Medical Device-Related Pressure Injuries in Infants and Children.
The purpose of this study was to describe medical device-related pressure injuries (MDRPIs) in hospitalized pediatric patients. A prospective, descriptive study. The sample comprised 625 patients cared for in 8 US pediatric hospitals. Participants were aged preterm to 21 years, on bed rest for at least 24 hours, and had a medical device in place. Two nursing teams, blinded to the other's assessments, worked in tandem to assess pressure injury risk, type of medical devices in use, and preventive interventions for each medical device. They also identified the presence, location, and stage of MDRPI. Subjects were observed up to 8 times over 4 weeks, or until discharge, whichever occurred first. Of 625 enrolled patients, 42 (7%) developed 1 or more MDRPIs. Two-thirds of patients with MDRPIs were younger than 8 years. Patients experiencing MDRPIs had higher acuity scores on hospital admission, were more frequently cognitively and/or functionally impaired, or were extreme in body mass index. Respiratory devices caused the most injuries (6.19/1000 device-days), followed by immobilizers (2.40/1000 device-days), gastric tubes (2.24/1000 device-days), and external monitoring devices (1.77/1000 device-days). Of the 6336 devices in place, 36% did not have an MDRPI preventive intervention in place. Clinical variables contributing to MDRPI development included intensive care unit care (odds ratio [OR] 8.9, 95% confidence interval [CI] 1.9-43.6), use of neuromuscular blockade (OR 3.7, 95% CI 1.7-7.8), and inotropic/vasopressor medications (OR 2.7, 95% CI 1.7-4.3). Multivariable analysis indicated that Braden QD scores alone predicted MDRPI development. Medical devices are common in hospitalized infants and children and these medical devices place patients at risk for MDRPI.


To Include or Not to Include: The Impact of Gene Filtering on Species Tree Estimation Methods.
With the increasing availability of whole genome data, many species trees are being constructed from hundreds to thousands of loci. Although concatenation analysis using maximum likelihood is a standard approach for estimating species trees, it does not account for gene tree heterogeneity, which can occur due to many biological processes, such as incomplete lineage sorting. Coalescent species tree estimation methods, many of which are statistically consistent in the presence of incomplete lineage sorting, include Bayesian methods that coestimate the gene trees and the species tree, summary methods that compute the species tree by combining estimated gene trees, and site-based methods that infer the species tree from site patterns in the alignments of different loci. Due to concerns that poor quality loci will reduce the accuracy of estimated species trees, many recent phylogenomic studies have removed or filtered genes on the basis of phylogenetic signal and/or missing data prior to inferring species trees; little is known about the performance of species tree estimation methods when gene filtering is performed. We examine how incomplete lineage sorting, phylogenetic signal of individual loci, and missing data affect the absolute and the relative accuracy of species tree estimation methods and show how these properties affect methods' responses to gene filtering strategies. In particular, summary methods (ASTRAL-II, ASTRID, and MP-EST), a site-based coalescent method (SVDquartets within PAUP*), and an unpartitioned concatenation analysis using maximum likelihood (RAxML) were evaluated on a heterogeneous collection of simulated multilocus data sets, and the following trends were observed. Filtering genes based on gene tree estimation error improved the accuracy of the summary methods when levels of incomplete lineage sorting were low to moderate but did not benefit the summary methods under higher levels of incomplete lineage sorting, unless gene tree estimation error was also extremely high (a model condition with few replicates). Neither SVDquartets nor concatenation analysis using RAxML benefited from filtering genes on the basis of gene tree estimation error. Finally, filtering genes based on missing data was either neutral (i.e., did not impact accuracy) or else reduced the accuracy of all five methods. By providing insight into the consequences of gene filtering, we offer recommendations for estimating species tree in the presence of incomplete lineage sorting and reconcile seemingly conflicting observations made in prior studies regarding the impact of gene filtering.


Universality of evolutionary trajectories under arbitrary forms of self-limitation and competition.
The assumption of constant population size is central in population genetics. It led to a large body of results that is robust to modeling choices and that has proven successful to understand evolutionary dynamics. In reality, allele frequencies and population size are both determined by the interaction between a population and the environment. Relaxing the constant-population assumption has two big drawbacks. It increases the technical difficulty of the analysis, and it requires specifying a mechanism for the saturation of the population size, possibly making the results contingent on model details. Here we develop a framework that encompasses a great variety of systems with an arbitrary mechanism for population growth limitation. By using techniques based on scale separation for stochastic processes, we are able to calculate analytically properties of evolutionary trajectories, such as the fixation probability. Remarkably, these properties assume a universal form with respect to our framework, which depends on only three parameters related to the intergeneration timescale, the invasion fitness, and the carrying capacity of the strains. In other words, different systems, such as Lotka-Volterra or a chemostat model (contained in our framework), share the same evolutionary outcomes after a proper remapping of their parameters. An important and surprising consequence of our results is that the direction of selection can be inverted, with a population evolving to reach lower values of invasion fitness.


Prognostic factors in choroidal and ciliary body melanomas with extrascleral extension.
In a retrospective study, 50 (8.2%) of 610 patients with malignant melanoma of the ciliary body or choroid had extrascleral extension. Of 46 patients for whom follow-up data were available, 24 (52%) survived five years, 20 (42%) survived ten years, and 17 (37%) survived 15 years. Factors that seemed to affect survival significantly included intraocular tumor size and extraocular tumor size and location. Our observations did not support the role of primary exenteration. Five patients (11%) with extrascleral extension had orbital recurrences and all died within 31 months of surgery regardless of treatment.


Metaphase chromosome anomaly: association with drug resistance and cell-specific products.
Large, homogeneously staining chromosome regions which lack the longitudinal differentiation ordinarily revealed by cytogenetic "banding" methods have been found in antifolate-resistant Chinese hamster cells and also in human neuroblastoma cells established in vitro. The drug-resistant cells are characterized by excessive production of the target enzyme, dihydrofolate reducatase, while the human neuroblastoma cells have phenotypes of normal neuronal cells. The homogeneously staining region appears to represent a novel metaphase chromosome anaomaly which may have functional significance in cells with specialized properties.


Radiological Evaluation of the Styloid Process Length Using 64-row Multidetector Computed Tomography Scan.
As elongated styloid process is one of the causes of recurrent oropharyngeal pain and carotid nerve plexus compression called Eagle's syndrome and this length is not similar in different communities, the aim of the current study is to determine average length of styloid process by paranasal multidetector computed tomography. This is a retrospective cross-sectional study about 393 patients who underwent paranasal MDCT scan for trauma in Radiology Department without pathologic finding. Styloid length from temporal bone junction to tip of the process was measured using Workstation software. Demographic data including age, sex, and height were gathered from the patients' records, and patients were questioned about symptoms of Eagle's syndrome before trauma. Data were analyzed using SPSS version 20 with the methods of t-test, Chi-square, and ANOVA. P < 0.05 was considered statistically significant. Two-hundred and sixteen males and 177 females underwent MDCT. The length of right, left, and mean length of both sides were 25.4 ± 7.3, 25.2 ± 7.8, 25.3 ± 7.1, respectively. The mean length of both sides' process was more among male that was statistically significant (P = 0.025 and 0.043, respectively). Right and left side styloid process' higher length was in correlation with patient's height (P = 0.002, r = 0.153, P = 0.029, r = 0.110, respectively) and number of symptoms (P < 0.001, r = 0.300, P < 0.001, r = 0.334, respectively). The mean length of styloid process was 25.3 ± 7.1 that was in accordance with some studies and different from others. Styloid process length is higher in males. The length of styloid process is in association with height and number of symptoms as well.


Motor unit recruitment cannot be inferred from surface EMG amplitude and basic reporting standards must be adhered to.
The study by Jenkins et al. attempted to elucidate the mechanisms behind the findings of Mitchell et al. (J Appl Physiol 113(1):71-77, 2012). However, we believe the work of Jenkins et al. contains methodological issues, does not meet electromyographic reporting standards, and deduces conclusions beyond which can be interpreted from the data provided.


Kinetics of early molecular events in duck hepatitis B virus replication in primary duck hepatocytes.
This paper describes the use of one-step growth conditions to study the kinetics of duck hepatitis B virus (DHBV) replication in primary duck hepatocytes. Synchronized infection was achieved using partially purified DHBV virions at an m.o.i. of 640 DHBV DNA-containing virions per cell, and these conditions were shown to produce a single cycle of infection. In this model, input purified DHBV DNA was rapidly internalized by cells at > or = 0.5 h, and localized to the nucleus by 4 h, but both covalently closed circular (CCC) DNA and single-stranded DNA were not detected until 48 h postinoculation (p.i.), suggesting that there was a > or = 40 h delay between DHBV localization to the nucleus and formation of CCC DNA. In contrast, CCC DNA can be first detected in hepatocytes at 6 h p.i. in in vivo infection of ducks with the same DHBV strain. In an analysis of the nuclear transport of the DHBV genome, release of nuclear viral DNA from a particulate form to a soluble nucleoplasmic form was only 50% complete by 48 h p.i. However, this process occurred simultaneously with genome uncoating since all soluble nucleoplasmic DHBV DNA was free of nucleocapsid material; this suggests that nucleocapsid disassembly and genome uncoating may occur at the nuclear membrane and not within the nucleus. Quantitative analysis demonstrated inefficiency in a number of steps including virus uptake and internalization, translocation of nucleocapsid across the nuclear membrane and antigen expression from intranuclear viral DNA.


The transpalatal approach to repair of congenital Basal skull base cephaloceles.
Basal skull base herniations, including meningoceles and encephaloceles, are rare and may present with characteristic facial and neurologic features. The traditional craniotomy approach has known morbidity, and nasal endoscopy may not allow for control of large posterior basal defects, especially in newborns. We present two cases of successful repair of basal transsphenoidal meningoceles using an oral-transpalatal approach. The first patient with an intact palate presented with respiratory distress, and a palatectomy was performed for access to the skull base. The second patient had a large basal herniation that was reduced through a congenital midline cleft palate, and a calvarial bone graft was used to repair the defect. A literature search revealed 10 previous successful cases using the transpalatal repair, which allows for excellent access, low morbidity, and a team-oriented method to skull base surgery.


Direction-Specific Jaw Dysfunction and Its Impact on Tongue Movement in Individuals With Dysarthria Secondary to Amyotrophic Lateral Sclerosis.
Purpose The current study tested jaw movement characteristics and their impact on tongue movement for speech production in individuals with amyotrophic lateral sclerosis (ALS). Specifically, the study examined tongue and jaw movement in multiple directions during jaw opening and closing strokes in individuals with ALS and controls. Method Twenty-two individuals with ALS and 22 controls participated in the current study. Tongue and jaw movements during the production of the words "Iowa" and "Ohio" (produced in a carrier phrase) were recorded using electromagnetic articulography. Tongue and jaw distances were measured for jaw opening and closing strokes. Distance was measured in the anterior-posterior and superior-inferior dimensions (retraction, advancement, lowering, and raising). Results Findings revealed that individuals with ALS exaggerated their jaw opening movements, but not their jaw closing movements, compared to controls. Between the groups, a comparable tongue lowering distance was observed during jaw opening movements. In contrast, reduced tongue raising was observed during the jaw closing movements in individuals with ALS compared to controls. Conclusion The findings suggest that individuals with ALS produce excessive jaw opening movements in the absence of excessive jaw closing movements. The lack of excessive jaw closing movements results in reduced tongue raising in these individuals. Excessive jaw opening movements alone suggest a direction-specific jaw dysfunction. Future studies should examine whether excessive jaw raising can be facilitated and if it enhances tongue raising movement for speech production in individuals with dysarthria secondary to ALS.


Composition of the cell wall of Chlorella fusca.
Isolated cell walls of mature Chlorella fusca consisted of about 80% carbohydrate, 7% protein, and 13% unidentified material. Mannose and glucose were present in a ratio of about 2.7:1 and accounted for most of the carbohydrate. Minor components were glucuronic acid, rhamnose, and traces of other sugars; galactose was absent. After treatment with 2 M trifluoroacetic acid or with 80% acetic acid/HNO3 (10/1, v/v), a residue with a mannose/glucose ratio of 0.3:1 was obtained, probably representing a structural polysaccharide. An X-ray diffraction diagram of the walls showed one diffuse reflection at 0.44 nm and no reflections characteristic of cellulose. Walls from young cells contained about 51% carbohydrate, 12% protein, and 37% unidentified material. Mannose and glucose were also the main sugars; their absolute amounts per wall increased 6-7 fold during cell growth. Walls isolated with omission of a dodecylsulphate/mercaptoethanol/urea extraction step had a higher protein content and, with young walls, a significantly higher glucose and fucose content. These data and other published cell wall analyses show a wide variability in cell wall composition of the members of the genus Chlorella.


Plasma free cortisol in depressive illness--a review of findings and clinical implications.
Measurements of a variety of parameters of biologically active cortisol indicate that a small number of patients with depressive illness have significantly elevated levels of unbound plasma cortisol. Abnormalities in corticosteroid binding globulin do not account for the hypercortisolemia, and elevated urinary levels of free cortisol confirm the data obtained for plasma free cortisol. Direct measurements of free cortisol suggest that the absence of physical effects of cortisol in patients with depression is related to the very mild elevation in plasma levels of free cortisol in these patients and that high levels are not sustained throughout the day as they are in patients with pathologic glucocorticoid excess. The apparent discrepancy between elevated total cortisol levels and the mild elevation of unbound plasma cortisol is best explained by the generous binding capacity of corticosteroid binding globulin. Total cortisol levels of greater than 25 micrograms/dl are necessary to saturate the binding sites of corticosteroid binding globulin. Only then can free cortisol be detected in plasma. Although these studies suggest that unbound plasma cortisol is elevated, whether these levels represent biologically active cortisol in other tissue sites as well, particularly the central nervous system, is still unclear. It is well accepted that discrete binding sites for cortisol and dexamethasone occur in hypothalamic and pituitary tissue, but the mechanism of glucocorticoid regulation of these binding sites has not been elucidated. Cortisol levels in cerebrospinal fluid correspond closely to plasma levels of unbound cortisol. Ruf and Steiner have shown that corticosteroid responsive neurons are present in the periventricular gray matter of the third ventricle, where other investigators have identified active ependymal transport mechanisms for cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)


A novel oncogene related to c-mil is transduced in chicken neuroretina cells induced to proliferate by infection with an avian lymphomatosis virus.
Non-dividing neuroretina cells from chicken embryos are induced to proliferate after a long latency, following infection with Rous associated virus type 1, an avian retrovirus which does not carry a transforming gene. We have isolated from these proliferating cells an acutely mitogenic retrovirus, designated IC10, which contains a novel oncogene. Nucleotide sequencing showed that the IC10 virus has transduced 1101 nucleotides of cellular origin inserted between the gag and env genes of RAV-1. This oncogene, designated v-Rmil, is 70.1% homologous to v-mil. v-Rmil encodes a protein of 40,976 daltons sharing 83.8% homology with the catalytic domain of the v-mil protein. Divergence with the v-mil gene product is observed at the NH2- and COOH-terminal portions of the v-Rmil protein. Restriction analysis of normal chicken DNA indicated that v-Rmil is derived from a cellular gene distinct from c-mil. The c-Rmil gene is transcribed through a major mRNA, greater than 10 kb in length, that is detected at much higher levels in neuroretinas, as compared to other embryonic tissues.


Myelination triggers local loss of axonal CNR/protocadherin alpha family protein expression.
The cadherin-related neuronal receptor (CNR)/protocadherin (Pcdh) alpha family is one of the diverse protocadherin families expressed in developing axons. We observed a strong axonal expression of these proteins at late embryonic and early postnatal stages corresponding to regions where fibers had not yet been myelinated. We therefore followed the postnatal localization of CNR/Pcdh alpha protein in major axonal tracts, such as the internal capsule, lateral olfactory tract, and optic nerve, and found that its axonal localization was dramatically lost in parallel with the increased expression of myelin markers. Moreover, the hypomyelinated optic nerve tracts of the myelin-deficient Shiverer mouse exhibited elevated levels of CNR/Pcdh alpha expression. These axonal expression patterns of CNR/Pcdh alpha in wild-type and Shiverer mice were similar to those of growth associated protein 43 (GAP-43) and L1, both of which are associated with axonal maturation. Thus, myelination may be a trigger for the local loss of axonal CNR/Pcdh alpha protein, and this process may be important in the maturation of neural circuits.


[Possibility of complete recovery in multiple myeloma].
In three patients with multiple myeloma, stage IIIA, a complete remission lasting from 6 to 8 years was attained, in spite of the fact that not all of them received treatment. In the latter case the remission lasted from 5 to 6 years. One of the patients had diffuse Gk + BIk myeloma, one presented with multiple focal one with protein BIk production, and one patient had multiple focal myeloma with spinal cord compression and complete lower paraplegia without verified secretion of monoclonal immunoglobulin. The times of therapy until the attainment of a complete remission were 3,5 and 13 years, whereas the total survival amounted to 9, 5 and 20 years since the appearance of the first disease symptoms. Sarcolysine was employed as the basic cytostatic agent in all the cases. Annual control examinations of the patients in a state of remission have not revealed any signs of myeloma. One patient is manifesting osteolytic deficiencies, however biopsy withdrawn from the focus of osteolysis have not shown any tumor. Immunochemical assay of serum and urine has failed to detect paraprotein, blood immunoglobulins have been discovered to be within normal. The author analyses 4 similar cases reported in literature. It is assumed that it would be premature to regard the patients described above as completely recovered from the biological standpoint and that it would be more wise to consider such cases as prolonged and fairly profound remissions.


Assessing and managing unawareness of self.
Awareness deficits present challenges to recovery and barriers to the rehabilitation process. This paper provides a clinical framework for assessing and managing awareness deficits. It begins with a review of several theoretical and clinical models of awareness in order to identify important characteristics of awareness disorders. A variety of methods for measuring awareness are reviewed. Questions to guide the assessment process are described along with sources for answering the questions. Considerations for implementing three different intervention approaches are also detailed. These interventions include an Individual Awareness Enhancement Program, Procedural Training and Environmental Support, and Caregiver Training and Education. The associated awareness literature is reviewed. An actual case study illustrating the assessment and intervention approaches is provided at the end of the paper.


Criterion validity of the Physical Activity Questionnaire for Schoolchildren (PAQ-S) in assessing physical activity levels: the Healthy Growth Study.
The aim of this paper was to evaluate the criterion validity of the Physical Activity Questionnaire for Schoolchildren (PAQ-S). The current study is a subcohort of the Healthy Growth Study, a large-scale cross-sectional study. 202 schoolchildren aged 9-13 years from Greece completed the PAQ-S and wore an accelerometer for 4 consecutive days. Time spent moderate (MPA), moderate to vigorous (MVPA) and vigorous (VPA) physical activity was calculated based on PAQ-S and accelerometer data. The average time spent on MPA and MVPA as derived from PAQ-S and from accelerometers were significantly moderately correlated (r=0.462, P<0.001 and r=0.483, P<0.001, respectively). No significant correlation was detected between PAQ-S and accelerometer-measured time spent performing VPA (rho=0.150, P=0.057). Intraclass Correlation Coefficient (ICC) indicated a moderate agreement between PAQ-S and accelerometer in estimating MPA (ICC=0.592, P<0.001) and MVPA (ICC=0.581, P<0.001). Bland-Altman analysis revealed a small mean difference (the "bias"), between the two methods, in estimating MPA, although this difference was found to be significantly higher than zero ("bias"=27.4% of the accelerometer-measured mean score, P=0.006). On the other hand, Bland-Altman analysis revealed a large mean difference in estimating MVPA and VPA ("bias"=84.2% and 357% of the accelerometer-measured mean score for MVPA and VPA, respectively and P<0.001). The high correlation coefficient between the average and difference values between all physical activity scores derived from accelerometers and PAQ-S, indicate a systematic overestimation of physical activity time with increasing physical activity for PAQ-S. The validity of PAQ-S for the estimation of MPA and MVPA was found to be slightly similar self-reported measures for schoolchildren. Therefore, this questionnaire could be used as a tool for physical activity assessment in large population studies.


Dupilumab and prurigo nodularis-like phenotype in atopic dermatitis: our experience of efficacy.
Atopic dermatitis (AD) is a common chronic multifactorial dermatosis that can occur through different clinical phenotypes although all exhibit identical pathogenetic mechanisms such as the prurigo nodularis (PN)-like phenotype. Here, we described 11 patients with PN-like AD treated with dupilumab, a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13). Efficacy outcomes were performed at baseline, at first and fourth month after starting treatment. We collected different scores such as NRSi as well as IGA. At the same time, patient subjective benefits were analyzed through DLQI, POEM, and HADS scores. Quality of sleep was also recorded by NRSS. All patients showed rapid clinical improvement of cutaneous lesions and no other new lesions were reported during treatment. Reduction of daily itching was referred already after the first month of treatment. These results show the effectiveness of dupilumab in this clinical setting of AD, supporting this treatment as a valid therapeutic approach in difficult-to-treat-PN-like clinical presentation of AD.


The Purpose of Bedside Robots: Exploring the Needs of Inpatients and Healthcare Professionals.
Robotic systems are used to support inpatients and healthcare professionals and to improve the efficiency and quality of nursing. There is a lack of scientific literature on how applied robotic systems can be used to support inpatients. This study uses surveys and focus group interviews to identify the necessary aspects and functions of bedside robots for inpatients. A total of 90 healthcare professionals and 108 inpatients completed the questionnaire, and four physicians and five nurses participated in the focus group interviews. The most highly desired functionalities were related to patient care and monitoring, including alerting staff, measuring vital signs, and sensing falls. Nurses and physicians reported different needs for human-robot interaction. Nurses valued robotic functions such as nonverbal expression recognition, automatic movement, content suggestion, and emotional expressions. The results of the patients' open-ended questions and healthcare professionals' focus groups indicate that the purpose of the robots should primarily be treatment and nursing. Participants believe bedside robots would be helpful but have concerns regarding safety and utility. This study attempts to determine which aspects of robots may increase their acceptance. Our findings suggest that if robots are used in healthcare institutions, they may improve the effectiveness of care.


Clostridial Genetics: Genetic Manipulation of the Pathogenic Clostridia.
The past 10 years have been revolutionary for clostridial genetics. The rise of next-generation sequencing led to the availability of annotated whole-genome sequences of the important pathogenic clostridia: Clostridium perfringens, Clostridioides (Clostridium) difficile, and Clostridium botulinum, but also Paeniclostridium (Clostridium) sordellii and Clostridium tetani. These sequences were a prerequisite for the development of functional, sophisticated genetic tools for the pathogenic clostridia. A breakthrough came in the early 2000s with the development of TargeTron-based technologies specific for the clostridia, such as ClosTron, an insertional gene inactivation tool. The following years saw a plethora of new technologies being developed, mostly for C. difficile, but also for other members of the genus, including C. perfringens. A range of tools is now available, allowing researchers to precisely delete genes, change single nucleotides in the genome, complement deletions, integrate novel DNA into genomes, or overexpress genes. There are tools for forward genetics, including an inducible transposon mutagenesis system for C. difficile. As the latest addition to the tool kit, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 technologies have also been adopted for the construction of single and multiple gene deletions in C. difficile. This article summarizes the key genetic technologies available to manipulate, study, and understand the pathogenic clostridia.


Discovery of a Dual Tubulin and Neuropilin-1 (NRP1) Inhibitor with Potent In Vivo Anti-Tumor Activity via Pharmacophore-based Docking Screening, Structure Optimization, and Biological Evaluation.
Dual inhibition of tubulin and neuropilin-1 (NRP1) may become an effective method for cancer treatment by simultaneously killing tumor cells and inhibiting tumor angiogenesis. Herein, we identified dual tubulin/NRP1-targeting inhibitor TN-2, which exhibited good inhibitory activity against both tubulin polymerization (IC50 = 0.71 ± 0.03 μM) and NRP1 (IC50 = 0.85 ± 0.04 μM). Importantly, it significantly inhibited the viability of several human prostate tumor cell lines. Further mechanism studies indicated that TN-2 could inhibit tubulin polymerization and cause G2/M arrest, thereby inducing cell apoptosis. It could also suppress cell tube formation, migration, and invasion. Moreover, TN-2 showed obvious antitumor effects on the PC-3 cell-derived xenograft model with negligible side effects and good pharmacokinetic profiles. These data demonstrate that TN-2 could be a promising dual-target chemotherapeutic agent for the treatment of prostate cancer.


Impacts of extreme winter warming events on plant physiology in a sub-Arctic heath community.
Insulation provided by snow cover and tolerance of freezing by physiological acclimation allows Arctic plants to survive cold winter temperatures. However, both the protection mechanisms may be lost with winter climate change, especially during extreme winter warming events where loss of snow cover from snow melt results in exposure of plants to warm temperatures and then returning extreme cold in the absence of insulating snow. These events cause considerable damage to Arctic plants, but physiological responses behind such damage remain unknown. Here, we report simulations of extreme winter warming events using infrared heating lamps and soil warming cables in a sub-Arctic heathland. During these events, we measured maximum quantum yield of photosystem II (PSII), photosynthesis, respiration, bud swelling and associated bud carbohydrate changes and lipid peroxidation to identify physiological responses during and after the winter warming events in three dwarf shrub species: Empetrum hermaphroditum, Vaccinium vitis-idaea and Vaccinium myrtillus. Winter warming increased maximum quantum yield of PSII, and photosynthesis was initiated for E. hermaphroditum and V. vitis-idaea. Bud swelling, bud carbohydrate decreases and lipid peroxidation were largest for E. hermaphroditum, whereas V. myrtillus and V. vitis-idaea showed no or less strong responses. Increased physiological activity and bud swelling suggest that sub-Arctic plants can initiate spring-like development in response to a short winter warming event. Lipid peroxidation suggests that plants experience increased winter stress. The observed differences between species in physiological responses are broadly consistent with interspecific differences in damage seen in previous studies, with E. hermaphroditum and V. myrtillus tending to be most sensitive. This suggests that initiation of spring-like development may be a major driver in the damage caused by winter warming events that are predicted to become more frequent in some regions of the Arctic and that may ultimately drive plant community shifts.


Protein Requirements of the Critically Ill Pediatric Patient.
This article includes a review of protein needs in children during health and illness, as well as a detailed discussion of protein metabolism, including nitrogen balance during critical illness, and assessment and prescription/delivery of protein to critically ill children. The determination of protein requirements in children has been difficult and challenging. The protein needs in healthy children should be based on the amount needed to ensure adequate growth during infancy and childhood. Compared with adults, children require a continuous supply of nutrients to maintain growth. The protein requirement is expressed in average requirements and dietary reference intake, which represents values that cover the needs of 97.5% of the population. Critically ill children have an increased protein turnover due to an increase in whole-body protein synthesis and breakdown with protein degradation leading to loss of lean body mass (LBM) and development of growth failure, malnutrition, and worse clinical outcomes. The results of protein balance studies in critically ill children indicate higher protein needs, with infants and younger children requiring higher intakes per body weight compared with older children. Monitoring the side effects of increased protein intake should be performed. Recent studies found a survival benefit in critically ill children who received a higher percentage of prescribed energy and protein goal by the enteral route. Future randomized studies should evaluate the effect of protein dosing in different age groups on patient outcomes, including LBM, muscle structure and function, duration of mechanical ventilation, intensive care unit and hospital length of stay, and mortality.


Complications following powered endoscopic sinus surgery: an 11 year study on 1190 patients in a single institute in Israel.
Over the past 20 years, advances in endoscopic sinus surgery (ESS) techniques have led to widespread applications of this technology in both adult and pediatric populations with better results and lower morbidity. To update data regarding the rate of minor and major complications following ESS procedures that used powered instrumentation. We retrospectively reviewed the charts of all patients who, with general anesthesia, underwent ESS utilizing powered instrumentation between January 1996 and December 2006. Age, gender, indication for surgery, length of hospitalization, and type and rate of surgical complications were recorded. A total of 1190 patients were included in our study (1309 surgeries). The male:female ratio was 1.7:1.0 and the average age was 39 years (range 4-86 years). The most common indication for surgery was chronic rhinosinusitis. The rate of major complications was 0.31% and that of minor complications 1.37%. The only major complication that occurred was cerebrospinal fluid leak. The minor complications included epistaxis, periorbital emphysema, ecchymosis and mucocele formation. Compared to previously published series, the rate of major and minor complications in our study was low. The results indicate that the use of powered instruments during ESS is safe.


Outlook of drug-eluting stent implantation for unprotected left main disease: insights on long-term clinical predictors.
Percutaneous coronary intervention (PCI) has been increasingly employed to treat unprotected left main coronary artery (LMCA) stenosis, with variable success. This strategy has been applied to patients undergoing drug-eluting stent (DES) implantation for unprotected LMCA stenosis. From April 2003 to June 2006, 114 consecutive patients with de novo unprotected LMCA stenosis underwent PCI with DES, and were followed over a mean period of 17.1 +/- 9.1 months. The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE) (cardiac death, myocardial infarction [MI] or target lesion revascularization [TLR]). LMCA stenting was successfully performed in all patients. In-hospital mortality was 3.5%, with no in-hospital non-fatal MI or emergency coronary artery bypass grafts. During the follow-up period, the all-cause mortality rate was 7.9%, with 3.5% cardiac-related deaths. TLR was performed in 7.9% of patients, and the MACE rate was 14.9%. All non-surviving patients were at high surgical risk (EuroSCORE > 6) and had a significantly higher EuroSCORE than surviving patients that patients with a EuroSCORE < or = 11 had significantly improved survival rates over those with a EuroSCORE > 11 (p < 0.0001). Moreover, most of the patients who died of cardiac causes were diabetic (71.4% vs. 26.6%; p < 0.05). Acute coronary syndromes, as clinical presentation, and non-ostial LMCA disease were also significantly more common within non-surviving patients (100% vs. 67%; p < 0.05, and 92.3% vs. 66.3%; p = 0.05, respectively). Stenting of unprotected LMCA appears to be associated with a favorable mid-term outlook, especially in selected patients.


Osteoporosis in hemiplegic stroke patients as studied with dual-energy X-ray absorptiometry.
To compare bone mineral densities (BMDs) of the affected and unaffected limbs in stroke patients at multiple sites; to study longitudinal changes during a 3-month rehabilitation program; and to relate BMDs to demographic, impairment, and disability variables. Descriptive study. Tertiary rehabilitation center. One hundred four consecutive hemiplegic inpatients, 69 men, age 56.5 +/- 13.2 yrs, 47 with left-sided brain lesion. Median days from onset to admission and median length of stay days were 83 and 105.5, respectively. BMDs of proximal humerus, distal radius, femoral neck, and calcaneus bilaterally, and third lumbar vertebra, measured with dual-energy x-ray absorptiometry (DXA), were compared between affected and unaffected sides at admission and discharge. Stroke Impairment Assessment Set (SIAS) motor scores, Functional Independence Measure (FIM) scores, grip strength, and awake/sleep heart rate counts (activity index) improved significantly at discharge. Affected/unaffected BMD ratios were 88.3% to 98.4% at admission and 79.6% to 98.8% at discharge, lowest for the humerus. Discharge/admission ratios were 89.1% to 97.8% for the affected and 97.4% to 100% for the unaffected side. All BMDs were intercorrelated (R = .438 to .873). They correlated significantly with age, body weight, grip strength, FIM scores, and activity index. Factors selected to explain BMD with multiple regression analysis differed according to the site and timing of the measurement. BMDs of the affected side were lower and most marked in the humerus. Longitudinally, not only the affected but the unaffected BMDs decreased. Age, sex, duration of stroke, anthropometric measurements, motor paralysis, muscle strength, and activity level contributed differently to bone loss according to the site and timing of the measurement.


Revision of the nomenclature of the differential host-pathogen interactions of Venturia inaequalis and Malus.
The apple scab (Venturia inaequalis-Malus) pathosystem was one of the first systems for which Flor's concept of gene-for-gene (GfG) relationships between the host plant and the pathogen was demonstrated. There is a rich resource of host resistance genes present in Malus germplasm that could potentially be marshalled to confer durable resistance against this most important apple disease. A comprehensive understanding of the host-pathogen interactions occurring in this pathosystem is a prerequisite for effectively manipulating these host resistance factors. An accurate means of identification of specific resistance and consistent use of gene nomenclature is critical for this process. A set of universally available, differentially resistant hosts is described, which will be followed by a set of defined pathogen races at a later stage. We review pertinent aspects of the history of apple scab research, describe the current status and future directions of this research, and resolve some outstanding issues.


Critical role of evolutionarily conserved glycosylation at Asn211 in the intracellular trafficking and activity of sialyltransferase ST3Gal-II.
ST3Gal-II, a type II transmembrane protein, is the main mammalian sialyltransferase responsible for GD1a and GT1b ganglioside biosynthesis in brain. It contains two putative N-glycosylation sites (Asn(92) and Asn(211)). Whereas Asn(92) is only conserved in mammalian species, Asn(211) is highly conserved in mammals, birds and fish. The present study explores the occupancy and relevance for intracellular trafficking and enzyme activity of these potential N-glycosylations in human ST3Gal-II. We found that ST3Gal-II distributes along the Golgi complex, mainly in proximal compartments. By pharmacological, biochemical and site-directed mutagenesis, we observed that ST3Gal-II is mostly N-glycosylated at Asn(211) and that this co-translational modification is critical for its exit from the endoplasmic reticulum and proper Golgi localization. The individual N-glycosylation sites had different effects on ST3Gal-II enzymatic activity. Whereas the N-glycan at position Asn(211) seems to negatively influence the activity of the enzyme using both glycolipid and glycoprotein as acceptor substrates, the single N-glycan mutant at Asn(92) had only a moderate effect. Lastly, we demonstrated that the N-terminal ST3Gal-II domain containing the cytosolic, transmembrane and stem region (amino acids 1-51) is able to drive a protein reporter out of the endoplasmic reticulum and to retain it in the Golgi complex. This suggests that the C-terminal domain of ST3Gal-II depends on N-glycosylation to attain an optimum conformation for proper exit from the endoplasmic reticulum, but it does not represent an absolute requirement for Golgi complex retention of the enzyme.


Care of the adolescent sexual assault victim.
Sexual assault is a broad-based term that encompasses a wide range of sexual victimizations including rape. Since the American Academy of Pediatrics published its last policy statement on sexual assault in 2001, additional information and data have emerged about sexual assault and rape in adolescents and the treatment and management of the adolescent who has been a victim of sexual assault. This report provides new information to update physicians and focuses on assessment and care of sexual assault victims in the adolescent population.


Activity in V4 reflects the direction, but not the latency, of saccades during visual search.
We constantly make eye movements to bring objects of interest onto the fovea for more detailed processing. Activity in area V4, a prestriate visual area, is enhanced at the location corresponding to the target of an eye movement. However, the precise role of activity in V4 in relation to these saccades and the modulation of other cortical areas in the oculomotor system remains unknown. V4 could be a source of visual feature information used to select the eye movement, or alternatively, it could reflect the locus of spatial attention. To test these hypotheses, we trained monkeys on a visual search task in which they were free to move their eyes. We found that activity in area V4 reflected the direction of the upcoming saccade but did not predict the latency of the saccade in contrast to activity in the lateral intraparietal area (LIP). We suggest that the signals in V4, unlike those in LIP, are not directly involved in the generation of the saccade itself but rather are more closely linked to visual perception and attention. Although V4 and LIP have different roles in spatial attention and preparing eye movements, they likely perform complimentary processes during visual search.


Questionable science and reproducibility in electrical brain stimulation research.
Electrical brain stimulation (EBS) is a trendy new technique used to change brain function and treat neurological, psychiatric and psychological disorders. We were curious whether the published literature, which is dominated by positive results, reflects the experience of researchers using EBS. Specifically, we wanted to know whether researchers are able to reproduce published EBS effects and whether they engage in, but fail to report, questionable research practices. We invited 976 researchers to complete an online survey. We also audited 100 randomly-selected published EBS papers. A total of 154 researchers completed the survey. Survey respondents had a median of 3 [1 to 6, IQR] published EBS papers (1180 total) and 2 [1 to 3] unpublished ones (380 total). With anodal and cathodal EBS, the two most widely used techniques, 45-50% of researchers reported being able to routinely reproduce published results. When asked about how study sample size was determined, 69% of respondents reported using the sample size of published studies, while 61% had used power calculations, and 32% had based their decision on pilot data. In contrast, our audit found only 6 papers where power calculations were used and a single paper in which pilot data was used. When asked about questionable research practices, survey respondents were aware of other researchers who selectively reported study outcomes (41%) and experimental conditions (36%), adjusted statistical analysis to optimise results (43%), and engaged in other shady practices (20%). Fewer respondents admitted to engaging in these practices themselves, although 25% admitted to adjusting statistical analysis to optimize results. There was strong agreement that such practices should be reported in research papers; however, our audit found only two such admissions. The present survey confirms that questionable research practices and poor reproducibility are present in EBS studies. The belief that EBS is effective needs to be replaced by a more rigorous approach so that reproducible brain stimulation methods can be devised and applied.


Quetiapine ameliorates anxiety-like behavior and cognitive impairments in stressed rats: implications for the treatment of posttraumatic stress disorder.
The purpose of this study was to determine preventive and protective effects of chronic orally administration with quetiapine (QUE) against anxiety-like behavior and cognitive impairments in rats exposed to the enhanced single prolonged stress (ESPS), an animal model that is used to study post-traumatic stress disorder (PTSD), and to detect changes in the expression of cortical phosphorylated p44/42 extracellular-regulated protein kinase (pERK1/2). Before or after exposure to ESPS paradigm, consisting of 2-h constraint, 20-min forced swimming, ether-induced loss of consciousness, and an electric foot shock, rats were given orally QUE (10 mg/kg daily) for 14 days. Animals were then tested in the open field (OF), elevated plus-maze (EPM), and Morris water maze (MWM). Brains were removed for immunohistochemical staining of pERK1/2. ESPS exposure resulted in pronounced anxiety-like behavior compared to unexposed animals. ESPS-exposed animals also displayed marked learning and spatial memory impairments. However, QUE treatment (both before and after ESPS exposure) significantly ameliorated anxiety-like behavior, learning and spatial memory impairments. ESPS also markedly reduced the expression of pERK1/2 in the prefrontal cortex, medial amygdala nucleus, and cingulate gyrus. Both before and after ESPS exposure QUE treatments significantly elevated the reduced pERK1/2 expression in the three brain regions. QUE has preventive and protective effects against stress-associated symptoms and the changes in pERK1/2 functions may be associated with the pathophysiology of traumatic stress and the therapeutic efficacy of anti-PTSD therapy.


Experimental radiosurgery simulations using a theoretical model of cerebral arteriovenous malformations.
A novel biomathematical arteriovenous malformation (AVM) model based on electric network analysis was used to investigate theoretically the potential role of intranidal hemodynamic perturbations in elevating the risk of rupture after simulated brain AVM radiosurgery. The effects of radiation on 28 interconnected plexiform and fistulous AVM nidus vessels were simulated by predefined random or stepwise occlusion. Electric circuit analysis revealed the changes in intranidal flow, pressure, and risk of rupture at intervals of 3 months during a 3-year latency period after simulated partial/complete irradiation of the nidus using doses <25 and >/=25 Gy. An expression for risk of rupture was derived on the basis of the functional distribution of the critical radii of component vessels. The theoretical effects of radiation were also tested on AVM nidus vessels with progressively increasing elastic modulus (E:) and wall thickness during the latency period, simulating their eventual fibrosis. In an AVM with E=5. 0x10(4) dyne/cm(2), 4 (14.3%) of a total 28 sets of AVM radiosurgery simulations revealed theoretical nidus rupture (risk of rupture >/=100%). Three of these were associated with partial nidus coverage and 1 with complete treatment. All ruptures occurred after random occlusion of nidus vessels in AVMs receiving low-dose radiosurgery. Intranidal hemodynamic perturbations were observed in all cases of AVM rupture; the occlusion of a fistulous component resulted in intranidal rerouting of flow and escalation of the intravascular pressure in adjacent plexiform components. Risk of rupture was found to correlate with nidus vessel wall strength: a low E: of 1.9x10(4) dyne/cm(2) resulted in a 92.8% incidence of AVM rupture, whereas a higher E: of 7.0x10(4) dyne/cm(2) resulted in only a 3.6% incidence of AVM rupture. A dramatic reduction in rupture incidence was observed when increasing fibrosis of the nidus was modeled during the latency period. It was found that the theoretical occurrence of AVM hemorrhage after radiosurgery was low, particularly when radiation-induced fibrosis of nidus vessels was considered. When rupture does occur, it would appear from a theoretical standpoint that the occlusion of intranidal fistulas or larger-caliber plexiform vessels could be a significant culprit in the generation of critical intranidal hemodynamic surges resulting in nidus rupture. The described AVM model should serve as a useful research tool for further theoretical investigations of cerebral AVM radiosurgery and its hemodynamic sequelae.


Discriminative topological features reveal biological network mechanisms.
Recent genomic and bioinformatic advances have motivated the development of numerous network models intending to describe graphs of biological, technological, and sociological origin. In most cases the success of a model has been evaluated by how well it reproduces a few key features of the real-world data, such as degree distributions, mean geodesic lengths, and clustering coefficients. Often pairs of models can reproduce these features with indistinguishable fidelity despite being generated by vastly different mechanisms. In such cases, these few target features are insufficient to distinguish which of the different models best describes real world networks of interest; moreover, it is not clear a priori that any of the presently-existing algorithms for network generation offers a predictive description of the networks inspiring them. We present a method to assess systematically which of a set of proposed network generation algorithms gives the most accurate description of a given biological network. To derive discriminative classifiers, we construct a mapping from the set of all graphs to a high-dimensional (in principle infinite-dimensional) "word space". This map defines an input space for classification schemes which allow us to state unambiguously which models are most descriptive of a given network of interest. Our training sets include networks generated from 17 models either drawn from the literature or introduced in this work. We show that different duplication-mutation schemes best describe the E. coli genetic network, the S. cerevisiae protein interaction network, and the C. elegans neuronal network, out of a set of network models including a linear preferential attachment model and a small-world model. Our method is a first step towards systematizing network models and assessing their predictability, and we anticipate its usefulness for a number of communities.


Factors predicting retreatment and residual aneurysms at 1 year after endovascular coiling for ruptured cerebral aneurysms: Prospective Registry of Subarachnoid Aneurysms Treatment (PRESAT) in Japan.
Endovascular treatment of cerebral aneurysms includes follow-up imaging to identify aneurysms that may need retreatment. The aim of this study was to determine predictors of incomplete aneurysm occlusion at 1 year after endovascular coiling for ruptured cerebral aneurysms. In 129 patients of the Prospective Registry of Subarachnoid Aneurysms Treatment cohort, ruptured aneurysms were coiled within 14 days of onset and both initial post-coiling and 1-year follow-up digital subtraction angiography or magnetic resonance angiography were obtained. Factors predicting 1-year incomplete aneurysm occlusion (retreatment within 1-year or residual aneurysms at 1 year) were determined using multivariate logistic regression analyses. One-year incomplete aneurysm occlusion was identified in 59 patients, including ten patients who were retreated within 1-year post-coiling. Dome size ≥7.5 mm (P = 0.007, odds ratio (OR) = 5.00, 95% confidence interval (CI) = 1.55-16.15), pre-treatment aneurysm re-rupture (P = 0.023, OR = 3.50, 95% CI = 1.19-10.31), non-small size/small neck aneurysm (dome size, ≥10 mm or neck size, ≥4 mm; P = 0.022, OR = 3.26, 95% CI = 1.19-8.96), and residual aneurysms on immediate post-coiling angiograms (P = 0.017, OR = 1.43, 95% CI = 1.07-1.93) significantly predicted incomplete aneurysm occlusion at 1-year post-coiling. In addition to the characteristics of aneurysm and initially incomplete aneurysm occlusion, this study showed pre-treatment aneurysm re-rupture to be a predictor that favors closer imaging follow-ups for coiled aneurysms.


Optimizing autologous nonmobilized mononuclear cell collections for cellular therapy in pediatric patients with high-risk leukemia.
The manufacturing of cellular products for immunotherapy, such as chimeric antigen receptor T cells, requires successful collection of mononuclear cells. Collections from children with high-risk leukemia present a challenge, especially because the established COBE Spectra apheresis device is being replaced by the novel Spectra Optia device (Optia) in many institutions. Published experience for mononuclear cell collections in children with Optia is lacking. Our aim was to compare the two collection devices and describe modified settings on the Optia to optimize mononuclear cell collections. As a quality initiative, we retrospectively collected and compared data from mononuclear cell collections on both devices. Collected data included patient's clinical characteristics; collection parameters, including precollection lymphocyte/CD3 counts, total blood volumes processed, runtimes, and side effects (including complete blood count and electrolyte changes); and product characteristics, including volumes and cell counts. Collection efficiencies and collection ratios were calculated. Twenty-six mononuclear cell collections were performed on 20 pediatric patients: 11 with COBE and 15 with Optia. Adequate mononuclear cell products were successfully collected with a single procedure from all patients except one, with mean calculated mononuclear cell collection efficiency that was significantly higher from Optia collections compared with COBE collections (57.9 ± 4.6% vs 40.3 ± 6.2%, respectively; p = 0.04). CD3-positive yields were comparable on both machines (p = 0.34) with significantly smaller blood volumes processed on Optia. Collected products had larger volumes on Optia. No significant side effects attributed to the procedure were noted. Mononuclear cell apheresis using the Optia device in children is more efficient and is as safe as that with the COBE device.


9-1-1 Activations from Ambulatory Care Centers: A Sicker Pediatric Population.
Pediatric patients transferred by Emergency Medical Services (EMS) from urgent care (UC) and office-based physician practices to the emergency department (ED) following activation of the 9-1-1 EMS system are an under-studied population with scarce literature regarding outcomes for these children. The objectives of this study were to describe this population, explore EMS level-of-care transport decisions, and examine ED outcomes. This was a retrospective review of patients zero to <15 years of age transported by EMS from UC and office-based physician practices to the ED of two pediatric receiving centers from January 2017 through December 2019. Variables included reason for transfer, level of transport, EMS interventions and medications, ED medications/labs/imaging ordered in the first hour, ED procedures, ED disposition, and demographics. Data were analyzed with descriptive statistics, X test, point biserial correlation, two-sample z test, Mann-Whitney U test, and 2-way ANOVA. A total of 450 EMS transports were included in this study: 382 Advanced Life Support (ALS) runs and 68 Basic Life Support (BLS) runs. The median patient age was 2.66 years, 60.9% were male, and 60.7% had private insurance. Overall, 48.9% of patients were transported from an office-based physician practice and 25.1% were transported from UC. Almost one-half (48.7%) of ALS patients received an EMS intervention or medication, as did 4.41% of BLS patients. Respiratory distress was the most common reason for transport (46.9%). Supplemental oxygen was the most common EMS intervention and albuterol was the most administered EMS medication. There was no significant association between level of transport and ED disposition (P = .23). The in-patient admission rate for transported patients was significantly higher than the general ED admission rate (P <.001). This study demonstrates that pediatric patients transferred via EMS after activation of the 9-1-1 system from UC and medical offices are more acutely ill than the general pediatric ED population and are likely sicker than the general pediatric EMS population. Paramedics appear to be making appropriate level-of-care transport decisions.


Elevation of transforming growth factor alpha and its relationship to the epidermal growth factor and alpha-fetoprotein levels in patients with hepatocellular carcinoma.
A radioimmunoassay for transforming growth factor alpha (TGF-alpha) using synthetic rat sarcoma transforming growth factor and its rabbit polyclonal antibody has been developed. Using radioimmunoassays, the urinary TGF-alpha and epidermal growth factor (EGF) concentrations in 31 patients with hepatocellular carcinoma (HCC), 15 probable HCC, four metastatic liver cancer, and 33 age, sex-matched healthy controls were determined. For the first time, we have shown that the average TGF-alpha concentration for HCC patients was 21.5 +/- 20.3 micrograms per g creatinine, significantly higher than that of healthy subjects, 4.9 +/- 2.8 micrograms per g creatinine (P less than 0.001). There was no statistical difference in the level of EGF between HCC patients and controls (40.9 +/- 29.3 versus 46.2 +/- 16.6 micrograms per g creatinine; P greater than 0.05). The ratio of EGF/TGF-alpha between HCC patients (3.37 +/- 4.42) and controls (15.5 +/- 13.0) was significantly different (P less than 0.001). Among patients, 65% (20 of 31) of HCC cases and 87% (13 of 15) of probable HCC cases showed a marked elevation of TGF-alpha levels. We found only 16% (five of 31) of HCC cases with increased EGF level. EGF excretion was inversely age related. Serum total protein concentration and alkaline phosphatase activity were positively correlated to EGF concentration (r = 0.522, P less than 0.01 and rt = 0.393, P less than 0.05, respectively). There was no correlation between biochemical functions of liver and TGF-alpha concentration in HCC patients. Our results also suggested that TGF-alpha may be a useful complementary tumor marker for management of patients with clinical manifestation of HCC who have low alpha-fetoprotein levels.


Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys.
Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5+ and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection). These follicles were strongly positive for IL-15, which was primarily presented in its membrane-bound form by follicular dendritic cells. NK cell depletion through treatment with anti-IL-15 monoclonal antibody during chronic SIVagm infection resulted in high viral replication rates in follicles and the T cell zone and increased viral DNA in lymph nodes. Our data suggest that, in nonpathogenic SIV infection, NK cells migrate into follicles and play a major role in viral reservoir control in lymph nodes.


Birth-related genomic and transcriptional changes in mouse lung. Modulation by transplacental N-acetylcysteine.
Birth is characterized by a sudden transition from the maternal-mediated respiration to the autonomous pulmonary respiration. Notwithstanding the importance of the involved functional and metabolic changes, little is known about possible DNA alterations occurring in the lung during the perinatal period. We comparatively evaluated genomic and transcriptional changes in the lung of fetuses and newborn Swiss albino mice, whose dams had either been untreated or treated with oral N-acetyl-L-cysteine (NAC) throughout the pregnancy period. In the less than 24h period elapsing between the end of fetal life and the start of post-natal life, nucleotide alterations occurred in mouse lung, as shown by a significant increase of both bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine levels, detected by 32P post-labeling procedures. The frequency of micronuclei in peripheral blood erythrocytes was not significantly increased after birth. Multigene expression analysis of 746 selected genes, by cDNA arrays, showed that 33 of them (4.4%) were upregulated in the lung of newborn mice, as compared with fetuses. The overexpressed genes were mainly involved in protective mechanism as a response to oxidative changes, alterations of glutathione metabolism, cellular stress, and damage to DNA and proteins. The transplacental treatment with NAC totally prevented birth-related genomic alterations in lung DNA. NAC did not change the basal gene expression in mouse fetal lung, but attenuated the upregulation of most genes involved in oxidative stress, stress response, and DNA repair in the lung of newborn mice. In fact, only 13 genes (1.7%) were overexpressed in newborns from NAC-treated dams. It therefore appears that administration of NAC during pregnancy is beneficial not only to counteract the adverse effects of toxic agents, as supported by previous studies, but also to attenuate birth-related DNA alterations.


Cost-Effectiveness Analysis of the Use of Point-of-Care C-Reactive Protein Testing to Reduce Antibiotic Prescribing in Primary Care.
More appropriate and measured use of antibiotics may be achieved using point-of-care (POC) C-reactive protein (CRP) testing, but there is limited evidence of cost-effectiveness in routine practice. A decision analytic model was developed to estimate the cost-effectiveness of testing, compared with standard care, in adults presenting in primary care with symptoms of acute respiratory tract infection (ARTI). Analyses considered (1) pragmatic use of testing, reflective of routine clinical practice, and (2) testing according to clinical guidelines. Threshold and scenario analysis were performed to identify cost-effective scenarios. In patients with symptoms of ARTI and based on routine practice, the incremental cost-effectiveness ratios of CRP testing were £19,705 per quality-adjusted-life-year (QALY) gained and £16.07 per antibiotic prescription avoided. Following clinical guideline, CRP testing in patients with lower respiratory tract infections (LRTIs) cost £4390 per QALY gained and £9.31 per antibiotic prescription avoided. At a threshold of £20,000 per QALY, the probabilities of POC CRP testing being cost-effective were 0.49 (ARTI) and 0.84 (LRTI). POC CRP testing as implemented in routine practice is appreciably less cost-effective than when adhering to clinical guidelines. The implications for antibiotic resistance and Clostridium difficile infection warrant further investigation.


Statin use and risk of prostate cancer: results from a population-based epidemiologic study.
Epidemiologic studies of statin use in relation to prostate cancer risk have been inconclusive. Recent evidence, however, suggests that longer-term use may reduce risk of more advanced disease. The authors conducted a population-based study of 1,001 incident prostate cancer cases diagnosed in 2002-2005 and 942 age-matched controls from King County, Washington, to evaluate risk associated with statin use. Logistic regression was used to generate odds ratios for ever use, current use, and duration of use. No overall association was found between statin use and prostate cancer risk (odds ratio (OR) = 1.0, 95% confidence interval (CI): 0.8, 1.2 for current use; OR = 1.1, 95% CI: 0.7, 1.8 for >10 years' use), even for cases with more advanced disease. Risk related to statin use, however, was modified by body mass index (interaction p = 0.04). Obese men (BMI > or =30 kg/m2) who used statins had an increased risk (OR = 1.5, 95% CI: 1.0, 2.2) relative to obese nonusers, with a stronger association for longer-term use (OR = 1.8, 95% CI: 1.1, 3.0 for > or =5 years' use). Although statin use was not associated with overall prostate cancer risk, the finding of an increased risk associated with statin use among obese men, particularly use for extended durations, warrants further investigation.


Analysis of origin and protein-protein interaction maps suggests distinct oncogenic role of nuclear EGFR during cancer evolution.
Receptor tyrosine kinase EGFR usually is localized on plasma membrane to induce progression of many cancers including cancers in children (Bodey et al. In Vivo. 2005, 19:931-41), but it contains a nuclear localization signal (NLS) that mediates EGFR nuclear translocation (Lin et al. Nat Cell Biol. 2001, 3:802-8). Here we report that NLS of EGFR has its old evolutionary origin. Protein-protein interaction maps suggests that nEGFR pathways are different from membrane EGFR and EGF is not found in nEGFR network while androgen receptor (AR) is found, which suggests the evolution of prostate cancer, a well-known AR driven cancer, through changes in androgen- or EGF-dependence. Database analysis suggests that nEGFR correlates with the tumor grades especially in prostate cancer patients. Structural predication analysis suggests that NLS can compromise the differential protein binding to EGFR through stretch linkers with evolutionary mutation from N to V. In experiment, elevation of nEGFR but not membrane EGFR was found in castration resistant prostate cancer cells. Finally, systems analysis of NLS and transmembrane domain (TM) suggests that NLS has old origin while NLS neighboring domain of TM has been undergone accelerated evolution. Thus nEGFR has an old origin resembling the cancer evolution but TM may interfere with NLS driven signaling for natural selection of survival to evade NLS induced aggressive cancers. Our data suggest NLS is a dynamic inducer of EGFR oncogenesis during evolution for advanced cancers. Our model provides novel insights into the evolutionary role of NLS of oncogenic kinases in cancers.


Enzyme linked immunosorbent assays with Treponema pallidum or axial filament of T phagedenis biotype Reiter as antigen: evaluation as screening tests for syphilis.
Enzyme linked immunosorbent assays with an ultrasonicate of Treponema pallidum (TP-ELISA) or axial filament of Treponema phagedenis biotype Reiter (AF-ELISA) were developed to detect treponemal antibody. TP-ELISA and AF-ELISA were compared with the T pallidum haemagglutination assay (TPHA), the fluorescent treponemal antibody-absorbed (FTA-ABS) test, and the Venereal Disease Research Laboratory (VDRL) test for sensitivity and specificity of serodiagnosis of syphilis. A total of 1423 serum samples, 253 from patients with various stages of syphilis, 500 from patients attending a sexually transmitted disease (STD) clinic, and 670 from people without syphilis, were investigated. At all stages of syphilis the sensitivity of the TP-ELISA, the AF-ELISA, the TPHA, and the FTA-ABS test did not differ significantly, except that the AF-ELISA was less sensitive than the TPHA (p less than 0.05) for treated syphilis. In primary syphilis, neurosyphilis, and treated syphilis the TP-ELISA and AF-ELISA were significantly more sensitive than the VDRL test (p less than 0.05). The specificity of all tests was comparable (p greater than 0.05). The TP-ELISA and AF-ELISA appear to be good alternatives to the TPHA as screening tests for syphilis. Because of the easy availability of a well defined antigen the AF-ELISA seems to be better suited for large scale testing.


Free energies of membrane stalk formation from a lipidomics perspective.
Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at coarse-grained resolution. The method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes.


SUBSTITUTION OF MANGANESE FOR TOMATO JUICE IN THE CULTIVATION OF LACTIC ACID BACTERIA.
Tomato juice was separated by chemical and physical methods into various active fractions, as measured by growth response and acid production by numerous lactic acid bacteria. Incineration of the treated extracts with little apparent loss in activity established the fact that the stimulatory component was of inorganic composition. Of the various cations tested, manganese was the only element that produced biological activity comparable to that of the original extract. Of the 71 strains of lactic acid bacteria tested, 63 strains showed a definite requirement for manganese or tomato juice.


Men's career development and marriage timing during a period of rising inequality.
Based on data from 1979-1990 NLSY interviews, we investigate the implications of rising economic inequality for young men's marriage timing. Our approach is to relate marriage formation to the ease or difficulty of the career-entry process and to show that large race/schooling differences in career development lead to substantial variations in marriage timing. We develop measures of current career "maturity" and of long-term labor-market position. Employing discrete-time event-history methods, we show that these variables have a substantial impact on marriage formation for both blacks and whites. Applying our regression results to models based on observed race/schooling patterns of career development, we then estimate cumulative proportions ever married in a difficult versus an easy career-entry process. We find major differences in the pace of marriage formation, depending on the difficulty of the career transition. We also find considerable differences in these marriage timing patterns across race/schooling groups corresponding to the large observed differences in the speed and difficulty of career transition between and within these groups.


Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells.
Most melanoma cells are characterized by the V600E mutation in B-Raf kinase. This mutation leads to increased expression of interleukin (CXCL8), which plays a key role in cell growth and angiogenesis. Thus CXCL8 appears to be an interesting therapeutic target. Hence, we performed vaccination of mice with GST-CXCL8, which results in a reduced incidence of syngenic B16 melanoma cell xenograft tumors. We next addressed the molecular mechanisms responsible for aberrant CXCL8 expression in melanoma. The CXCL8 mRNA contains multiples AU-rich sequences (AREs) that modulate mRNA stability through the binding of tristetraprolin (TTP). Melanoma cell lines express very low TTP levels. We therefore hypothesized that the very low endogenous levels of TTP present in different melanoma cell lines might be responsible for the relative stability of CXCL8 mRNAs. We show that TTP is actively degraded by the proteasome and that extracellular-regulated kinase inhibition results in TTP accumulation. Conditional expression of TTP in A375 melanoma cells leads to CXCL8 mRNA destabilization via its 3' untranslated regions (3'-UTR), and TTP overexpression reduces its production. In contrast, downregulation of TTP by short hairpin RNA results in upregulation of CXCL8 mRNA. Maintaining high TTP levels in melanoma cells decreases cell proliferation and autophagy and induces apoptosis. Sorafenib, a therapeutic agent targeting Raf kinases, decreases CXCL8 expression in melanoma cells through reexpression of TTP. We conclude that loss of TTP represents a key event in the establishment of melanomas through constitutive expression of CXCL8, which constitutes a potent therapeutic target.


Isolation of leptospires from the genital tract and kidneys of aborted sows.
Twenty sows were examined as part of an investigation into the relative importance of the genital and urinary tracts as sites of leptospiral persistence in pigs. The sows had previously either aborted leptospire-infected fetuses or aborted on farms where leptospire infection had been demonstrated in other litters. Leptospires belonging to the Australis serogroup were recovered from the upper genital tract of all the sows. In contrast, leptospires were only recovered from 75 per cent of their kidneys. Isolates from 10 of the sows were identified to serovar level: six were serovar muenchen and four were bratislava. Persistence was observed in renal and genital tissues for up to 147 days after abortion.


Obesity is associated with decreased μ-opioid but unaltered dopamine D2 receptor availability in the brain.
Neurochemical pathways involved in pathological overeating and obesity are poorly understood. Although previous studies have shown increased μ-opioid receptor (MOR) and decreased dopamine D2 receptor (D2R) availability in addictive disorders, the role that these systems play in human obesity still remains unclear. We studied 13 morbidly obese women [mean body mass index (BMI), 42 kg/m(2)] and 14 nonobese age-matched women, and measured brain MOR and D2R availability using PET with selective radioligands [(11)C]carfentanil and [(11)C]raclopride, respectively. We also used quantitative meta-analytic techniques to pool previous evidence on the effects of obesity on altered D2R availability. Morbidly obese subjects had significantly lower MOR availability than control subjects in brain regions relevant for reward processing, including ventral striatum, insula, and thalamus. Moreover, in these areas, BMI correlated negatively with MOR availability. Striatal MOR availability was also negatively associated with self-reported food addiction and restrained eating patterns. There were no significant differences in D2R availability between obese and nonobese subjects in any brain region. Meta-analysis confirmed that current evidence for altered D2R availability in obesity is only modest. Obesity appears to have unique neurobiological underpinnings in the reward circuit, whereby it is more similar to opioid addiction than to other addictive disorders. The opioid system modulates motivation and reward processing, and low μ-opioid availability may promote overeating to compensate decreased hedonic responses in this system. Behavioral and pharmacological strategies for recovering opioidergic function might thus be critical to curb the obesity epidemic.


Collagen deposition limits immune reconstitution in the gut.
Despite suppression of human immunodeficiency virus (HIV) replication by antiretroviral therapy, reconstitution of CD4+ cells is variable and incomplete, particularly in gut-associated lymphatic tissues (GALT). We have previously shown that immune activation and inflammation in HIV-infected and simian immunodeficiency virus-infected lymph nodes results in collagen deposition and disruption of the lymphatic tissue architecture, and this damage contributes to CD4+ cell depletion before treatment and affects the extent of immune reconstitution after treatment. In the present study, we compared collagen deposition and the extent of depletion and reconstitution of total CD4+ cells and subsets in peripheral blood, lymph nodes, and inductive and effector sites in GALT. We show that CD4+ cell depletion in GALT correlates with the rapidity and greater magnitude of collagen deposition in this compartment, compared with that in peripheral lymph nodes, and that although treatment does not restore CD4+ cells to effector sites, treatment in the early stages of infection can increase CD4+ central memory cells in Peyer patches.


The health management information system of Pakistan under devolution: health managers' perceptions.
Devolution implies that use of data for decision making starts at the level of data generation. However under a newly decentralized system, managers may face different hurdles in utilizing the preexisting Health Management Information System (HMIS). This qualitative research explores the perceptions of health managers regarding HMIS under the devolution reforms enacted in 2001 in Pakistan. The study was carried out by interviewing 26 managers at various levels in seven selected districts in all provinces. There was general dissatisfaction and confusion over roles and responsibility: respondents reported that the overall atmosphere was characterized by the reluctance of provincial managers to release data under their authority, the absence of prerequisite human resources, and conflicts of interests between political and administrative leadership. The devolution didn't bring immediate good effects for the HMIS. Treated as a least priority area, staff was distributed from provincial HMIS cells, causing overburdening of remaining staff and jeopardizing data analysis. Reporting regularity from the districts was also compromised secondary to political interference and loss of provincial control. The present HMIS is in need of redesigning so that it may keep pace with the devolved system. The HMIS reforms are needed to improve information systems at the district level, capacity building of district managers, political commitment, and administrative ownership of the system and to earmark and make available resource and promote evidence-based decision making. Change in the public administration culture towards encouraging initiative taking at lower levels, introduction of performance incentives, inculcating work ethics, encouraging local accountability, and good governance are all essential.


Peroxidase uptake by photoreceptor terminals of the skate retina.
The photoreceptors of dark-adapted skate retinas bathed in a Ringer solution containing horseradish peroxidase (HRP) incorporate the tracer into membrane-bound compartments within the synaptic terminal of the cell; after 1 or 2 h of incubation, approx. 10-38% of the synaptic vesicles were labeled. The receptors appeared to be functioning normally throughout the incubation period, since electrical potentials of normal amplitude could be elicited in response to dimphotic stimuli. However, it was possible to block the uptake of peroxidase by a regimen of light adaptation that effectively suppressed light-induced activity in the electroretinogram. If, during incubation with peroxidase, retinas were exposed at 10-min intervals to an intense 1-ms flash from a xenon discharge tube, the receptor terminals were almost completely devoid of peroxidase; fewer than 2% of the vesicles were labeled. The suppression of HRP uptake could also be achieved in dark-adapted retinas by adding magnesium to the bathing solution, suggesting that calcium is necessary for transmitter release from vesicles in the receptor terminals. These findings are consistent with the view that vertebrate photoreceptors discharge a neurotransmitter in darkness, and that light decreases the release of this substance. It seems likely that the incorporation of peroxidase into vesicles of physiologically active receptor terminals reflects a mechanism for the retrieval of vesicle membrane after exocytosis.


Flexible High-Dimensional Unsupervised Learning with Missing Data.
The mixture of factor analyzers (MFA) model is a famous mixture model-based approach for unsupervised learning with high-dimensional data. It can be useful, inter alia, in situations where the data dimensionality far exceeds the number of observations. In recent years, the MFA model has been extended to non-Gaussian mixtures to account for clusters with heavier tail weight and/or asymmetry. The generalized hyperbolic factor analyzers (MGHFA) model is one such extension, which leads to a flexible modelling paradigm that accounts for both heavier tail weight and cluster asymmetry. In many practical applications, the occurrence of missing values often complicates data analyses. A generalization of the MGHFA is presented to accommodate missing values. Under a missing-at-random mechanism, we develop a computationally efficient alternating expectation conditional maximization algorithm for parameter estimation of the MGHFA model with different patterns of missing values. The imputation of missing values under an incomplete-data structure of MGHFA is also investigated. The performance of our proposed methodology is illustrated through the analysis of simulated and real data.


Toward guidelines for evidence-based assessment of depression in children and adolescents.
We aim to provide a starting point toward the development of an evidence-based assessment of depression in children and adolescents. We begin by discussing issues relevant to the diagnosis and classification of child and adolescent depression. Next, we review the prevalence, selected clinical correlates, course, and treatment of juvenile depression. Along with some general considerations in assessment, we discuss specific approaches to assessing depression in youth (i.e., interviews, rating scales) and briefly summarize evidence on the reliability and validity of a few selected instruments. In addition, we touch on the assessment of several other constructs that are important in a comprehensive evaluation of depression (i.e., social functioning, life stress, and family history of psychopathology). Last, we highlight areas in which further research is necessary and conclude with some broad recommendations for clinical practice given the current state of the knowledge.


The influence of patient-related factors and the position of the acetabular component on the rate of dislocation after total hip replacement.
The senior one of us performed 438 primary and 181 revision total hip arthroplasties with use of so-called modern prostheses between July 1983 and January 1994. Fifty-three patients, who had had forty-seven primary procedures and twelve revisions, either died or were lost to follow-up less than two years after the operation and were excluded from the study. The results for the remaining 446 patients (391 primary procedures and 169 revisions) were analyzed to determine the influence of patient-related and operative factors and the position of the acetabular component on the rate of dislocation. Dislocation occurred after thirty-two (6 per cent) of the 560 total hip arthroplasties: seventeen (4 per cent) of the 391 primary procedures and fifteen (9 per cent) of the 169 revisions (p = 0.046). There was no relationship between the variables of age, gender, obesity, or preoperative diagnosis and dislocation after either primary or revision arthroplasty. Seven (23 per cent) of the thirty arthroplasties in the patients who had a history of excessive intake of alcoholic beverages (more than 2.1 liters [seventy-two ounces] of beer or more than 0.2 liter [six ounces] of other alcoholic beverages a day) were followed by a dislocation compared with twenty-five (5 per cent) of the 530 arthroplasties in the patients who did not have such a history. This difference was significant for the patients who had had a revision arthroplasty (p = 0.00005), but with the numbers available we could not detect a difference for those who had had a primary arthroplasty (p = 0.264). Radiographic analysis was performed for thirty-two hips that had dislocated and thirty-two that had not (seventeen primary procedures and fifteen revisions in each group), matched exactly according to the type of prosthesis and the operative approach (but not age). We detected no association between either the version or the abduction angle of the acetabular component (within the range of 39 to 56 degrees for the primary prostheses and 38 to 57 degrees for the revision prostheses) and the risk of dislocation. Thirty of the thirty-two hips in each group had an abduction angle of the acetabular component that was in the so-called safe range of 30 to 50 degrees.


Open-label pilot study of extended-release naltrexone to reduce drinking and driving among repeat offenders.
A high proportion of persons convicted of driving while impaired repeat the offense. Many continue drinking and driving, even when faced with long jail terms. Hence, they pose a serious public health threat. This preliminary study evaluated extended-release, injectable naltrexone suspension (XR-NTX) and supportive therapy in reducing (1) drinking and (2) attempts to drive after drinking among repeat driving while impaired offenders with an ignition interlock device installed in their vehicles. Treatment-seeking volunteers received medical management therapy and 3 monthly injections of XR-NTX. We compared data on alcohol consumption, alcohol biomarkers, and interlock information before, during, and after treatment using summary measures and Sign tests. Of 12 consented subjects, 10 received at least 1 injection, and 7 received all 3 injections. All subjects receiving medication reported a decrease in average drinks per day (P < 0.01) and abstinent days (P = 0.02) while on treatment versus pretreatment levels. Average daily drinks decreased by 77%, from 3.0 to 0.69 (P < 0.01), during treatment with XR-NTX. Average drinks per drinking day also declined by 39% during treatment, from 6.6 to 4.0 (P = 0.04). Percent days abstinent increased by 31%, from 56.8 to 81.96 (P = 0.02), which persisted after treatment completion. Biomarkers were consistent with reduced drinking. The percentage of vehicular failures to start due to elevated breath alcohol decreased from 3.1% of tests to 1.29% of tests. A randomized, controlled clinical trial is needed to demonstrate the efficacy of this promising treatment regimen for repeat offenders.


Polaribacter undariae sp. nov., isolated from a brown alga reservoir.
A Gram-stain-negative, non-flagellated, non-gliding, aerobic and rod-shaped or ovoid bacterial strain, designated W-BA7(T), was isolated from a brown alga reservoir on the South Sea in South Korea. This strain grew optimally at 25 °C, at pH 7.0-8.0 and in the presence of approximately 2.0% (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain W-BA7(T) belonged to the genus Polaribacter, clustering coherently with the type strain of Polaribacter sejongensis, showing 99.3% sequence similarity. Strain W-BA7(T) exhibited 16S rRNA gene sequence similarity of 93.4-98.6% to the type strains of the other species of the genus Polaribacter. Strain W-BA7(T) contained MK-6 as the predominant menaquinone and iso-C15 : 0 3-OH and anteiso-C15 : 0 as the major fatty acids. The major polar lipids of strain W-BA7(T) were phosphatidylethanolamine, three unidentified lipids, one unidentified glycolipid, one unidentified aminolipid and one unidentified aminophospholipid. The DNA G+C content of strain W-BA7(T) was 31.9 mol%, and the mean DNA-DNA relatedness with the type strains of four phylogenetically related species of the genus Polaribacter was 12-27%. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain W-BA7(T) is separated from recognized species of the genus Polaribacter. On the basis of the data presented, strain W-BA7(T) is considered to represent a novel species of the genus Polaribacter, for which the name Polaribacter undariae sp. nov. is proposed. The type strain is W-BA7(T) ( =KCTC 42175(T) =CECT 8670(T)).


Induction of apoptotic genes by a p73-phosphatase and tensin homolog (p73-PTEN) protein complex in response to genotoxic stress.
The p53 family member, p73, has been characterized as a tumor suppressor and functions in a similar manner as p53 to induce cellular death. The phosphatase and tensin homolog (PTEN) can function as a dual specificity lipid/protein phosphatase. However, recent data have described multiple roles for nuclear PTEN independent of its lipid phosphatase activity. PTEN can directly or indirectly activate p53 to promote apoptosis. We examined whether PTEN would interact and regulate p73 independent of p53. Co-localization in the nucleus and complex formation of p73/PTEN were observed after DNA damage. Furthermore, we also demonstrate that p73α/PTEN proteins directly bind one another. Both overexpressed and endogenous p73-PTEN interactions were determined to be the strongest in the nuclear fraction after DNA damage, which suggested formation of a transcriptional complex. We employed chromatin immunoprecipitation (ChIP) and found that p73 and PTEN were associated with the PUMA promoter after genotoxic stress in TP53-null cells. We found that another p73 target, BAX, had an increased expression in the presence of p73 and PTEN. In addition, in virus-transduced cell lines stably expressing p73, PTEN, or both p73/PTEN, we found that the p73/PTEN cells were more sensitive to genotoxic stress and cellular death as measured by increased poly(ADP-ribose) polymerase cleavage and PUMA/Bax induction. Conversely, knockdown of PTEN dramatically reduced Bax and PUMA levels. Thus, a p73-PTEN protein complex is engaged to induce apoptosis independent of p53 in response to DNA damage.


On the identification of thyroid nodules using semi-supervised deep learning.
Detecting malign cases from thyroid nodule examinations is crucial in healthcare particularly to improve the early detection of such cases. However, malign thyroid nodules can be extremely rare and is hard to find using the traditional rule based or expert-based methods. For this reason, the solutions backed by Machine Learning (ML) algorithms are key to improve the detection rates of such rare cases. In this paper, we investigate the application of ML in the healthcare domain for the detection of rare thyroid nodules. The utilized dataset is collected from 636 distinct patients in 99 unique days in Turkey. In addition to the texture feature data of the Ultrasound (US), we have also included the scores of different assessment methods created by different health institutions (e.g., Korean, American and European thyroid societies) as additional features. For detection of extremely rare malign cases, we use auto-encoder based neural network model. Through numerical results, it is shown that the auto-encoder based model can result in an average Recall score of 0.98 and a Sensitivity score of 1.00 for detecting malign and non-malign cases from the healthcare dataset outperforming the traditional classification algorithms that are trained after Synthetic Minority Oversampling Technique (SMOTE) oversampling.


Analysis of the role of von Willebrand factor, platelet glycoprotein VI-, and α2β1-mediated collagen binding in thrombus formation.
Rare missense mutations in the von Willebrand factor (VWF) A3 domain that disrupt collagen binding have been found in patients with a mild bleeding phenotype. However, the analysis of these aberrant VWF-collagen interactions has been limited. Here, we have developed mouse models of collagen-binding mutants and analyzed the function of the A3 domain using comprehensive in vitro and in vivo approaches. Five loss-of-function (p.S1731T, p.W1745C, p.S1783A, p.H1786D, A3 deletion) and 1 gain-of-function (p.L1757A) variants were generated in the mouse VWF complementary DNA. The results of these various assays were consistent, although the magnitude of the effects were different: the gain-of-function (p.L1757A) variant showed consistent enhanced collagen binding whereas the loss-of-function mutants showed variable degrees of functional deficit. We further analyzed the impact of direct platelet-collagen binding by blocking glycoprotein VI (GPVI) and integrin α2β1 in our ferric chloride murine thrombosis model. The inhibition of GPVI demonstrated a comparable functional defect in thrombosis formation to the VWF(-/-) mice whereas α2β1 inhibition demonstrated a milder bleeding phenotype. Furthermore, a delayed and markedly reduced thrombogenic response was still evident in VWF(-/-), GPVI, and α2β1 blocked animals, suggesting that alternative primary hemostatic mechanisms can partially rescue the bleeding phenotype associated with these defects.


European Consensus Guidelines on the Management of Respiratory Distress Syndrome, 2022 : What is New?
We present a summary of the European Consensus guidelines on management of respiratory distress syndrome, which were released in 2022, and compare these with the current National Neonatology Forum of India guidelines, and discuss the feasibility of their application in the Indian settings.


GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer.
Recurrent prostate cancer remains a major problem. Staging, grading and prostate specific antigen level at surgery are helpful but still imperfect predictors of recurrence. For this reason there is an imperative need for additional biomarkers that add to the prediction of currently used prognostic factors. We evaluated the extent of promoter methylation of genes previously reported as aberrantly methylated in prostate cancer (AIM1, APC, CCND2, GPX3, GSTP1, MCAM, RARβ2, SSBP2 and TIMP3) by quantitative fluorogenic methylation-specific polymerase chain reaction. We used cancer tissue from a nested case-control study of 452 patients surgically treated for prostate cancer. Recurrence cases and controls were compared and the association between methylation extent and recurrence risk was estimated by logistic regression adjusting for patient age at prostatectomy, prostatectomy year, stage, grade, surgical margins and preprostatectomy prostate specific antigen. All statistical tests were 2-sided with p ≤0.05 considered statistically significant. The extent of GSTP1 methylation was higher in patients with recurrence than in controls (p = 0.01), especially patients with early disease, ie organ confined or limited extraprostatic extension (p = 0.001). After multivariate adjustment GSTP1 promoter methylation at or above the median was associated with an increased risk of recurrence, including in men with early disease (each p = 0.05). Greater GSTP1 promoter methylation in cancer tissue was independently associated with the risk of recurrence in patients with early prostate cancer. This suggests that GSTP1 promoter methylation may be a potential tissue based recurrence marker.


[The late treatment results in cancer of the lower lip].
Analysis of late results of treatment of carcinoma of the lower lip in 106 patients followed up for 4-5 years has confirmed that these results are worse if a patient consults a doctor late and if the process is disseminated. Our data evidence that late results do not depend on the method used to manage the primary focus on the lip, though radiotherapy may be considered as the optimal treatment modality. Histologic study of operation material after preventive surgery has not revealed metastases to regional lymph nodes, therefore if the lymph nodes are clinically intact, a dynamic follow-up is recommended after the primary focus is cured.


Correlation between internal structure and electrochemical impedance spectroscopy of multiphase slurry systems.
Slurry for lithium-ion batteries is prepared from an active material, a carbon conductive additive, and a polymeric binder in a solvent, and its morphological change is evaluated over time using electrochemical impedance spectroscopy. A schematic model of the internal structure and dispersion states of the slurry components during 7 days of storage is proposed on the basis of the electrochemical impedance spectroscopy (EIS) measurement. The EIS results reveal that the conductive path constructed by the network structure of the slurry components breaks over time, which can be worsened by mechanical agitation. In order to confirm the morphological change, the slurry is freeze-dried and then prepared to fixate the locations of the slurry components. The existence of a network structure (or flocculation) is verified by morphological observations. In addition, the dispersity index and Micro-CT are introduced as new methods representing the dispersion state of the slurry components.