Persistent Inflammation and Non-AIDS Comorbidities During ART: Coming of the Age of Monocytes.
Monocytes are innate immune cells that serve as the first line of defense against pathogens by engulfing and destroying pathogens or by processing and presenting antigens to initiate adaptive immunity and stimulate immunological responses. Monocytes are classified into three types: classical, intermediate, and non-classical monocytes, each of which plays a particular function in response to pathogens. Human immunodeficiency virus type 1 (HIV-1) infection disrupts the balance of monocyte subsets, and the quantity and function of monocytes will not fully recover even with long-term antiretroviral therapy (ART). Monocytes are vital for the establishment and maintenance of HIV-1 latent viral reservoirs and are closely related to immune dysfunction even after ART. Therefore, the present review focuses on the phenotypic function of monocytes and their functions in HIV-1 infection to elucidate their roles in HIV patients.


Nonlinearity in color space measured by apparent motion.
We used an apparent motion technique to examine the intensity coding along the three cardinal axes of color space: achromatic (L + M + S), L-M cone, and S cone axes. Two horizontal bars of different colors were alternated to produce a vertical displacement. The color of the background was a mixture varied between the colors of the two bars. When the background color was close to either of the test colors, only the bar that was more salient appeared to jump. Observers adjusted the color of the background until they saw either the two bars moved equally frequently or both bars moved at once. If the color difference in a linear cone excitation space controls this apparent motion, the setting should be midway between the two colors. All of the three cardinal axes showed some deviation from linear behavior. The nonlinearity was less extreme than a logarithmic function for both the achromatic and S cone axes and could be attributed to a small compressive nonlinearity, possibly at the level of cone responses. However, the L-M stimuli showed a more extreme departure from linearity, which suggested a nonlinearity at an opponent site. A test of perceived contrast judgments did not show this nonlinearity for L-M axis, suggesting that it is specific to the L-M contribution to apparent motion.


Durable cytotoxic immune responses against gp120 elicited by recombinant SV40 vectors encoding HIV-1 gp120 +/- IL-15.
BACKGROUND: A vaccine that elicits durable, powerful anti-HIV immunity remains an elusive goal. In these studies we tested whether multiple treatments with viral vector-delivered HIV envelope antigen (gp120), with and without IL-15, could help to approach that goal. For this purpose, we used recombinant Tag-deleted SV40-derived vectors (rSV40s), since they do not elicit neutralizing antibody responses, and so can be given multiply without loss of transduction efficiency. METHODS: SV(gp120) carried the coding sequences for HIV-1NL4-3 Env, and SV(mIL-15) carried the cDNA for mouse IL-15. Singly, and in combination, these two vectors were given monthly to BALB/cJ mice. Cytotoxic immunity and cytotoxic memory were tested in direct cytotoxicity assays using unselected effector cells. Antibody vs. gp120 was measured in a binding assay. In both cases, targets were P815 cells that were stably transfected with gp120. RESULTS: Multiple injections of SV(gp120) elicited powerful anti-gp120 cytolytic activity (>70% specific lysis) by unselected spleen cells. Cells from multiply-immunized mice that were rested 1 year after their last injections still showed >60% gp120-specific lysis. Anti-gp120 antibody was first detected after 2 monthly injections of SV(gp120) and remained elevated thereafter. Adding SV(mIL-15) to the immunization regimen dramatically accelerated the development of memory cytolytic responses, with >/= 50% specific lysis seen 1 month after two treatments. IL-15 did not alter the development of antibody responses. CONCLUSIONS: Thus, rSV40s encoding antigens and immunostimulatory cytokines may be useful tools for priming and/or boosting immune responses against HIV.


Anaemia and nutritional status of adolescent girls in Babile District, Eastern Ethiopia.
Nutritional status during adolescence plays an important role in the human lifecycle that influences growth and development and during this period nutrient needs are the greatest. The objective of this study is to assess anaemia and nutritional status of adolescent girls in the Babile district, Eastern Ethiopia. Data were collected from 547 adolescent aged 10-19 years by cross sectional study design. WHO Anthro-plus software was used to analyse Nutritional statuses of adolescents and magnitudes were determined using WHO 2007 references point. Haemoglobin was measured on site by hem cue machine. Descriptive and inferential statistical analysis was carried out depending on the nature of variables. The result of the study show that 21.6% thin, 4.8% were over weighted and 1.1% was obese, 32% were anaemic and 15% of adolescents were stunted/ short stature than normal. Nutritional status of adolescent were low both in urban and rural adolescents, but severe thinness were higher among of rural (39.3%) compared to urban (37.5%) adolescents. Factors independently associated with stunting were place of residence, father occupation source of drinking water and age of the adolescents. Nutritional status of adolescent girls contributes to the nutritional status of the community. There is a need to initiate intervention measures to improve the nutritional status of adolescent girls who are the future 'mothers-to-be'. Hence, there is a need to create awareness among adolescents and their family about nutrition and health.


Topographic and Neural Anatomy of the Depressor Anguli Oris Muscle and Implications for Treatment of Synkinetic Facial Paralysis.
Synkinetic patients often fail to produce a satisfactory smile because of antagonistic action of a hypertonic depressor anguli oris muscle and concomitantly weak depressor labii inferioris muscle. This study investigated their neurovascular anatomy to partially explain this paradoxical depressor anguli oris hypertonicity and depressor labii inferioris hypotonicity and delineated consistent anatomical landmarks to assist in depressor anguli oris muscle injection and myectomy. Ten hemifaces from five fresh human cadavers were dissected to delineate the neurovascular supply of the depressor anguli oris and depressor labii inferioris muscles in addition to the depressor anguli oris muscle relation to consistent anatomical landmarks. The depressor anguli oris muscle received innervation from both lower buccal and marginal mandibular facial nerve branches, whereas the depressor labii inferioris muscle was solely innervated by marginal mandibular branches. The mandibular depressor anguli oris origin was on average 39 mm wide, and its medial and lateral borders were located 17 mm from the symphysis and 41 mm from the mandibular angle, respectively. The depressor anguli oris fibers consistently passed anterior to the first mandibular molar toward their insertion into the modiolus, which was located 10 mm lateral and 10 mm caudal to the oral commissure. Depressor anguli oris muscle dual innervation versus depressor labii inferioris single innervation may explain why depressor anguli oris hypertonicity and depressor labii inferioris weakness are commonly observed concomitantly in synkinetic patients. Based on treatment goals, diagnostic percutaneous injection with lidocaine can be performed on the depressor anguli oris muscle along a cutaneous line from the modiolus to the mandibular first molar border, and an intraoral depressor anguli oris myectomy can be performed along that same transmucosal line.


Open education resources to support the WHO nurse educator core competencies.
This paper describes an innovative approach to tackling the shortage of qualified nurse educators, which is a major constraining factor or 'bottle-neck' to improve the global supply of nurses, especially in low- and middle-income countries. The World Health Organization commissioned experts to develop Nurse Educator Core Competencies that describe expectations for this cadre of workers. In their deliberations, the WHO experts cited the challenges affecting the adoption of these competencies, particularly the lack of resources available for implementation. To address this specific challenge, a USA-based non-government organiization, Nurses International, has developed Open Education Resources (NI-OER) to support nurse educators with freely accessible curriculum materials and remote mentoring support. This paper applies item analysis to consider how the NI-OER could assist higher education institutes and individual faculty members in meeting each of the WHO Nurse Educator Core Competencies. The NI-OER is a good fit with six of the Nurse Educator Core Competencies and a partial fit with the other two. Congruence with the WHO Nurse Educator Core Competencies is an important validity check for the NI-OER. The ultimate goal of the NI-OER is to promote sustainable development through intermediate goals related to supporting faculty as they prepare nurses for current and future service needs. Technological solutions like the NI-OER cannot solve all aspects of a complex problem like the global nursing shortage but are an important tool. This resource has significant implications for nursing and health policy because it tackles several constraints to the global goal of increasing production and capacity of nurses. Combined with the organization's remote mentoring and communities of practice, the NI-OER appears to have the potential to support novice nurse educators with accessible, adaptable resources.


Contribution of acidic amino residues to the adsorption of peptides onto a stainless steel surface.
The role of the acidic amino acid residues in the adsorption of peptides/proteins onto stainless steel particles was investigated using a peptide fragment from bovine beta-lactoglobulin, Thr-Pro-Glu-Val-Asp-Asp-Glu-Ala-Leu-Glu-Lys (T5 peptide), which has a high affinity to a stainless steel surface at acidic pHs, and its mutant peptides substituted with different numbers of acidic amino acid residues. The adsorption behavior of the mutant peptides as well as the T5 peptide were studied at pH 3 with respect to concentration and ionic strength dependencies and the reversibility of the adsorption process. The behavior of the peptides was generally characterized as two distinct irreversible adsorption modes, Mode I and Mode II. In Mode I, the amounts adsorbed lay on the ordinate at zero equilibrium concentration in the solution, while in Mode II, the amount adsorbed increased with increased equilibrium concentration. The area occupied by the peptides was predicted by molecular mechanics and molecular dynamics. The state of the peptides, when adsorbed, was investigated using FT-IR analysis. The FT-IR analyses revealed that the side carboxylic groups of the peptides adsorbed on the stainless steel surface were ionized, while they were unionized in the solution at pH 3. Thus, the interactions between the carboxylic groups of the peptide and the stainless steel surface can be considered to be largely electrostatic. The peptide having four acidic amino acid residues took a maximum adsorbed amount, the reason for which is discussed.


Immunological localization and quantitation of the androgen-dependent secretory protease of the canine prostate.
We have recently reported on the isolation and characterization of the predominant protein of canine prostatic fluid and the subsequent identification of this protein as a proteolytic enzyme. In this report, we described the preparation and characterization of a rabbit antiserum against this secretory protease which was purified from canine prostatic fluid by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Specificity of the antiserum has been established by immunoblot analysis and immunoprecipitation of the secretory protease present in canine prostatic fluid and tissue homogenates. The antiserum was used to localize (by immunofluorescence) and quantitate (by single radial immunodiffusion) the secretory protease in prostatic tissue obtained from intact and castrated dogs. These analyses can be summarized as follows: the secretory protease is strictly localized in the apical portions of the columnar epithelial cells in prostates of intact dogs, where it comprises almost 60% of the total Triton X-100-soluble protein; and the level of secretory protease decreases at least 500-fold in prostates of castrated dogs, demonstrating the androgen-dependent nature of this enzyme. Proteins immunologically related to the secretory protease were detected at low levels in the pancreas and salivary glands of the dog. Such proteins were not detectable in canine liver, kidney, vas deferens, testis, epididymis, lung, spleen, skin, small intestine, or sartorius muscle, suggesting a high degree of prostatic specificity for the secretory protease. These results demonstrate that the canine prostate is highly specialized with respect to its androgen-dependent synthesis and secretion of this secretory protease and that the antiserum specific for this protein can be used to assess canine prostatic function under varying hormonal conditions.


Is there role of adjuvant radiotherapy after complete resection of locally advanced nonsmall cell lung cancer?
This review aims to provide a timely and relevant overview of the role of postoperative radiotherapy (PORT) in completely resected stage IIIA-N2 nonsmall cell lung cancer (NSCLC). Given the controversy surrounding the use of PORT and the emergence of advanced radiation techniques and therapies, this review provides valuable insight into current and potential treatment strategies. The Lung ART and PORT-C trials have provided valuable insights into the efficacy of PORT in stage IIIA-N2 NSCLC. While the results have been mixed, studies have shown that advanced radiation techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy, can reduce cardiopulmonary toxicities associated with PORT. Molecular targeted therapies and immunotherapies have also shown potential in improving NSCLC treatment outcomes. The role of radiotherapy becomes smaller and smaller in new era. However, it is too early to abolish radiotherapy for all the patients after complete resection of locally advanced NSCLC. Nowadays, it is recommended to adopt individualized treatment approaches guided by multidisciplinary team consultations. The integration of IMRT, proton therapy, and emerging therapies offers the potential to enhance treatment efficacy while minimizing toxicity. Further research is needed to optimize the use of PORT and explore the method to identify the patients who can really benefit from PORT.


Pharmacokinetic and pharmacodynamic interactions of mefloquine and quinine.
This study was carried out to investigate the pharmacokinetic and pharmacodynamic interactions between two antimalarial drugs, mefloquine and quinine. A randomized, comparative, three-way crossover study was performed in seven healthy male Thais after the administration of three drug regimens on three occasions i.e., a single oral dose of quinine sulfate (600 mg), mefloquine (750 mg) alone, or the combination of mefloquine (750 mg) and quinine (600 mg given 24 h after mefloquine). QTc interval was significantly prolonged in subjects following the combination regimen (at 2.5, 3, 4, 6, 8, 12, 18, 24 h after the quinine dose) but no abnormal clinical signs or symptoms were found. There were no significant changes in vital signs or routine laboratory values in any of the subjects. The pharmacokinetics of mefloquine and quinine were influenced by the presence of the other drug. Greater blood schizonticidal activities were collected from the sera of subjects on the combination regimen than from the sera of subjects the quinine or mefloquine regimens. The minimum inhibitory concentrations (MICs) of the equivalent concentrations (Eqs) of quinine or mefloquine, which completely inhibited the growth of the K1 strain of Plasmodium falciparum in vitro (MICs of quinine Eq and mefloquine Eq) were significantly lower in the sera of subjects on the combination regimens, than in the sera of subjects on mefloquine or quinine alone [MICs of quinine Eq: 41.2 (21.25-73.5) vs. 135 (118-150) ng/ml; MICs of mefloquine Eq: 18.2 (17-19.2) vs. 25.2 (24.4-26.8) ng/ml].


Discordant bilateral bronchoalveolar lavage findings in a patient with acute eosinophilic pneumonia associated with counterfeit tetrahydrocannabinol oil vaping.
Vaping has emerged as a popular alternative form of inhalation of nicotine and marihuana derivates (including Tetrahydrocannabinol, THC) in part due to the avoidance of combustion byproducts. Unfortunately, THC oil (especially that produced by unregulated individuals) may contain dilutants such as propylene glycol, vitamin E, and flavoring ingredients that can lead to adverse respiratory effects. Acute eosinophilic pneumonia (AEP) has been described in association with e-cigarette and vaping associated lung injury (EVALI) but the majority of bronchoalveolar lavage (BAL) samples reported in the literature do not show eosinophils as the predominant cell lineage. Only two other cases of AEP have been published, and here we present the first case reported in the literature of a patient with EVALI with AEP pattern associated with counterfeit tetrahydrocannabinol (THC) oil vaping and discordant bilateral BAL cell count differential.


Gain and loss of gastrointestinal symptoms in diabetes mellitus: associations with psychiatric disease, glycemic control, and autonomic neuropathy over 2 years of follow-up.
To prospectively determine the turnover (gain or loss) of gastrointestinal (GI) symptoms in diabetic subjects in relation to glycemic control, autonomic neuropathy and psychiatric disease over a 2-year follow-up. Type 1 and type 2 diabetic subjects were recruited from the community, as were community controls. Individual GI symptoms were examined by a validated questionnaire and classified as diarrhea, irritable bowel syndrome, upper GI symptoms, and any GI symptoms at baseline, 12 and 24 months. Glycemic control (glycated hemoglobin), autonomic function (using standardized tests), and psychiatric disease (using the Composite International Diagnostic Interview) were also assessed at these time points. Baseline and 2-year follow-up data were available for 139 diabetic subjects and 55 controls. Glycated hemoglobin at baseline was 7.7% (+/-1.36) in the diabetic group; 5% had severe autonomic dysfunction. There was a significantly higher prevalence of diarrhea in the diabetic subjects. GI symptom turnover varied between 15% and 25% in the diabetic group and was not significantly different from the controls. There was no clear association between turnover of GI symptoms and either glycemic control or autonomic neuropathy. The appearance of depression was associated with gaining of most symptoms apart from irritable bowel syndrome, although the associations did not always reach significance. The univariate results were confirmed after adjusting for age, gender, body mass index, and metformin use. The turnover of GI symptoms in diabetic subjects was not associated with glycemic control but there was a positive association with change in depression.


Genetic predictors of long-term graft function in kidney and pancreas transplant patients.
Kidney and pancreas transplantation have helped transform the lives of people with end-stage renal failure and individuals with type 1 diabetes who have poor glycaemic control/severe secondary complications, respectively. Despite an improvement in immunosuppressive regimes, operative techniques and decreased initial rejection rates, there has been little improvement in long-term graft survival rates over the past decade. Whilst limited progress has been made in establishing clinical markers of graft function, several genetic markers of long-term graft function have been identified. These genetic markers have the potential to (i) assist in selecting marginal donor organs for transplantation, (ii) provide better understanding of the mechanisms behind graft loss enabling identification of new, or repurposing, current treatments to extend graft function and (iii) provide a window of opportunity to identify and treat individuals before graft failure has occurred. This review will discuss the different genetic variants screened for a role in predicting transplant longevity, examine their findings and limitations and introduce where the future of genetic research within the transplantation field lies.


Malleability of Attitudes or Malleability of the IAT?
In the current set of experiments, we establish, and explore the consequences of, the imprecision that characterizes the attribute response labels typically employed in the Implicit Association Test (IAT). In Experiment 1, we demonstrate the malleability of the IAT, as conventionally implemented. IAT scores are shown to be influenced by perspective mindsets induced by an unrelated preceding task. Then, we explore how the malleability of the IAT can lead to the inference that attitude change has occurred even when there is very good reason to believe it has not (Experiment 2), and conversely, how it can obscure the detection of attitude change when such change is indeed likely to have occurred (Experiment 3). We provide conceptual explanations for these discrepancies and suggest methodological improvements to enhance the specificity of IAT measures.


Systematic review of CT and MR perfusion imaging for assessment of acute cerebrovascular disease.
Perfusion imaging sequences are an important part of imaging studies designed to provide information to guide therapy for treatment of cerebrovascular disease. The purpose of this study was to perform a meta-analysis of the medical literature on perfusion imaging to determine its role in clinical decision making for patients with acute cerebral ischemia. We searched MEDLINE by using a strategy that combined terms related to perfusion imaging with terms related to acute cerebral ischemia and brain tumors. We identified 658 perfusion imaging articles and classified them according to the clinical usefulness criteria of Thornbury and Fryback. We found 59 articles with promise of indicating usefulness in clinical decision making. We devised and implemented a clinical decision making scoring scale more appropriate to the topic of acute cerebral ischemia. Several articles provided important insights into the physiologic processes underlying acute cerebral ischemia by correlation of initial perfusion imaging deficits with clinical outcome or ultimate size of the infarct. However, most articles showed relatively low relevance to influencing decisions in implementing treatment. Most perfusion imaging articles are oriented toward important topics such as optimization of imaging parameters, determination of ischemia penumbra, and prediction of outcome. However, information as to the role of perfusion imaging in clinical decision making is lacking. Studies are needed to demonstrate that use of perfusion imaging changes outcome of patients with acute cerebral ischemia.


Can the PageRank centrality be manipulated to obtain any desired ranking?
The significance of the PageRank algorithm in shaping the modern Internet cannot be overstated, and its complex network theory foundations continue to be a subject of research. In this article, we carry out a systematic study of the structural and parametric controllability of PageRank's outcomes, translating a spectral graph theory problem into a geometric one, where a natural characterization of its rankings emerges. Furthermore, we show that the change of perspective employed can be applied to the biplex PageRank proposal, performing numerical computations on both real and synthetic network datasets to compare centrality measures used.


Effect of sodium loading on the urinary excretion of prostaglandins E2 and F2 alpha in rats with hereditary diabetes insipidus (Brattleboro rats).
Current evidence suggests that the antidiuretic hormone (ADH) and changes in sodium balance influence renal prostaglandins (PGs). To separate these two mechanisms, the effect of sodium loading on the urinary excretion of PGE2 and PGF2 alpha was studied in female Brattleboro rats with diabetes insipidus (DIHO) and compared with that in female, age matched, heterozygous Long Evans controls (LEHE). Ten DIHO and ten LEHE rats had a normal sodium intake. In ten DIHO rats a 0.16% NaCl solution was supplied instead of drinking water for either 8 days (n = 5) or 14 days (n = 5). In two groups of LEHE rats, sodium loading was obtained with a 0.80% NaCl solution for the same study periods. Urine PGs were measured by radioimmunoassay in three 24 h urine collections for each rat. Urine PGs were significantly increased in the 8 day loaded but not in the 14 day loaded LEHE rats. In DIHO rats, a non-significant increase in both PGE2 and PGF2 alpha was present after 8 days of sodium loading, while PGE2 and the E/F ratio were decreased after 14 days of salt loading. The findings suggest that the natriuresis induced by sodium loading in the rat may be mediated in part by increased production of PGs. In addition, it seems that ADH plays a role in this response.


Myosin phosphorylation in permeabilized rabbit psoas fibers.
The 18,000-Da myosin light chains in segments of rabbit psoas fibers were stably phosphorylated to assess the mechanical effects of this modification. Before and after phosphorylation of the same fiber, the maximal shortening velocity (Vmax) was measured at 12 degrees C by a quick-release slack test and by extrapolation to Vmax of hyperbolic force-velocity curves from isotonic releases. The experiments were performed at saturating concentrations of Ca2+, as determined from isometric force-pCa curves, under conditions in which the pH and ATP-ADP ratio were buffered. No effect of phosphorylation on isometric force, Vmax, or the shape of the force-velocity curve was detected under conditions of maximal calcium activation. Thus we find no mechanical evidence for a modulation by light chain phosphorylation of actomyosin interaction in these fiber segments.


[The bank of biological material in the SU.VI.MAX study].
The "SUpplémentation en VItamines et Minéraux AntioXydants" (SU.VI.MAX) study is a randomized double-blind, placebo-controlled, primary-prevention trial designed to test the efficacy of a daily supplementation with antioxidant vitamins and minerals at nutritional doses, in reducing several major health problems in industrialized countries, and especially the main causes of premature death (cancers and cardiovascular diseases). This 8-year cohort study started in 1994 in France; 13,535 eligible subjects (women aged 35 to 60, and men aged 45 to 60) were included in 1994 and will be followed up for 8 years. In this paper are described conditions and practical aspects for the realisation of the biological bank developped on the first sample (1994) and completed in 1996 and 1999. Biological material (buffy coat and plasma samples) are saved and stored at -196 degrees C, -80 degrees C and -20 degrees C for any further tests planned at later date (case-control studies and/or validation of new hypothesis).


The Influence of Human-Animal Interactions on Mental and Physical Health during the First COVID-19 Lockdown Phase in the U.K.: A Qualitative Exploration.
The coronavirus disease 2019 (COVID-19) pandemic presents an opportunity to explore the role of animals as sources of emotional and physical support during a period when most of the population is experiencing social and environmental challenges. We investigated how companion animal owners perceived the influence of human-animal interaction on their physical and mental health during the first COVID-19 lockdown phase in the U.K., and what concerns they had regarding their animals at this time. We also explored the impact of participants' interaction with non-companion animals during this phase. A cross-sectional online survey of U.K. residents aged over 18 was conducted between April and June 2020. The final item of the survey invited open-ended free-text responses, allowing participants to describe any experiences and/or perceptions of their human-animal relationships during the COVID-19 lockdown phase. A qualitative thematic analysis of responses was undertaken. Four main themes related to the following aspects of human-animal interactions during the COVID-19 lockdown phase were identified: the positive impact of animal ownership during the COVID-19 lockdown (e.g., amelioration of wellbeing and mental health), concerns relating to animal ownership during the COVID-19 lockdown (e.g., concerns over animals carrying the COVID-19 virus), grief and loss of an animal during the COVID-19 lockdown and the impact of engaging with non-companion animals during the COVID-19 lockdown. The findings complement and extend previous insights into the impact of human-animal interaction with both companion and non-companion animals. They also highlight the challenges of caring for an animal during the lockdown phase and indicate the need to consider the development of further targeted support strategies, such as "day care" for the companion animals of key workers in this context.


Gait Coordination Deteriorates in Independent Old-Old Adults.
Human gait is symmetric and bilaterally coordinated in young healthy persons. In this study, we aimed to explore the differences in bilateral coordination of gait as measured by the phase coordination index (PCI), gait asymmetry, and stride time variability of gait between four age groups. A total of 44 older adults were recruited: nine young-old (age 70-74 years), 26 old (age 75-84 years), nine old-old (>85 years and older), and 13 young adults (age 20-30 years). Subjects walked on a treadmill; walking speed was systematically increased from 0.5 to 0.9 m/s in steps of 0.1 m/s. There were marginal effects of age on PCI, significant main effects of walking speeds without interaction between walking speeds and age group. A difference in PCI could distinguish between young's and late aging group, and only during their preferred treadmills walking speed. This study explicitly shows that bilateral coordination of walking is modified by gait speed, and deteriorates only at a very old age.


High quality SNP calling using Illumina data at shallow coverage.
Detection of single nucleotide polymorphisms (SNPs) has been a major application in processing second generation sequencing (SGS) data. In principle, SNPs are called on single base differences between a reference genome and a sequence generated from SGS short reads of a sample genome. However, this exercise is far from trivial; several parameters related to sequencing quality, and/or reference genome properties, play essential effect on the accuracy of called SNPs especially at shallow coverage data. In this work, we present Slider II, an alignment and SNP calling approach that demonstrates improved algorithmic approaches enabling larger number of called SNPs with lower false positive rate. In addition to the regular alignment and SNP calling, as an optional feature, Slider II is capable of utilizing information about known SNPs of a target genome, as priors, in the alignment and SNPs calling to enhance it's capability of detecting these known SNPs and novel SNPs and mutations in their vicinity.


Subjective Perception Of Trifocal IOL Performance, Including Toric Models.
To study the patients' perception of trifocal IOL (Panoptix™) performance. 60 eyes of 35 were implanted with trifocal IOL. Refractive (sphere - S, cylinder - Cyl and spherical equivalent - SE, all in D) and visual (distance uncorrected - VAsc, distance corrected - VAcc, intermediate - IntVA, near uncorrected - NVAsc and distance corrected near - NVAcc, all in LogMAR) results were recorded. Patients were asked about satisfaction (per eye), spectacle independence, near and intermediate activities, distance activities in quantity and quality, finally about personal facial care (per patient). Comparison was made between non-toric (48) and toric models, genders (18 males) and between bilateral (25 patients) and unilateral implantations. Results were correlated to age and IOL power. With a SE of mean -0.3 ± 0.5 D, cases achieved mean VAsc 0.09 ± 0.1 (~20/25), VAcc 0.05 ± 0.1 (~20/22), IntVA 0.05 ± 0.9 (~20/22), NVAsc 0.05 ± 0.09 (~~20/22) and NVAcc 0.04 ± 0.8 (~~20/22). Mean level of satisfaction was 85.7 ± 16.5, spectacle independence 96.0 ± 10.6, near activities 95.4 ± 9.8, intermediate activities 97.7 ± 6.4, quantity of distance activities 90.2 ± 10.1, quality of distance activities 88.0 ± 12.1 and facial care 92.6 ± 11.9. All comparisons (non-toric and toric, male and female and bilateral and unilateral implantation) were statistically insignificant (P>0.05). Correlation with age and IOL power was also statistically insignificant (P>0.05). As perceived by patients, trifocal IOL resulted in very high level of satisfaction. This satisfaction is reflected on diverse visual activities. This level is achieved regardless of gender, IOL model or even unilateral implantation. It is also achieved regardless the age of patients or preoperative eye status.


[Erythrocyte in pathology: speculations at the electron microscope].
The article summarizes the results of several years of research devoted to the surface architectonics and ultrastructure of erythrocyte in patients with pathology of different genesis. Diversity of changes in the shape of red blood cells, their surface and ultrastructure obtained by scanning and transmission microscopy is presented. The question is discussed on the non-specific character of erythrocyte transformation, disorganization of surface architectonics and ultrastructure of red blood cells in different pathological processes. The existence of typical morphological changes of erythrocyte in different pathological processes is suggested, considering it to be an evolutionary form of adaptation.


Measuring constitutional preferences: A new method for analyzing public consultation data.
Public consultation has become an indispensable part of constitutional design, yet the voluminous, narrative data produced are often impractical to analyze. There are also few, if any, standards for such analysis. Using a comprehensive reference ontology from the Comparative Constitutions Project (CCP), we develop a new methodology to identify constitutional topics of most concern to citizens and compare these to topics in constitutions globally. We analyze data from Chile's 2016 public consultations-an ambitious process that produced nearly 265,000 narrative responses and launched the constitutional reform process that remains underway today. We leverage advances in natural language processing, in particular sentence-level semantic similarity technology, to classify consultation responses with respect to constitutional topics. Our methodology has potential for advocates, drafters, and researchers seeking to analyze public consultation data that too often go unexamined.


Automatic genome-wide reconstruction of phylogenetic gene trees.
Gene duplication and divergence is a major evolutionary force. Despite the growing number of fully sequenced genomes, methods for investigating these events on a genome-wide scale are still in their infancy. Here, we present SYNERGY, a novel and scalable algorithm that uses sequence similarity and a given species phylogeny to reconstruct the underlying evolutionary history of all genes in a large group of species. In doing so, SYNERGY resolves homology relations and accurately distinguishes orthologs from paralogs. We applied our approach to a set of nine fully sequenced fungal genomes spanning 150 million years, generating a genome-wide catalog of orthologous groups and corresponding gene trees. Our results are highly accurate when compared to a manually curated gold standard, and are robust to the quality of input according to a novel jackknife confidence scoring. The reconstructed gene trees provide a comprehensive view of gene evolution on a genomic scale. Our approach can be applied to any set of sequenced eukaryotic species with a known phylogeny, and opens the way to systematic studies of the evolution of individual genes, molecular systems and whole genomes. Supplementary data are available at Bioinformatics online.


Presynaptic BK channels modulate ethanol-induced enhancement of GABAergic transmission in the rat central amygdala nucleus.
Large-conductance calcium-activated potassium BK channels are widely expressed in the brain and are involved in the regulation of neuronal functions such as neurotransmitter release. However, their possible role in mediating ethanol-induced GABA release is still unknown. We assessed the role of BK channels in modulating the action of ethanol on inhibitory synaptic transmission mediated via GABAA receptors in the rat central nucleus of the amygdala (CeA). Evoked IPSCs (eIPSCs) mediated by GABAA receptors were isolated from CeA neurons under whole-cell voltage clamp, and their response to selective BK channel antagonists, channel activators, or ethanol was analyzed. Blocking BK channels with the specific BK channel antagonist paxilline significantly increased the mean amplitude of eIPSCs, whereas the activation of BK channels with the channel opener NS1619 reversibly attenuated the mean amplitude of eIPSCs. Ethanol (50 mM) alone enhanced the amplitude of eIPSCs but failed to further enhance eIPSCs in the slices pretreated with paxilline. Bath application of either BK channel blockers significantly increased the frequency of miniature IPSCs (mIPSCs). Similarly, 50 mM ethanol alone also enhanced mIPSC frequency. Increases in mIPSC frequency by either selective BK channel antagonists or ethanol were not accompanied with changes in the amplitude of mIPSCs. Furthermore, following bath application of BK channel blockers for 10 min, ethanol failed to further increase mIPSC frequency. Together, these results suggest that blocking BK channels mimics the effects of ethanol on GABA release and that presynaptic BK channels could serve as a target for ethanol effects in CeA.


Biodiversity of the Pantanal: response to seasonal flooding regime and to environmental degradation.
Seasonal flooding is the most important ecological phenomenon in the Pantanal. Every year many parts of the biome change from terrestrial into aquatic habitats and vice-versa. The degree of inundation creates a range of major habitats. Flooding occupies about 80% of the whole Pantanal. In contrast, during the dry season, most of the flooded areas stay dry, when the water returns to the river beds or evaporates. The Pantanal is a large continental savanna wetland (147,574 km(2) in Brazil), touching Bolivia to the north and Paraguay to the south. The maze of fluctuating water levels, nutrients, and biota forms a dynamic ecosystem. The vegetation comprises 1,863 phanerogam plant species listed for the floodplain and 3,400 for the whole basin and 250 species of aquatic plants. The complex vegetation cover and seasonal productivity support a diverse and abundant fauna within the floodplain: 263 species of fish, 41 of amphibians, 113 of reptiles (177 for the basin), 463 of birds and 132 mammal species. Many endangered species occur, including jaguar (Panthera onca Linnaeus, 1758). Waterfowl are exceptionally abundant during the dry season. Analysis of the root causes of the threats to biodiversity indicated that deforestation (17% of the Pantanal and 63% of the surrounding uplands) with modification and loss of natural habitats due to cattle ranching, unsustainable agriculture, mining, environmental contamination (including mercury, pesticides, urban sewage), non organized tourism, fire, disturbances at the upstream region modifying hydrological flow, erosion, weak implementation and enforcement of legislation are the major issues to face conservation action and sustainable use. Under an evolutionary focus, local biodiversity seems to be well adapted to seasonal shrinking and expansion of natural habitats due to flooding. However, the conversion of natural vegetation due to human occupation is a real threat to biodiversity.


Three Toxoplasma gondii Dense Granule Proteins Are Required for Induction of Lewis Rat Macrophage Pyroptosis.
Upon invasion of Lewis rat macrophages, Toxoplasma rapidly induces programmed cell death (pyroptosis), which prevents Toxoplasma replication, possibly explaining the resistance of the Lewis rat to Toxoplasma Using a chemical mutagenesis screen, we identified Toxoplasma mutants that no longer induced pyroptosis. Whole-genome sequencing led to the identification of three Toxoplasma parasitophorous vacuole-localized dense granule proteins, GRA35, GRA42, and GRA43, that are individually required for induction of Lewis rat macrophage pyroptosis. Macrophage infection with Δgra35, Δgra42, and Δgra43 parasites led to greatly reduced cell death rates and enhanced parasite replication. Lewis rat macrophages infected with parasites containing a single, double, or triple deletion of these GRAs showed similar levels of cell viability, suggesting that the three GRAs function in the same pathway. Deletion of GRA42 or GRA43 resulted in GRA35 (and other GRAs) being retained inside the parasitophorous vacuole instead of being localized to the parasitophorous vacuole membrane. Despite having greatly enhanced replication in Lewis rat macrophages in vitro, Δgra35, Δgra42, and Δgra43 parasites did not establish a chronic infection in Lewis rats. Toxoplasma did not induce F344 rat macrophage pyroptosis, but F344 rats infected with Δgra35, Δgra42, and Δgra43 parasites had reduced cyst numbers. Thus, these GRAs determined parasite in vivo fitness in F344 rats. Overall, our data suggest that these three Toxoplasma dense granule proteins play a critical role in establishing a chronic infection in vivo, independently of their role in mediating macrophage pyroptosis, likely due to their importance in regulating protein localization to the parasitophorous vacuole membrane.IMPORTANCE Inflammasomes are major components of the innate immune system and are responsible for detecting various microbial and environmental danger signals. Upon invasion of Lewis rat macrophages, the parasite rapidly activates the NLRP1 inflammasome, resulting in pyroptosis and elimination of the parasite's replication niche. The work reported here revealed that Toxoplasma GRA35, GRA42, and GRA43 are required for induction of Lewis rat macrophage pyroptosis. GRA42 and GRA43 mediate the correct localization of other GRAs, including GRA35, to the parasitophorous vacuole membrane. These three GRAs were also found to be important for parasite in vivo fitness in a Toxoplasma-susceptible rat strain, independently of their role in NLRP1 inflammasome activation, suggesting that they perform other important functions. Thus, this study identified three GRAs that mediate the induction of Lewis rat macrophage pyroptosis and are required for pathogenesis of the parasite.


Immunotherapy, the promise for present and future of malignant pleural mesothelioma (MPM) treatment.
Due to occupational asbestosis exposure, the incidence of malignant pleural mesothelioma (MPM) has continuously increased over the last 30 years, with a plateau anticipated around the year 2030 in Western countries. Molecular MPM carcinogenesis involves alterations of NF2, RASSF1, LATS2WT1, p16, as well as BAP-1tumor-suppressor genes, which usually regulate apoptosis, cell invasion, motility, cell division, chromatin remodeling, as well as control of DNA repair. In few selected patients, debulking surgery consisting of pleurectomy-decortication is carried out, resulting in unsatisfactory long-term results. For about 15 years, first-line chemotherapy has been primarily based on a doublet of pemetrexed and cisplatin. Adding the monoclonal antibody bevacizumab (Avastin®), which targets vascular endothelial growth factor (VEGF), has been shown to improve overall survival (OS) by nearly 19 months. The emergence of immune check-point inhibitors (ICIs) in MPM treatment has recently been associated with substantial survival improvements in both second- and first-line settings. Similarly to non-small-cell lung cancer (NSCLC) patients, on-going trials are presently exploring the chemotherapy-ICI combination in MPM management, and depending on their results, this combination could represent a further major advance in this previously orphan disease. The current article reviews recent clinical trial results, as well as future clinical developments in this moving field.


Etretin therapy for severe psoriasis. Evaluation of initial clinical responses.
We have investigated the clinical responses of 21 patients with severe psoriasis to therapy with etretin, a metabolite of etretinate. In a preliminary double-blind dose-finding study, the optimum dose of etretin was determined to be 50 mg/d (mean, 0.66 mg/kg/d). In an open study, patients receiving etretin therapy were followed up for a minimum of six months. An excellent or good response (greater than 50% clearance) was obtained in 18 of 21 patients. The incidence of mucocutaneous side effects from etretin therapy was similar to that previously reported with etretinate therapy. As a group, patients who received etretin therapy for six or more months showed no significant aberrations from normal levels of serum lipids or serum liver enzymes. However, five patients had mild elevation of liver enzymes or blood lipids, which were corrected by dose reduction. Etretin showed equivalent efficacy to that previously reported with etretinate in severe recalcitrant plaque psoriasis vulgaris. Taken with the reportedly more rapid clearance of etretin from the body, there may be clinical advantages of the use of etretin over the use of etretinate.


Improved methods to capture the total societal benefits of zoonotic disease control: Demonstrating the cost-effectiveness of an integrated control programme for Taenia solium, soil transmitted helminths and classical swine fever in northern Lao PDR.
Control and elimination of zoonotic diseases requires robust information about their effect on both human and livestock health in order to enable policy formulation and the allocation of resources. This study aimed to evaluate the cost-effectiveness of controlling Taenia solium taeniasis/cysticercosis in both humans and pigs, and soil-transmitted helminths (STH) in humans by integrating their control to on-going human and animal health control programmes in northern Lao People's Democratic Republic. A cross-sectional study was carried out in 49 households, focusing on the prevalence of T. solium taenias/cysticercosis and soil transmitted helminths before and after a twelve month intervention. The village data was collected using a semi-structured questionnaire through a door-to-door survey. The village data was then projected to the wider northern Lao PDR population using stochastic modelling and cost-effectiveness ratio (after aggregating the net cost to capture both human and animal health parameters) and GDP per capita as a threshold, to determine the cost-effectiveness of the integrated control of T. solium taeniasis/ cysticercosis and STH, assuming linear scaling out of the intervention. The zoonotic DALY (zDALY) approach was also used as an alternative method of estimating the cost-effectiveness ratio of controlling T. solium taeniasis/cysticercosis in humans and pigs. Using cost-effectiveness analysis after aggregating the net cost and control of T. solium taeniasis/cysticercosis alone as the base case, the study found that simultaneous control of T. solium taeniasis/cysticercosis in humans and pigs, STH in humans and Classical Swine Fever (CSF) in pigs was USD 14 per DALY averted and USD 234 per zDALY averted using zDALY method hence considered highly cost-effective whereas controlling T. solium taeniasis/cysticercosis without incorporating STH and CSF was the least cost-effective (USD 3,672 per DALY averted). Additionally, the cost-effectiveness of controlling T. solium taeniasis/cysticercosis in people and pigs using zDALY as an alternative method was USD 3,662 per zDALY averted which was quite close to our findings using the aggregate net cost method. The study showed that control of T. solium taeniasis/cysticercosis alone in humans and pigs is not cost-effective in northern Lao PDR whereas control of STH is. Consequently, integrating T. solium taeniasis/cysticercosis control with other cost-effective programmes such as STH and CSF markedly improved the cost-effectiveness of the intervention. This is especially important in low resource countries where control of zoonotic neglected tropical diseases could be integrated with the human and animal health sectors to optimize use of the limited resources. Australia New Zealand Clinical Trials Registry (ANZCTR) ACTRN12614001067662.


The adenosine deaminase gene polymorphism is associated with chronic heart failure risk in Chinese.
Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10-2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF.


[Loss of an eye due to hyper-IgE syndrome after corneal transplantation].
A 37-year-old patient with bilateral keratoconus underwent a perforating cornea transplantation after acute onset of pain and hydrops of the right cornea. One day after operation endophthalmitis developed, caused by a viridans streptococcus. Hyper-IgE syndrome was suspected because of the patient's crude facial features. His medical history brought up additional symptoms of this disease. IgE levels were extremely elevated (7320 kU/l), the eosinophil count was slightly raised (0.25 x 10(9)/l). The patient was treated with several local antibiotics but his vision was only light perception at the time of discharge from the hospital. This case illustrates how an usually successful operation may have a disastrous outcome in case of late diagnosis of the hyper-IgE syndrome. The hyper-IgE syndrome can be recognized by the characteristic facial features in combination with the often extensive (juvenile) medical history with infections, and by elevated serum IgE levels. As patients with the hyper-IgE syndrome are extremely susceptible to develop infections, prophylactic antibiotic therapy is indicated in surgical procedures.


Testing for a difference in means of a single feature after clustering.
For many applications, it is critical to interpret and validate groups of observations obtained via clustering. A common validation approach involves testing differences in feature means between observations in two estimated clusters. In this setting, classical hypothesis tests lead to an inflated Type I error rate. To overcome this problem, we propose a new test for the difference in means in a single feature between a pair of clusters obtained using hierarchical or $k$-means clustering. The test based on the proposed $p$-value controls the selective Type I error rate in finite samples and can be efficiently computed. We further illustrate the validity and power of our proposal in simulation and demonstrate its use on single-cell RNA-sequencing data.


Targeting vascular endothelial growth factor in renal cell carcinoma.
Renal cancer is the most lethal of all urological malignancies with overall 5-year survival rates of around 60%. The predominant reason for the poor prognosis of this cancer has been the relative lack of effective systemic therapy for advanced metastatic disease. Until recently immunotherapy with interleukin-2 or interferon-alpha has been the standard of care for metastatic renal cell carcinoma (RCC); however, the response rates for these treatments were at best only 3-21%. The use of molecular biological techniques has led to a greater understanding of the genetic basis of RCC. Mutations of the von Hippel-Lindau (VHL) gene on chromosome 3p25 with the resultant overexpression of hypoxia-inducible factors (HIFs) have been shown to lead to the development of clear-cell RCC. The unearthing of the pathways downstream of VHL has led to the development of numerous novel therapies that specifically target HIF-related genes such as vascular endothelial growth factor (VEGF). In this article, we explore the VHL-HIF-VEGF pathway that plays a fundamental role in the development of renal cancer. In addition, we review the evidence base for the use of these new targeted therapies for advanced RCC and uniquely include the latest practice guidelines from the European Association of Urology, the United States National Comprehensive Cancer Network and the National Institute for Health and Clinical Excellence.


Protective antibodies against Clostridium difficile are present in intravenous immunoglobulin and are retained in humans following its administration.
The prevalence of serum antibodies against Clostridium difficile (CD) toxins A and B in healthy populations have prompted interest in evaluating the therapeutic activity of intravenous immunoglobulin (IVIg) in individuals experiencing severe or recurrent C. difficile infection (CDI). Despite some promising case reports, a definitive clinical role for IVIg in CDI remains unclear. Contradictory results may be attributed to a lack of consensus regarding optimal dose, timing of administration and patient selection as well as variability in specific antibody content between commercial preparations. The purpose of this study was to investigate retrospectively the efficacy of three commercial preparations of IVIg for treating severe or recurrent CDI. In subsequent mechanistic studies using protein microarray and toxin neutralization assays, all IVIg preparations were analysed for specific binding and neutralizing antibodies (NAb) to CD antigens in vitro and the presence of anti-toxin NAbs in vivo following IVIg infusion. A therapeutic response to IVIg was observed in 41% (10 of 17) of the CDI patients. Significant variability in multi-isotype specific antibodies to a 7-plex panel of CD antigens and toxin neutralization efficacies were observed between IVIg preparations and also in patient sera before and after IVIg administration. These results extend our current understanding of population immunity to CD and support the inclusion of surface layer proteins and binary toxin antigens in CD vaccines. Future strategies could enhance IVIg treatment response rates by using protein microarray to preselect donor plasma/serum with the highest levels of anti-CD antibodies and/or anti-toxin neutralizing capacities prior to fractionation.


Methodology case study of the application of haptics to combat medic training programs.
Of the available training methods for emergency responders, including other methods based on computer technology, virtual reality video game training with haptics (tactile) features will be shown to provide the most effective transfer of skills to real-world emergency situations, providing a model for the development of new training products for combat medics and civilian first responders. This paper aims to provide a methodological case study of haptics use in medical training programs and highlight achievements in terms of performance. Review of these cases show that the addition of haptics to an existing simulation-based training program increases user performance in terms of completion time, error rates, and learning rate. With this case study, haptics can be further incorporated into training programs designed for military combat medics.


The antidiabetic agent thiazolidinedione stimulates the interaction between PPAR gamma and CBP.
The peroxisome proliferator-activated receptor (PPAR) gamma is a member of the nuclear hormone receptor family, which is predominantly expressed on adipocytes and considered to be involved in the process of adipogenesis. The new thiazolidinedione (TZD) compound, T-174, developed as an antidiabetic drug, stimulated the transcription of PPAR gamma and the adipocyte differentiation of 3T3-L1 cells. Interestingly, T-174 induced the interaction between PPAR gamma and CBP (cAMP response element binding protein (CREB) binding protein), a co-factor of various transcription regulators. CBP mRNA was expressed in both preadipocytes and adipocytes. These results suggest that CBP plays a role in the PPAR gamma-mediated signaling pathway activated by TZD, including adipogenesis.


A Cell Electrofusion Chip for Somatic Cells Reprogramming.
Cell fusion is a potent approach to explore the mechanisms of somatic cells reprogramming. However, previous fusion methods, such as polyethylene glycol (PEG) mediated cell fusion, are often limited by poor fusion yields. In this study, we developed a simplified cell electrofusion chip, which was based on a micro-cavity/ discrete microelectrode structure to improve the fusion efficiency and to reduce multi-cell electrofusion. Using this chip, we could efficiently fuse NIH3T3 cells and mouse embryonic stem cells (mESCs) to induce somatic cells reprogramming. We also found that fused cells demethylated gradually and 5-hydroxymethylcytosine (5hmC) was involved in the demethylation during the reprogramming. Thus, the cell electrofusion chip would facilitate reprogramming mechanisms research by improving efficiency of cell fusion and reducing workloads.


Unique cost dynamics elucidate the role of frameshifting errors in promoting translational robustness.
There is now considerable evidence supporting the view that codon usage is frequently under selection for translational accuracy. There are, however, multiple forms of inaccuracy (missense, premature termination, and frameshifting errors) and pinpointing a particular error process behind apparently adaptive mRNA anatomy is rarely straightforward. Understanding differences in the fitness costs associated with different types of translational error can help us devise critical tests that can implicate one error process to the exclusion of others. To this end, we present a model that captures distinct features of frameshifting cost and apply this to 641 prokaryotic genomes. We demonstrate that, although it is commonly assumed that the ribosome encounters an off-frame stop codon soon after the frameshift and costs of mis-elongation are therefore limited, genomes with high GC content typically incur much larger per-error costs. We go on to derive the prediction, unique to frameshifting errors, that differences in translational robustness between the 5' and 3' ends of genes should be less pronounced in genomes with higher GC content. This prediction we show to be correct. Surprisingly, this does not mean that GC-rich organisms necessarily carry a greater fitness burden as a consequence of accidental frameshifting. Indeed, increased per-error costs are often more than counterbalanced by lower predicted error rates owing to more diverse anticodon repertoires in GC-rich genomes. We therefore propose that selection on tRNA repertoires may operate to reduce frameshifting errors.


Susan Nolen-Hoeksema (1959-2013).
Presents an obituary for Susan Nolen-Hoeksema. Susan received her bachelor's degree from Yale University and her doctorate in clinical psychology from the University of Pennsylvania. Her undergraduate and graduate school mentors were Irving Janis, Robert Sternberg, and Martin Seligman. Susan began her career at Stanford University, where she became a tenured associate professor in 1993, and moved to the University of Michigan, where she was promoted to the rank of professor and directed the Institute for Research on Women and Gender. Susan joined the Yale University Department of Psychology in 2004 as a professor and served as its chair and director of graduate studies. Few words can capture Susan's masterful approach to research, which balanced creativity with pragmatism. A pioneer in the study of depression and a leading figure in research on sex differences in depression, she transformed clinical psychology with her research. Raised in the small town of Stonington, Illinois, Susan acquired a decency, kindness, and strength of character that lasted her lifetime. Despite her academic achievements and stature in the field, she treated everyone with respect and dignity. She was remarkable in her ability to support people through difficult circumstances, fairly treat all individuals, and be a kind and dedicated mentor and colleague to those of us fortunate enough to know her. Our field is richer for her presence, and her untimely death is a tragic loss. There could be no better colleague and friend. (PsycINFO Database Record (c) 2013 APA, all rights reserved).


Self-stabilized gradient algorithms for blind source separation with orthogonality constraints.
Recently, developments in self-stabilized algorithms for gradient adaptation of orthonormal matrices have resulted in simple but powerful principal and minor subspace analysis methods. In this paper, we extend these ideas to develop algorithms for instantaneous prewhitened blind separation of homogeneous signal mixtures. Our algorithms are proven to be self-stabilizing to the Stiefel manifold of orthonormal matrices, such that the rows of the adaptive demixing matrix do not need to be periodically reorthonormalized. Several algorithm forms are developed, including those that are equivariant with respect to the prewhitened mixing matrix. Simulations verify the excellent numerical properties of the proposed methods for the blind source separation task.


Evaluation and Management of Aortic Stenosis for the Emergency Clinician: An Evidence-Based Review of the Literature.
Aortic stenosis is a common condition among older adults that can be associated with dangerous outcomes, due to both the disease itself and its influence on other conditions. This review provides an evidence-based summary of the current emergency department (ED) evaluation and management of aortic stenosis. Aortic stenosis refers to significant narrowing of the aortic valve and can be caused by calcific disease, congenital causes, or rheumatic valvular disease. Symptoms of advanced disease include angina, dyspnea, and syncope. Patients with these symptoms have a much higher mortality rate than asymptomatic patients. Initial evaluation should include an electrocardiogram, complete blood count, basic metabolic profile, coagulation studies, troponin, brain natriuretic peptide, type and screen, and a chest radiograph. Transthoracic echocardiogram is the test of choice, but point-of-care ultrasound has been found to have good accuracy when a formal echocardiogram is not feasible. Initial management should begin with restoring preload and ensuring a normal heart rate, as both bradycardia and tachycardia can lead to clinical decompensation. For patients with high blood pressure and heart failure symptoms, nitrate agents may be reasonable, but hypotension should be avoided. Dobutamine can increase inotropy. For hypotensive patients, vasopressors should be used at the lowest effective dose. The treatment of choice is valve replacement, but extracorporeal membrane oxygenation and percutaneous balloon dilatation of the aortic valve have been described as temporizing measures. Aortic stenosis is an important condition that can lead to dangerous outcomes and requires prompt recognition and disease-specific management in the ED.


Factor VIII related antigen in gestational trophoblastic disease.
Serum factor VIII related antigen (factor VIII R:Ag) levels were determined in 34 patients with hydatidiform mole at diagnosis and at 2, 4 and 6 weeks after evacuation of uterus and in 272 normal pregnant women. Serum factor VIII R:Ag levels in molar pregnancies before evacuation of the uterus were significantly higher than those in normal pregnancies of the same gestation age. Serum factor VIII R:Ag levels in the group of patients with residual trophoblastic disease were significantly higher than those in the group without residual trophoblastic disease before evacuation and at 6 weeks after evacuation of uterus, but there is considerable overlap in the levels of factor VIII R:Ag between the two groups of patients especially before evacuation of uterus. Factor VIII R:Ag level does not appear to be an useful marker in predicting the outcome of hydatidiform mole.


Endometrial glandular dysplasia: a newly defined precursor lesion of uterine papillary serous carcinoma. Part I: morphologic features.
Dysplastic epithelium frequently bridges the changes between normal epithelium and noninvasive carcinoma. However, such a dysplastic lesion has not been previously described in the development of uterine papillary serous carcinoma (UPSC) or between resting endometrium and serous endometrial intraepithelial carcinoma (EIC), which is composed of indisputably malignant noninvasive cancer cells. In this study, we hypothesize that there is a lesion bridging benign endometrium and serous EIC. Based on current understanding of carcinogenesis in general, the lesion should exhibit dysplastic features that are more atypical than "resting endometrium" but fall short of serous EIC. If the putative dysplastic endometrial lesion exists, it should be highly associated with UPSC rather than uterine endometrioid carcinoma (UEC). We examined the morphologic appearance of the endometrium from 32 uteri with UPSC, 16 with serous EIC, and 60 with UEC. The endometrial dysplastic lesions were identified and their pathologic features were characterized. Immunohistochemical staining with p53 and MIB-1 were performed in all sections containing endometrial dysplastic lesions, serous EICs, and benign areas. In addition, 25 postmenopausal endometrial biopsies including 6 benign resting endometria, 8 dysplastic lesions, and 11 serous EICs were also compared for the level of p53 overexpression and cellular proliferative activity. We found that endometrial dysplastic lesions do exist in the endometrial specimens we speculated and examined. We designate it as endometrial glandular dysplasia (EmGD). EmGD was present in 17 (53%) uteri with UPSC compared with 1 (1.7%) uterus removed for UEC (p = 0.001). EmGD was identified in 12 (75%) of 16 serous EIC uteri. Areas of both EmGD and serous EIC were found in 15 (47%) of the 32 UPSC uteri. Transitions from either EmGD to serous EIC or serous EIC to UPSC were present in 8 (25%) of the UPSC cases. No transitions from EmGD to UPSC were identified in any hysterectomy specimen. EmGD was frequently found in endometrial polyps. There was no statistically significant difference between EmGD in a polyp (48%) and EmGD in nonpolypoid endometrium (52%). The majority of EmGDs were multifocal and involved superficial endometrial glands. However, single glandular involvement and endometrial surface epithelial involvement were also seen. Immunohistochemically, EmGD lesions mostly showed intermediate scores/indices of p53 and MIB-1 in comparison with serous EIC and resting endometrium. EmGD is a morphologically distinct entity, which is commonly and specifically associated with uterine tumors with serous differentiation. EmGD may represent the earliest identifiable morphologic change in the development of UPSC. Characteristics of p53 and MIB-1 immunostains of EmGD may be of diagnostic usage in surgical pathology practice. Recognition of EmGD may provide an opportunity to improve the management of UPSC.


Porphyrin-fullerene C60 dyads with high ability to form photoinduced charge-separated state as novel sensitizers for photodynamic therapy.
The photodynamic activities of a porphyrin-C60 dyad (P-C60) and its metal complex with Zn(II) (ZnP-C60) were compared with 5-(4-acetamidophenyl)-10,15,20-tris(4-methoxyphenyl)porphyrin (P), both in homogeneous medium-bearing photooxidizable substrates and in vitro on the Hep-2-human-larynx-carcinoma cell line. This study represents the first evaluation of dyads, with a high capacity to form a photoinduced charge-separated state, to act as agents to inactivate cells by photodynamic therapy (PDT). Absorption and fluorescence spectroscopic studies were performed in toluene and N,N-dimethylformamide (DMF). The emission of the porphyrin moiety in the dyads is strongly quenched by the attached fullerene C60 moiety. The singlet molecular oxygen, O2(1delta(g)), productions (phi(delta)) were determined using 9,10-dimethylanthracene (DMA). The values of phi(delta) were strongly dependent on the solvent's polarity. Comparable phi(delta) values were found for dyads and P in toluene, while O2(1delta(g)) production was significantly diminished for the dyads in DMF. In more polar solvent, the stabilization of charge-transfer state takes place, decreasing the efficiency of porphyrin triplet-state formation. Also, both dyads photosensitize the decomposition of L-tryptophan in DMF. In biological medium, no dark cytotoxicity was observed using sensitizer concentrations < or = 1 microM and 24 h of incubation. The uptake of sensitizers into Hep-2 was studied using 1 microM of sensitizer and different times of incubation. Under these conditions, a value of approximately 1.5 nmol/10(6) cells was found between 4 and 24 h of incubation. The cell survival after irradiation of the cells with visible light was dependent upon light-exposure level. A higher photocytotoxic effect was observed for P-C60, which inactivates 80% of cells after 15 min of irradiation. Moreover, both dyads keep a high photoactivity even under argon atmosphere. Thus, depending on the microenvironment where the sensitizer is localized, these compounds could produce biological photodamage through either an O2(1delta(g))-mediated photoreaction process or a free-radicals mechanism under low oxygen concentration. These results show that molecular dyads, which can form a photoinduced charge-separated state, are a promising model for phototherapeutic agents, with potential applications in cell inactivation by PDT.


mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote KrasG12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis.
Oncogenic KrasG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of KrasG12D, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. A mouse model of inflammation-accelerated KrasG12D-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote KrasG12D-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents KrasG12D-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.


Pretreatment with ascorbic acid prevents lethal gastrointestinal syndrome in mice receiving a massive amount of radiation.
While bone marrow or stem cell transplantation can rescue bone marrow aplasia in patients accidentally exposed to a lethal radiation dose, radiation-induced irreversible gastrointestinal damage (GI syndrome) is fatal. We investigated the effects of ascorbic acid on radiation-induced GI syndrome in mice. Ascorbic acid (150 mg/kg/day) was orally administered to mice for 3 days, and then the mice underwent whole body irradiation (WBI). Bone marrow transplantation (BMT) 24 h after irradiation rescued mice receiving a WBI dose of less than 12 Gy. No mice receiving 14 Gy-WBI survived, because of radiation-induced GI syndrome, even if they received BMT. However, pretreatment with ascorbic acid significantly suppressed radiation-induced DNA damage in the crypt cells and prevented denudation of intestinal mucosa; therefore, ascorbic acid in combination with BMT rescued mice after 14 Gy-WBI. DNA microarray analysis demonstrated that irradiation up-regulated expressions of apoptosis-related genes in the small intestine, including those related to the caspase-9-mediated intrinsic pathway as well as the caspase-8-mediated extrinsic pathway, and down-regulated expressions of these genes in ascorbic acid-pretreated mice. Thus, pretreatment with ascorbic acid may effectively prevent radiation-induced GI syndrome.


The Epstein-Barr virus carrier state: dominance of a single growth-transforming isolate in the blood and in the oropharynx of healthy virus carriers.
Epstein-Barr virus (EBV) isolates can be broadly classified as type 1 or type 2 on the basis of allelic polymorphism of the virus-encoded nuclear antigens EBNAs 2, 3a, 3b and 3c, and individually identified based on Mr values of their EBNA proteins (EBNA type). Here we have used this natural heterogeneity amongst isolates to re-examine the question of EBV persistence in vivo, asking in particular whether virus carriage in oropharyngeal epithelium and/or in B lymphoid tissues involves infection with a single or with multiple virus strains. Firstly, 76 healthy virus carriers were classified into serotype groups on the basis of preferential antibody reactivity to type 1 EBNAs (serotype 1) or to type 2 EBNAs (serotype 2); 60 of the 76 donors were serotype 1, four of the 76 donors were serotype 2 and 12 of the 76 donors were anti-EBNA 2, 3a, 3b, 3c antibody-negative and therefore could not be serotyped. Representative donors from each group were then selected for virus isolations from blood (by spontaneous in vitro transformation) and from throat washings (by cord blood cell transformation). All 13 serotype 1 donors tested and six of seven non-serotypeable donors gave a type 1 virus isolate, whereas all four serotype 2 donors and one of the seven non-serotypeable donors gave a type 2 isolate. Multiple transforming virus isolates from any one donor, whether from blood or throat washings, were all of the one strain characteristic of that particular donor; sequential isolations showed retention of the same strain over several years. Finally, throat washing samples from these same donors were examined for amplifiable EBV DNA in the polymerase chain reaction using EBV type-specific oligonucleotide primers and probes derived from the polymorphic EBNA 2 and EBNA 3c loci. The results were consistent with earlier virus isolation studies, each individual donor showing amplification either of type 1 or type 2 sequences. We conclude that multiple EBV infections must occur rarely, if at all, in healthy virus carriers; EBV persistence in vivo is characterized by dominance of a single transforming virus strain.


Which fMRI clustering gives good brain parcellations?
Analysis and interpretation of neuroimaging data often require one to divide the brain into a number of regions, or parcels, with homogeneous characteristics, be these regions defined in the brain volume or on the cortical surface. While predefined brain atlases do not adapt to the signal in the individual subject images, parcellation approaches use brain activity (e.g., found in some functional contrasts of interest) and clustering techniques to define regions with some degree of signal homogeneity. In this work, we address the question of which clustering technique is appropriate and how to optimize the corresponding model. We use two principled criteria: goodness of fit (accuracy), and reproducibility of the parcellation across bootstrap samples. We study these criteria on both simulated and two task-based functional Magnetic Resonance Imaging datasets for the Ward, spectral and k-means clustering algorithms. We show that in general Ward's clustering performs better than alternative methods with regard to reproducibility and accuracy and that the two criteria diverge regarding the preferred models (reproducibility leading to more conservative solutions), thus deferring the practical decision to a higher level alternative, namely the choice of a trade-off between accuracy and stability.


Emergence of scaling in human-interest dynamics.
Human behaviors are often driven by human interests. Despite intense recent efforts in exploring the dynamics of human behaviors, little is known about human-interest dynamics, partly due to the extreme difficulty in accessing the human mind from observations. However, the availability of large-scale data, such as those from e-commerce and smart-phone communications, makes it possible to probe into and quantify the dynamics of human interest. Using three prototypical "Big Data" sets, we investigate the scaling behaviors associated with human-interest dynamics. In particular, from the data sets we uncover fat-tailed (possibly power-law) distributions associated with the three basic quantities: (1) the length of continuous interest, (2) the return time of visiting certain interest, and (3) interest ranking and transition. We argue that there are three basic ingredients underlying human-interest dynamics: preferential return to previously visited interests, inertial effect, and exploration of new interests. We develop a biased random-walk model, incorporating the three ingredients, to account for the observed fat-tailed distributions. Our study represents the first attempt to understand the dynamical processes underlying human interest, which has significant applications in science and engineering, commerce, as well as defense, in terms of specific tasks such as recommendation and human-behavior prediction.


The mystery of Etruscan origins: novel clues from Bos taurus mitochondrial DNA.
The Etruscan culture developed in Central Italy (Etruria) in the first millennium BC and for centuries dominated part of the Italian Peninsula, including Rome. The history of the Etruscans is at the roots of Mediterranean culture and civilization, but their origin is still debated: local or Eastern provenance? To shed light on this mystery, bovine and human mitochondrial DNAs (mtDNAs) have been investigated, based on the well-recognized strict legacy which links human and livestock populations. In the region corresponding to ancient Etruria (Tuscany, Central Italy), several Bos taurus breeds have been reared since historical times. These breeds have a strikingly high level of mtDNA variation, which is found neither in the rest of Italy nor in Europe. The Tuscan bovines are genetically closer to Near Eastern than to European gene pools and this Eastern genetic signature is paralleled in modern human populations from Tuscany, which are genetically close to Anatolian and Middle Eastern ones. The evidence collected corroborates the hypothesis of a common past migration: both humans and cattle reached Etruria from the Eastern Mediterranean area by sea. Hence, the Eastern origin of Etruscans, first claimed by the classic historians Herodotus and Thucydides, receives strong independent support. As the Latin philosopher Seneca wrote: Asia Etruscos sibi vindicat (Asia claims the Etruscans back).


[The problem of representiveness in epidemiological research in psychiatry].
A group of schizophrenic patients registered by the city psychoneurological center (Petrozavodsk) is compared to a standard sample. It is shown that there is a possibility of defining to what extent the test group differs from the representative one and by what the differences are determined. In accordance with this, the limits of the use of the research data are outlined.


[Morphologic characteristics of lesions of the small intestinal mucosa in chronic ischemia].
The results of morphologic examination of the small bowel mucosa of 32 patients with the ischemic disease of the alimentary organs provoked by stenosis of a. iliaca are analyzed. The diagnosis was confirmed angiographically and in the course of operation. Aspiration biopsy of the jejunum was performed by means of Ts. G. Masevich's sound. Chronic intestinal ischemia provokes the development of the atrophic changes in the mucosa with the decrease of its thickness due to the lowering of the height of its villi. The number of the goblet cells is increasing as well as the cell infiltration, the degenerative changes in the epithelium are observed. These alterations correlate with the degree of both the vessel narrowing and collateral circulation.


Tail regeneration in Xenopus laevis as a model for understanding tissue repair.
Augmentation of regenerative ability is a powerful strategy being pursued for the biomedical management of traumatic injury, cancer, and degeneration. While considerable attention has been focused on embryonic stem cells, it is clear that much remains to be learned about how somatic cells may be controlled in the adult organism. The tadpole of the frog Xenopus laevis is a powerful model system within which fundamental mechanisms of regeneration are being addressed. The tadpole tail contains spinal cord, muscle, vasculature, and other terminally differentiated cell types and can fully regenerate itself through tissue renewal--a process that is most relevant to mammalian healing. Recent insight into this process has uncovered fascinating molecular details of how a complex appendage senses injury and rapidly repairs the necessary morphology. Here, we review what is known about the chemical and bioelectric signals underlying this process and draw analogies to evolutionarily conserved pathways in other patterning systems. The understanding of this process is not only of fundamental interest for the evolutionary and cell biology of morphogenesis, but will also generate information that is crucial to the development of regenerative therapies for human tissues and organs.


Modified horizontal muscle transposition without tenotomy and splitting for a case of inferior rectus and inferior oblique muscles aplasia with hemifacial microsomia.
Aplasia of the inferior rectus and inferior oblique muscles is extremely rare. Failure of the normal embryologic development of the inferior mesodermal complex can lead to agenesis of inferior rectus, inferior oblique, and lower sections of the lateral rectus muscles. This rare condition is usually seen in association with craniofacial syndromes or in conjunction with microcornea, microphthalmos, Axenfeld-Rieger syndrome, and coloboma. The usual treatment for this condition is a reverse Knapp procedure to improve the vertical alignment; however, this procedure can lead to complications, such as anterior segment ischemia, undercorrection, and torsional problems. To our knowledge, unilateral inferior rectus and inferior oblique muscle aplasia has not been described previously in a patient with congenital facial nerve palsy and optic nerve hypoplasia. In the present case, the patient was successfully treated with a modified minimally invasive horizontal rectus muscle transposition procedure.


Psychiatric effects of exposure to suicide among the friends and acquaintances of adolescent suicide victims.
The friends and acquaintances (N = 58) of 10 adolescent suicide victims were interviewed 6 months after the death of the victims, and the rates of psychiatric disorders that had onset after the death were compared with the 6-month incidence of psychopathology in 58 demographically and psychiatrically matched unexposed controls. The exposed group showed higher rates of any new onset major depressive disorder, but the rate of incident suicide attempts was the same in both groups. The median onset of incident depression among the exposed group was within the first month after exposure, and the majority of those exposed youth with incident depression were still depressed at interview 6 months after the death. Adolescent friends and acquaintances of suicide victims experience considerable psychiatric morbidity subsequent to exposure to suicide, most consistent with pathological grief.


Individual/neighborhood social factors and blood pressure in the RECORD Cohort Study: which risk factors explain the associations?
Recent studies have started to suggest that, beyond effects of individual socioeconomic profiles, socioeconomic characteristics of residential neighborhoods are independently associated with blood pressure. However, mechanisms involved in these associations remain unknown. To distinguish between different mechanisms, we investigated whether specific risk factors of hypertension (physical inactivity, alcohol consumption, smoking, body mass index, waist circumference, and resting heart rate) intervene as mediators in the associations between individual or neighborhood socioeconomic characteristics and systolic blood pressure. We relied on data from the RECORD Cohort Study (Residential Environment and CORonary heart Disease) on 5941 participants recruited in 2007-2008, aged 30 to 79 years, residing in 1824 neighborhoods in the Paris metropolitan area. Systolic blood pressure increased independently and regularly with both decreasing individual education and decreasing residential neighborhood education. Body mass index/waist circumference and resting heart rate mediated an appreciable share of the associations between education and blood pressure and, adding validity to the finding, were the 2 most significant mediators for the effects of both individual education and neighborhood education. We found that 52% (95% CI: 25% to 79%) of the association between neighborhood education and blood pressure was mediated by body mass index/waist circumference and 20% (95% CI: 5% to 36%) by resting heart rate. Future research will have to clarify the exact mechanisms through which body weight and shape and resting heart rate intervene as mediators in the associations between individual/neighborhood education and blood pressure.


MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A.
To assess the role of microRNAs (miR) in hepatocellular carcinoma (HCC), we performed comprehensive microRNA expression profiling using HCC cell lines and identified miR-93 as a novel target associated with HCC. We further verified miR-93 expression levels in advanced HCC tumors (n=47) by a direct PCR assay and found that elevated miR-93 expression level is significantly correlated with poor prognosis. Elevated miR-93 expression significantly stimulated in vitro cell proliferation, migration and invasion, and additionally inhibited apoptosis. We confirmed that miR-93 directly bound with the 3' untranslated regions of the tumor-suppressor genes PTEN and CDKN1A, respectively,and inhibited their expression. As a result of this inhibition, the c-Met/PI3K/Akt pathway activity was enhanced. IHC analysis of HCC tumors showed significant correlation between c-Met protein expression levels and miR-93 expression levels. Knockdown of c-Met inhibited the activation of the c-Met/PI3K/Akt pathway regardless of hepatocyte growth factor (HGF) treatment, and furthermore reduced the expression of miR-93 in these HCC cells. miR-93 also rendered cells to be more sensitive to sorafenib and tivantinib treatment. We concluded that miR-93 stimulated cell proliferation, migration, and invasion through the oncogenic c-Met/PI3K/Akt pathway and also inhibited apoptosis by directly inhibiting PTEN and CDKN1A expression in human HCC.


Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome.
Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.


Development and validation of the ICF-CY-Based Functioning Scale of the Disability Evaluation System--Child Version in Taiwan.
The International Classification of Functioning, Disability, and Health-Children and Youth version (ICF-CY) depicts human functioning [body functions (b), structures (s), and activities and participation (d) components] as the product of the interaction between health conditions and contextual factors [environmental factors (e) and personal factors]. In Taiwan, testers use the Functioning Scale of the Disability Evaluation System-Child version (FUNDES-Child) to collect information related to b, d, and e for children aged 6.0-17.9 years in the Disability Eligibility System (DES). The purpose of this study was to examine the content and construct validity of the FUNDES-Child. We developed the FUNDES-Child through translating the existing questionnaires, cross-cultural adaptation, expert consensus, and field tests. Consensus meetings were conducted to link items from the FUNDES-Child to ICF-CY codes. To investigate construct validity, we examined associations among scores from the FUNDES-Child that reflected ICF-CY chapter-linked components. The FUNDES-Child items were successfully linked to all nine d-, five b-, and four e-chapters of the ICF-CY. Moderate correlations were found between scores that were expected to be related to specific chapters in the b, d, and e components. The scores of the b-chapters had stronger relationships with the d independence scores, while attitudes of others (e4) had stronger relationships with the d participation frequency scores. The FUNDES-Child had acceptable content validity and construct validity in the DES. The associations found among the ICF-CY chapter scores provided a model for investigating the impact of body functions and environmental factors on children's activities and participation.


Supplementation of Caricol®-Gastro reduces chronic gastritis disease associated pain.
Papaya and oats are natural food and used in traditional medicine in many parts of the world. Papaya has a high content of enzymes supporting digestive function. Oats are a source of minerals, beta-glucan fibres, immunmodulatory and antiinflammatory probiotic substances. Caricol®-Gastro combines both constituents, it was designed as vegan organic preparation for intestinal inflammatory diseases. We performed a randomized, double blind placebo controlled clinical trial to investigate the potential of Caricol®-Gastro as add on therapy in patients with diagnosed chronic gastritis. 60 Patients with endoscopically confirmed mild chronic disease were recruited. A structured interview documented the baseline data. Then the patients were allocated to the verum or placebo group by handing out a numbered study package with the study substance for the daily intake at home. A single dose was 20 g, taken twice per day. After 30 days the participants were interviewed again. After the intake phase the disease related symptoms were found improved in both groups, indicating a strong placebo effect. However, the pain load reduction in the Caricol®-Gastro group was significantly larger (p=0.048). Due to the inherent biological activities of ingredients of papaya and of oats and their known effects (anti-inflammatory, epithelial integrity), the observed beneficial effects may be owed to the constituents synergisms to reduce chronic inflammation. We conclude, that the regular intake is a safe add on therapeutic option for patients with chronic gastritis to support standard medical care.


Cardiac emergencies in neurosurgical patients.
Perioperative safety concerns are a major area of interest in recent years. Severe cardiac perturbation such as cardiac arrest is one of the most dreaded complications in the intraoperative period; however, little is known about the management of these events in the patients undergoing elective neurosurgery. This special group needs further attention, as it is often neither feasible nor appropriate to apply conventional advanced cardiac life support algorithms in patients undergoing neurosurgery. Factors such as neurosurgical procedure and positioning can also have a significant effect on the occurrence of cardiac arrest. Therefore, the aim of this paper is to describe the various causes and management of cardiac emergencies with special reference to cardiac arrest during elective neurosurgical procedures, including discussion of position-related factors and resuscitative considerations in these situations. This will help to formulate possible guidelines for management of such events.


Fc-receptor function in Henoch-Schönlein disease of childhood.
The Fc-receptor function of circulating monocytes (CM) and/or of splenic macrophages (SM) was followed in eight children presenting with rheumatoid purpura. The Fc-receptor of CM and/or of SM was decreased in all cases during the acute phase of the disease without any correlation with the plasma values of C3, C4, C3PA or immune complexes. When a clinical improvement occurred, a reversal of the Fc-receptor blockade was noted. In contrast, the Fc-receptor function remained abnormal in three children with persistent nephritis. The sequential measurement of Fc-receptor function may be of predictive value in rheumatoid purpura of childhood.


The OxyR regulon.
Treatment of Salmonella typhimurium and Escherichia coli cells with low doses of hydrogen peroxide results in the induction of thirty proteins and resistance to killing by higher doses of hydrogen peroxide. The expression of nine of the hydrogen peroxide-inducible proteins, including catalase, glutathione reductase and a novel alkyl hydroperoxide reductase is controlled by the positive regulator oxyR. OxyR is homologous to the LysR-NodD family of bacterial regulatory proteins and binds to the promoters of oxyR-regulated genes. The oxidized but not reduced form of the OxyR protein activates transcription of oxyR-regulated genes in vitro suggesting that oxidation of the OxyR protein brings about a conformational change by which OxyR both senses and transduces an oxidative stress signal to RNA polymerase.


CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2.
CDK9 is a CDC2-related kinase and the catalytic subunit of the positive-transcription elongation factor b and the Tat-activating kinase. It has recently been reported that CDK9 is a short-lived protein whose levels are regulated during the cell cycle by the SCF(SKP2) ubiquitin ligase complex (R. E. Kiernan et al., Mol. Cell. Biol. 21:7956-7970, 2001). The results presented here are in contrast to those observations. CDK9 protein levels remained unchanged in human cells entering and progressing through the cell cycle from G(0), despite dramatic changes in SKP2 expression. CDK9 levels also remained unchanged in cells exiting from mitosis and progressing through the next cell cycle. Similarly, the levels of CDK9 protein did not change as cells exited the cell cycle and differentiated along various lineages. In keeping with these observations, the kinase activity associated with CDK9 was found to not be regulated during the cell cycle. We have also found that endogenous CDK9 is a very stable protein with a half-life (t(1/2)) of 4 to 7 h, depending on the cell type. In contrast, when CDK9 is overexpressed, it is not stabilized and is rapidly degraded, with a t(1/2) of less than 1 h, depending on the level of expression. Treatment of cells with proteasome inhibitors blocked the degradation of short-lived proteins, such as p27, but did not affect the expression of endogenous CDK9. Ectopic overexpression of SKP2 led to reduction of p27 protein levels but had no effect on the expression of endogenous CDK9. Finally, downregulation of endogenous SKP2 gene expression by interfering RNA had no effect on CDK9 protein levels, whereas p27 protein levels increased dramatically. Therefore, the SCF(SKP2) ubiquitin ligase does not regulate CDK9 expression in a cell cycle-dependent manner.