Questionnaire-free machine-learning method to predict depressive symptoms among community-dwelling older adults.
The 15-item Geriatric Depression Scale (GDS-15) is widely used to screen for depressive symptoms among older populations. This study aimed to develop and validate a questionnaire-free, machine-learning model as an alternative triage test for the GDS-15 among community-dwelling older adults. The best models were the random forest (RF) and deep-insight visible neural network by internal validation, but both performances were undifferentiated by external validation. The AUROC of the RF model was 0.619 (95% CI 0.610 to 0.627) for the external validation set with a non-local ethnic group. Our triage test can allow healthcare professionals to preliminarily screen for depressive symptoms in older adults without using a questionnaire. If the model shows positive results, then the GDS-15 can be used for follow-up measures. This preliminary screening will save a lot of time and energy for healthcare providers and older adults, especially those persons who are illiterate.


Morning-evening preference: sleep pattern spectrum and lifestyle habits among Japanese junior high school pupils.
We surveyed the sleep-wake patterns and lifestyle habits in a sample of Japanese first to third year junior high school children (n=638, age 12 to 15 yrs), of whom 29.3% were evening type, 64.1% intermediate type, and 6.6% morning type in preference. The morningness-eveningness (M-E) score was lower (more evening typed), 16.1 vs. 15.4 in first compared to third year students. There were significant gender differences, with girls showing a greater evening preference. Evening preference was associated with longer sleep latency, shortened sleep duration during schooldays and weekends, bad morning feeling, and episodes of daytime sleepiness. In contrast, morning preference was associated with higher sleep drive and better sleep-wake parameters and lifestyle habits. Our results suggest the morning preference should be promoted among junior high school children to increase the likelihood of more regular sleep-wake patterns and lifestyle habits.


Insulin-stimulated glycogen synthesis and glycogen synthase activation after electrical stimulation of epitrochlearis muscles with different initial glycogen contents.
Glycogen synthesis increases after muscle contraction and during insulin stimulation, and insulin-stimulated glycogen synthesis is enhanced after contraction. We hypothesized that the initial glycogen content influences the magnitude of additive effect of contraction on insulin-stimulated glycogen synthesis. Contraction and insulin had full additive effect on rate of glycogen synthesis measured after contraction in muscles with normal and high glycogen content. In muscles with low glycogen, contraction increased insulin-stimulated glycogen synthesis nearly as much as in muscles with normal glycogen, but not to the sum of the two stimuli studied separately; still glycogen synthesis was generally highest in muscles with low glycogen. Glycogen synthase fractional activity inversely correlated with glycogen content and contraction increased glycogen synthase fractional activity. Contraction and insulin additively increased glycogen synthase fractional activity at all glycogen contents. In conclusion, after contraction insulin-stimulated glycogen synthesis was increased by rather similar magnitude at all glycogen contents in concert with increased glycogen synthase activation.


Recent advances in the management of large and complex colonic polyps.
The endoscopic management of large colonic polyps is a rapidly changing field. Rapid evolution in endoscopic techniques and skills has resulted in diminishing the role of surgery in the management of larger and complex polyps. This is resulting in organ preservation for many who otherwise would have undergone surgery. However, it also poses new challenges. This article reviews these new advances and the developments which are overcoming these difficulties.


[Dynamics of the lipid peroxidation process in the body of patients with manic-depressive psychosis].
Using gas chromatography the authors have studied the time course of lipid peroxidation (LPO) in patients with manic depressive psychosis (a depressive phase) during a course of antidepressive therapy. The results indicate that the levels of LPO in young patients (up to 30 years) with a disease standing of up to 5 years are significantly higher than in age-matched controls whereas with increasing duration of the disease the levels of this parameter decrease and in elderly patients (over 50 years) with a longer duration of the disease (over 15 years) this parameter is significantly lower than in age-matched controls. A decrease of LPO is particularly pronounced in a bipolar course of manic depressive psychosis.


Engagement With a Mobile Phone-Based Life Skills Intervention for Adolescents and Its Association With Participant Characteristics and Outcomes: Tree-Based Analysis.
Mobile phone-delivered life skills programs are an emerging and promising way to promote mental health and prevent substance use among adolescents, but little is known about how adolescents actually use them. The aim of this study is to determine engagement with a mobile phone-based life skills program and its different components, as well as the associations of engagement with adolescent characteristics and intended substance use and mental health outcomes. We performed secondary data analysis on data from the intervention group (n=750) from a study that compared a mobile phone-based life skills intervention for adolescents recruited in secondary and upper secondary school classes with an assessment-only control group. Throughout the 6-month intervention, participants received 1 SMS text message prompt per week that introduced a life skills topic or encouraged participation in a quiz or individual life skills training or stimulated sharing messages with other program participants through a friendly contest. Decision trees were used to identify predictors of engagement (use and subjective experience). The stability of these decision trees was assessed using a resampling method and by graphical representation. Finally, associations between engagement and intended substance use and mental health outcomes were examined using logistic and linear regression analyses. The adolescents took part in half of the 50 interactions (mean 23.6, SD 15.9) prompted by the program, with SMS text messages being the most used and contests being the least used components. Adolescents who did not drink in a problematic manner and attended an upper secondary school were the ones to use the program the most. Regarding associations between engagement and intended outcomes, adolescents who used the contests more frequently were more likely to be nonsmokers at follow-up than those who did not (odds ratio 0.86, 95% CI 0.76-0.98; P=.02). In addition, adolescents who read the SMS text messages more attentively were less likely to drink in a problematic manner at follow-up (odds ratio 0.43, 95% CI 1.29-3.41; P=.003). Finally, participants who used the program the most and least were more likely to increase their well-being from baseline to 6-month follow-up compared with those with average engagement (βs=.39; t586=2.66; P=.008; R2=0.24). Most of the adolescents participating in a digital life skills program that aimed to prevent substance use and promote mental health engaged with the intervention. However, measures to increase engagement in problem drinkers should be considered. Furthermore, efforts must be made to ensure that interventions are engaging and powerful across different educational levels. First results indicate that higher engagement with digital life skills programs could be associated with intended outcomes. Future studies should apply further measures to improve the reach of lower-engaged participants at follow-up to establish such associations with certainty.


Correlation between Negative Rapid Influenza Diagnostic Test and Severe Disease in Hospitalized Adults with Laboratory-Confirmed Influenza Virus Infection.
False-negative rapid influenza diagnostic test (RIDT) results could mislead physicians to exclude an influenza diagnosis. We sought to evaluate the association between negative RIDT and intensive care unit (ICU) admission. We reviewed data from hospitalized adults with laboratory-confirmed influenza virus infections in a tertiary referral hospital in Taiwan from July 2009 to February 2011. The diagnosis was documented by real-time PCR or virus culture. Of 134 hospitalized adults infected with influenza virus, 38 (28%) were admitted to the ICU. Compared with RIDT-positive patients, the percentage of ICU admission was significantly higher among RIDT-negative patients (46% versus 13%, P < 0.001). The RIDT-negative patients had higher percentages of lower respiratory symptoms and more chest radiograph infiltrates. The time interval between the RIDT and antiviral treatment was longer in RIDT-negative than RIDT-positive patients (1.94 days versus 0.03 days, P < 0.001). Among patients presenting with mild illness, only a negative RIDT and delayed antiviral treatment were associated with ICU admission after adjusting for potential confounding factors. To conclude, patients with a negative RIDT were more likely to have severe disease and a delay in initiating antiviral treatment. Our findings should help improve treatment outcomes of hospitalized patients with influenza infection.


Pediatricians' attitudes, experience and referral patterns regarding Complementary/Alternative Medicine: a national survey.
To assess pediatricians' attitudes toward & practice of Complementary/Alternative Medicine (CAM) including their knowledge, experience, & referral patterns for CAM therapies. An anonymous, self-report, 27-item questionnaire was mailed nationally to fellows of the American Academy of Pediatrics in July 2004.648 of 3500 pediatricians' surveyed responded (18%). The median age ranged from 46-59 yrs; 52% female, 81% Caucasian, 71% generalists, & 85% trained in the US. Over 96% of pediatricians' responding believed their patients were using CAM. Discussions of CAM use were initiated by the family (70%) & only 37% of pediatricians asked about CAM use as part of routine medical history. Majority (84%) said more CME courses should be offered on CAM and 71% said they would consider referring patients to CAM practitioners. Medical conditions referred for CAM included; chronic problems (headaches, pain management, asthma, backaches) (86%), diseases with no known cure (55.5%) or failure of conventional therapies (56%), behavioral problems (49%), & psychiatric disorders (47%). American born, US medical school graduates, general pediatricians, & pediatricians who ask/talk about CAM were most likely to believe their patients used CAM (P < 0.01). Pediatricians' have a positive attitude towards CAM. Majority believe that their patients are using CAM, that asking about CAM should be part of routine medical history, would consider referring to a CAM practitioner and want more education on CAM.


Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice.
Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) plays key roles in neurologic function in health and disease. Neuronal SUMOylation is essential for emotionality and cognition, and this pathway is dramatically activated in post-ischemic neurons, a neuroprotective response to ischemia. It is also known from cell culture studies that SUMOylation modulates gene expression. However, it remains unknown how SUMOylation regulates neuronal gene expression in vivo, in the physiologic state and after ischemia, and modulates post-ischemic recovery of neurologic function. To address these important questions, we used a SUMO1-3 knockdown (SUMO-KD) mouse in which a Thy-1 promoter drives expression of 3 distinct microRNAs against SUMO1-3 to silence SUMO expression specifically in neurons. Wild-type and SUMO-KD mice were subjected to transient forebrain ischemia. Microarray analysis was performed in hippocampal CA1 samples, and neurologic function was evaluated. SUMOylation had opposite effects on neuronal gene expression before and after ischemia. In the physiological state, most genes regulated by SUMOylation were up-regulated in SUMO-KD compared to wild-type mice. Brain ischemia/reperfusion significantly modulated the expression levels of more than 400 genes in wild-type mice, with a majority of those genes upregulated. The extent of this post-ischemic transcriptome change was suppressed in SUMO-KD mice. Moreover, SUMO-KD mice exhibited significantly worse functional outcome. This suggests that suppression of global gene expression response in post-ischemic brain due to SUMO knockdown has a negative effect on post-ischemic neurologic function. Together, our data provide a basis for future studies to mechanistically link SUMOylation to neurologic function in health and disease.


Application of image analysis in the fungal fermentation of Trichoderma reesei RUT-C30.
Trichoderma reesei was grown in a stirred-tank bioreactor (STB) and a reciprocating plate bioreactor (RPB) at four different agitation speeds. A semiautomatic image analysis protocol that was developed to characterize the mycelium morphology during the fermentation process based on four morphological types (unbranched, branched, entangled, and clumped microorganisms) was applied to study the effect of agitation on the morphology of T. reesei. It was shown via statistical validation that broth samples used for image analysis represented the whole population of the fungi in the bioreactor. High shear was found to be damaging to T. reesei grown in the STB. The gentler shear produced in the RPB was not detrimental to the microorganism even at higher agitation speed. Better productivity was obtained for T. reesei grown in the STB and the highest productivity, 0.121 IU/mL h, was obtained at 400 rpm. The morphological parameter, the hyphal growth unit, was found to be correlated to the productivity. Understanding the effect of agitation on the morphology and productivity of T. reesei could lead to the design of better bioreactors and the selection of operating conditions of bioreactors to optimize the production of cellulase.


Cross-talker generalization in the perception of nonnative speech: A large-scale replication.
Speech perception depends on the ability to generalize previously experienced input effectively across talkers. How such cross-talker generalization is achieved has remained an open question. In a seminal study, Bradlow & Bent (2008, henceforth BB08) found that exposure to just 5 min of accented speech can elicit improved recognition that generalizes to an unfamiliar talker of the same accent (N = 70 participants). Cross-talker generalization was, however, only observed after exposure to multiple talkers of the accent, not after exposure to a single accented talker. This contrast between single- and multitalker exposure has been highly influential beyond research on speech perception, suggesting a critical role of exposure variability in learning and generalization. We assess the replicability of BB08's findings in two large-scale perception experiments (total N = 640) including 20 unique combinations of exposure and test talkers. Like BB08, we find robust evidence for cross-talker generalization after multitalker exposure. Unlike BB08, we also find evidence for generalization after single-talker exposure. The degree of cross-talker generalization depends on the specific combination of exposure and test talker. This and other recent findings suggest that exposure to cross-talker variability is not necessary for cross-talker generalization. Variability during exposure might affect generalization only indirectly, mediated through the informativeness of exposure about subsequent speech during test: Similarity-based inferences can explain both the original BB08 and the present findings. We present Bayesian data analysis, including Bayesian meta-analyses and replication tests for generalized linear mixed models. All data, stimuli, and reproducible literate (R markdown) code are shared via OSF. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Adjustment disorders: prevalence in a representative nationwide survey in Germany.
This is the first study to estimate the prevalence of adjustment disorder (AjD) in the general population. A new conceptualisation of AjD as a stress response syndrome was applied, which allowed AjD to be assessed directly from its symptom profile, including intrusive, avoidance and failure-to-adapt symptoms (Maercker et al., Psychopathology 40:135-146, 2007). Prevalence rates of distressing life events and AjD were estimated from a representative sample of the German general population (n = 2,512) with a broad age range (14-93 years). A questionnaire including a life events checklist and self-rating questions that assessed AjD symptoms and symptom duration were personally handed out by an interviewer. The prevalence of AjD fulfilling the criterion of clinically significant impairment was 0.9%; a further 1.4% of the sample was diagnosed with AjD without fulfilling the impairment criterion. In ~72.5% of AjD cases, symptoms had developed 6-24 months prior to assessment. AjD was most often associated with acute events such as moving or chronic stressors such as serious illness, conflicts at the respondent's job or with friends or neighbours (with ~5% conditional probability each). The results correspond with the few other studies that have examined the prevalence of AjD, even though a new conceptualisation of the disorder was used. Explorative results regarding the duration of AjD syndromes and symptoms call for further redefinition and empirical investigation of this under-researched mental condition.


CD11b is required for the resolution of inflammation induced by Bordetella bronchiseptica respiratory infection.
CD11b is a cell surface receptor that contributes to many cellular processes which are involved in the generation of a protective immune response against pathogenic organisms. In this work, the natural host-pathogen model of murine Bordetella bronchiseptica infection was used to explore the role of CD11b in respiratory immunity. Following intranasal inoculation, CD11b-/- mice rapidly succumb to B. bronchiseptica respiratory infection, highlighting the prominent role of CD11b in the generation of a protective immune response in this model. CD11b appears to be required for both the control of bacterial numbers and the regulation of cellular responses in the lungs. An increased accumulation of neutrophils in the lungs of CD11b-/- mice as compared with wild-type mice suggests that CD11b contributes to the regulation of cellular responses to respiratory infection. This accumulation may be explained by a decrease in apoptosis that is observed in the absence of CD11b following cellular interactions with B. bronchiseptica. Interestingly, this role for CD11b in the regulation of cellular accumulation appears to be critically important for the resolution of damage associated with the type III secretion system (TTSS) of B. bronchiseptica. These data provide new insight into the key role CD11b plays in the resolution of damage in the lower respiratory tract, as well as the B. bronchiseptica virulence determinant that induces it.


Endocrine and metabolic assessment in adults with Langerhans cell histiocytosis.
Diabetes insipidus (DI) is one of most common complications of Langerhans cell histiocytosis (LCH) but prevalence of anterior pituitary deficiencies and metabolic alterations have not been clearly defined yet. Evaluate prevalence of endocrine and metabolic manifestations in a cohort of patients affected by Pulmonary LCH. Observational cross-sectional study on 18 adults (7 M/11 F, 42±12years) studied for complete basal and dynamic endocrine lab tests and glucose metabolism. Hypothalamic-pituitary endocrine alterations were found in 9 patients: 9 had DI, 5 Growth Hormone Deficiency (GHD), 5 central hypogonadism, 3 central hypothyroidism and 1 central hypoadrenalism. Hyperprolactinemia and hypothalamic syndrome were found in 2 patients each. All these central endocrine alterations were always associated to DI. Five of the 10 MRI performed showed abnormalities. Prevalence of obesity and glucose alterations (either DM or IFG/IGT) were respectively 39% and 33%, higher than expected basing on epidemiological data on general Italian population. Multi-system-LCH without risk-organ involvement (LCH MS-RO-) seems to have slightly higher prevalence of insulin resistance, glucose alterations and metabolic syndrome than LCH with isolated lung involvement (LCH SS lung+). A papillary BRAFV600E positive thyroid carcinoma was diagnosed in one patient. The presence of anterior pituitary deficiencies should be systematically sought in all LCH patients with DI both at diagnosis and during the follow-up by basal and dynamic hormonal assessment. Patients with pulmonary LCH, particularly those with MS disease, have a worse metabolic profile than general population. Occurrence of papillary thyroid carcinoma has been reported.


Enhancement of symbiotic dinitrogen fixation by a toxin-releasing plant pathogen.
An approximate doubling in plant growth, total plant nitrogen, nodulation, and overall dinitrogen fixation of alfalfa are the consequences of the action of a toxin delivered by a Pseudomonas infesting the alfalfa rhizosphere. The toxin, tabtoxinine-beta-lactam, inactivates selectively one form of glutamine synthetase in the nodules. Thus, normal glutamine synthetase-catalyzed ammonia assimilation is significantly impaired; yet these plants assimilated about twice the normal amount of nitrogen. How plants regulate dinitrogen fixing symbiotic associations is an important and unresolved question; the current results imply that the glutamine synthetase-catalyzed step in ammonia assimilation, a plant function, strongly influences overall dinitrogen fixation in legumes.


The alginate polymer OligoG alters susceptibility of biofilm-embedded non-typeable Haemophilus influenzae to ampicillin and ciprofloxacin.
Treatment of respiratory infections with non-typeable Haemophilus influenzae (NTHi) in COPD patients is complicated by biofilm formation, protecting the bacteria against the hosts' immune response and antibiotics. We investigated the antibiofilm and antibacterial effects of the alginate polymer OligoG, alone or combined with ampicillin or ciprofloxacin, on mature NTHi biofilms. Two unrelated COPD strains with PBP3-mediated β-lactam resistance, with additional TEM-1 β-lactamase (Hi-022) or quinolone resistance due to altered GyrA and ParC (Hi-072) were used. Antibiofilm and antibacterial effects were assessed macroscopically, by measurement of biofilm biomass (OD), and by viable cell counts, with determination of minimum biofilm inhibitory concentration (MBIC) and the novel parameter 'minimum concentration for 2 log10 drop in viable cells in biofilm' (MB2LDC). Drug interactions between OligoG and antibiotics were assessed by comparing expected and observed inhibitory effects (percent inhibition of no-treatment control) of combined treatment. OligoG had dose-dependent biofilm disruptive abilities and a weak inhibitory effect on viable cells. Combination with OligoG (64 g/L) significantly lowered MBIC for ampicillin (both strains) and MB2LDC for ciprofloxacin (Hi-022). For Hi-022, there was significant synergism between OligoG and both antibiotics. For Hi-072, interactions were subtle, but a tendency in direction of antagonism was significant at two concentrations of ciprofloxacin. OligoG shows promise as a potential adjuvant to antibiotics in NTHi infections, but strain-specific factors appear to affect drug interactions and may lead to antagonism. More research is needed to clarify the mechanisms of action of OligoG and interactions with antibiotics.


Adverse effects associated with non-opioid and opioid treatment in patients with chronic pain.
Chronic pain is a debilitating condition that is associated with many common diseases; this places a major burden on the healthcare system. There are currently numerous analgesic agents available for the treatment of chronic pain. In general, the oral non-opioid analgesic, paracetamol, is recommended for the initial treatment of mild to moderate pain. Therapeutic doses of paracetamol do not appear to result in hepatotoxicity, although overdose may lead to acute liver failure. Current data suggest that paracetamol has acceptable gastrointestinal tolerability. Another class of non-opioid analgesic with confirmed efficacy for the treatment of chronic mild to moderate pain are non-steroidal anti-inflammatory drugs (NSAIDs), although this efficacy is offset by the potential of adverse gastrointestinal events. In particular, non-selective NSAIDs, also known as cyclooxygenase (COX) inhibitors, carry an increased risk of serious upper gastrointestinal complications, including ulcers, perforation and bleeding. The introduction of COX-2 inhibitors provided a NSAID-based option with improved gastrointestinal safety, but increased risk of cardiovascular effects. Opioids are powerful analgesic agents used to treat moderate to severe chronic pain. However, treatment with opioids is associated with a number of common adverse effects, including constipation, nausea or vomiting, pruritus, somnolence or cognitive impairment, dry mouth, tolerance or dependence and urinary retention. Although there are multiple strategies in place to manage adverse events that arise from both non-opioid and opioid analgesic therapy, a better understanding of the mechanisms involved in the development of specific drug-related adverse effects is required along with proper prescribing practices and adequate physician/patient education. Balanced against the adverse effects of pain management medications, there is a need to be mindful of the widespread, often serious, adverse consequences of poorly managed pain itself.


Socially dependent auditory laterality in domestic horses (Equus caballus).
Laterality is now known to be an ubiquitous phenomenon among the vertebrates. Particularly, laterality of auditory processing has been demonstrated in a variety of species, especially songbirds and primates. Such a hemispheric specialization has been shown to depend on factors such as sound structure, species specificity and types of stimuli. Much less is known on the possible influence of social familiarity although a few studies suggest such an influence. Here we tested the influence of the degree of familiarity on the laterality of the auditory response in the domestic horse. This species is known for its social system and shows visible reactions to sounds, with one or two ears moving towards a sound source. By comparing such responses to the playback of different conspecific whinnies (group member, neighbor and stranger), we could demonstrate a clear left hemisphere (LH) preference for familiar neighbor calls while no preference was found for group member and stranger calls. Yet, we found an opposite pattern of ear side preference for neighbor versus stranger calls. These results are, to our knowledge, the first to demonstrate auditory laterality in an ungulate species. They open further lines of thought on the influence of the social "value" of calls and the listener's arousal on auditory processing and laterality.


Transcranial Electrical Neurostimulation as a Potential Addiction Treatment.
Addiction remains difficult to treat, but non-invasive transcranial electrical and magnetic neurostimulation methods may provide promising and cost-effective treatment approaches. We provide a narrative review of recent developments and evidence of effectiveness and consider newer technology that may yield improved treatment approaches. In particular, we review temporal interference electrical neurostimulation, which allows non-invasive and focal stimulation of deep brain regions. This provides a promising new potential approach to treat addiction, because many of the brain regions that seem most important for addiction are deeper in the brain, out of reach of existing technologies such as transcranial direct current stimulation.


Mortality in patients with HIV-1 infection starting antiretroviral therapy in South Africa, Europe, or North America: a collaborative analysis of prospective studies.
High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America. Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0-3, 3-6, 6-12, 12-24, and 24-48 months on ART for the period 2001-2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count <50 cells/µl. Cumulative mortality at 4 years was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. Mortality was initially much lower in Europe and North America than South Africa, but the differences were reduced or reversed (North America) at longer durations on ART (adjusted rate ratios 0.46, 95% CI 0.37-0.58, and 1.62, 95% CI 1.27-2.05 between 24 and 48 months on ART comparing Europe and North America to South Africa). While bias due to under-ascertainment of mortality was minimised through death registry linkage, residual bias could still be present due to differing approaches to and frequency of linkage. After accounting for under-ascertainment of mortality, with increasing duration on ART, the mortality rate on HIV treatment in South Africa declines to levels comparable to or below those described in participating North American cohorts, while substantially narrowing the differential with the European cohorts. Please see later in the article for the Editors' Summary.


The long non-coding RNA PVT1 represses ANGPTL4 transcription through binding with EZH2 in trophoblast cell.
Despite progress in diagnostics and treatment for preeclampsia, it remains the foremost cause of maternal and foetal perinatal morbidity and mortality worldwide. Over recent years, various lines of evidence have emphasized long non-coding RNAs (lncRNAs) which function as an innovative regulator of biological behaviour, as exemplified by proliferation, apoptosis and metastasis. However, the role of lncRNAs has not been well described in preeclampsia. Here, we identified a lncRNA, PVT1, whose expression was down-regulated in qRT-PCR analyses in severe preeclampsia. The effects of PVT1 on development were studied after suppression and overexpression of PVT1 in HTR-8/SVneo and JEG3 cells. PVT1 knockdown notably inhibited cell proliferation and stimulated cell cycle accumulation and apoptosis. Exogenous PVT1 significantly increased cell proliferation. Based on analysis of RNAseq data, we found that PVT1 could affect the expression of numerous genes, and then investigated the function and regulatory mechanism of PVT1 in trophoblast cells. Further mechanistic analyses implied that the action of PVT1 is moderately attributable to its repression of ANGPTL4 via association with the epigenetic repressor Ezh2. Altogether, our study suggests that PVT1 could play an essential role in preeclampsia progression and probably acts as a latent therapeutic marker; thus, it might be a useful prognostic marker when evaluating new therapies for patients with preeclampsia.


Knowledge, attitude and practices towards surgical wound care and healing among the public in the Jazan Region, Saudi Arabia.
The purpose of this research was to evaluate how much the people in the Jazan region know about the care and healing of surgical wounds. Proper care of surgical wounds is very important to achieve the best treatment outcomes and to avoid negative consequences. However, factors like obesity, diabetes, and certain medications can impair wound healing, with surgical site infections being a major problem in the healthcare system. Therefore, this study aimed to determine public awareness and perceptions of surgical wound care to help improve education and raise awareness of the importance of proper wound care for better results. We run an observational cross-sectional study among adults above 18 years in the Jazan region. An online self-administered questionnaire was used in the collection of data. Simple random sampling was the used technique and 384 participants were calculated. The study used Statistical Package for the Social Sciences (SPSS) for data analysis and employed descriptive statistics, independent t test, Analysis of Variance (ANOVA), Pearson's correlation, and multivariate logistic regression to identify factors associated with knowledge of surgical site infection and wound care. This study analyzed 599 participants' knowledge, attitude, and practice about surgical site infection and wound management. While participants had a strong general understanding of surgical wounds, only 17% had a high degree of knowledge about surgical site infection and wound management. Medical students had the highest degree of knowledge, and being a medical student was the only significant predictor of having a high level of knowledge about surgical site infection (SSI) and wound care. The study emphasizes the necessity of enhanced patient education and investment in medical education quality. The participants in this study had high overall knowledge regarding surgical wounds but lacked particular knowledge concerning surgical site infection and wound management. Medical education was discovered to be a strong predictor of having a high level of knowledge about surgical site infection and wound management. Healthcare professionals should take the lead in giving accurate and reliable information regarding wound care techniques to patients, and legislators should invest in enhancing medical education quality.


Molecular characterization and expression analysis of three novel autophagy-related genes from the cattle tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae).
The cattle tick Rhipicephalus (Boophilus) microplus is a hematophagous ectoparasite of major importance for the livestock industry. It shows a remarkable ability to survive over long periods without feeding. However, the mechanisms used to endure long-term starvation are poorly understood. It is believed that autophagy, a process of intracellular protein degradation, may play a significant role to confront adverse environmental conditions. To advance our understanding of autophagy in R. microplus, in the present study we report the molecular characterization of three autophagy-related (ATG) genes, namely, RmATG3, RmATG4 and RmATG6, as well as their expression profiles in different developmental stages and organs of the parasite. The deduced amino acid sequences derived from the characterized gene sequences were subjected to Basic Local Alignment Search Tool analysis. The testing produced significant alignments with respective ATG proteins from Haemaphysalis longicornis and Ixodes scapularis ticks. Real-time polymerase chain reaction assays revealed that RmATG4 and RmATG6 transcripts were elevated in egg and ovary tissue, when compared with larva and midgut samples, while RmATG3 expression in midgut was 2-fold higher than in egg, larva and ovary samples.


Autophagy, the Trojan horse to combat glioblastomas.
Malignant gliomas, among which glioblastomas constitute the largest group, are characterized by a dramatically diffuse infiltration into the brain parenchyma with, as a consequence, the fact that no patient with glioblastoma multiforme (GBM) has been cured to date. Migrating GBM cells are resistant to apoptosis (Type I programmed cell death), and thus to radiotherapy and conventional chemotherapy, because of the constitutive activation of several intracellular signaling pathways, of which the most important identified to date are the pathways controlled by phosphatidylinositol 3-kinase, Akt, and the mammalian target of rapamycin (mTOR). Migrating GBM cells seem to be less prone to resist autophagy (Type II programmed cell death), and disruption of the pathway controlled by mTOR induces marked autophagic processes in GBM cells. Temozolomide is the most efficacious cytotoxic drug employed today to combat glioblastoma, and this drug exerts its cytotoxic activity through proautophagic processes. Thus, autophagy represents a kind of Trojan horse that can be used to bypass, at least partly, the dramatic resistance of glioblastoma to radiotherapy and proapoptotic-related chemotherapy.


Operative experience of surgery residents: trends and challenges.
To evaluate trends in operative experience and to determine the effect of establishing the Surgical Council on Resident Education (SCORE) operative classification system on changes in operative volume among graduating surgery residents. The general surgery operative logs of graduating surgery residents from 2005 were retrospectively compared with residents who completed training in 2010 and 2011. Nonparametric statistical analyses were used (Mann-Whitney and median test) with significance set at p<0.01. A total of 1022 residents completing residency in 2005 were compared with 1923 residents completing training in 2010-2011. Total operations reported increased from a median of 1023 to 1238 (21%) between 2005 and 2010-2011 (p<0.001). Cases increased in most SCORE categories. The median numbers of total, basic, and complex laparoscopic operations increased by 49%, 37%, and 82%, respectively, over the 5-year interval (p<0.001). Open cavitary (thoracic + abdominal) operations decreased by 5%, whereas other major operations increased by 35% (both p<0.001). The frequency of discrete operations done at least 10 times during residency did not change. The median number of SCORE essential-common operations performed ranged from 1 to 107, whereas essential-uncommon operations ranged from 0 to 4. Twenty-three of 67 SCORE essential-common operations (34%) had a median of less than 5 and 4 had a median of 0. The operative volume of graduating surgical residents has increased by 21% since 2005; however, the number of operations done 10 times or greater has not changed. Although open cavitary procedures continue to decline, there has been a large increase in endoscopy, complex laparoscopic, and other major operations. Some essential-common operations continue to be performed infrequently. These results suggest that education in the operating room must improve and alternate methods for teaching infrequently performed procedures are needed.


Saccades guided by somatosensory stimuli.
The accuracy of somatosensory saccades defined by proprioceptive cues with and without an additional tactile stimulus was investigated over a wide range of stimulus amplitudes in 16 normal subjects. The present results confirm that somatosensory saccades are less accurate and more variable than visual saccades. Accuracy was minimal for saccades directed to hand distances of 40-50 deg and increased for larger stimulus amplitudes. The additional application of a tactile cue on the fingertip was not found to influence the accuracy of somatosensory saccades significantly.


Conversion of yeast phosphoglycerate kinase into amyloid-like structure.
Yeast phosphoglycerate kinase is a structurally well-characterized enzyme consisting of 415 amino acids without disulfide bonds. Anion-induced refolding from its acid-unfolded state gives rise to the formation of worm-like amyloid fibrils with a persistence length of 73 nm. Electron microscopy and small-angle X-ray scattering data indicate that the fibrils have an elliptical cross-section with dimensions of 10.2 nm x 5.1 nm. About half of all amino acids are organized in form of cross-beta structure which gives rise to typical infrared spectra, X-ray diffraction and yellow-green birefringence after Congo red staining. The kinetics of amyloid formation, monitored by infrared spectroscopy, dynamic light scattering and X-ray scattering, was found to be strongly dependent on protein concentration. The infrared data indicate that the formation of cross-beta structure practically comes to an end already after some hours, whereas the length-growth of the amyloid fibrils, monitored by small-angle X-ray scattering, was not yet completed after 1,300 hours.


The Effect of the Menstrual Cycle and Oral Contraceptive Cycle on Muscle Performance and Perceptual Measures.
Most reproductive-aged women are exposed to fluctuating female steroid hormones due to the menstrual cycle or oral contraceptive use. This study investigated the potential effect of the menstrual cycle and combined monophasic oral contraceptive cycle on various aspects of muscle performance. Thirty active females (12 with a natural menstrual cycle, 10 taking a high-androgenicity oral contraceptive and 8 taking a low-androgenicity oral contraceptive), aged 18 to 30 years, were tested three times throughout one menstrual or oral contraceptive cycle. Counter-movement jumps, bilateral hop jumps, handgrip strength, isometric knee extensor strength and isokinetic knee flexion and extension were assessed. Perceptual ratings of fatigue, muscle soreness, pain and mood were recorded. Most variables showed no significant changes over the menstrual or oral contraceptive cycle. However, for the menstrual cycle group, isokinetic knee flexion at 240° s-1, and time of flight in bilateral hopping and counter movement jumps showed better results during the mid-luteal phase compared with the late follicular phase. For the high-androgenicity oral contraceptive group, isokinetic knee flexion at 240° s-1 was significantly higher in the late hormone phase compared with the early hormone phase. For the low-androgenicity oral contraceptive group, time of flight for the counter-movement jumps was lower in the late hormone phase compared with the early hormone phase. The findings indicate that faster and explosive aspects of muscle performance may be influenced by endogenous and exogenous female hormones.


A Retrospective Review of Physician-related Patient Complaints from a Tertiary Pediatric Hospital.
Trends in patient concerns can identify systematic problems in health care delivery that may not be detected when addressing individual concerns. It can be difficult identifying trends without using a standardized taxonomy. The study objectives were to describe patient complaints from a tertiary care pediatric hospital and categorize them using a standardized complaint taxonomy. Physician-based patient complaints were compiled from April 2011 to May 2014 from a tertiary pediatric hospital. These complaints were coded independently by 2 reviewers using the Reader taxonomy, a published standardized taxonomy. Complaints were placed into 3 domains: clinical, management, and relationships then organized into categories. Inter-rater reliability for domain classification between the 2 reviewers was calculated using Cohen's unweighted κ. Eighty-seven patient complaints were identified, representing approximately 1 per 10,000 physician-patient encounters. Half (48/87) were related to care in the emergency department. When adjusted for volume, pediatric hospital medicine had the highest number of complaints, with 12.1 per 10,000 encounters. The majority of patient complaints, 66% (57/87), were of the clinical domain (κ = 0.61). Sixty percent (52/87) were in the relationship domain (κ = 0.68), and 16% (14/87) were in the management domain (κ = 0.65). We found a low overall complaint rate. Our results indicate that interventions to improve patient experience should initially be targeted at emergency and hospital medicine on the clinical and relationship domains. The inter-rater reliability of the Reader taxonomy was moderate with implications for processing patient complaints at a hospital level.


Revision of the Venezuelan spider genus Stenosfemuraia González-Sponga, with new generic and specific synonymies (Araneae, Pholcidae).
The Venezuelan genus Stenosfemuraia González-Sponga, 1998 is revised, with redescriptions of its three named species: S. parva González-Sponga, 1998 (type species); S. cuadrata González-Sponga, 2005; and S. pilosa (González-Sponga, 2005) n. comb. The latter species was originally described as Codazziella pilosa, and six years later again as Chichiriviche costanero González-Sponga, 2011 (n. syn.). The monotypic genera Codazziella González-Sponga, 2005 and Chichiriviche González-Sponga, 2011 are thus newly synonymized with Stenosfemuraia. The genus appears restricted to the Cordillera de la Costa region where the spiders occupy near-ground microhabitats in medium to high elevation forests.


Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data.
With efforts to reduce cytochrome P450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, the prediction of plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison with that for compounds with passively mediated pharmacokinetics (PK). In this study, we have assessed the predictability of human PK for seven organic anion-transporting polypeptide (OATP) substrates (pravastatin, cerivastatin, bosentan, fluvastatin, rosuvastatin, valsartan, and repaglinide) for which clinical intravenous data were available. In vitro data generated from the sandwich culture human hepatocyte system were simultaneously fit to estimate parameters describing both uptake and biliary efflux. Use of scaled active uptake, passive distribution, and biliary efflux parameters as inputs into a PBPK model resulted in the overprediction of exposure for all seven drugs investigated, with the exception of pravastatin. Therefore, fitting of in vivo data for each individual drug in the dataset was performed to establish empirical scaling factors to accurately capture their plasma concentration-time profiles. Overall, active uptake and biliary efflux were under- and overpredicted, leading to average empirical scaling factors of 58 and 0.061, respectively; passive diffusion required no scaling factor. This study illustrates the mechanistic and model-driven application of in vitro uptake and efflux data for human PK prediction for OATP substrates. A particular advantage is the ability to capture the multiphasic plasma concentration-time profiles for such compounds using only preclinical data. A prediction strategy for novel OATP substrates is discussed.


Function of the minor duodenal papilla in pancreas divisum as determined by duodenoscopy using indigo carmine dye and a pH sensor.
The objective of this study was to evaluate the function of the minor duodenal papilla and to investigate the relationship between the history of acute pancreatitis and individual dorsal pancreatogram findings and the minor papilla function in pancreas divisum. Eight of the 21 patients with PD diagnosed by endoscopic retrograde cholangiopancreatography had a history of acute pancreatitis (group A), and 13 patients did not (group B). The reaction of pancreatic juice excreted via the minor papilla was evaluated after intravenous administration of secretin, by observing the repulsion of indigo carmine dye scattered on the surface of the minor papilla. The function of the minor papilla was classified into two types. In 12 patients, all of the pigment on the minor papilla was repelled within 5 min of secretin administration (type I), and in the remaining nine patients it was not (type II). After secretin administration, the pH of the minor papilla surface in type I was significantly higher than that in type II. There was no significant difference between the type I and type II patients in exocrine pancreatic function, as evaluated by a BT-PABA test. In the group A patients, the rate of occurrence of dorsal duct dilation (including changes of the terminal shape) was significantly greater than in the group B patients. The function of the minor papilla in the group A patients was significantly worse than in the group B patients. Outflow obstruction of pancreatic group B patients. Outflow obstruction of pancreatic juice, i.e., "relative stenosis of the minor papilla," was considered to be present in the patients with type II papilla, and, therefore, the patients with type II papilla might suffer from acute pancreatitis resulting from poor drainage of pancreatic juice and excessive pressure in the dorsal duct. The finding that patients with PD have one of two types of minor papilla will be useful for understanding the condition and selecting the therapeutic plan for individual patients.


Intrinsic STAT4 Expression Controls Effector CD4 T Cell Migration and Th17 Pathogenicity.
Effector CD4 T cells are central to the development of autoimmune chronic inflammatory diseases, yet factors that mediate pathogenicity remain ill-defined. Single-nucleotide polymorphisms in the human STAT4 locus are associated with susceptibility to multiple autoimmune disorders, and Stat4 is linked to the pathogenic Th17 gene signature; however, Th17 cells differentiate independently of STAT4. Hence the interplay between STAT4 and CD4 T cell function, especially Th17 cells, during autoimmune disease is unclear. In this article, we demonstrate that CD4 T cell-intrinsic STAT4 expression is essential for the induction of autoimmune CNS inflammation in mice, in part by regulating the migration of CD4 T cells to the inflamed CNS. Moreover, unbiased transcriptional profiling revealed that STAT4 controls the expression of >200 genes in Th17 cells and is important for the upregulation of genes associated with IL-23-stimulated, pathogenic Th17 cells. Importantly, we show that Th17 cells specifically require STAT4 to evoke autoimmune inflammation, highlighting, to our knowledge, a novel function for STAT4 in Th17 pathogenicity.


Alcohol and drug treatment involvement, 12-step attendance and abstinence: 9-year cross-lagged analysis of adults in an integrated health plan.
This study explored causal relationships between post-treatment 12-step attendance and abstinence at multiple data waves and examined indirect paths leading from treatment initiation to abstinence 9-years later. Adults (N = 1945) seeking help for alcohol or drug use disorders from integrated healthcare organization outpatient treatment programs were followed at 1-, 5-, 7- and 9-years. Path modeling with cross-lagged partial regression coefficients was used to test causal relationships. Cross-lagged paths indicated greater 12-step attendance during years 1 and 5 and were casually related to past-30-day abstinence at years 5 and 7 respectfully, suggesting 12-step attendance leads to abstinence (but not vice versa) well into the post-treatment period. Some gender differences were found in these relationships. Three significant time-lagged, indirect paths emerged linking treatment duration to year-9 abstinence. Conclusions are discussed in the context of other studies using longitudinal designs. For outpatient clients, results reinforce the value of lengthier treatment duration and 12-step attendance in year 1.


Impact of diabetes on clinical presentation and treatment outcome of pulmonary tuberculosis in Beijing.
Diabetes mellitus (DM) is currently known to be one of the risk factors for pulmonary tuberculosis (PTB) and the proportion of DM in PTB is rising along with the increased prevalence of DM in countries with high PTB burden. This study was designed to explore the impact of DM on clinical presentation and treatment outcome of PTB in China. In an urban setting in Beijing, 1126 PTB patients, 30·6% with positive sputum smear, registered in two PTB dispensaries from January 2010 to December 2011 were screened for DM and were followed up prospectively during PTB treatment. DM was observed in 16·2% of patients with PTB. PTB with DM appeared to be associated with older age and a higher proportion of re-treatment. On presentation, DM was associated with more severe PTB signs with higher proportions of smear positivity [odds ratio (OR) 2·533, 95% confidence interval (CI) 1·779-3·606], cavity (OR 2·253, 95% CI 1·549-3·276) and more symptoms (OR 1·779, 95% CI 1·176-2·690). DM was also associated with non-TB deaths (OR 5·580, 95% CI 2·182-14·270, P < 0·001) and treatment failure (OR 6·696, 95% CI 2·019-22·200, P = 0·002). In Beijing, the findings of this study underlined the need to perform early bi-directional screening programmes and explore the underlying mechanism for different treatment outcomes for PTB with DM.


Requirement for phosphoinositide 3-OH kinase in growth hormone signalling to the mitogen-activated protein kinase and p70s6k pathways.
Pituitary growth hormone (GH) co-ordinately stimulates three distinct signalling pathways in 3T3-F442A preadipocytes, the STAT (signal transducer and activator of transcription) pathway, the mitogen-activated protein (MAP) kinase cascade and p70s6k. The mechanisms linking the GH receptor to these signals have not been fully identified. In this study we have examined the role of phosphoinositide 3-OH kinase (PI 3-kinase). Pretreatment of cells with wortmannin, a specific inhibitor of PI 3-kinase, prevented the activation of p70s6k and partially inhibited the activation of p42 and p44 MAP kinases by GH. In contrast, wortmannin failed to appreciably affect the GH-stimulated tyrosyl phosphorylation of JAK-2 or STAT-1. GH transiently increased the activity of PI 3-kinase recovered in antiphosphotyrosine immunoprecipitates. In addition, several tyrosyl-phosphorylated proteins were specifically adsorbed from lysates of cells exposed to GH by a glutathione S-transferase fusion protein containing the 85 kDa regulatory subunit of PI 3-kinase. GH also induced an increase in the PI 3-kinase activity associated with both JAK-2 and insulin receptor substrate-1 (IRS-1) immunoprecipitates. These results establish PI 3-kinase as an important mediator of GH signalling to the MAP kinase and p70s6k pathways and suggest that PI 3-kinase is activated by a mechanism involving JAK-2 and IRS-1.


Differential expression of VegT and Antipodean protein isoforms in Xenopus.
The VegT/Antipodean (Apod) gene is important for germ layer formation in Xenopus. To investigate the role of this gene at the protein level, as opposed to the RNA level, we have generated affinity purified polyclonal antibodies to Apod, and for comparison, to the other early T-box proteins Xbrachyury and Eomesodermin. An anti-VegT/Apod antibody reveals that there are two protein isoforms in Xenopus, one that we refer to as VegT and a smaller molecular weight isoform that we refer to as Apod. These isoforms have different N-terminal domains resulting from developmentally regulated alternative splicing of a primary transcript arising from a single VegT/Apod gene. VegT is maternally expressed. Its translation is blocked during oogenesis but the protein is present from the egg until gastrulation in the presumptive endoderm. There is no evidence for zygotic expression of this isoform. Conversely, the Apod protein isoform is expressed only after the onset of zygotic transcription in the presumptive mesoderm and is inducible by activin. We conclude that the developmental role of VegT/Apod is mediated by two different proteins, with entirely different patterns of expression and response to growth factors.


Broad 4-hydroxyphenylpyruvate dioxygenase inhibitor herbicide tolerance in soybean with an optimized enzyme and expression cassette.
With an optimized expression cassette consisting of the soybean (Glycine max) native promoter modified for enhanced expression driving a chimeric gene coding for the soybean native amino-terminal 86 amino acids fused to an insensitive shuffled variant of maize (Zea mays) 4-hydroxyphenylpyruvate dioxygenase (HPPD), we achieved field tolerance in transgenic soybean plants to the HPPD-inhibiting herbicides mesotrione, isoxaflutole, and tembotrione. Directed evolution of maize HPPD was accomplished by progressively incorporating amino acids from naturally occurring diversity and novel substitutions identified by saturation mutagenesis, combined at random through shuffling. Localization of heterologously expressed HPPD mimicked that of the native enzyme, which was shown to be dually targeted to chloroplasts and the cytosol. Analysis of the native soybean HPPD gene revealed two transcription start sites, leading to transcripts encoding two HPPD polypeptides. The N-terminal region of the longer encoded peptide directs proteins to the chloroplast, while the short form remains in the cytosol. In contrast, maize HPPD was found almost exclusively in chloroplasts. Evolved HPPD enzymes showed insensitivity to five inhibitor herbicides. In 2013 field trials, transgenic soybean events made with optimized promoter and HPPD variant expression cassettes were tested with three herbicides and showed tolerance to four times the labeled rates of mesotrione and isoxaflutole and two times the labeled rates of tembotrione.


Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma.
Rac1 is a ubiquitously expressed Rho GTPase and an important regulator of the actin cytoskeleton. Its splice variant Rac1b exhibits a 19-amino acid (aa) in-frame insertion and is predominantly active. Both proteins were described in tumorigenesis or metastasis. We investigated the contribution of Rac1 and Rac1b to tumor progression of human non-small-cell lung adenocarcinoma (NSCLA). Rac1 protein was present in 8/8 NSCLA cell lines analyzed, whereas Rac1b was expressed in only 6/8. In wound-healing assays, enhanced green fluorescence protein (EGFP)-Rac1 slightly decreased cell migration, whereas proliferation was increased in both, Rac1- and Rac1b-expressing cells. In the in vivo chorioallantoic invasion model, EGFP-Rac1-expressing cells formed more invasive tumors compared to EGFP-Rac1b. This increased invasiveness correlated with enhanced phosphorylation of p38α, AKT and glycogen synthase kinase 3β (GSK3β), and activation of serum response- and Smad-dependent gene promoters by Rac1. In contrast, Rac1b solely activated the mitogen-activated protein kinase (MAPK) JNK2, together with TCF/LEF1- and nuclear factor kappa B (NFκB)-responsive gene reporters. Rac1b, as Rac1, phosphorylated p38α, AKT and GSK3β. Knockdown of the splicing factor epithelial splicing regulatory protein 1 (ESRP1), which mediates out-splicing of exon 3b from Rac1 pre-messenger RNA, resulted in increased Rac1b messenger RNA (mRNA) and suppression of the epithelial-mesenchymal transition (EMT)-associated transcription factor ZEB1. Our data demonstrate different signaling and functional activities of Rac1 and Rac1b and an important role for Rac1 in lung cancer metastasis.


Stabilizing liquid drops in nonequilibrium shapes by the interfacial crosslinking of nanoparticles.
Droplets are spherical due to the principle of interfacial energy minimization. Here, we show that nonequilibrium droplet shapes can be stabilized via the interfacial self-assembly and crosslinking of nanoparticles. This principle allows for the stability of practically infinitely long liquid tubules and monodisperse cylindrical droplets. Droplets of oil-in-water are elongated via gravitational or hydrodynamic forces at a reduced interfacial tension. Silica nanoparticles self-assemble and cross-link on the interface triggered by the synergistic surface modification with hexyltrimethylammonium- and trivalent lanthanum-cations. The droplet length dependence is described by a scaling relationship and the rate of nanoparticle deposition on the droplets is estimated. Our approach potentially enables the 3D-printing of Newtonian Fluids, broadening the array of material options for additive manufacturing techniques.


Binding, interiorization and degradation of cholesteryl ester-labelled chylomicron-remmant particles by rat hepatocyte monolayers.
1. The cholesteryl ester of isolated chylomicron-remnant particles was efficiently degraded by hepatocyte monolayers. The degradation was sensitive to metabolic inhibitors. 2. With increasing amounts of remnant cholesteryl ester the rate of uptake approached saturation and conformed to a linear double-reciprocal plot. The V(max.) was determined as 80ng of cholesteryl ester/h per mg of protein and the apparent K(m) as 1.4mug of cholesteryl ester per mg of protein. The time course for the uptake and hydrolysis suggested that binding of particles to the cell surface preceded the degradation. 3. Cholesteryl esters of native chylomicrons were degraded to a much smaller extent and their presence had only a small inhibitory effect on the degradation of chylomicron remnants. Intestinal very-low-density lipoproteins were degraded somewhat faster than chylomicrons, and caused more inhibition of remnant degradation. Rat high-density lipoproteins inhibited the hydrolysis of remnant cholesteryl ester by up to 50%, but had less influence on the amount of cholesteryl ester that was bound to the cells. Serum decreased both the uptake and hydrolysis, whereas d=1.21 infranatant had no effect. 4. The cholesteryl ester hydrolysis after the uptake by the cells was inhibited by chloroquine and by colchicine. Only 28-36% of the unhydrolysed cholesteryl ester could be released from these cells by trypsin treatment, indicating that the major portion was truly intracellular. The particles that could be released from the cell surface by trypsin and those remaining in the medium had the same triacylglycerol/cholesteryl ester ratio as the added remnant particles. Significant amounts of denser particles were thus not formed during contact with the cell surface. 5. The presence of heparin, as well as preincubation of the cells with heparin, increased the uptake of chylomicron remnants. This effect was most marked in the presence of serum. A much smaller proportion of the other serum lipoproteins was taken up, and this proportion was not increased by heparin.


Chemoproteomic methods for covalent drug discovery.
Covalent drugs constitute cornerstones of modern medicine. The past decade has witnessed growing enthusiasm for development of covalent inhibitors, fueled by clinical successes as well as advances in analytical techniques associated with the drug discovery pipeline. Among these, mass spectrometry-based chemoproteomic methods stand out due to their broad applicability from focused analysis of electrophile-containing compounds to surveying proteome-wide inhibitor targets. Here, we review applications of both foundational and cutting-edge chemoproteomic techniques across target identification, hit discovery, and lead characterization/optimization in covalent drug discovery. We focus on the practical aspects necessary for the general drug discovery scientist to design, interpret, and evaluate chemoproteomic experiments. We also present three case studies on clinical stage molecules to further showcase the real world significance and future opportunities of these methodologies.


Effects of food availability on metabolism, behaviour, growth and their relationships in a triploid carp.
Metabolism, behaviour and growth are highly flexible in fish species, and inter-individual variation in these traits is evolutionarily and ecologically significant. It has long been suggested that these traits co-vary, although their relationships are debated. In the present study, we investigated whether metabolism, behaviour, growth and the potential relationships among them vary with food availability in sterile triploid carp. In this experimental animal model, we investigated the standard metabolic rate (SMR), growth performance and personality traits (i.e. activity, exploration and boldness) of juvenile individuals before and after 25 days of rearing in which fish were fed either once or twice a day to satiation. Inter-individual differences in SMR in each group showed high repeatability across the experimental period, and twice-fed fish showed higher SMRs than once-fed fish after 25 days of rearing. Compared with the once-fed group, the twice-fed group showed higher feeding rates (FRs) and lower feeding efficiencies (FEs) but similar specific growth rates (SGRs). None of the personality traits was affected by food availability. Furthermore, both boldness and exploration were highly repeatable throughout the experiment in the group fed twice a day, whereas only exploration showed repeatability in the group fed once a day. In the once-fed group, SMR and the personality traits were positively correlated with FR and negatively correlated with FE and/or SGR; however, these relationships did not exist in the twice-fed group due to the surplus of food. These results suggest that food availability significantly affects physiological, behavioural and ecological processes in these fish by altering the trade-off between metabolism and growth.


Now the work begins….
RCN congress 2005 has provided great challenges for the RCN Forum for Nurses Working with Older People and the RCN Mental Health and Older People's Forum. 'So what?' I hear you say. 'How will this affect me or the clients I care for?' If you attended our fringe event during congress, kindly sponsored by Nursing Older People, you will have heard all about our work to influence and improve care for older people and how this may also benefit you. CN congress 2005 has provided great challenges for the RCN Forum for Nurses Working with Older people and how this may also benefit you.


Dysregulation of Aldosterone Secretion in Mast Cell-Deficient Mice.
Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice. We have also investigated the regulation of aldosterone secretion in mast cell-deficient C57BL/6 KitW-sh/W-sh mice in comparison with wild-type C57BL/6 mice. KitW-sh/W-sh mice submitted to normal sodium diet had basal plasma aldosterone levels similar to those observed in wild-type animals. Conversely, low-sodium diet unexpectedly induced an exaggerated aldosterone response, which seemed to result from an increase in adrenal renin and angiotensin type 1 receptor expression. Severe hyperaldosteronism was associated with an increase in systolic blood pressure and marked hypokalemia, which favored polyuria. Adrenal renin and angiotensin type 1 receptor overexpression may represent a compensatory mechanism aimed at activating aldosterone production in the absence of mast cells. Finally, C57BL/6 KitW-sh/W-sh mice represent an unexpected animal model of primary aldosteronism, which has the particularity to be triggered by sodium restriction.


Mexiletine in Myotonic Dystrophy Type 1: A Randomized, Double-Blind, Placebo-Controlled Trial.
To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1). We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months. Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants. There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period. This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months.


Preimplantation development of in vitro-matured and in vitro-fertilized ovine zygotes: comparison between coculture on oviduct epithelial cell monolayers and culture under low oxygen atmosphere.
The roles of medium composition, serum source, embryo coculture, and culture under low O2 conditions on the development of in vitro-matured and in vitro-fertilized (IVMF) ovine zygotes were investigated in three separate experiments. In the first experiment, the proportion of cocultured IVMF zygotes developing to the blastocyst stage was significantly higher (38.0% vs. 3.5%; p < 0.05) than that of non-cocultured zygotes treated within three embryo culture media (TCM-199 + 10% fetal bovine serum [FBS]; bicarbonate-buffered, glucose-free synthetic oviduct fluid medium [mod-SOFM] + 10% FBS; and bicarbonate-buffered BSA-free Tyrode's salt solution [mod-TALP] + 10% FBS) under a 5% CO2 atmosphere in air. In a second experiment, a significantly higher (p < 0.05) proportion of cocultured zygotes placed in TCM-199 medium survived to the blastocyst stage (37.4% blastocysts vs. 23.4% in mod-SOFM). No significant effect of serum (FBS vs. human serum [HS]) was observed on embryonic development, but coculture was confirmed to exert a significant influence on development to the blastocyst stage. In the final experiment, survival of the embryo under a reduced oxygen (5% CO2:5% O2:90% N2) atmosphere was investigated. In contrast to results in the initial experiments, embryonic survival was significantly higher (p < 0.05) in the non-cocultured treatment groups (21.9% blastocysts vs. 0.4% for cocultured zygotes). Serum source also had a significant (p < 0.05) influence upon the development of non-cocultured zygotes: 32.3% of zygotes cultured with HS progressed to the blastocyst stage vs. 11.5% of zygotes cultured in FBS-supplemented medium. These results have characterized two distinct culture environments, each capable of supporting the development of high frequencies of unselected IVMF zygotes to the blastocyst stage in vitro.


Accidental hypothermia: core rewarming with partial bypass.
Three patients with profound hypothermia were treated by rewarming on partial bypass. Two surivived and have normal mental and metabolic functions. The resuscitation of the hypothermic patient should be approached with enthusiasm since the outcome is often much better than expected from initial vital signs and neurologic examination. To avoid ventricular fibrillation the patient should be handled gently and an effort should be made to keep the patient well oxygenated and the pH normal. Blood gases should be measured often and corrected for temperature. The potassium concentration and hydration status of the patient should also be monitored closely. The rewarming of profoundly hypothermic patients can readily be accomplished with a pump oxygenator and heat exchanger. The indications for this method are not established from our small experience and the few cases reported in the literature. Certainly ventricular fibrillation is a compelling indication. Patients with frozen extremities might also benefit from this method since theoretically tissue salvage would be increased. Finally, those patients who do not respond rapidly to external rewarming may be at less risk of ventricular fibrillation if rewarmed on bypass.


Beta-helical fibrils from a model peptide.
A synthetic peptide, KLEG13 (Ac-KLKLKLELELELG-NH2), composed of alternating bulky hydrophilic and hydrophobic amino acid residues formed clear, viscous dispersions of fibrils in saline solutions. The fibrils had a uniform diameter of 2 nm as measured on electron micrographs of negatively stained preparations. 13C solid-state nuclear magnetic resonance spectroscopy of the fibrils indicated the presence of a beta-conformation. Circular dichroic spectra of the dispersion of fibrils were essentially identical to the calculated spectrum of a 100% beta-helix. Space-filling CPK models of a proposed beta-helical conformation of the peptide, in which the leucine side chains form a hydrophobic core and the hydrophilic lysine and glutamate side chains extend outwards from the helix, had a diameter consistent with the observed 2-nm diameter of the fibrils. This study may have implications regarding the structure of amyloid fibrils.


Psoralens and ocular effects in humans.
The safety of psoralen photochemotherapy (PUVA) in relation to the eye has been an area of research at the Washington Hospital Center for the last 6 years. Our studies indicate that, with proper shielding of the eye, safety for acute lenticular damage can be established. However, the potential for cataract formation from low-dose, long-term ambient UVA exposure is not known. The guidelines for proper shielding of the eye with PUVA therapy have been established and are enumerated in the text. Our studies on 68 patients for an average length of 4 years and 7 months while they received PUVA have established that the rate in the development of cataracts in treated patients had not increased as compared with the Framingham Eye Study.


Effectiveness of an opting-out strategy for HIV testing: evaluation of 4 years of standard HIV testing in a STI clinic.
A high proportion of individuals infected with HIV are unaware of the infection. They miss the opportunity for timely treatment. Our sexually transmitted infection (STI) clinic (South Limburg, The Netherlands) recognised the need to increase test rates and from 2004 routinely includes a HIV test, unless the client refuses, in each consultation. We evaluated the effectiveness of this opting-out approach for HIV testing. We used anonymised data from our STI clinic from 2003-2007 to assess trends in HIV testing and (reasons for) test refusal using multivariate analyses and interview. Laboratory registry data from the area that is served by the clinic were evaluated as well. In South Limburg the number of HIV tests increased, which was mostly due to increasing STI clinic requests and antenatal screening. Of STI clinic attendees, 84% (1616/1920) were tested in 2003 and this proportion increased to 96% (3699/3836) in 2007. However, 88% (n = 57/65) of men who have sex with men and 44% (191/424) of heterosexuals who refused HIV testing after 2004 were linked to higher STI/HIV risk. Our clinic now uses these findings to develop more effective and tailored HIV/STI counselling in order to further optimise HIV testing practice. Standard testing on HIV in a STI clinic is feasible and effective in increasing awareness of one's HIV status. It should be an essential part of STI screening in STI clinics and should be considered in other healthcare settings for specific risk groups.


Clinical tasks of the dynamic interview.
We examined psychodynamic interview tasks and techniques to identify clinical actions that improve or impede exploration of subjects' emotional responses, conflicts, defenses, and central relationship themes. This article extends previous quantitative studies (Perry, Fowler, & Greif, unpublished; Perry, Fowler, & Semeniuk, 2005) by examining interview vignettes in 50-minute psychodynamic research interviews. We conducted qualitative analyses on 72 dynamic research interviews given by 26 subjects to delineate categories of tasks and interventions. Results indicated five broad tasks of the dynamic interview: 1) Frame Setting; 2) Offering Support; 3) Exploring Affect; 4) Offering Trial Interpretations; and 5) Providing a Formulation and Feedback of relationship themes and conflicts. We further selected two interviews each from 10 subjects, in which there was a difference of one standard deviation or greater on the Overall Dynamic Interview Adequacy scale (Perry, 1999), and interviewer errors from the Therapeutic Alliance Analogue scale (Perry, Brysk, & Cooper, 1989). We utilized excerpts from these interviews to highlight the importance of these tasks and techniques in deepening discussion of dynamically meaningful material.


[Orbital abscess secondary to sinusitis in a child].
We present the case of a 10-year-old patient who was admitted as an emergency to our hospital with right ocular infection due to pansinusitis. He presented fever and malaise. Clinical, ophthalmic and radiologic examination confirmed the existence of an orbital abscess. Due to the poor evolution, surgical treatment was needed. Orbital cellulitis and orbital abscess are two different types of orbital infections. Being able to differentiate between then is very important for selecting the appropriate medical and surgical therapy. Medical treatment is a good solution for infections without abscesses, but surgery is usually needed for infections with an abscess. Abscess formation sometimes require surgical drainage of the orbital abscess with associated treatment of paranasal sinus.


Elucidation of Triacylglycerol Overproduction in the C4 Bioenergy Crop Sorghum bicolor by Constraint-Based Analysis.
Upregulation of triacylglycerols (TAGs) in vegetative plant tissues such as leaves has the potential to drastically increase the energy density and biomass yield of bioenergy crops. In this context, constraint-based analysis has the promise to improve metabolic engineering strategies. Here we present a core metabolism model for the C4 biomass crop Sorghum bicolor (iTJC1414) along with a minimal model for photosynthetic CO2 assimilation, sucrose and TAG biosynthesis in C3 plants. Extending iTJC1414 to a four-cell diel model we simulate C4 photosynthesis in mature leaves with the principal photo-assimilatory product being replaced by TAG produced at different levels. Independent of specific pathways and per unit carbon assimilated, energy content and biosynthetic demands in reducing equivalents are about 1.3 to 1.4 times higher for TAG than for sucrose. For plant generic pathways, ATP- and NADPH-demands per CO2 assimilated are higher by 1.3- and 1.5-fold, respectively. If the photosynthetic supply in ATP and NADPH in iTJC1414 is adjusted to be balanced for sucrose as the sole photo-assimilatory product, overproduction of TAG is predicted to cause a substantial surplus in photosynthetic ATP. This means that if TAG synthesis was the sole photo-assimilatory process, there could be an energy imbalance that might impede the process. Adjusting iTJC1414 to a photo-assimilatory rate that approximates field conditions, we predict possible daily rates of TAG accumulation, dependent on varying ratios of carbon partitioning between exported assimilates and accumulated oil droplets (TAG, oleosin) and in dependence of activation of futile cycles of TAG synthesis and degradation. We find that, based on the capacity of leaves for photosynthetic synthesis of exported assimilates, mature leaves should be able to reach a 20% level of TAG per dry weight within one month if only 5% of the photosynthetic net assimilation can be allocated into oil droplets. From this we conclude that high TAG levels should be achievable if TAG synthesis is induced only during a final phase of the plant life cycle.


Recto-vagino-vestibuloplasty using a vagino-colonic flap with double colonic implantation for rectocloacal fistula.
This technique was devised to obtain a good cosmetic appearance of the perineum and a functional neovagina, without any need for a dilator, by using a vaginocolonic flap marsupialized to the perineum and by creating a vestibule with noncornifying squamous epithelium. The technique was used to treat a 2 year old girl who had a single small orifice in the upper part of a featureless perineum, with a high-confluence rectocloacal fistula between a short urethra and double vagina, which was separated by a septum. A long inverted U-shaped flap at the posterior wall of the vagina was reversed to become the anterior wall of the distal vagina. The urogenital sinus (UGS) was preserved to serve as the urethra. The colon distal to the colostomy was divided into two loops; a segment of the distal loop was opened and trimmed to form a flap, and served as the posterior wall of the distal vagina. The proximal segment was pulled down to become the rectum. To construct the vestibule, a vertical midline incision was made from the fused labia minora to the perineum, cutting back the UGS. The anterior wall of the vagina, which was pulled through just behind the UGS, was divided vertically and sutured around the opened UGS and the suitably prepared labia minora. The posterior wall, which consisted of the colonic flap, was sutured to the incised perineal skin, creating a posterior commissure. At present, 2 1/2 years after the repair, the patient is dry between completely continent urinations and has little vaginal discharge.(ABSTRACT TRUNCATED AT 250 WORDS)


Light-Emitting GaAs Nanowires on a Flexible Substrate.
Semiconductor nanowire-based devices are among the most promising structures used to meet the current challenges of electronics, optics and photonics. Due to their high surface-to-volume ratio and excellent optical and electrical properties, devices with low power, high efficiency and high density can be created. This is of major importance for environmental issues and economic impact. Semiconductor nanowires have been used to fabricate high performance devices, including detectors, solar cells and transistors. Here, we demonstrate a technique for transferring large-area nanowire arrays to flexible substrates while retaining their excellent quantum efficiency in emission. Starting with a defect-free self-catalyzed molecular beam epitaxy (MBE) sample grown on a Si substrate, GaAs core-shell nanowires are embedded in a dielectric, removed by reactive ion etching and transferred to a plastic substrate. The original structural and optical properties, including the vertical orientation, of the nanowires are retained in the final plastic substrate structure. Nanowire emission is observed for all stages of the fabrication process, with a higher emission intensity observed for the final transferred structure, consistent with a reduction in nonradiative recombination via the modification of surface states. This transfer process could form the first critical step in the development of flexible nanowire-based light-emitting devices.


Evolution of the Habits of Physical Activity and Television Viewing in Spanish Children and Pre-Adolescents between 1997 and 2017.
Promoting healthy lifestyles in children, has become a priority for public health institutions. However, electronic devices with screens encourage sedentary behaviors. The aim of this study was to analyze the evolution of the habits of physical activity practice and television watching in a cohort of 20 years of research in Spanish children. A cross-sectional, observational study was based on data from the Spain National Health Surveys between 1997 and 2017 (N = 11,444). The dependent variables considered were the frequency with which the minor practiced physical activity (PA) in his/her spare time, the daily TV viewing habit, and the daily hours of TV viewing. The children who practiced physical activity daily has decreased 7.3% throughout the study period. The proportion of children who watched the television daily for more hours increased significantly (6.3%). Such increase was constant throughout the years, and the analysis by sex showed that the proportion of boys who watched television for more than three hours per day increased three percent, and that of girls increased fourfold. The habits of physical activity practice and television viewing have changed towards sedentary lifestyle. Particularly, the girls and the children between 12 and 14 years showed the most sedentary behavior. Public health policies must consider the differences between sexes in order for such interventions to be effective in the population of pre-adolescents, in general, and girls, in particular.


The identification and treatment of "difficult" babies.
The "difficult" baby can grow into the difficult child unless the early signs of behavior disruption are identified and treated. The best person to spot these warning signals and to aid and educate the new mother in techniques for overcoming them is the public health nurse. In her home visits and pre-and postnatal classes she is the key figure in an important preventive exercise.


Biological reaction control using topography regulation of nanostructured titanium.
The micro- and nanosize surface topography of dental implants has been shown to affect the growth of surrounding cells. In this study, standardized and controlled periodic nanopatterns were fabricated with nanosized surface roughness on titanium substrates, and their influence on bone marrow stromal cells investigated. Cell proliferation assays revealed that the bare substrate with a 1.7 nm surface roughness has lower hydrophilicity but higher proliferation ability than that with a 0.6 nm surface roughness. Further, with the latter substrate, directional cell growth was observed for line and groove patterns with a width of 100 nm and a height of 50 or 100 nm, but not for those with a height of 10 or 25 nm. With the smooth substrate, time-lapse microscopic analyses showed that more than 80% of the bone marrow cells on the line and groove pattern with a height of 100 nm grew and divided along the lines. As the nanosized grain structure controls the cell proliferation rate and the nanosized line and groove structure (50-100 nm) controls cell migration, division, and growth orientation, these standardized nanosized titanium structures can be used to elucidate the mechanisms by which surface topography regulates tissue responses to biomaterials.


Purification and properties of arylsulphatase A from rabbit testis.
Rabbit testis arylsulphatase A was purified 140-fold with a recovery of 20% from detergent extracts of an acetone-dried powder by using DE-52 cellulose column chromatography, gel filtration on Sephadex G-200 and preparative isoelectric focusing. The purified enzyme showed one major band with one minor contaminant on electrophoresis in a 7.5% (w/v) polyacrylamide gel at pH8.3. On sodiumdodecyl sulphate/polyacrylamidegel electrophoresis, a single major band was observed with minor contaminants. The final preparation of enzyme was free from general proteolytic, esterase, hyaluronidase, beta-glucuronidase and beta-galactosidase activities. Rabbit testicular arylsulphatase A exists as a dimer of mol.wt. 110000 at pH7.1. At pH5.0 the enzyme is a tetramer of mol.wt. 220000. Arylsulphatase A appears to consist of two identical subunits of mol.wt. 55000 each. The highly purified enzyme has pI4.6. The enzyme hydrolyses p-nitrocatechol sulphate with Km and Vmax, of 4.1 mM and 80nmol/min respectively, but has no activity toward p-nitrophenyl sulphate. The pH optimum of the enzyme varies with the incubation time. By applying Sephacex G-200 chromatography and preparative isoelectric focusing, one form of enzyme was obtained. The enzyme has properites common to arylsulphatase A of other sources with respect to the anomalous time-activity relationship, pI, inhibition by PO42-, SO32- and Ag+ ions and substrate affinity to p-nitrocatechol sulphate. However, the enzyme shows the temperature optimum of arylsulphatase B of other species.


A review of antisense therapeutic interventions for molecular biological targets in asthma.
Modern tools of genomics and proteomics reveal potential therapeutic antisense targets in asthma, increasing the interest in the development of anti-mRNA drugs. In allergic asthma experimental models, antisense oligonucleotides (ASO) are administered by inhalation or systemically. ASO can be used for a large number of molecular targets: cell membrane receptors (G-protein coupled receptors, cytokine and chemokine receptors), membrane proteins, ion channels, cytokines and related factors, signaling non-receptor protein kinases (tyrosine kinases, and serine/threonine kinases) and regulators of transcription belonging to Cys4 zinc finger of nuclear receptor type or beta-scaffold factors with minor groove contacts classes/superclasses of transcription factors. A respirable ASO against the adenosine A(1) receptor was investigated in human trials. RNase P-associated external guide sequence (EGS) delivered into pulmonary tissues represents a potentially new therapeutic approach in asthma as well as ribozyme strategies. Small interfering RNA (siRNA) targeting key molecules involved in the patho-physiology of allergic asthma are expected to be of benefit as RNAi immunotherapy. Antagomirs, synthetic analogs of microRNA (miRNA), have important roles in regulation of gene expression in asthma. RNA interference (RNAi) technologies offer higher efficiency in suppressing the expression of specific genes, compared with traditional antisense approaches.


Impact of ivabradine on the cardiac function of chronic heart failure reduced ejection fraction: Meta-analysis of randomized controlled trials.
Elevated resting heart rate in chronic heart failure (HF) patients has been associated with higher mortality and poor prognosis. Ivabradine is a new pure bradycardic agent that has been used to treat angina or heart failure reduced ejection fraction (HFrEF) with sinus heart rate above 70 beats per minute. However, the effect of ivabradine for chronic HF patients on rehospitalization and cardiac function is still inconsistent. Thus, this meta-analysis aimed to elucidate the effect of Ivabradine in chronic HFrEF patients. We systematically searched PubMed, Medline, Clinical Trials.gov, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) of ivabradine with search terms Ivabradine (MeSH Terms), chronic heart failure and beta-blocker. The primary endpoints of the study include the impact of Ivabradine on heart rate, left ventricle ejection fraction (LVEF), left ventricular remodeling, exercise capacity, and quality of life (QoL) in patients with chronic HFrEF. Secondary endpoints were safety analysis of Ivabradine including cardiovascular mortality, worsening HF readmission, visual disturbances, and asymptomatic bradycardia. The analysis was done by Review Manager 5.4 Analyzer, to analyze the mean differences (MD) for continuous data and risks ratio (RR) for dichotomous data. A total of six RCTs and one subgroup analysis showed add of Ivabradine to standard HF therapy was associated with greater resting heart rate reduction (MD = -9.57; 95% CI -11.15, -8.00), improved LVEF (MD = 3.89; 95% CI 2.61, 5.17), left ventricular reverse remodeling improvement (MD = -3.73; 95% CI -4.25, -3.21, LVESV; MD = -17.00, 95%CI -29.65, -4.35, LVEDD; MD = -1.43, 95%CI -2.78, -0.08, LVEDV; MD = -14.75, 95%CI -34.36, 4.87), increased exercise capacity (exercise duration; MD = 8.52; 95%CI 0.09, 16.94), and significant reduction on rehospitalization due to worsening HF (RR = 0.76, 95%CI 0.69, 0.84). However, Ivabradine has no significant effect on the quality of life (MD = 0.65; 95%CI -10.52, 11.82), and cardiovascular mortality (RR = 0.92; 95%CI 0.82, 1.03). Moreover, there were some events of visual disturbances and asymptomatic bradycardia observed in the Ivabradine group compared to the placebo group (RR = 4.76; 95%CI 3.03, 7.48; RR = 3.78; 95%CI 2.77, 5.15, respectively). Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.


Ultrastructural findings in epidermolysis bullosa.
Electron microscopy of skin provides diagnostic criteria for distinguishing the simplex, junctional, and dystrophic forms of inherited epidermolysis bullosa (EB). The plane of cleavage in blister formation indicates the localization of structural weakness within the epidermis and basement membrane zone, and, together with ultrastructural changes in affected skin, these are clues to the underlying genetic bases for these disorders. Skin biopsy specimens from individuals with EB were evaluated by electron microscopy to identify structural changes and determine the subtype of EB. Discrete, circumscribed clumps of keratin filaments present in the basal keratinocytes are pathognomonic for EB simplex Dowling-Meara. These and other observations of keratin filament disruption have led to the identification of mutations in keratin genes in Dowling-Meara and Koebner forms of EB simplex. Changes in the density and structure of anchoring fibrils and the relative amount of type VII collagen detected by immunostaining of the dermoepidermal junction in dystrophic EB have led to sequencing of mutations in the type VII collagen gene. Although mutations in junctional EB have not been reported, findings of structural alterations in hemidesmosomes and immunohistochemical studies of kalinin (BM600 and epiligrin), and in junctional EB with pyloric atresia alterations in the integrin alpha 6 beta 4, indicate molecules involved in basal keratinocyte adhesion to the basement membrane that are candidate genes for junctional EB. Electron microscopy of skin when correlated with mutations in EB will help us understand the significance of these structural molecules in normal skin and the pathogenesis of EB.


Variability in blood and blood component utilization as assessed by an anesthesia information management system.
Data can be collected for various purposes with anesthesia information management systems. The authors describe methods for using data acquired from an anesthesia information management system to assess intraoperative utilization of blood and blood components. Over an 18-month period, data were collected on 48,086 surgical patients at a tertiary care academic medical center. All data were acquired with an automated anesthesia recordkeeping system. Detailed reports were generated for blood and blood component utilization according to surgical service and surgical procedure, and for individual surgeons and anesthesiologists. Transfusion hemoglobin trigger and target concentrations were compared among surgical services and procedures, and between individual medical providers. For all patients given erythrocytes, the mean transfusion hemoglobin trigger was 8.4 ± 1.5, and the target was 10.2 ± 1.5 g/dl. Variation was significant among surgical services (trigger range: 7.5 ± 1.2-9.5 ± 1.1, P = 0.0001; target range: 9.1 ± 1.2-11.3 ± 1.4 g/dl, P = 0.002), surgeons (trigger range: 7.2 ± 0.7-9.8 ± 1.0, P = 0.001; target range: 8.8 ± 0.9-11.8 ± 1.3 g/dl, P = 0.001), and anesthesiologists (trigger range: 7.2 ± 0.8-9.6 ± 1.2, P = 0.001; target range: 9.0 ± 0.9-11.7 ± 1.3 g/dl, P = 0.0004). The use of erythrocyte salvage, fresh frozen plasma, and platelets varied threefold to fourfold among individual surgeons compared with their peers performing the same surgical procedure. The use of data acquired from an anesthesia information management system allowed a detailed analysis of blood component utilization, which revealed significant variation among surgical services and surgical procedures, and among individual anesthesiologists and surgeons compared with their peers. Incorporating these methods of data acquisition and analysis into a blood management program could reduce unnecessary transfusions, an outcome that may increase patient safety and reduce costs.


The pathogenesis of ALS: implications for treatment strategies.
Besides the free radical hypothesis raised by the identification of Superoxide Dismutase I mutations in a subset of familiar Amyotrophic Lateral Sclerosis (ALS) patients, three etiopathogenic hypotheses for sporadic ALS, namely autoimmune, neurofilament, and glutamate toxicity, have attracted interest in the last few years. The role of autoimmunity in ALS has been seriously questioned. The excitotoxic hypothesis for ALS spurred two clinical trials with riluzole. The results of both studies showed a modest benefit in prolonging survival that was statistically significant. Riluzole was the first drug made available for ALS patients. It began a new era in both basic and clinical research. Various human recombinant neurotrophic molecules (CNTF, BDNF, IGF-I) were administered to ALS patients. IGF-I slowed the progression of functional impairment in patients with ALS with no adverse effects. The recent demonstration of the specific viral echovirus 7 RNA sequences in the spinal cord of ALS patients refocused research on the viral hypothesis of the disease and antiviral drugs are ready to be used in clinical settings. New treatment strategies are today under study: intrathecal infusion with BDNF, intrathecal capsules for neurotrophic factor secretion or in vivo gene therapy using viral vectors. New research findings are, more than for other diseases, immediately transferred to clinical ground for the desperate need of a curative treatment of the patients affected by ALS.