harmonizing established criteria and expanding lists to reflect the unique characteristics of preference-based measures.


Update on anemia and neutropenia in copper deficiency.
Copper deficiency is an under-recognized cause of reversible refractory anemia and leukopenia, particularly neutropenia, often misdiagnosed as myelodysplastic syndrome (MDS). Clinicians and hematopathologists need to be aware of distinct morphologic findings to distinguish these entities including cytoplasmic vacuolization of both erythroid and myeloid precursors, excess iron stores, ringed sideroblasts, iron incorporation in plasma cells, and variable marrow cellularity. In contrast, the findings in MDS do not include myeloid lineage vacuolization, abnormal nuclear lobulation of both erythroid and myeloid precursors, nuclear/cytoplasmic dyssynchrony, or dysmegakaryopoiesis with abnormalities of nuclear lobulation and size. The mechanism of neutropenia remains unknown; however, the study by Peled and coworkers suggests that copper deficiency results in the inhibition of differentiation and self-renewal of CD34(+) hematopoietic progenitor cells. A number of recent studies have reported on the association of copper deficiency with the development of concomitant neurologic deficits manifested as peripheral neuropathies and myeloneuropathy indistinguishable from the findings seen in vitamin B12 deficiency. Patients presenting with refractory anemia and leukopenia with or without associated neurologic deficits should have copper and ceruloplasmin levels measured as part of their diagnostic evaluation.


Regulation of ingestion by CRF and bombesin-like peptides: distinct meal-related peptide level changes.
Bombesin (BN) and corticotropin-releasing factor (CRF) have both been shown to induce satiety in rats when injected centrally. The present study assessed temporal changes in the utilization of BN- and CRF-like peptides in relationship to feeding status, fluctuations that may indicate the physiological participation of these peptides in the regulation of feeding. Alterations in the endogenous levels of CRF- and BN-like peptides associated with the initial spontaneous meal of the nocturnal cycle were determined in 15 hypothalamic and extrahypothalamic brain nuclei in the following three groups of rats: 1) a preprandial group consisting of rats killed before feeding, 2) a prandial group consisting of rats killed during the meal, and 3) a postprandial group consisting of rats killed 8-12 min after the meal. Findings revealed site-specific changes in BN and CRF content during the course of a meal. During ingestion, levels of BN were significantly elevated at the paraventricular, arcuate, and dorsomedial nuclei of the hypothalamus and reduced at the nucleus accumbens. In the case of CRF, feeding-related alterations were observed at the lateral (LH) and ventromedial (VMH) hypothalamic nuclei and at the central nucleus of the amygdala (Ce). At the LH, CRF content decreased after feeding compared with preprandial levels. At the VMH, CRF levels were significantly elevated both before and after food intake compared with prandial levels. In contrast, at the Ce marked increases in CRF concentrations were observed during ingestion. These data demonstrate, for the first time, site-specific fluctuations of BN and CRF in relationship to the animal's feeding status and suggest that these peptides may play a role in the regulation of food intake.


Upregulation of notch2 and six1 is associated with progression of early-stage lung adenocarcinoma and a more aggressive phenotype at advanced stages.
Lung adenocarcinoma often manifests as tumors with mainly lepidic growth. The size of invasive foci determines a diagnosis of in situ, minimally invasive adenocarcinoma, or invasive types and suggests that some adenocarcinomas undergo malignant progression in that order. This study investigates how transcriptional aberrations in adenocarcinoma cells at the early stage define the clinical phenotypes of adenocarcinoma tumors at the advanced stage. We comprehensively searched for differentially expressed genes between preinvasive and invasive cancer cells in one minimally invasive adenocarcinoma using laser capture microdissection and DNA microarrays. We screened expression of candidate genes in 11 minimally invasive adenocarcinomas by reverse transcriptase PCR and examined their involvement in preinvasive-to-invasive progression by transfection studies. We then immunohistochemically investigated the presence of candidate molecules in 64 samples of advanced adenocarcinoma and statistically analyzed the findings, together with clinicopathologic variables. The transcription factors Notch2 and Six1 were upregulated in invasive cancer cells in all 11 minimally invasive adenocarcinomas. Exogenous Notch2 transactivated Six1 followed by Smad3, Smad4, and vimentin, and enlarged the nuclei of NCI-H441 lung epithelial cells. Immunochemical staining for the transcription factors was double positive in the invasive, but not in the lepidic growth component of a third of advanced Ads, and the disease-free survival rates were lower in such tumors. Paired upregulation of Notch2 and Six1 is a transcriptional aberration that contributes to preinvasive-to-invasive adenocarcinoma progression by inducing epithelial-mesenchymal transition and nuclear atypia. This aberration persisted in a considerable subset of advanced adenocarcinoma and conferred a more malignant phenotype on the subset.


Metformin inhibits SUV39H1-mediated migration of prostate cancer cells.
Prostate cancer (PCa) is a leading cause of cancer-related death among men, largely due to incurable distant metastases. Metformin, the most common used anti-type-2 diabetes medicine, has been linked to reduced cancer risk and better diagnosis. We found that metformin was able to inhibit PCa cell migration, which correlates with tumor metastatic capability. The pathogenesis and progression of tumors are closely related to dysregulated gene expression in tumor cells through epigenetic alterations such as DNA methylation and histone modifications. We found that the level of SUV39H1, a histone methyltransferase of H3 Lys9, was reduced in metformin-treated PCa cells in a time-dependent manner. SUV39H1 overexpression increased PCa migration, whereas SUV39H1 depletion suppressed PCa cell migration. There is a positive correlation between SUV39H1 expression and PCa pathological stages. We further showed that both metformin treatment and SUV39H1 knockout in PCa cells can reduce integrin αV and β1 proteins, as well as their downstream phosphorylated focal adhesion kinase (FAK) levels, which is essential for functional adhesion signaling and tumor cell migration. Taken together, metformin reduced SUV39H1 to inhibit migration of PCa cells via disturbing the integrin-FAK signaling. Our study suggests SUV39H1 as a novel target to inhibit PCa cell migration.


First experience in ambulatory ultrafiltration therapy for congested heart failure patients in Israel: a feasibility study.
The prevalence of heart failure (HF) is increasing rapidly with high readmission rates, mainly due to fluid retention. Ultrafiltration (UF) is a mechanical method for removing fluids. Since UF was introduced only recently in Israel, the skill and experience required for outpatient congested HF patients is scarce. OBJECTIVEs: To evaluate the feasibility and safety of UF therapy in congested HF patients in outpatient clinics under a strict protocol of monitoring and therapy that we developed. Between April and September 2013 we applied UF in our outpatient clinic to seven chronically congested HF patients with NYHA III-IV who did not respond adequately to diuretics. We administered a total of 38 courses. On average, 1982 ml fluid per course was removed without significant adverse events and with patients' subjective feeling of improvement. Only two courses were interrupted prematurely due to mechanical problems but were completed without harm to the patients. Under appropriate professional medical supervision, UF therapy in an outpatient setting is a safe and effective procedure and serves as an additional tool for managing congested HF patients who do not respond adequately to diuretics.


Cytotoxicity of eluates from a gamma-ray-polymerized poly(methyl methacrylate).
The purpose of this study was to evaluate the cytotoxicity of gamma-ray-polymerized poly(methyl methacrylate) (PMMA). A total of 32 disk-shaped PMMA specimens were polymerized by gamma-irradiation with 1 Mrad for 4 h (Group 1), 2 Mrad for 8 h (Group 2), 3 Mrad for 12 h (Group 3), and thermally polymerized (Group 4). Four- and 6-day eluates of the specimens were prepared in Eagle's Minimal Essential Medium (EMEM) without Fetal Calf Serum (FCS). The eluates and EMEM supplemented by 20% FCS were placed into Vero (green African monkey kidney) cell cultures, and incubated at 37 degrees C for 24, 48, and 72 h. EMEM kept at 37 degrees C for 4 and 6 days was also tested up to 72 h, and served as controls. After each incubation period, the number of viable cells were counted and stained at the termination of the experiments for histological evaluation. The number of viable cells for Group 1 was slightly lower than that of other groups after 24 h. The time-dependent increase in cells exposed to Group 3 eluates was comparable with the control group. There was a dose-dependent effect on cell response for gamma-ray-polymerized specimens. The number of viable cells and the morphological appearance of cells in all groups were similar. Eluates from PMMA polymerized by low doses of gamma-ray with reduced polymerization periods have early inhibitory effects on cell response. Higher doses of gamma-irradiation lead to better cellular response, and therefore, may be future candidates for polymerization of PMMA.


A cross-sectional study of hepatitis E virus infection in pigs in different-sized farms in northern Thailand.
Pigs are an important reservoir of hepatitis E virus (HEV) in many countries throughout the world. We evaluated the association between farm size and presence of serum antibodies against HEV, as well as other risk factors for infection in pigs raised in Nan Province, Thailand in a cross-sectional study. The sampling frame was a total-population census of all pig herds, stratified into three classes of the farm size according to criteria developed by the Nan provincial livestock health office. One-eighth of all pigs in each farm were sampled randomly. All pig-farm owners were interviewed to elicit information on general characteristics of their farms, biosecurity and hygienic procedures, and farm management. We obtained sera and fecal samples from 879 pigs to test for antibodies to HEV and HEV RNA. Odds ratios (OR) and 95% confidence intervals (CI) for risk factors for HEV seroprevalence were estimated by multivariate logistic regression. The overall prevalence of anti-HEV immunoglobulin G antibodies was 9.9%. Pigs studied from medium-sized farms had a higher HEV seroprevalence than those from larger farms (adjusted OR 4.95, 95% CI: 1.79, 13.70). Factors associated with HEV seropositivity included feeding pigs with agro-industrial byproducts, having veterinarians on farms, and presence of other pig farms within 100 m. Twenty-five (2.9%) of 875 sampled pig stools were positive for HEV RNA. Phylogenetic analysis revealed that all HEV isolates clustered to HEV genotype 3.


The role of halide ions in the anisotropic growth of gold nanoparticles: a microscopic, atomistic perspective.
We provide a microscopic view of the role of halides in controlling the anisotropic growth of gold nanorods through a combined computational and experimental study. Atomistic molecular dynamics simulations unveil that Br(-) adsorption is not only responsible for surface passivation, but also acts as the driving force for CTAB micelle adsorption and stabilization on the gold surface in a facet-dependent way. The partial replacement of Br(-) by Cl(-) decreases the difference between facets and the surfactant density. Finally, in the CTAC solution, no halides or micellar structures protect the gold surface and further gold reduction should be uniformly possible. Experimentally observed nanoparticle's growth in different CTAB/CTAC mixtures is more uniform and faster as the amount of Cl(-) increases, confirming the picture from the simulations. In addition, the surfactant layer thickness measured on nanorods exposed to CTAB and CTAC quantitatively agrees with the simulation results.


Long term treatment of severe obesity: four year follow up of results of combined behavioural modification programme.
A four year programme of treatment for severe obesity combining standard techniques such as behavioural modification, exercise, nutritional advice, and, in addition, readmission of patients who relapse has been developed. One hundred and seven subjects of both sexes were treated. Thirty nine had their jaws fixed from the start. After four years 104 out of 107 subjects were traced; 33 (31%) had left the programme. The mean loss of weight in the remaining 74 subjects was 11.7 kg (range -20 to 55.5): 14 had lost more than 20 kg, 35 had lost 5-20 kg, 17 had lost 0-5 kg, and eight were above their weight before treatment. The rate of dropping out in this study was lower than that generally reported. Our data suggest that combined behavioural modification used as a programme for reducing weight may result in a substantial loss of weight for several years even for severely obese subjects.


UPK1B promotes the invasion and metastasis of bladder cancer via regulating the Wnt/β-catenin pathway.
The aim of this study was to investigate the expression of UPK1B in bladder cancer (BCa), and to further explore the correlation between UPK1B expression and pathological parameters as well as the prognosis of BCa. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of UPK1B in 92 pairs of BCa tissues and adjacent normal tissues. The relationship between UPK1B expression and pathological features as well as the prognosis of BCa patients was further analyzed. For in vitro experiments, the mRNA expression level of UPK1B in BCa cell lines (EJ and T-24) was detected by qRT-PCR. In addition, knockdown of UPK1B in BCa cells was constructed using small interfering RNA. Effects of UPK1B knockdown on biological functions of BCa cells were analyzed by Cell Counting Kit-8 (CCK-8), colony formation assay and transwell assay, respectively. Furthermore, the underlying mechanism of UPK1B in regulating BCa was evaluated by Western blot and qRT-PCR, respectively. The expression of UPK1B in BCa tissues was remarkably higher than that of adjacent normal tissues (p<0.05). Compared with BCa patients with lower UPK1B expression, those with higher UPK1B expression exhibited higher tumor stage, lymph node metastasis and distant metastasis. In vitro experiments indicated that cell proliferation, invasion and metastasis were remarkably decreased in cells transfected with si-UPK1B when compared with those transfected with negative controls. Western blot showed that the expression of key proteins in the Wnt/β-catenin signaling pathway in cells transfected with si-UPK1B was significantly down-regulated compared with those transfected with negative controls, including β-catenin, c-myc and cyclinD1. In addition, rescue experiments found that UPK1B was regulated by β-catenin. UPK1B is upregulated in BCa, and is significantly correlated with tumor stage, lymph node metastasis, distant metastasis and poor prognosis of BCa. Moreover, UPK1B promotes the proliferation, invasion and migration of BCa via regulating the Wnt/β-catenin signaling pathway.


The regulation of transmitter expression in postembryonic lineages in the moth Manduca sexta. I. Transmitter identification and developmental acquisition of expression.
The majority of the neurons in the adult nervous system of Manduca sexta are born postembryonically, during larval life. Stereotypic arrays of identifiable neuroblasts generate their clonal families or lineages commencing at the end of the second larval instar through pupal day 2, when the neuroblasts die (Booker and Truman, 1987a). We have used immunohistochemical techniques to follow the neurochemical differentiation of GABA and a peptide similar to molluscan small cardioactive peptide B (SCPB) in identified lineages. We report here the distribution and developmental acquisition of the expression of these putative transmitters. There are 24 postembryonic lineages in the second thoracic ganglion of the larvae (Booker and Truman, 1987a). Immunoreactivity against GABA and SCPB is seen only in a subset of these 24 clonal families. GABA immunoreactivity is confined to the progeny of the E, K, M, N, T, and X neuroblasts and is expressed by most or all of the neurons in these lineages. The SCPB-like immunoreactivity is found in a subset of the neurons in only two clonal groups, the K and M groups, and is colocalized with GABA. These results show that, though heterogeneity in transmitter type exists (GABA, GABA/SCPB), members of a given lineage share at least some features (GABA) in common. The onset of transmitter expression was followed in detail for the K- and M-lineage neurons. During the larval stages, the postembryonic lineage cells are developmentally arrested in a partially differentiated state (Booker and Truman, 1987a) and do not express transmitter immunoreactivity at this time. Their maturation resumes with the onset of metamorphosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Signal Transduction of Streptococci by Cyclic Dinucleotide Second Messengers.
Since the discovery of cyclic dimeric guanosine 3',5'-monophosphate (c-di-GMP) in 1987, the role of cyclic dinucleotides in signal pathways has been extensively studied. Many receptors and effectors of cyclic dinucleotides have been identified which play important roles in cellular processes. Example of such effectors include cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP)-binding proteins and endoplasmic reticulum membrane adaptor. Accumulating evidence indicate that cyclic dinucleotides act as second messengers that not only regulate the bacterial physiological processes but also affect host immune responses during infections. Streptococci species, which produce cyclic dinucleotides, are responsible for many human diseases. Numerous studies suggest that the cyclic dinucleotides are vital in signal transduction pathways as second messengers and influence the progression of infectious diseases. Here, we provide an overview of the molecular principles of cyclic dinucleotides synthesis and degradation and discuss recent progress on streptococcal signal transduction pathways by cyclic dinucleotide second messengers and their role in regulating host immune reaction. This review will provide a better understanding of the molecular mechanisms of streptococcal cyclic dinucleotide second messengers thereby revealing novel targets for preventing infections.


Metabolic Potential of the Gut Microbiome Is Significantly Impacted by Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.
Allogeneic hematopoietic stem cell transplantation (aHSCT) is a putative curative treatment for malignant hematologic disorders. During transplantation, the immune system is suppressed/eradicated through a conditioning regimen (non-myeloablative or myeloablative) and replaced with a donor immune system. In our previous study, we showed changes in gut taxonomic profiles and a decrease in bacterial diversity post-transplant. In this study, we expand the cohort with 114 patients and focus on the impact of the conditioning regimens on taxonomic features and the metabolic functions of the gut bacteria. This is, to our knowledge, the first study to examine the metabolic potential of the gut microbiome in this patient group. Adult aHSCT recipients with shotgun sequenced stool samples collected day -30 to +28 relative to aHSCT were included. One sample was selected per patient per period: pre-aHSCT (day -30-0) and post-aHSCT (day 1-28). In total, 254 patients and 365 samples were included. Species richness, alpha diversity, gene richness and metabolic richness were all lower post-aHSCT than pre-aHSCT and the decline was more pronounced for the myeloablative group. The myeloablative group showed a decline in 36 genera and an increase in 15 genera. For the non-myeloablative group, 30 genera decreased and 16 increased with lower fold changes than observed in the myeloablative group. For the myeloablative group, 32 bacterial metabolic functions decreased, and one function increased. For the non-myeloablative group, three functions decreased, and two functions increased. Hence, the changes in taxonomy post-aHSCT caused a profound decline in bacterial metabolic functions especially in the myeloablative group, thus providing new evidence for associations of myeloablative conditioning and gut dysbiosis from a functional perspective.


[Modern problems of the pharmacology of nootropic agents: the status and outlook].
The information about the current state and perspectives of research in the field of development and study of the mechanisms of action of nootropic drugs is presented. The methodology of experimental study of nootropics is covered which is based on modelling different disorders of the integrative activity of the brain including old animals. The modern concepts of the mechanisms of action of agents are given. The most promising new trends in the investigation and search for nootropics on the basis of neuropeptides, ligands of GABA-benzodiazepine receptor complex, antioxidants, membrane stabilizers, protein synthesis stimulants, agents influencing glutamatergic system, etc. are analyzed.


Intradiscal inflammatory stimulation induces spinal pain behavior and intervertebral disc degeneration in vivo.
Degeneration of the intervertebral disc (IVD) results in a range of symptomatic (i.e., painful) and asymptomatic experiences. Components of the degenerative environment, including structural disruption and inflammatory cytokine production, often correlate with pain severity. However, the role of inflammation in the activation of pain and degenerative changes has been complex to delineate. The most common IVD injury model is puncture; however, it initiates structural damage that is not representative of the natural degenerative cascade. In this study, we utilized in vivo injection of lipopolysaccharide (LPS), a pro-inflammatory stimulus, into rat caudal IVDs using 33G needles to induce inflammatory activation without the physical tissue disruption caused by puncture using larger needles. LPS injection increased gene expression of pro-inflammatory cytokines (Tnfa, Il1b) and macrophage markers (Inos, Arg1), supported by immunostaining of macrophages (CD68, CCR7, Arg1) and systemic changes in blood cytokine and chemokine levels. Disruption of the IVD structural integrity after LPS injection was also evident through changes in histological grading, disc height, and ECM biochemistry. Ultimately, intradiscal inflammatory stimulation led to local mechanical hyperalgesia, demonstrating that pain can be initiated by inflammatory stimulation of the IVD. Gene expression of nociceptive markers (Ngf, Bdnf, Cgrp) and immunostaining for neuron ingrowth (PGP9.5) and sensitization (CGRP) in the IVD were also shown, suggesting a mechanism for the pain exhibited. To our knowledge, this rat IVD injury model is the first to demonstrate local pain behavior resulting from inflammatory stimulation of caudal IVDs. Future studies will examine the mechanistic contributions of inflammation in mediating pain.


[Regularity of Acupoint Selection for Simple Obesity Treated by Acupoint Catgut Embedding Based on Complex Network Technology].
To analyze the core acupoints and acupoint combinations of catgut embedding for simple obesity based on the complex network technology. Articles about acupoint catgut embedding for simple obesity were collec-ted from databases of PubMed, CNKI, Wanfang and VIP from 1980 to 2016 by using keywords "simple obesity" "obesity" "acupoint embedding" "acupuncture" and "traditional Chinese medicine", followed by constructing a database of acupoint prescription. Acupoint node (one node means an acupoint) weighted complex network was constructed by using complex network technique, followed by conducting centrality analysis and clustering analysis about the nodes using Matlab 2014, a software for revealing the core acupoint node and compatibility relations. At last, theresults (complex network diagram) were displayed using software Gephi 0.9.1. A total of 238 articles (all in Chinese) including 278 acupoints (of which 115 are meridian acupoints) were collected. The top 15 core acupoints are Tianshu (ST 25), Zusanli (ST 36), Zhongwan (CV 12), Fenglong (ST 40), San-yinjiao (SP 6), Quchi (LI 11), Yinlingquan (SP 9), Guanyuan (CV 4), Pishu (BL 20), Qihai (CV 6), Shenshu (BL 23), Shangjuxu (ST 37), Daheng (SP 15), Shuifen (CV 9), and Ganshu (BL 18), mainly distributing in the abdomen, lower limbs and back. Those acupoints with the highest core degree are attributed to the Stomach Meridian, Conception Vessel, Bladder Meri-dian, Spleen Meridian and Large Intestine Meridian. Regarding the compatibility of these acupoints, ST 25 and CV 12 have the highe-st correlation frequency, followed by ST 25 and ST 36, and ST 40 and ST 25, indicating the principle of different combinations being regional acupoints and meridian acupoints. In the treatment of simple obesity with catgut embedding, top 15 core acupoints as ST 25, ST 36, CV 12, ST 40, etc, and acupoint recipes as ST 25 and CV 12, ST 25 and ST 36, ST 40 and ST 25 are most frequently used in clinical practice.


Bioactivity determination of methanol and water extracts for roots and leaves of Kenyan Psidium guajava L landraces against pathogenic bacteria.
Guava (Psidium guajava L) is native to South America and exists as both wild and cultivated. Guava has been used as a source of food and raw materials for pharmaceuticals. The aim of this study was to determine bioactivity of methanol and water extracts from root and leaves of Kenyan guava landraces against selected pathogenic bacteria. Study samples were collected from Western and South Coast of Kenya. One hundred grams of leaf and root ground powders were used for sequential extraction using methanol and water. Extracts were evaporated and 0.2gms dissolved using the extraction solvent and tested against gram positive (Staphylococcus aureus, Bacillus subtilis) and negative bacteria (Escherichia coli). Data on inhibition zone was taken in mm and analyzed at 95% confidence interval. Extracts from Western region had significant inhibition compared to Coastal region. The two regions have different climatic conditions that result in these plants having different compounds even though they are the same species. Roots had higher inhibition compared to the leaves as they contain high levels of tannins compared to leaves. Water as an extracting solvent had higher inhibition than methanol as it is more polar and it absorbs more bioactive compounds. S. aureus was most inhibited followed by E. coli and B. subtilis respectively. There was no significant difference between the gram positive and negative bacteria. Remarkably, some methanol and water root extracts had significant inhibition against bacteria when compared to some commercial antibiotics used. Results of this study indicate that Kenyan guava roots from Western Kenya extracted with methanol and water have a potential to be used as a source of active compounds in treatment of gram positive and gram negative bacteria pathogens.


Acute testis toxicity of bisphenol A diglycidyl ether in Sprague-Dawley rats.
Bisphenol A diglycidyl ether (BADGE) is a liquid compound obtained by condensation of two molecules of epichlorohydrin with one molecule of bisphenol A. General and reproductive toxicity with BADGE has been reported higher than 1000 mg/kg/day. This study was performed to show the effects of acute exposure to BADGE below 1000 mg/kg/day on the testis in adult male rats. BADGE was administered by gastric lavage in a single dose of 500, 750, 1000, and 2000 mg/kg/day in 8-week old male SPF Sprague-Dawley rats. The right testis was processed for light microscopic analysis. The left testis was homogenized and spermatids were counted to determine the daily sperm production and daily abnormal sperm production. The sperm count, sperm motility, and incidence of abnormal sperm were estimated in the epididymis. In testicular sections, the seminiferous tubules were observed for qualitative changes. The progression of spermatogenesis was arbitrarily classified as full-matured, maturing, and immature. The specimen slide was observed at 3 points and 10 seminiferous tubules were evaluated at each point. The male rats exposed to single oral dose of BADGE at 750, 1000, and 2000 mg/kg/day were significantly increased the number of immature and maturing sperm on the testis. There were no significant differences with respect to sperm head count, sperm motility, and sperm abnormality in the BADGE treatment groups. These results suggest that single oral exposure of BADGE 750 mg/kg/day can affect adult male testis development.


Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: a report of 2 cases.
Linezolid is a new oxazolidinone antibiotic active against most Gram-positive microorganisms the renal elimination of which accounts for about 30% to 35% of all the clearance. Its pharmacokinetic ability was assessed during continuous venovenous hemofiltration (CVVH) in 2 anuric patients with severe postsurgical intraabdominal infections who were receiving standard dosages (600 mg intravenously twice a day). Blood samples for quantification of linezolid in plasma and in filtrate were collected after more than 4 days of therapy before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9, and 11 hours after the morning 1-hour intravenous infusion, and concentrations were determined by means of high-performance liquid chromatography. Linezolid was partially cleared by CVVH in both the patients (hemofiltration clearance [CL CVVH ] = 0.38 and 0.35 mL/min/kg), with high sieving coefficient values (0.76 to 0.92). Efficacious plasma exposure for time-dependent antibacterial activity of linezolid, either in terms of trough levels above minimum inhibitory concentration (MIC) at which 90% of the isolates are inhibited (Cmin >MIC90 ) or of area under the plasma concentration time curve to MIC90 ratio (AUC/MIC90 ) >100 hours, was ensured during CVVH in both patients. However, despite similar CL CVVH , significant interindividual pharmacokinetic variability was found in the 2 patients (AUC during the observational period [AUC 0-tau ] 334.71 versus 109.34 mg/L x h), mainly owing to substantial differences in non-CVVH-related clearance of linezolid (total CL, 0.55 versus 1.21 mL/min/kg). Our findings indicate that linezolid, although partially removed, does not warrant dosage modification during the first 48 hours when CVVH (with polysulfide hemofilter) at standard 2,000 mL/h substitution flow rate in predilution is applied to anuric patients. Thereafter, this choice is a reasonable one with the exception of those patients who have other features of linezolid toxicity and in which non-CVVH-related clearance might be impaired, although further evaluations are warranted.


Trajectories of psychosocial and cognitive functioning in pediatric patients with brain tumors treated with radiation therapy.
Pediatric patients with brain tumors who are treated with radiation therapy (RT) are at risk for neurocognitive and psychosocial late effects. Research to date has primarily examined these outcomes at a group level and in isolation. Advanced statistical techniques allow for person-centered analyses, as well as examination of relationships between domain-specific trajectories. Patients with brain tumors (craniopharyngioma, ependymoma, low-grade astrocytoma, high-grade astrocytoma) were enrolled on a phase II clinical trial of RT. Three hundred and fifty patients completed serial neurocognitive assessments as part of their treatment monitoring, including pre-RT baseline, 6 months post-RT, and then yearly for 5 years. This secondary analysis focused on outcomes of cognition (estimated IQ, parent-reported attention problems) and psychosocial effects (parent-reported socialization and social problems) post-RT. Latent growth curve modeling indicated that estimated IQ and socialization were best served by quadratic models, while attention and social problems were best served by linear models. Growth mixture modeling indicated 3-class models were the best fit for IQ and socialization, and 2-class models for attention and social problems. Baseline IQ and socialization scores were associated, but there was no association over time. Young age at diagnosis and pre-RT treatments (surgery, chemotherapy) were associated with class membership. Person-centered statistical analyses provide rich information regarding the variability in neurocognitive and psychosocial functioning following RT for pediatric brain tumor. While many patients do well over time, a subset are exhibiting significant cognitive and/or psychosocial deficits. Class membership was associated with some medical factors (eg, pre-radiation surgery/chemotherapy, age at diagnosis, shunted hydrocephalus).


Extracorporeal therapy requirements for patients with acute renal failure.
Renal replacement therapy (RRT) requirements for critically ill patients with acute renal failure (ARF) depend on numerous factors, including the degree of hypercatabolism, patient size, and desired level of metabolic control. However, the current practice at many institutions is to prescribe generally similar amounts of RRT to ARF patients essentially without regard for the above factors. In this study, a computer-based model designed to permit individualized RRT prescription to ARF patients was developed. The critical input parameter is the desired level of metabolic control, which is the time-averaged BUN (BUNa) or steady-state BUN (BUNs) for intermittent hemodialysis (IHD) or continuous RRT (CRRT), respectively. The basis for the model was a group of 20 patients who received uninterrupted CRRT for at least 5 days. In these patients, the normalized protein catabolic rate (nPCR) increased linearly (r = 0.974) from 1.55 +/- 0.14 g/kg per day (mean +/- SEM) on day 1 to 1.95 +/- 0.15 g/kg per day on day 6. The daily urea generation rate (G), determined from the above linear relationship, was utilized to produce BUN versus time curves by the direct quantification method for simulated patients of varying dry weights (50 to 100 kg) who received variable CRRT urea clearances (500 to 2000 ml/h). Steady-state BUN versus time profiles for the same simulated patient population treated with IHD regimens (K = 180 ml/min, T = 4 h) of variable frequency were generated by use of a variable-volume, single-pool kinetic model. From these profiles, regression lines of required IHD frequency (per week) versus patient weight for desired BUNa values of 60, 80, and 100 mg/dl were obtained. Regression lines of required CRRT urea K (ml/h) versus patient weight for desired BUNs values of 60, 80, and 100 mg/dl were also generated. For the attainment of intensive IHD metabolic control (BUNa = 60 mg/dl) at steady state, a required treatment frequency of 4.4 dialyses per week is predicted for a 50-kg patient. However, the model predicts that the same degree of metabolic control cannot be achieved even with daily IHD therapy in patients > or = 90 kg. On the other hand, for the attainment of intensive CRRT metabolic control (BUNs = 60 mg/dl), required urea clearance rates of approximately 900 ml/h and 1900 ml/h are predicted for 50- and 100-kg patients, respectively. This model suggests that, for many patients, rigorous azotemia control equivalent to that readily attainable with most CRRT can only be achieved with intensive IHD regimens. Following prospective clinical validation, this methodology may be a useful RRT prescription tool for critically ill ARF patients.


Therapeutic non-equivalence of digoxin tablets in the United Kingdom: correlation with tablet dissolution rate.
Seven types of digoxin 0.25 mg tablet in common use in the United Kingdom were administered to a total of 38 patients. Significant differences were found in the mean plasma digoxin levels and in the control of atrial fibrillation achieved with these brands. There was a close correlation between the dissolution rate of the tablets and the plasma digoxin levels. Measurement of in-vitro dissolution rate appears to be a valid method of ensuring that different tablets of digoxin are of equal efficacy. However, in some patients absorption of the drug is markedly sensitive to changes in dissolution rate and new pharmacopoeal standards should not be defined until very rapidly-dissolving formulations have been studied.


Methicillin resistant Staphylococcus aureus outbreak in a neonatal intensive care unit.
The global and national burden of communicable and noncommunicable diseases continues to rise, thus making access to Healthcare workers (HCWs) colonized with methicillin-resistant Staphylococcus aureus (MRSA) may pose transmission risk to vulnerable patients including neonates. This study reports an MRSA outbreak in a level-II neonatal intensive care unit (NICU) of a secondary care hospital in Pakistan. Once identified, an infection control team from the parent hospital visited the facility, risk factors were listed and infection control measures taken to control the outbreak. Screening cultures of NICU staff and environmental cultures from NICU were obtained for the presence of MRSA. Five neonates were positive for MRSA; one HCW was found to be colonized with MRSA, the antibiogram pattern of which matched with that of the outbreak strain. Decolonization of colonized HCWs and re-deployment from NICU to outpatient department were taken and the outbreak was declared over once no further MRSA cases were identified. Identification of an outbreak situation is the cornerstone for its control and multiple measures taken simultaneously help in curbing the outbreak. Although an epidemiological link was established with the HCW, a molecular link could not be proven.


Lethal Dengue Virus Infection: A Forensic Overview.
Dengue virus is a single-stranded RNA virus that is a member of the family Flaviviridae, genus Flavivirus. It is usually transmitted by the female Aedes aegypti mosquito. Dengue fever is a febrile illness caused by 1 of 4 serotypes of the virus, which may progress to dengue hemorrhagic fever or dengue shock syndrome. The mortality rate of untreated dengue shock syndrome is more than 20%. The reported incidence has increased 30-fold for the past 50 years with an estimated 50 to 100 million dengue infections globally each year, which includes 22,000 deaths. Because of this rapid increase in numbers, more cases will be seen in forensic mortuaries, with diagnostic problems arising from nonspecific or unusual manifestations. In this review, the clinicopathological features of dengue viral infection are evaluated. Adequate blood and tissue sampling at the time of autopsy is mandatory for successful microbiological identification and characterization.