Efficient conversion of astrocytes to functional midbrain dopaminergic neurons using a single polycistronic vector.
Direct cellular reprogramming is a powerful new tool for regenerative medicine. In efforts to understand and treat Parkinson's Disease (PD), which is marked by the degeneration of dopaminergic neurons in the midbrain, direct reprogramming provides a valuable new source of these cells. Astrocytes, the most plentiful cells in the central nervous system, are an ideal starting population for the direct generation of dopaminergic neurons. In addition to their potential utility in cell replacement therapies for PD or in modeling the disease in vitro, astrocyte-derived dopaminergic neurons offer the prospect of direct in vivo reprogramming within the brain. As a first step toward this goal, we report the reprogramming of astrocytes to dopaminergic neurons using three transcription factors - ASCL1, LMX1B, and NURR1 - delivered in a single polycistronic lentiviral vector. The process is efficient, with 18.2±1.5% of cells expressing markers of dopaminergic neurons after two weeks. The neurons exhibit expression profiles and electrophysiological characteristics consistent with midbrain dopaminergic neurons, notably including spontaneous pacemaking activity, stimulated release of dopamine, and calcium oscillations. The present study is the first demonstration that a single vector can mediate reprogramming to dopaminergic neurons, and indicates that astrocytes are an ideal starting population for the direct generation of dopaminergic neurons.


Interplay of the proto-oncogene proteins CrkL and CrkII in insulin-like growth factor-I receptor-mediated signal transduction.
The closely related proto-oncogene proteins CrkII and CrkL consist of one SH2 and two SH3 domains and share 60% overall homology with the highest identity within their functional domains. In this study we show that CrkL and CrkII may play overlapping but different roles in insulin-like growth factor (IGF)-I receptor-mediated signal transduction. While both proteins are substrates involved in IGF-I receptor signaling, they apparently demonstrate important different properties and different biological responses. Evidence supporting this hypothesis includes (a) the oncogenic potential of CrkL versus the absence of this potential in CrkII overexpressing cell lines, (b) the inhibition of IGF-I-dependent cell cycle progression by overexpression of CrkII, and (c) the differential regulation of the phosphorylation status of selective proteins in CrkII and CrkL overexpressing cell lines. In addition we demonstrate the specific association of CrkL and CrkII with the newly characterized IRS-4 protein, again in a differential manner. Whereas CrkL strongly interacts with IRS-4 via its SH2 and N-terminal SH3 domains, CrkII interacts only via its SH2 domain, possibly explaining the unstable nature of IRS-4-CrkII association. The results obtained allow us to propose a unique mechanism of CrkL and CrkII tyrosine phosphorylation in response to IGF-I stimulation. Thus these highly homologous proteins apparently possess structural features that allow for the differential association of each protein with different effector molecules, thereby activating different signaling pathways and resulting in unique biological roles of these proteins.


Developmental changes in renal tubular transport-an overview.
The adult kidney maintains a constant volume and composition of extracellular fluid despite changes in water and salt intake. The neonate is born with a kidney that has a small fraction of the glomerular filtration rate of the adult and immature tubules that function at a lower capacity than that of the mature animal. Nonetheless, the neonate is also able to maintain a constant extracellular fluid volume and composition. Postnatal renal tubular development was once thought to be due to an increase in the transporter abundance to meet the developmental increase in glomerular filtration rate. However, postnatal renal development of each nephron segment is quite complex. There are isoform changes of several transporters as well as developmental changes in signal transduction that affect the capacity of renal tubules to reabsorb solutes and water. This review will discuss neonatal tubular function with an emphasis on the differences that have been found between the neonate and adult. We will also discuss some of the factors that are responsible for the maturational changes in tubular transport that occur during postnatal renal development.


A Review on the Use of Wearable Functional Near-Infrared Spectroscopy in Naturalistic Environments.
The development of novel miniaturized wireless and wearable functional Near-Infrared Spectroscopy (fNIRS) devices have paved the way to new functional brain imaging that can revolutionize the cognitive research fields. Over the past few decades, several studies have been conducted with conventional fNIRS systems that have demonstrated the suitability of this technology for a wide variety of populations and applications, to investigate both the healthy brain and the diseased brain. However, what makes wearable fNIRS even more appealing is its capability to allow measurements in everyday life scenarios that are not possible with other gold-standard neuroimaging modalities, such as functional Magnetic Resonance Imaging. This can have a huge impact on the way we explore the neural bases and mechanisms underpinning human brain functioning. The aim of this review is to provide an overview of studies conducted with wearable fNIRS in naturalistic settings in the field of cognitive neuroscience. In addition, we present the challenges associated with the use of wearable fNIRS in unrestrained contexts, discussing solutions that will allow accurate inference of functional brain activity. Finally, we provide an overview of the future perspectives in cognitive neuroscience that we believe would benefit the most by using wearable fNIRS.


Robust backstepping control of induction motors using neural networks.
In this paper, we present a new robust control technique for induction motors using neural networks (NNs). The method is systematic and robust to parameter variations. Motivated by the well-known backstepping design technique, we first treat certain signals in the system as fictitious control inputs to a simpler subsystem. A two-layer NN is used in this stage to design the fictitious controller. Then we apply a second two-layer NN to robustly realize the fictitious NN signals designed in the previous step. A new tuning scheme is proposed which can guarantee the boundedness of tracking error and weight updates. A main advantage of our method is that we do not require regression matrices, so that no preliminary dynamical analysis is needed. Another salient feature of our NN approach is that the off-line learning phase is not needed. Full state feedback is needed for implementation. Load torque and rotor resistance can be unknown but bounded.


Whey versus soy protein diets and renal status in rats.
Different dietary protein sources can promote different renal statuses. We examined the effects of whey protein (WP) and soy protein (SP) intake on plasma, urinary, and morphological renal parameters in rats. One hundred and twenty Wistar rats were randomly distributed into 2 experimental groups fed with either WP or SP diets over 12 weeks. These diets were based on commercial WP or SP isolates. The urinary calcium content was higher in the WP diet compared to the SP diet group (P<.001) whereas the urinary citrate level was lower (P<.001). The urinary pH was more acidic in the WP diet group compared to the SP diet group (P<.001); however, no differences were observed between the groups for any of the renal morphological parameters analyzed (all, P>.05) or other plasma renal markers such as albumin or urea concentrations. The increase of acid and urinary calcium and the lower urinary citrate level observed in the WP diet group could increase the incidence of nephrolithiasis compared to the SP diet group. Despite the WP showed poorer acid-base profile, no significant morphological renal changes were observed. These results suggest that the use of SP instead of WP appears to promote a more alkaline plasma and urinary profile, with their consequent renal advantages.


Jumping the Gun: Mapping Neural Correlates of Waiting Impulsivity and Relevance Across Alcohol Misuse.
Why do we jump the gun or speak out of turn? Waiting impulsivity has a preclinical basis as a predictor for the development of addiction. Here, we mapped the intrinsic neural correlates of waiting and dissociated it from stopping, both fundamental mechanisms of behavioral control. We used a recently developed translational task to assess premature responding and assess response inhibition using the stop signal task. We mapped the neural correlates in 55 healthy volunteers using a novel multi-echo resting-state functional magnetic resonance imaging sequence and analysis, which robustly boosts signal-to-noise ratio. We further assessed 32 young binge drinkers and 36 abstinent subjects with alcohol use disorders. Connectivity of limbic and motor cortical and striatal nodes mapped onto a mesial-lateral axis of the subthalamic nucleus. Waiting impulsivity was associated with lower connectivity of the subthalamic nucleus with ventral striatum and subgenual cingulate, regions similarly implicated in rodent lesion studies. This network was dissociable from fast reactive stopping involving hyperdirect connections of the pre-supplementary area and subthalamic nucleus. We further showed that binge drinkers, like those with alcohol use disorders, had elevated premature responding and emphasized the relevance of this subthalamic network across alcohol misuse. Using machine learning techniques we showed that subthalamic connectivity differentiates binge drinkers and individuals with alcohol use disorders from healthy volunteers. We highlight the translational and clinical relevance of dissociable functional systems of cortical, striatal, and hyperdirect connections with the subthalamic nucleus in modulating waiting and stopping and their importance across dimensions of alcohol misuse.


Experimental infection dynamics: using immunosuppression and in vivo parasite tracking to understand host resistance in an amphibian-trematode system.
Although naturally occurring hosts often exhibit pronounced differences in infection and pathology, the relative importance of factors associated with host life history and immunity in explaining such patterns often remains speculative. Research in eco-immunology highlights the trade-offs between host physiology and immunity, for which natural variations in disease susceptibility offer a valuable platform to test predictions within this framework. Here, we combined use of a novel, in vivo assay for tracking parasite fate and an experimental manipulation of host immune function (via chronic corticosterone exposure) to assess the role of host immunity in regulating susceptibility of amphibian hosts to three larval trematodes: Ribeiroia ondatrae, Echinostoma trivolvis and Alaria sp. 2. Results from the in vivo parasite-tracking assay revealed marked differences in initial parasite penetration and subsequent host clearance. Relative to infections in a highly susceptible species (Pseudacris regilla), the virulent trematode R. ondatrae was -25% less successful at penetrating larvae of three hylid frog species and was cleared > 45(×) faster, such that all parasites were rapidly cleared from hylid hosts over 72 h following a Weibull distribution. Immune suppression of Hyla versicolor sharply reduced this resistance and increased infection of all three trematodes by 67 to 190%, with particularly strong increases for R. ondatrae. Diminished resistance correlated with a 62% decrease in circulating eosinophils. Correspondingly, 10 days after corticosterone exposures ended, infections declined dramatically while eosinophil levels returned to normal. In light of ongoing declines and deformities in amphibian populations, these findings have application potential for mitigating disease-driven effects.


[Optimizing epilepsy therapy in children and adolescents with lamotrigine].
Lamotrigine is a broadly effective antiepileptic drug in mono- and add-on therapy for children and adolescents with focal and generalized epilepsies. Some epileptologists consider lamotrigine as the drug of primary choice in older school children and adolescents because of its good tolerability (no increase of body weight, no impairment of cognitive functions, due to new data probably no teratogenic properties). Lamotrigine can be used with good efficacy in numerable epilepsy diseases, such as tuberous sclerosis, juvenile neuronal lipofuscinosis and Rett syndrome. The first studies show that lamotrigine is also effective in children under 2 years of age. For therapy of difficult-to-treat epilepsies the combination of lamotrigine with valproate has proved as especially useful. This clinical observation is supported by new results of animal experiments. The dose-dependant and typical CNS side effects vertigo, ataxia, nausea, tremor and diplopia are found most frequently. The rate of allergic skin rashes which was very high before 1998 has decreased markedly by new dosage guidelines and is now as low as in older antiepileptic drugs. Lamotrigine does not impair cognitive functions, especially not memory and language. It has mood-stabilizing features and may improve quality of life. In animal experiments lamotrigine shows antiepileptogenic and neuroprotective effects.


Variability of M-mode versus two-dimensional echocardiography measurements in children with dilated cardiomyopathy.
M-mode and 2-dimensional (2D) echocardiographic imaging are routinely used to quantify left-ventricular (LV) size and function in pediatric patients with dilated cardiomyopathy (DCM). The reproducibility of and correlation between these techniques are unknown. This analysis sought to compare interreader, intrareader, and interacquisition reproducibility of M-mode versus 2D measurements in pediatric DCM patients. The Ventricular Volume Variability study of the Pediatric Heart Network is a multicenter, prospective, observational study assessing the course of chronic DCM in children. Two sonographers performed baseline image acquisitions locally, and two readers performed measurements at the echocardiographic core laboratory. One reader repeated measurements 1 month later. These data were used to assess reproducibility and agreement between M-mode and 2D measurements. One hundred sixty-nine subjects were enrolled. M-mode had similar or greater reproducibility in both intrareader and interreader settings for LV dimensions, shortening fraction (SF), and most wall thicknesses. In contrast, 2D reproducibility was similar or better for nearly all variables in the interacquisition setting but not for SF. Interacquisition variability was approximately twice the intrareader variability. LV dimensions by either modality consistently had high reproducibility and had the highest agreement between modalities. In pediatric DCM patients, variability of linear echocardiographic assessment could be minimized by relying on a single reader and using a consistent method (M-mode or 2D) for serial measurements, preferably M-mode when SF is the primary variable of interest. Except for LV dimensions, M-mode and 2D values should not be used interchangeably due to poor agreement.


The presence of acylated ghrelin during in vitro maturation of bovine oocytes induces cumulus cell DNA damage and apoptosis, and impairs early embryo development.
The aim of this study was to investigate the effects of acylated ghrelin supplementation during in vitro maturation (IVM) of bovine oocytes. IVM medium was supplemented with 20, 40 or 60 pM acylated ghrelin concentrations. Cumulus expansion area and oocyte nuclear maturation were studied as maturation parameters. Cumulus-oocyte complexes (COC) were assessed with the comet, apoptosis and viability assays. The in vitro effects of acylated ghrelin on embryo developmental capacity and embryo quality were also evaluated. Results demonstrated that acylated ghrelin did not affect oocyte nuclear maturation and cumulus expansion area. However, it induced cumulus cell (CC) death, apoptosis and DNA damage. The damage increased as a function of the concentration employed. Additionally, the percentages of blastocyst yield, hatching and embryo quality decreased with all acylated ghrelin concentrations tested. Our study highlights the importance of acylated ghrelin in bovine reproduction, suggesting that this metabolic hormone could function as a signal that prevents the progress to reproductive processes.


Informed consent and standard of care: what must be disclosed.
The Office for Human Research Protections (OHRP) was correct in determining that the consent forms for the National Institutes of Health (NIH)-sponsored SUPPORT study were seriously flawed. Several articles defended the consent forms and criticized the OHRP's actions. Disagreement focuses on three central issues: (1) how risks and benefits should be described in informed consent documents; (2) the meaning and application of the concept of "standard of care" in the context of research; and (3) the proper role of OHRP. Examination of the consent forms reveals that they failed to disclose the reasonably foreseeable risks of the experimental interventions in the study, as well as the potential for differences in the degree of risk between these interventions. Although the concept of "standard of care" may be helpful in determining the ethical acceptability of other aspects of research, such as clinical equipoise, it is not helpful in discussing consent requirements.


Essential oils as green promising alternatives to chemical preservatives for agri-food products: New insight into molecular mechanism, toxicity assessment, and safety profile.
Microbial food spoilage caused by food-borne bacteria, molds, and associated toxic chemicals significantly alters the nutritional quality of food products and makes them unpalatable to the consumer. In view of potential adverse effects (resistance development, residual toxicity, and negative effects on consumer health) of some of the currently used preservative agents and consumer preferences towards safe, minimally processed, and chemical-free products, food industries are looking for natural alternatives to the chemical preservatives. In this context, essential oils (EOs) showed broad-range antimicrobial effectiveness, low toxicity, and diverse mechanisms of action, and could be considered promising natural plant-based antimicrobials. The existing technical barriers related to the screening of plants, extraction methods, characterization, dose optimization, and unpredicted mechanism of toxicity in the food system, could be overcome using recent scientific and technological advancements, especially bioinformatics, nanotechnology, and mathematical approaches. The review focused on the potential antimicrobial efficacy of EOs against food-borne microbes and the role of recent scientific technology and social networking platform in addressing the major obstacles with EOs-based antimicrobial agents. In addition, a detailed mechanistic understanding of the antimicrobial efficacy of EOs, safety profile, and risk assessment using bioinformatics approaches are summarized to explore their potential application as food preservatives.


Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches.
Headache is a common medical problem. In view of recent discoveries about the role of serotonin in pain mechanisms, selective serotonin re-uptake inhibitors (SSRIs) have been evaluated for the prevention of migraine and tension-type headaches (TTH). To evaluate the efficacy and tolerability of SSRIs for preventing migraine and TTH. We searched MEDLINE (1966-2004), EMBASE (1994-2003), the Cochrane Central Register of Controlled Trials (Issue 4, 2003), and reference lists of retrieved articles. Headache Quarterly was hand searched from 1990 to 2003. We included randomised controlled trials comparing SSRIs with any type of control intervention in patients of either sex, over 18 years of age, with migraine or TTH. Two authors independently extracted data (headache frequency, index, severity, and duration; use of symptomatic/analgesic medication; days off work; quality of life; mood improvement; cost-effectiveness; and adverse events) and assessed the methodological quality of trials. Thirteen studies utilizing five SSRIs met the inclusion criteria (636 participants). Most of the included studies had methodological and/or reporting shortcomings; follow up rarely extended beyond 3 months. After 2 months SSRIs did not significantly lower headache index scores in patients with migraine when compared to placebo (SMD -0.14; 95% CI -0.57 to 0.30). Patients with chronic TTH treated with an SSRI had a significantly higher analgesic intake of 5 more doses per month when compared to patients treated with a tricyclic antidepressant (WMD 4.98; 95% CI 1.12 to 8.84). Tricyclics also significantly reduced headache duration by 1.26 hours per day (WMD 1.26; 95% CI 0.06 to 2.45) and marginally reduced headache indexes (SMD 0.42; 95% CI 0.00 to 0.85) when compared to SSRIs in patients with chronic TTH. When the data on adverse events were considered without regard to headache diagnostic subgroups, there were no significant differences between SSRIs and placebo for withdrawals due to adverse events (Peto OR 1.02; 95% CI 0.31 to 3.34). For minor adverse events, SSRIs were generally more tolerable than tricyclics (OR 0.34; 95% CI 0.13 to 0.92). However, there were no differences in the number of patients withdrawing due to any reason in the SSRI and tricyclic groups (OR 1.01; 95% CI 0.56 to 1.80). Over 2 months of treatment, SSRIs are no more efficacious than placebo in patients with migraine. In patients with chronic TTH, SSRIs are less efficacious than tricyclic antidepressants. In comparison with SSRIs, the burden of adverse events in patients receiving tricyclics was greater. These results are based on short-term trials and may not generalise to longer-term treatment.


Retrograde ureteroscopy in the management of distal ureteric stones: A retrospective analysis of outcome and complications.
Urinary stones affect 8%-15% of the world population. In Nigeria, contemporary reports have shown that the incidence of urinary stones is rising. The distal ureter has been described as the most common location of ureteric stones. This study seeks to review our experience in the ureteroscopic management of distal ureteric stones with a view to appraising the stone clearance rate and the complications seen in our patients. This descriptive study reviewed the record of 21 patients, who had semirigid ureteroscopy and pneumatic lithotripsy for distal ureteric stone between October 2015 and September 2018. All patients had computed tomography urography preoperatively to locate the stone. Data on patients' demographics, indication for the surgery, location and size of stone, preoperative double-J (DJ) placement, postoperative DJ stent placement, intraoperative and postoperative complications, and status of stone clearance were retrieved and subjected to statistical analysis. The mean age of the patients was 37.95 ± 11.09 (range, 21-67) years. The mean stone size was 8.06 ± 2.87 mm with a range of 4.8 mm-15.0 mm. Out of the 21 patients, 20 (95.2%) had the procedure for recurrent ureteric colic and 1 (48%) was for hematuria. Four (19.0%) patients had DJ stent preoperatively, whereas 17 (81.0%) patients did not have. Fourteen (66.7%) patients had intraoperative ureteric dilatation. Postoperative DJ stent was placed in 17 (81.0%) patients, whereas 4 (19.0%) patients did not have. Three (14.3%) patients had mucosal flap, 6 (14.3%) had mucosal abrasion, 2 (9.5%) had bleeding, 1 (4.8%) patient had transient hematuria postoperatively, and 2 (9.5%) patients had urinary tract infection. Nineteen (90.5%) patients had complete clearance in a single surgery. Two (9.5%) patients had symptomatic residual fragments that required repeat ureteroscopy. Our study has shown that ureteroscopy is a useful and safe technique in the removal of stones in distal ureter.


Optical coherence tomography angiography of foveal neovascularisation in proliferative diabetic retinopathy.
A 52-year-old man, a known case of type 2 diabetes mellitus and hypertension, who presented to us with bilateral diminution of vision since 1 year. He was diagnosed as a case of bilateral proliferative diabetic retinopathy and hypertensive retinopathy. A non-invasive imaging modality, optical coherence tomography angiography (OCTA), detected foveal neovascularisation in a background of diffuse diabetic macular oedema which would have been obscured by other investigations like fluorescein angiography.


Description of the karyotypes of Stejneger's beaked whale (Mesoplodon stejnegeri) and Hubbs' beaked whale (M. carlhubbsi).
The genus Mesoplodon (Cetacea: Odontoceti: Ziphiidae) is one of the few cetacean genera with the karyotype 2n = 42. The 2n = 42 karyotype of M. europaeus and M. carlhubbsi is largely consistent with the general cetacean karyotype 2n = 44, although other 2n = 42 karyotypes do not exhibit clear homologies with the general cetacean karyotype. Therefore, the chromosomes of Mesoplodon species may be the key to understanding cetacean karyological evolution. In the present study, the male karyotypes of M. stejnegeri and M. carlhubbsi were examined. In both species, the diploid number of the male karyotype was 42. Both species had the following characteristics: 1) a huge subtelocentric X chromosome with a large C-block; 2) a small metacentric Y chromosome; 3) nucleolus organizer regions (NORs) in the terminal regions of a large autosome and one or two small metacentric autosomes; 4) small metacentric autosomes; 5) large submetacentric and subtelocentric autosomes; 6) less accumulated C-heterochromatin in the centromeric region; and 7) heteromorphism in C-heterochromatin accumulation between homologues. Characteristics 1 and 3 are peculiar to only the karyotypes of Mesoplodon species, whereas characteristics 4, 5, 6, and 7 are also found in the species with the general cetacean karyotype 2n = 44.


Ecotoxicological mechanisms and models in an impact analysis tool for oil spills.
In an international collaborative effort, an impact analysis tool is being developed to predict the effect of accidental oil spills on recruitment and production of Atlantic cod (Gadus morhua) in the Barents Sea. The tool consisted of three coupled ecological models that describe (1) plankton biomass dynamics, (2) cod larvae growth, and (3) fish stock dynamics. The discussions from a series of workshops are presented in which variables and parameters of the first two ecological models were listed that may be affected by oil-related compounds. In addition, ecotoxicological algorithms are suggested that may be used to quantify such effects and what the challenges and opportunities are for algorithm parameterization. Based on model exercises described in the literature, survival and individual growth of cod larvae, survival and reproduction of zooplankton, and phytoplankton population growth are denoted as variables and parameters from the ecological models that might be affected in case of an oil spill. Because toxicity databases mostly (67%) contain data for freshwater species in temperate environments, parameterization of the ecotoxicological algorithms describing effects on these endpoints in the subarctic marine environment is not straightforward. Therefore, it is proposed that metadata analyses be used to estimate the sensitivity of subarctic marine species from available databases. To perform such analyses and reduce associated uncertainty and variability, mechanistic models of varying complexity, possibly aided by new experimental data, are proposed. Lastly, examples are given of how seasonality in ecosystems may influence chemical effects, in particular in the subarctic environment. Food availability and length of day were identified as important characteristics as these determine nutritional status and phototoxicity, respectively.


CK13 in craniopharyngioma versus related odontogenic neoplasms and human enamel organ.
The monoclonal antibody NCL-CK13 was studied in specimens of craniopharyngioma, ameloblastoma and calcifying odontogenic cyst neoplasms and the mandible and maxillae of normal human fetuses. There was a decrease in NCL-CK13 as the dental lamina developed, with a complete loss in the enamel organ. The neoplastic epithelia of the neoplasms revealed a clear phenotypic and immunohistochemical reactive relationship to the stratified embroyonic mucosa, away from the enamel organ. This suggests that these neoplasms might have their histogenesis from early stage epithelium, the oral part of the dental lamina or its remnants.


Cancer morbidity among woodworkers in the U.S. automotive industry.
In October 1979, concern was expressed about suspected excess cancer among woodworkers in several automobile manufacturing plants of the major automobile corporations located in Detroit. Cancer incidence rates for this group were compared with corresponding data for white males in the Detroit metropolitan area. Determination of standardized morbidity ratios (SMRs) showed significant increases for all types of cancer combined and for colorectal and salivary gland cancer in the study group. Further investigation is required to determine whether occupational exposure is responsible for these increases or if some other etiological mechanism is operating.


Engaging patients in health care: an empirical study of the role of engagement on attitudes and action.
Identify the role of engaging people affected by cancer in service development in influencing healthcare professionals and service-users' attitudes toward, and enactment of, engagement. Focus group discussions with healthcare professionals and people affected by lung cancer, prior to and following an intervention where lung cancer teams were supported to engage with patients and family members. Staff and people affected by cancer who participated displayed more positive attitudes toward involvement than those who did not participate. Progressing the involvement agenda requires the use of supported, small scale, projects where staff and patients/family members can develop their skills and knowledge of involvement. Doing patient engagement work is a vital step toward changing attitudes and actions toward the involvement agenda.


The role of ambient temperature and body mass on body temperature, standard metabolic rate and evaporative water loss in southern African anurans of different habitat specialisation.
Temperature and water availability are two of the most important variables affecting all aspects of an anuran's key physiological processes such as body temperature (T b), evaporative water loss (EWL) and standard metabolic rate (SMR). Since anurans display pronounced sexual dimorphism, evidence suggests that these processes are further influenced by other factors such as vapour pressure deficit (VPD), sex and body mass (M b). However, a limited number of studies have tested the generality of these results across a wide range of ecologically relevant ambient temperatures (T a), while taking habitat use into account. Thus, the aim of this study was to investigate the role of T a on T b, whole-animal EWL and whole-animal SMR in three wild caught African anuran species with different ecological specialisations: the principally aquatic African clawed frog (Xenopus laevis), stream-breeding common river frog (Amietia delalandii), and the largely terrestrial raucous toad (Sclerophrys capensis). Experiments were conducted at a range of test temperatures (5-35 °C, at 5 °C increments). We found that VPD better predicted rates of EWL than T a in two of the three species considered. Moreover, we found that T b, whole-animal EWL and whole-animal SMR increased with increasing T a, while T b increased with increasing M b in A. delalandii and S. capensis but not in X. laevis. Whole-animal SMR increased with increasing M b in S. capensis only. We did not find any significant effect of VPD, M b or sex on whole-animal EWL within species. Lastly, M b did not influence T b, whole-animal SMR and EWL in the principally aquatic X. laevis. These results suggest that M b may not have the same effect on key physiological variables, and that the influence of M b may also depend on the species ecological specialisation. Thus, the generality of M b as an important factor should be taken in the context of both physiology and species habitat specialisation.


[A possibility of using increased oxygen consumption as a criterion for mechanical respiration weaning in pediatric practice].
The body oxygen consumption and the oxygen cost of breathing (which is the difference in oxygen consumption measured during controlled ventilation and again during spontaneous ventilation) were measured in 46 children with congenital heart diseases after open-heart surgery. There was a significant exponential correlation between the body oxygen consumption (ml/m(2)/min) and the oxygen cost of breathing as a percentage of total oxygen consumption during spontaneous ventilation and the duration of weaning in minutes (r=+0,882, p<0,02). Therefore, as the oxygen cost of breathing was correlated with the total weaning time, this may be a useful index on the weaning process (sensitivity 92%, specificity 85%).


Neonatology in Singapore: the way we were, the way forward.
Singapore has a maternity hospital since 1924, but for many decades the newborns could only receive basic care. Neonatal and perinatal mortality rates were high. Marked improvement in neonatal care began from the 1980s when many neonatal departments were set up to provide intensive care. Improved socioeconomic status, better healthcare facilities, effective infection control, immunisation programmes and availability of potent antibiotics contributed to the decline of perinatal and neonatal mortality. Following the implementation of the glucose-6-phosphate dehydrogenase (G6PD) deficiency screening programme, severe neonatal jaundice and kernicterus were largely reduced. Exchange blood transfusions initiated in the 1960s and phototherapy in the 1970s had saved many babies. Kernicterus is almost not seen now. With more neonatal-trained staff, organised resuscitation teams, advances in respiratory management and better monitoring equipment, more babies have survived. Closer cooperation between obstetricians and neonatologists was a great leap forward towards perinatal medicine. Physicians should endeavour to reduce the incidence and prevalence of birth defects and metabolic errors. Perinatal asphyxia should be promptly detected and managed effectively, including neuroprotective strategies. There should be markers to predict the outcome of asphyxiated babies for decision-making. Neonatologists should be mindful of safe introduction of new technologies and rapid diagnostic techniques for infections, including group B streptococcal screening and chemoprophylaxis when required. Other current issues include prevention of major morbidities, preservation of brain function, improved neurodevelopmental outcome of premature babies, use of blood substitutes, optimal nutrition, fetal surgery, evidence-based medicine, better information systems, avoidance of medication errors, adequate sedation and pain relief of the baby, and the use of nitric oxide. One should bear in mind the need to enhance the neonatal intensive care environment, improve non-invasive monitoring and minimise invasive procedures. Physicians should prioritise neonatal care for their country and utilise less costly neonatal care. Ethical issues in neonatology that arise following advancement in neonatal care deserve attention. Advances in life sciences, such as the completion of the human genome project, cloning of tissues and organs, human stem cell research and technology, gene therapy, deoxyribonucleic acid vaccines and nanomedicine, should benefit neonatology.


Continual exposure to cigarette smoke extracts induces tumor-like transformation of human nontumor bronchial epithelial cells in a microfluidic chip.
Heavy cigarette smoking-related chronic obstructive pulmonary disease is an independent risk factor for lung squamous carcinoma. However, the mechanisms underlying the malignant transformation of bronchial epithelial cells are unclear. In our study, human tumor-adjacent bronchial epithelial cells were obtained from 10 cases with smoking-related chronic obstructive pulmonary disease and lung squamous carcinoma and cultured in an established microfluidic chip for continual exposure to cigarette smoke extracts (CSE) to investigate the potential tumor-like transformation and mechanisms. The integrated microfluidic chip included upstream concentration gradient generator and downstream cell culture chambers supplied by flowing medium containing different concentrations of CSE. Our results showed that continual exposure to low doses of CSE promoted cell proliferation whereas to high doses of CSE triggered cell apoptosis. Continual exposure to CSE promoted reactive oxygen species production in human epithelial cells in a dose-dependent manner. More importantly, continual exposure to low dose of CSE promoted the epithelial-to-mesenchymal transition process and anchorage-independent growth, and increased chromosome instability in bronchial epithelial cells, accompanied by activating the GRP78, NF-κB, and PI3K pathways. The established microfluidic chip is suitable for primary culture of human tumor-adjacent bronchial epithelial cells to investigate the malignant transformation. Continual exposure to low doses of CSE promoted tumor-like transformation of human nontumor bronchial epithelial cells by inducing reactive oxygen species production and activating the relevant signaling.


Ebola virus antibody decay-stimulation in a high proportion of survivors.
Neutralizing antibody function provides a foundation for the efficacy of vaccines and therapies1-3. Here, using a robust in vitro Ebola virus (EBOV) pseudo-particle infection assay and a well-defined set of solid-phase assays, we describe a wide spectrum of antibody responses in a cohort of healthy survivors of the Sierra Leone EBOV outbreak of 2013-2016. Pseudo-particle virus-neutralizing antibodies correlated with total anti-EBOV reactivity and neutralizing antibodies against live EBOV. Variant EBOV glycoproteins (1995 and 2014 strains) were similarly neutralized. During longitudinal follow-up, antibody responses fluctuated in a 'decay-stimulation-decay' pattern that suggests de novo restimulation by EBOV antigens after recovery. A pharmacodynamic model of antibody reactivity identified a decay half-life of 77-100 days and a doubling time of 46-86 days in a high proportion of survivors. The highest antibody reactivity was observed around 200 days after an individual had recovered. The model suggests that EBOV antibody reactivity declines over 0.5-2 years after recovery. In a high proportion of healthy survivors, antibody responses undergo rapid restimulation. Vigilant follow-up of survivors and possible elective de novo antigenic stimulation by vaccine immunization should be considered in order to prevent EBOV viral recrudescence in recovering individuals and thereby to mitigate the potential risk of reseeding an outbreak.


Addressing NCDs through research and capacity building in LMICs: lessons learned from tobacco control.
Confronting the global non-communicable diseases (NCDs) crisis requires a critical mass of scientists who are well versed in regional health problems and understand the cultural, social, economic, and political contexts that influence the effectiveness of interventions. Investments in global NCD research must be accompanied by contributions to local research capacity. The National Institutes of Health (NIH) and the Fogarty International Center have a long-standing commitment to supporting research capacity building and addressing the growing burden of NCDs in low- and middle-income countries. One program in particular, the NIH International Tobacco and Health Research and Capacity Building Program (TOBAC program), offers an important model for conducting research and building research capacity simultaneously. This article describes the lessons learned from this unique funding model and demonstrates how a relatively modest investment can make important contributions to scientific evidence and capacity building that could inform ongoing and future efforts to tackle the global burden of NCDs.


The effect of home-use and in-office bleaching treatments combined with experimental desensitizing agents on enamel and dentin.
This study aimed to evaluate in vitro the effect of formulations containing Biosilicate to treat enamel and dentin bovine samples exposed to dental bleaching agents. On enamel and dentin bleached with commercial gels containing 16% carbamide peroxide (CP) (14 days/4 h) or 35% hydrogen peroxide (single session/45 min), desensitizing dentifrices (Sensodyne(®); experimental dentifrice of Biosilicate(®); Odontis RX(®); Sorriso(®)) were applied along 14 days and desensitizing pastes (Biosilicate(®)/water 1:1; Dessensebilize NanoP(®); Bioglass type 45S5/water 1:1) were applied on days 1, 3, 7, 10 and 14. Distilled water was the control. Microhardness (MH) and roughness measurements were the variables measured on the samples before and after the treatments. Student's t-test analyzed differences before and after the treatments. Two-way analysis of variance and post-hoc Tukey test analyzed differences among the factors desensitizing, bleaching agents and substrate. Tukey test showed no differences in roughness for both bleaching treatments and among the desensitizing agents (P > 0.05). Differences in MH appeared on enamel treated with in-home bleaching when control group (lower values) was compared with Sensodyne, Biosilicate dentifrice, Biosilicate paste, and Bioglass paste (higher values). Comparisons between desensitizing agents on dentin treated with both bleaching gels showed no statistical differences. The effect of formulations containing Biosilicate (Biosilicate dentifrice and paste) was significant in the MH of enamel bleached with 16% CP.


How Indigenous Communities Are Adapting To Climate Change: Insights From The Climate-Ready Tribes Initiative.
Climate change directly threatens human health, with substantial impacts on Indigenous peoples, who are uniquely vulnerable as climate-related events affect their practices, lifeways, self-determination, and physical and cultural health. At the same time, Indigenous communities are leading the way in innovative health-related climate change adaptation work, using traditional knowledges and novel approaches. In 2016 the Centers for Disease Control and Prevention and the National Indian Health Board created the Climate-Ready Tribes Initiative to support these efforts. The initiative has funded tribes, shared information nationally, and supported a learning cohort, resulting in pioneering work to protect health from climate hazards. We describe how two tribes-the Pala Band of Mission Indians and the Swinomish Indian Tribal Community-implemented their Climate-Ready Tribes Initiative projects, and we provide recommendations for making climate and health policy more effective for tribes. Lessons learned from the Climate-Ready Tribes Initiative can inform climate and health policy and practice nationwide.


Improvement of sexual functioning during treatment of MDD with adjunctive pimavanserin: A secondary analysis.
Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study. Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined. Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo. Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction.


Precise visual distinction of brain glioma from normal tissues via targeted photoacoustic and fluorescence navigation.
The vexing difficulty in distinguishing glioma from normal tissues is a major obstacle to prognosis. In an attempt to solve this problem, we used a joint strategy that combined targeted-cancer stem cells nanoparticles with precise photoacoustic and fluorescence navigation. We showed that traditional magnetic resonance imaging (MRI) did not represent the true morphology of tumors. Targeted nanoparticles specifically accumulated in the tumor area. Glioma was precisely revealed at the cellular level. Tumors could be non-invasively detected through the intact skull by fluorescence molecular imaging (FMI) and photoacoustic tomography (PAT). Moreover, PAT can be used to excise deep gliomas. Histological correlation confirmed that FMI imaging accurately delineated scattered tumor cells. The combination of optical PAT and FMI navigation fulfilled the promise of precise visual imaging in glioma detection and resection. This detection method was deeper and more intuitive than the current intraoperative pathology.


Health care providers' experiences and perceptions participating in a chronic pain telementoring education program: A qualitative study.
Chronic pain affects one in five Canadians. Frontline health care providers (HCPs) manage the majority of patients with chronic pain yet receive minimal training to do so. The Extension for Community Healthcare Outcomes (ECHO) model™ is an education intervention aimed at HCPs (not patients) to support and improve care in underserviced communities. ECHO Ontario Chronic Pain and Opioid Stewardship (ECHO PAIN) is an adaptation of the ECHO model where the program goals are to support and improve chronic pain and opioid management in the province of Ontario, Canada. This study aimed to investigate the perceptions of HCPs participating in ECHO PAIN. Thirteen HCPs attending ECHO PAIN participated in in-depth semistructured phone interviews. Resulting data were analyzed through a qualitative descriptive lens. Analysis uncovered four themes: (1) HCPs' motivation for joining ECHO PAIN, (2) interprofessional collaboration through ECHO PAIN, (3) the use of opioids for pain management, and (4) barriers and facilitators to participation and satisfaction in ECHO PAIN. HCPs joined ECHO PAIN because of their struggles managing their complex patients with chronic pain. HCPs also recognized the importance of interprofessional collaboration in pain management and shared examples of integration of different professional approaches in their clinical teams. Opioids for pain management remained a controversial issue, and ECHO served as an opportunity to decrease this knowledge gap. Finally, HCPs described how time constraints, organizational support, and session structure acted as barriers to their participation and satisfaction in the ECHO PAIN program; technology mediated satisfaction. This study was the first in Canada to explore the motivations of HCPs in attending a chronic pain telementoring program as well as to examine the interprofessional effects of participation. HCPs increased their knowledge about management of chronic pain and increased their interprofessional approach.


Atrial fibrillation and acute respiratory failure: unique presentation of diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma is the most common lymphoid neoplasm, accounting for approximately 25% of all non-Hodgkin lymphomas. Patients typically present with nodal enlargement, fever, weight loss, or night sweats. Extranodal extramedullary disease occurs in up to 40% of cases with the most common site of extranodal involvement being the gastrointestinal tract. However, diffuse large B-cell lymphoma can present in virtually any area, including the testes, bones, thyroid, salivary glands, tonsils, skin, liver, breasts, adrenals, kidneys, nasal cavity, paranasal sinuses, cervix, and central nervous system. We present a unique case of atrial fibrillation and respiratory failure as an initial presentation of diffuse large B-cell lymphoma with cardiac and cavitary pulmonary involvement. The recent advances in chemotherapeutic options allow for and reinforce the importance of tailoring the chemotherapy regimen to the individual patient's unique presentation. In our patient, presentation included extensive intracardiac involvement resulting in arrhythmias, cavitary pulmonary nodules, and acute hypoxemic respiratory failure requiring ventilator support.


Hemodynamic, vascular, and reproductive impact of FMS-like tyrosine kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse pregnancy.
To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling during pregnancy, mice were injected with anti-FLT1 neutralizing antibody (Ab) beginning on Gestational Day 8 or 12 and every other day thereafter until Day 18; vehicle-only injected mice served as controls. Uterine artery blood flow was measured with ultrasound on Days 13 and 18, and morphometric measurements of the uterine arcade were carried out on Day 19 to provide a measure of gestational vascular remodeling; reproductive performance was evaluated by determining litter size, resorption rates, and pup and placental weights. Ab injections beginning on Day 8 or Day 12 resulted in significant reductions of uterine artery peak systolic and diastolic flows at Days 13 and 18. In addition, normal reproductive function was compromised, as evidenced by a significant reduction in average number of viable pups along with enhanced resorption rates. Reproductive performance was also significantly compromised in this group, although less severely. There was no evidence of a reduction in main uterine artery diameters, though arterial distensibility was reduced, and the diameter of the main uterine vein was significantly smaller in the Ab-injected mice. Significant reductions in main uterine artery and segmental artery length were also noted. Placental and pup weights were similar in all the groups. FLT1 inhibition during murine pregnancy impaired blood flow to the fetal-placental unit, compromised several indices of vascular remodeling, reduced fecundity, and increased fetal reabsorptions. The effects of FLT1 inhibition are most pronounced when targeted during early pregnancy.


Selection-Based Biodiversity at a Small Spatial Scale in a Low-Dispersing Insular Bird.
The blue tit is a highly mobile small passerine found in deciduous and evergreen oaks. In mainland populations, gene flow results in local maladaptive timing of breeding in evergreen oak forests, the rarer habitat. However, on the island of Corsica, two populations only 25 kilometers apart are highly specialized and differ between the two habitat types in breeding and morphological traits. In contrast to theoretical predictions about the homogenizing effects of gene flow, this highlights evolutionary consequences of habitat diversification and isolation at a small spatial scale in insular organisms, which should be taken into account in conservation policies.


Automated three-dimensional reconstruction and morphological analysis of dendritic spines based on semi-supervised learning.
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Recent research shows that the morphological changes of dendritic spines have a close relationship with some specific diseases. The distribution of different dendritic spine phenotypes is a key indicator of such changes. Therefore, it is necessary to classify detected spines with different phenotypes online. Since the dendritic spines have complex three dimensional (3D) structures, current neuron morphological analysis approaches cannot classify the dendritic spines accurately with limited features. In this paper, we propose a novel semi-supervised learning approach in order to perform the online morphological classification of dendritic spines. Spines are detected by a new approach based on wavelet transform in the 3D space. A small training data set is chosen from the detected spines, which has the spines labeled by the neurobiologists. The remaining spines are then classified online by the semi-supervised learning (SSL) approach. Experimental results show that our method can quickly and accurately analyze neuron images with modest human intervention.


Effects of orthopedic polymer particles on chemotaxis of macrophages and mesenchymal stem cells.
Wear particles generated from total joint arthroplasty (TJA) stimulate macrophages to release chemokines. The role of chemokines released from wear particle-stimulated macrophages on the migration of macrophages and osteoprogenitor cells in vitro has not been elucidated. In this study, we challenged murine macrophages (RAW 264.7) with clinically relevant polymethyl methacrylate (PMMA, 1-10 microm) and ultra high molecular weight polyethylene (UHMWPE, 2-3 microm) particles. The chemotactic effects of the conditioned media (CM) were tested in vitro using human macrophages (THP-1) and human mesenchymal stem cells (MSCs) as the migrating cells. CM collected from both particle types had a chemotactic effect on human macrophages, which could be eliminated by monocyte chemotactic protein-1 (MCP-1) neutralizing antibody. Blocking the CCR1 receptor eliminated the chemotactic effect, while CCR2 antibody only partially decreased THP-1 cell migration. CM from PMMA but not UHMWPE-exposed macrophages led to chemotaxis of MSCs; this effect could be eliminated by macrophage inflammatory protein-1 alpha (MIP-1alpha) neutralizing antibody. Neither CCR1 nor CCR2 blocking antibodies showed an effect on the migration of MSCs. Chemokines released by macrophages stimulated by wear particles can have an effect on the migration of macrophages and MSCs. This effect seems to be dependent on the particle type, and may be modulated by MCP-1 and MIP-1alpha, however, more than one chemokine may be necessary for chemotaxis.


Propionibacterium acnes-induced IL-8 production may be mediated by NF-kappaB activation in human monocytes.
Propionibacterium acnes (P. acnes) causes an inflammatory acne that is characterized by massive neutrophilic infiltration. IL-8 is thought to play an important role in the pathophysiology of P. acnes, although the mechanisms by which P. acnes up-regulates the release of IL-8, a neutrophilic chemokine, from target cells is not well understood. In this study, we investigated the mechanisms through which heat-killed P. acnes induces IL-8 production in THP-1 cells (a human monocytic cell line). We found that P. acnes is able to directly induce IL-8 production and IL-8 mRNA expression in human monocytic cells in a dose- and time-dependent manner through a mechanism requiring transcription factor NF-kappaB activation. Additionally, P. acnes-induced IL-8 secretion was inhibited by roxithromycin, a macrolide antibiotic, and its inhibitory effect seemed to be partially associated with the inhibition of P. acnes-induced NF-kappaB activation. This is the first study to show that NF-kappaB activation is involved in the IL-8 production of monocytic cells stimulated by P. acnes.


Tunable micro-optofluidic prism based on liquid-core liquid-cladding configuration.
The integration of optical components into microfluidic systems has the potential to reduce the amount of bulky external devices and thus reduce the cost. However, one of the challenges of this concept is the accurate alignment of the optical path among multiple optical components inside a chip. We propose a tunable micro-optofluidic prism based on the liquid-core liquid-cladding structure formed in a sector-shape chamber. The optical interface of the prism is maintained in a straight line shape by distributing a row of pressure barriers in the chamber. By adjusting the flow rate ratio between core and cladding streams, the apex angle of the prism can be tuned accordingly. As a consequence, the deviation angle of the light beam refracted by the prism can be changed continuously. This tunability of our optofluidic prism can be utilized for the alignment of the optical path inside a chip or for the development of optical switches.


The oral administration of bacterial extracts prevents asthma via the recruitment of regulatory T cells to the airways.
The prevalence of asthma has steadily increased during the last decade, probably as the result of changes in the environment, including reduced microbial exposure during infancy. Accordingly, experimental studies have shown that deliberate infections with live pathogens prevent the development of allergic airway diseases in mice. Bacterial extracts are currently used in children suffering from repeated upper respiratory tract infections. In the present study, we have investigated whether bacterial extracts, commercially available as Broncho-Vaxom (BV), could prevent allergic airway disease in mice. Oral treatment with BV suppressed airway inflammation through interleukin-10 (IL-10)-dependent and MyD88 (myeloid differentiation primary response gene (88))-dependent mechanisms and induced the conversion of FoxP3 (forkhead box P3)(-) T cells into FoxP3(+) regulatory T cells. Furthermore, CD4(+) T cells purified from the trachea of BV-treated mice conferred protection against airway inflammation when adoptively transferred into sensitized mice. Therefore, treatment with BV could possibly be a safe and efficient strategy to prevent the development of allergic diseases in children.


Genetic analysis of rapid tolerance to ethanol's incoordinating effects in mice: inbred strains and artificial selection.
Ethanol tolerance, a decrease in drug responsiveness with repeated administrations, is an important diagnostic criterion for alcoholism. Rapid tolerance develops within 8-24 hours of an initial ethanol exposure and shares many similarities with chronic tolerance. The genetic contribution to rapid tolerance to ethanol-induced ataxia was estimated using a panel of inbred strains of mice. Strains differed significantly in the degree of rapid tolerance development, which had a broad-sense heritability estimate of 0.11. Artificial selection was carried out to develop lines of mice that would show High (HRT) and Low (LRT) levels of Rapid Tolerance. Starting with HS/Npt mice, derived from a systematic cross of eight inbred strains, a significant response to selection was seen in replicate 1 by the third selection generation. No difference was found in replicate 2. Heritability estimates after the fourth generation were 0.25 for HRT-1 mice and 0.06 for LRT-1 mice. HRT-1 and LRT-1 mice also differed significantly in chronic tolerance development to four doses of ethanol. These studies provide evidence for a genetic contribution to rapid tolerance and support a genetic link between rapid and chronic tolerance to ethanol's ataxic effects.


Selective Recruitment of Large Lower Lobe Atelectasis on Donor Back Table in Rejected Donor Lungs.
Large atelectatic areas in donor lungs are frequently resistant to standard recruitment maneuvers, producing a tenaciously low PO2/FiO2 ratio. The aim of this study is to investigate the optimal protocol for the recruitment of large atelectatic areas in the context of ex vivo lung perfusion (EVLP). Seventeen rejected lungs with large lower lobe atelectasis (≥40%) were divided into 2 groups: manual resuscitation (n = 5) and selective recruitment (n = 12). Transplant suitability was then evaluated in cellular EVLP. In the manual resuscitation group, following bronchoscopy, if the conventional recruitment maneuver was not successful, a bagging technique was utilized to resolve atelectasis in EVLP. In the selective recruitment group, a pediatric endotracheal tube was introduced to the lower lobe bronchus on the back table of the donor hospital. Selective recruitment of the lower lobe was accomplished while keeping peak inspiratory pressure <30 cm H2O for 30 seconds. The average atelectasis size and lung weight in 17 donor lungs was 75.4 ± 20.6% and 960 ± 221 g, respectively. There were no significant differences between the 2 groups in all donor variables, except cold ischemic time (P = 0.001, 5.2 ± 0.5 versus 6.4 ± 0.7 hours). The selective recruitment group was associated with better transplant suitability (P = 0.035, 75% versus 20%), better PO2/FiO2 ratio (P = 0.186, 324 ± 89 versus 258 ± 87 mm Hg), lower lung weight (P = 0.057, 997.9 ± 229.2 versus 1377.2 ± 452.9 g), and better pathological score (P < 0.05, 1.0 ± 1.3 versus 2.8 ± 0.8) than the manual resuscitation group. A selective recruitment procedure is a safe and effective method of eliminating large atelectasis before EVLP.


Endocrine disrupting alkylphenolic chemicals and other contaminants in wastewater treatment plant effluents, urban streams, and fish in the Great Lakes and Upper Mississippi River Regions.
Urban streams are an integral part of the municipal water cycle and provide a point of discharge for wastewater treatment plant (WWTP) effluents, allowing additional attenuation through dilution and transformation processes, as well as a conduit for transporting contaminants to downstream water supplies. Domestic and commercial activities dispose of wastes down-the-drain, resulting in wastewater containing complex chemical mixtures that are only partially removed during treatment. A key issue associated with WWTP effluent discharge into streams is the potential to cause endocrine disruption in fish. This study provides a long-term (1999-2009) evaluation of the occurrence of alkylphenolic endocrine disrupting chemicals (EDCs) and other contaminants discharged from WWTPs into streams in the Great Lakes and Upper Mississippi River Regions (Indiana, Illinois, Michigan, Minnesota, and Ohio). The Greater Metropolitan Chicago Area Waterways, Illinois, were evaluated to determine contaminant concentrations in the major WWTP effluents and receiving streams, and assess the behavior of EDCs from their sources within the sewer collection system, through the major treatment unit processes at a WWTP, to their persistence and transport in the receiving stream. Water samples were analyzed for alkylphenolic EDCs and other contaminants, including 4-nonylphenol (NP), 4-nonylphenolpolyethoxylates (NPEO), 4-nonylphenolethoxycarboxylic acids (NPEC), 4-tert-octylphenol (OP), 4-tert-octylphenolpolyethoxylates (OPEO), bisphenol A, triclosan, ethylenediaminetetraacetic acid (EDTA), and trace elements. All of the compounds were detected in all of the WWTP effluents, with EDTA and NPEC having the greatest concentrations. The compounds also were detected in the WWTP effluent dominated rivers. Multiple fish species were collected from river and lake sites and analyzed for NP, NPEO, NPEC, OP, and OPEO. Whole-body fish tissue analysis indicated widespread occurrence of alkylphenolic compounds, with the highest concentrations occurring in streams with the greatest WWTP effluent content. Biomarkers of endocrine disruption in the fish indicated long-term exposure to estrogenic chemicals in the wastewater impacted urban waterways.


Tissue-engineered constructs based on SPCL scaffolds cultured with goat marrow cells: functionality in femoral defects.
This study aims to assess the in vivo performance of cell-scaffold constructs composed of goat marrow stromal cells (GBMCs) and SPCL (a blend of starch with polycaprolactone) fibre mesh scaffolds at different stages of development, using an autologous model. GBMCs from iliac crests were seeded onto SPCL scaffolds and in vitro cultured for 1 and 7 days in osteogenic medium. After 1 and 7 days, the constructs were characterized for proliferation and initial osteoblastic expression by alkaline phosphatase (ALP) activity. Scanning electron microscopy analysis was performed to investigate cellular morphology and adhesion to SPCL scaffolds. Non-critical defects (diameter 6 mm, depth 3 mm) were drilled in the posterior femurs of four adult goats from which bone marrow and serum had been collected previously. Drill defects alone and defects filled with scaffolds without cells were used as controls. After implantation, intravital fluorescence markers, xylenol orange, calcein green and tetracycline, were injected subcutaneously after 2, 4 and 6 weeks, respectively, for bone formation and mineralization monitoring. Subsequently, samples were stained with Lévai-Laczkó for bone formation and histomorphometric analysis. GBMCs adhered and proliferated on SPCL scaffolds and an initial differentiation into pre-osteoblasts was detected by an increasing level of ALP activity with the culture time. In vivo experiments indicated that bone neoformation occurred in all femoral defects. The results obtained provided important information about the performance of SPCL-GBMC constructs in an orthotopic goat model that enabled future studies to be designed to investigate in vivo the functionality of SPCL-GBMC constructs in more complex models, viz. critical sized defects, and to evaluate the influence of in vitro cultured autologous cells in the healing and bone regenerative process.


[Psychosocial therapy of patients with dementia].
The progressive cognitive and behavourial disturbancies in dementia diseases cause great emotional burden to patients, their families and caregivers. To relief this burden and to facilitate adequate coping strategies, psychosocial therapies intend to improve cognitive functions, self care abilities and emotional wellbeing of dementia patients. The therapeutic interventions address the patients, their caregivers and the adaption of the environment. Psychosocial therapies can be divided into cognitive training methods, behaviour orientated concepts, emotional orientated approaches and family interventions (1, 2, 12, 19). Most of these psychosocial therapies are only poor validated in randomized controlled trials. Nevertheless, they hold great promise to improve the quality of life and wellbeing of dementia patients and their caregivers. Thus they should be considered to be an integral part of a comprehensive therapeutic approach to dementia patients and their families.


Proteomic study of pilocytic astrocytoma pediatric brain tumor intracystic fluid.
Liquid chromatography in coupling with high-resolution ESI-LTQ-Orbitrap mass spectrometry was applied for a proteomic study of pediatric pilocytic astrocytoma brain tumor intracystic fluid by an integrated top-down/bottom-up platform. Both of the proteomic strategies resulted complementary and support each other in contributing to a wide characterization of the protein and peptide content of the tumor fluid. Top-down approach allowed to identify several proteins and peptides involved in different biological activities together with the characterization of interesting proteoforms such as fibrinopeptide A and its truncated form, fibrinopeptide B, complement C3f fragments, β-thymosin peptides, ubiquitin, several apolipoproteins belonging to A and C families, apolipoprotein J and D, and cystatin C. Of particular interest resulted the identification of a N-terminal truncated cystatin C proteoform, likely involved in immune response mechanism modulations and the identification of oxidized and glycosylated apolipoproteins including disulfide bridge dimeric forms. The bottom-up approach confirmed some of the experimental data findings together with adding the characterization of high-molecular-mass proteins in the samples. These data could contribute to elucidate the molecular mechanisms involved in onset and progression of the disease and cyst development.


Sliding on the surface: bacterial spreading without an active motor.
Bacteria are able to translocate over surfaces using different types of active and passive motility mechanisms. Sliding is one of the passive types of movement since it is powered by the pushing force of dividing cells and additional factors facilitating the expansion over surfaces. In this review, we describe the sliding proficient bacteria that were previously investigated in details highlighting the sliding facilitating compounds and the regulation of sliding motility. Besides surfactants that reduce the friction between cells and substratum, other compounds including exopolysaccharides, hydrophobic proteins, or glycopeptidolipids where discovered to promote sliding. Therefore, we present the sliding bacteria in three groups depending on the additional compound required for sliding. Despite recent accomplishments in sliding research there are still many open questions about the mechanisms underlying sliding motility and its regulation in diverse bacterial species.


The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer's disease.
Age-dependent cognitive decline is a major debilitating event affecting even individuals who are otherwise healthy. Understanding the molecular basis underlying these changes may increase the healthspan of the elderly population. It may also reveal insights into the pathogenesis of numerous neurodegenerative disorders characterized by cognitive deficits, as aging is the major risk factor for most of these disorders. Alzheimer's disease (AD), the most common neurodegenerative disorder, first manifests itself as deficits in encoding new memories. As AD progresses, these deficits spread to other cognitive domains that further debilitate the person before contributing to their demise. Suppression of the mammalian target of rapamycin (mTOR) increases healthspan and lifespan in several organisms. Numerous reports have linked alterations in mTOR signaling to age-dependent cognitive decline and the pathogenesis of AD. This review will discuss recent work highlighting the complex role of mTOR in cognitive aging and in the pathogenesis of AD.


The association between orthostatic hypertension and all-cause mortality in hospitalized elderly persons.
Little is known about the prevalence of orthostatic hypertension (OHT) and its effect on long-term mortality in the elderly. We evaluated the prevalence of OHT and its effect on mortality in hospitalized elderly patients. Out of 1852 patients admitted between 31/12/1999 and 31/12/2000 to an acute geriatric ward, 474 patients (48% males) with a mean age of 81.5 ± 6.8 years were enrolled in this study. Blood pressure (BP) was measured three times during the day in a supine and standing position. Patients with at least one increase in systolic or diastolic BP levels upon standing were diagnosed with OHT. Medical history, physical examination and laboratory parameters were retrieved from the medical records. Mortality data until 18(th) June 2014 were retrieved from the computerized system of the Ministry of the Interior. Four hundred and seven patients (86%) were diagnosed with OHT. Those without OHT had a lower body mass index and were more likely males, smokers, had a higher rate of Parkinson's disease and less congestive heart failure compared with those with OHT. Patients with OHT had a better survival rate than those without OHT (P = 0.024). Hazard ratios (HRs) for mortality in those with OHT adjusted to age and multiple risk factors were: 0.67 [95% confidence interval (CI): 0.51-0.87] and 0.73 (95% CI: 0.55-0.97), respectively; a similar tendency was noticed in a sensitivity analysis by gender. Hospitalized elderly patients with OHT had a better survival rate than those without OHT.


Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma.
Objective It has been postulated that the normal counterpart of angioimmunoblastic T-cell lymphoma (AITL) is the follicular helper T-cell (TFH). Recent immunological studies have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with T-cell, helper T-cell (Th), and TFH differentiation are reportedly BCL11B, Th-POK, and BCL6, respectively. We explored the postulated normal counterpart of AITL with respect to the expression of the master regulators of T-cell differentiation. Methods We performed an immunohistochemical analysis in 15 AITL patients to determine the expression of the master regulators and several surface markers associated with T-cell differentiation. Results BCL11B was detected in 10 patients (67%), and the surface marker of T-cells (CD3) was detected in all patients. Only 2 patients (13%) expressed the marker of naïve T-cells (CD45RA), but all patients expressed the marker of effector T-cells (CD45RO). Nine patients expressed Th-POK (60%), and 7 (47%) expressed a set of surface antigens of Th (CD4-positive and CD8-negative). In addition, BCL6 and the surface markers of TFH (CXCL13, PD-1, and SAP) were detected in 11 (73%), 8 (53%), 14 (93%), and all patients, respectively. Th-POK-positive/BCL6-negative patients showed a significantly shorter overall survival (OS) than the other patients (median OS: 33.0 months vs. 74.0 months, p=0.020; log-rank test). Conclusion Many of the AITL patients analyzed in this study expressed the master regulators of T-cell differentiation. The clarification of the diagnostic significance and pathophysiology based on the expression of these master regulators in AITL is expected in the future.


Microbial communities associated with ferromanganese nodules and the surrounding sediments.
The formation and maintenance of deep-sea ferromanganese/polymetallic nodules still remains a mystery 140 years after their discovery. The wealth of rare metals concentrated in these nodules has spurred global interest in exploring the mining potential of these resources. The prevailing theory of abiotic formation has been called into question and the role of microbial metabolisms in nodule development is now an area of active research. To understand the community structure of microbes associated with nodules and their surrounding sediment, we performed targeted sequencing of the V4 hypervariable region of the 16S rRNA gene from three nodules collected from the central South Pacific. Results have shown that the microbial communities of the nodules are significantly distinct from the communities in the surrounding sediments, and that the interiors of the nodules harbor communities different from the exterior. This suggests not only differences in potential metabolisms between the nodule and sediment communities, but also differences in the dominant metabolisms of interior and exterior communities. We identified several operational taxonomic units (OTUs) unique to both the nodule and sediment environments. The identified OTUs were assigned putative taxonomic identifications, including two OTUs only found associated with the nodules, which were assigned to the α-Proteobacteria. Finally, we explored the diversity of the most assigned taxonomic group, the Thaumarchaea MG-1, which revealed novel OTUs compared to previous research from the region and suggests a potential role as a source of fixed carbon for ammonia oxidizing archaea in the environment.


Custom Workflow for the Confident Identification of Sulfotyrosine-Containing Peptides and Their Discrimination from Phosphopeptides.
Protein tyrosine sulfation (sY) is a post-translational modification (PTM) catalyzed by Golgi-resident tyrosyl protein sulfo transferases (TPSTs). Information on sY in humans is currently limited to ∼50 proteins, with only a handful having verified sites of sulfation. As such, the contribution of sulfation to the regulation of biological processes remains poorly defined. Mass spectrometry (MS)-based proteomics is the method of choice for PTM analysis but has yet to be applied for systematic investigation of the "sulfome", primarily due to issues associated with discrimination of sY-containing from phosphotyrosine (pY)-containing peptides. In this study, we developed an MS-based workflow for sY-peptide characterization, incorporating optimized Zr4+ immobilized metal-ion affinity chromatography (IMAC) and TiO2 enrichment strategies. Extensive characterization of a panel of sY- and pY-peptides using an array of fragmentation regimes (CID, HCD, EThcD, ETciD, UVPD) highlighted differences in the generation of site-determining product ions and allowed us to develop a strategy for differentiating sulfated peptides from nominally isobaric phosphopeptides based on low collision energy-induced neutral loss. Application of our "sulfomics" workflow to a HEK-293 cell extracellular secretome facilitated identification of 21 new sulfotyrosine-containing proteins, several of which we validate enzymatically, and reveals new interplay between enzymes relevant to both protein and glycan sulfation.


Identification of dust storm source areas in West Asia using multiple environmental datasets.
Sand and Dust storms are common phenomena in arid and semi-arid areas. West Asia Region, especially Tigris-Euphrates alluvial plain, has been recognized as one of the most important dust source areas in the world. In this paper, a method is applied to extract SDS (Sand and Dust Storms) sources in West Asia region using thematic maps, climate and geography, HYSPLIT model and satellite images. Out of 50 dust storms happened during 2000-2013 and collected in form of MODIS images, 27 events were incorporated as demonstrations of the simulated trajectories by HYSPLIT model. Besides, a dataset of the newly released Landsat images was used as base-map for the interpretation of SDS source regions. As a result, six main clusters were recognized as dust source areas. Of which, 3 clusters situated in Tigris-Euphrates plain were identified as severe SDS sources (including 70% dust storms in this research). Another cluster in Sistan plain is also a potential source area. This approach also confirmed six main paths causing dust storms. These paths are driven by the climate system including Siberian and Polar anticyclones, monsoon from Indian Subcontinent and depression from north of Africa. The identification of SDS source areas and paths will improve our understandings on the mechanisms and impacts of dust storms on socio-economy and environment of the region.


A retrospective analysis of selective internal radiation therapy (SIRT) with yttrium-90 microspheres in patients with unresectable hepatic malignancies.
To evaluate the efficacy and safety of selective internal radiation therapy (SIRT). A retrospective analysis was undertaken of all patients who underwent SIRT at a single institution. Diagnostic and therapeutic angiograms, computed tomography (CT) images, positron-emission tomography (PET) images, and planar isotope images were analysed. The response to SIRT was analysed using radiological data and tumour markers. Overall survival, complications, and side effects of SIRT were also analysed. The initial 12 patients were included on an intention-to-treat basis, between 21/09/2005 and 07/05/2008. All patients had advanced disease and multiple prior courses of chemotherapy. One patient did not receive yttrium-90 due to complex vascular anatomy; the remaining 11 patients underwent 13 SIRT treatment episodes following work-up angiography. A response was seen using PET in 80% of patients. Using CT, the response of the tumour to therapy in the treated hepatic segments demonstrated a 20% partial response, stable disease in 50%, and progressive disease in 30%. Estimated median survival was 229 days, with 64% of patients still alive at the time of writing. No major complications were observed, although 82% of patients experienced side-effects following SIRT, mainly nausea, vomiting, and abdominal pain. There have been no complications in the 12 SIRT patients. Tumour response was seen in four out of five patients who underwent PET. Objective CT response rates were mixed and are perhaps partially explained by advanced disease and limitations of using measurements to assess response. This complex and potentially hazardous service has been successfully and safely established.


Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.
Restrictive dermopathy (RD), also called tight skin contracture syndrome (OMIM 275210), is a rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. We explored nine fetuses/newborns children with RD. Two were found to have an heterozygous splicing mutation in the LMNA gene, leading to the complete or partial loss of exon 11 in mRNAs encoding Lamin A and resulting in a truncated Prelamin A protein. Lamins are major constituents of the nuclear lamina, a filamentous meshwork underlying the inner nuclear envelope. In the other seven patients, a unique heterozygous insertion leading to the creation of a premature termination codon was identified in the gene ZMPSTE24, also known as FACE-1 in human. This gene encodes a metalloproteinase specifically involved in the post-translational processing of Lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of Lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of Lamin-associated proteins was evidenced. Our results indicate that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in all RD cases. RD is thus one of the most deleterious laminopathies identified so far in humans caused by (primary or secondary) A-type Lamin defects and nuclear structural and functional alterations.


Engineered cell lines for fish health research.
As fish farming continues to increase worldwide, the related research areas of fish disease and immunology are also expanding, aided by the revolution in access to genomic information and molecular technology. The genomes of most fish species of economic importance are now available and annotation based on sequence homology with characterised genomes is underway. However, while useful, functional homology is more difficult to determine, there being a lack of widely distributed and well characterised reagents such as monoclonal antibodies, traditionally used in mammalian studies, to help with confirming functions and cellular interactions of fish molecules. In this context, fish cell lines and the possibility of their genetic engineering offer good prospects for studying functional genomics with respect to fish diseases. In this review, we will give an overview of available permanently genetically engineered fish cell lines, as cell-based reporter systems or platforms for expression of endogenous immune or pathogen genes, to investigate interactions and function. The advantages of such systems and the technical challenge for their development will be discussed.


Grammomys surdaster, the Natural Host for Plasmodium berghei Parasites, as a Model to Study Whole-Organism Vaccines Against Malaria.
AbstractInbred mice are commonly used to test candidate malaria vaccines, but have been unreliable for predicting efficacy in humans. To establish a more rigorous animal model, we acquired African woodland thicket rats of the genus Grammomys, the natural hosts for Plasmodium berghei. Thicket rats were acquired and identified as Grammomys surdaster by skull and teeth measurements and mitochondrial DNA genotyping. Herein, we demonstrate that thicket rats are highly susceptible to infection by P. berghei, and moderately susceptible to Plasmodium yoelii and Plasmodium chabaudi: 1-2 infected mosquito bites or 25-100 sporozoites administered by intravenous injection consistently resulted in patent parasitemia with P. berghei, and resulted in patent parasitemia with P. yoelii and P. chabaudi strains for at least 50% of animals. We then assessed efficacy of whole-organism vaccines to induce sterile immunity, and compared the thicket rat model to conventional mouse models. Using P. berghei ANKA radiation-attenuated sporozoites, and P. berghei ANKA and P. yoelii chemoprophylaxis vaccination approaches, we found that standard doses of vaccine sufficient to protect laboratory mice for a long duration against malaria challenge, are insufficient to protect thicket rats, which require higher doses of vaccine to achieve even short-term sterile immunity. Thicket rats may offer a more stringent and pertinent model for evaluating whole-organism vaccines.


Selective Estrogen Receptor Modulator (SERM)-like Activities of Diarylheptanoid, a Phytoestrogen from Curcuma comosa, in Breast Cancer Cells, Pre-osteoblast Cells, and Rat Uterine Tissues.
Diarylheptanoids from Curcuma comosa, of the Zingiberaceae family, exhibit diverse estrogenic activities. In this study we investigated the estrogenic activity of a major hydroxyl diarylheptanoid, 7-(3,4 -dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound 092) isolated from C. comosa. The compound elicited different transcriptional activities of estrogen agonist at low concentrations (0.1-1 μM) and antagonist at high concentrations (10-50 μM) using luciferase reporter gene assay in HEK-293T cells. In human breast cancer (MCF-7) cells, compound 092 showed an anti-estrogenic activity by down-regulating ERα-signaling and suppressing estrogen-responsive genes, whereas it attenuated the uterotrophic effect of estrogen in immature ovariectomized rats. Of note, compound 092 promoted mouse pre-osteoblastic (MC3T3-E1) cell differentiation and the related bone markers, indicating its positive osteogenic effect. Our findings highlight a new, nonsteroidal, estrogen agonist/antagonist of catechol diarylheptanoid from C. comosa, which is scientific evidence supporting its potential as a dietary supplement to prevent bone loss with low risk of breast and uterine cancers in postmenopausal women.


Risk factors for recurrent ureteropelvic junction obstruction after open pyeloplasty in a large pediatric cohort.
Recurrent ureteropelvic junction obstruction after open pyeloplasty is a serious complication for which treatment remains challenging. We identified risk factors for persistent obstruction. We retrospectively reviewed the charts of 401 children who underwent open dismembered pyeloplasty between 1997 and 2005. Of these children 21 (5.2%) experienced recurrent ureteropelvic junction obstruction. Age, prenatal diagnosis, hydronephrosis grade, differential renal function, incision location (flank or dorsal lumbotomy), retrograde pyelography and stent placement were analyzed. Univariate and multivariate analyses were performed to identify risk factors for pyeloplasty failure. Median age at surgery was 21 months and median followup was 36 months. Of the 401 patients dorsal lumbotomy was performed in 171 (42.6%) and a flank incision was used in 230 (57.4%). Retrograde pyelography was done in 195 patients (48.6%) and stents were used in 352 (87%). Age, prenatal diagnosis, degree of hydronephrosis, differential renal function and stent placement did not have an impact on pyeloplasty outcome on univariate analysis. Recurrent ureteropelvic junction obstruction developed in 14 of 171 patients who had originally undergone dorsal lumbotomy vs 7 of 230 who had originally undergone a flank incision (8.1% vs 3.1%, p = 0.02) as well as in 17 of 206 who did not undergo initial retrograde pyelography vs 4 of 195 who did (8.3% vs 2.1%, p = 0.005). On multivariate analysis incision type and lack of retrograde pyelography showed significant association with pyeloplasty failure despite adjustment for other risk factors (p <0.05, OR 3.2 and 4.4, respectively). In this series lack of retrograde pyelography and dorsal lumbotomy were independently associated with a higher risk of recurrent ureteropelvic junction obstruction. While retrograde pyelography or a flank approach could not be directly shown to prevent recurrent ureteropelvic junction obstruction, electing to perform retrograde pyelography may be a proxy for better perioperative planning, including the choice of incision, and it may ultimately increase the chances of successful pyeloplasty.


The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations.
Chromosomal translocations are common in leukemia, but little is known about their mechanism. Metnase (also termed SETMAR) is a fusion of a histone methylase and transposase protein that arose specifically in primates. Transposases were thought to be extinct in primates because they would mediate deleterious DNA movement. In primates, Metnase interacts with DNA Ligase IV (Lig IV) and promotes nonhomologous end-joining (NHEJ) DNA repair. We show here that the primate-specific protein Metnase can also enhance NHEJ in murine cells and can also interact with murine Lig IV, indicating that it integrated into the preexisting NHEJ pathway after its development in primates. Significantly, expressing Metnase in murine cells significantly reduces chromosomal translocations. We propose that the fusion of the histone methylase SET domain and the transposase domain in the anthropoid lineage to form primate Metnase promotes accurate intrachromosomal NHEJ and thereby suppresses interchromosomal translocations. Metnase may have been selected for because it has a function opposing transposases and may thus play a key role in suppressing translocations that underlie oncogenicity.


Perspective on insulin use in gestational diabetes: A phenomenological study.
Gestational diabetes mellitus (GDM) is characterized by carbohydrate metabolism intolerance during pregnancy in individuals with normal blood glucose levels before pregnancy. The first-line treatment for GDM is nutrition and exercise, and insulin therapy is initiated when these are insufficient. Pregnant women who are started on insulin often think that they use drugs that may be harmful to the baby. Therefore, this study aimed to examine the perspectives of women diagnosed with gestational diabetes on insulin use using a phenomenological approach. Qualitative research was conducted using phenomenological patterns. The interviews were recorded on an online/face-to-face voice recorder in a semi-structured form, and thematic content analysis was performed using MAXQDA22. Based on the inclusion criteria of the 2 hospitals specific to the study, 15 patients were included, and the study reached saturation. Three main themes and 2 subthemes were obtained from the coding. The main themes were derived from, "fear," "baby protector," and "last remedy" coding. Pregnant women diagnosed with GDM can define gestational diabetes because of the training provided. Because the pregnancy period is sensitive, pregnant women delay control and insulin application for the health of their babies. Moreover, they sometimes experience pain during the injection, and believe that it may harm their babies.


Regulation of a plant SNF1-related protein kinase by glucose-6-phosphate.
One of the major protein kinases (PK(III)) that phosphorylates serine-158 of spinach sucrose-phosphate synthase (SPS), which is responsible for light/dark modulation of activity, is known to be a member of the SNF1-related family of protein kinases. In the present study, we have developed a fluorescence-based continuous assay for measurement of PK(III) activity. Using the continuous assay, along with the fixed-time-point (32)P-incorporation assay, we demonstrate that PK(III) activity is inhibited by glucose-6-phosphate (Glc-6-P). Relative inhibition by Glc-6-P was increased by decreasing pH from 8. 5 to 5.5 and by reducing the concentration of Mg(2+) in the assay from 10 to 2 mM. Under likely physiological conditions (pH 7.0 and 2 mM Mg(2+)), 10 mM Glc-6-P inhibited kinase activity approximately 70%. Inhibition by Glc-6-P could not be ascribed to contaminants in the commercial preparations. Other metabolites inhibited PK(III) in the following order: Glc-6-P > mannose-6-P, fructose-1,6P(2) > ribose-5-P, 3-PGA, fructose-6-P. Inorganic phosphate, Glc, and AMP were not inhibitory, and free Glc did not reverse the inhibition by Glc-6-P. Because SNF1-related protein kinases are thought to function broadly in the regulation of enzyme activity and gene expression, Glc-6-P inhibition of PK(III) activity potentially provides a mechanism for metabolic regulation of the reactions catalyzed by these important protein kinases.


How good is general practice developmental screening?
All developmental screening in Somerset is performed by general practitioners and health visitors. A retrospective review of a cohort of 1504 7 year old children living in semirural Somerset found that the development assessment by a health visitor at age 3 1/2 years had a sensitivity of 45% for identifying the 103 children with special educational needs, whereas the sensitivity of the preschool examination by a general practitioner was 56%. There was no relation between results of preschool developmental assessment and later reading ability. Of the 23 children in special schools, 22 had been identified independently of the developmental screening programme before starting school. Intervention was started at a mean age of 1 year 5 months (range 2 months to 3 years) for children with severe learning difficulties, and 3 years 9 months (2 years 3 months to 6 years 6 months) for children with moderate learning difficulties. The preschool medical examination revealed fairly minor medical problems: 29 of 81 children referred for specialist opinions were shown to be medically normal, and for only seven of the medically abnormal children was information about their conditions given to their teachers. In Somerset screening the development of all children at predetermined ages has not been very useful.


Cultural and linguistic validation of the Italian version of the intensive care delirium screening checklist.
The purposes of this study were to identify the most suitable rating scale for the diagnosis of delirium in the Italian setting and to develop and validate an Italian version of a delirium screening checklist. The findings are reported.


[Neck skin-muscular flap use in cases of expanded operations on the occasion of malignant neoplasms of maxillo-facial region].
Comparative analysis of the results of different flaps, cut out on side surface of the neck for plastic cover of extensive defects of maxillo-facial region (MFR) formed after malignant tumors ablation, use was carried out. Reconstructive plastic operations were performed in 84 patients: displacement of neck skin-facial flap on the stem in 54 (64.1%) patients, use of neck skin-muscle flap (SMF) in 20 (23.8%) patients, use of improved method of skin-muscle transplant forming from only medial part of nodding muscle in 10 (12.1%) patients. Good cosmetic and functional results were received in 62 (73.8%) observations. Use of complex SMF after surgical interventions in cases of malignant tumors in MFR let reduce the number of postoperative complications and provide earlier rehabilitation of this heavy group of patients.


Influences of the size and hydroxyl number of fullerenes/fullerenols on their interactions with proteins.
In this study, we systematically investigated the interaction of fullerenes/fullerenols with model proteins using a widely used computational docking program Autodock 4.0. We found that pi-pi interaction existed in all the proteins-fullerene/fullerenol systems investigated here, and contributed greatly to the overall interaction energy. We also found that with the increase of the carbon cage size, the binding strength between proteins and fullerenes/fullerenols increased constantly. In addition, our results show that functionalization of fullerenes with polar groups, such as hydroxyl groups, decreases the binding between proteins and fullerene derivatives. In other words, the more hydroxyl groups on fullerenols, the weaker binding between proteins and fullerenols.