Foraging Economics of the Hunt Bumble Bee, a Viable Pollinator for Commercial Agriculture.
Globally, there are only five bumble bee (Hymenoptera: Apidae, Bombus) species that have been successfully commercialized for agriculture. The Hunt bumble bee, Bombus huntii Green, 1860, has been recognized as a suitable pollinator of crops and has a broad distribution in western North America, making it a viable candidate for commercialization. In this study, our goal was to characterize the foraging dynamics of B. huntii female workers under open field conditions. To accomplish this goal, we monitored three B. huntii colonies over an 8-wk period in the summer of 2012 in northern Utah. Using marked bees, we studied the relationship between foraging duration/offloading and pollen/nonvisible pollen collection. In total, we observed 921 foraging events across all three colonies. Of our observations, 82% (n = 756) were foraging events that included both a departure and arrival time observation. Average duration of pollen and nonpollen (i.e., nectar) trips across foragers is 41.86 ± 5.65 min (±SE) and 32.18 ± 5.89 min, respectively. Workers spent a significantly longer time offloading pollen in the nest after a foraging trip relative to workers without pollen present on their corbicula. Pollen foraging rate increases over the course of the day, likely due to the time it takes to learn how to forage on a diverse array of flower morphologies. Our study provides data on how long it takes for B. huntii to forage in open field conditions and will be useful when comparing foraging rates in controlled crop systems.


Creating or taking opportunity: Strategies for implementing expert by experience positions in mental health academia.
WHAT IS KNOWN ON THE SUBJECT?: Experts by experience involvement in the education of health professionals demonstrate positive attitudinal change. Meaningful positions for Experts by Experience are limited and ad hoc, due to attitudinal and other barriers to innovation within the higher education sector. Experiences of allies who have supported the implementation of Expert by Experience positions have not been researched. This is important knowledge that could be utilized by potential allies. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: Academic allies to experts by experience have a crucial role to play in identifying opportunities to establish, implement and sustain expert by experience positions. Allies who have successfully implemented positions for experts by experience have identified influential factors including: right person, right role, collaboration and coproduction, support, and career pathways. Understanding these factors can provide an important basis for other academics to support a widespread increase in academic roles for experts by experience in mental health education. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Establishing and maintaining genuine relationships with service users require significant attitudinal change on the part of mental health professionals. Involving experts by experience in mental health education provides an innovative approach to the challenging of attitudes and the enhancement of more collegial relationships with service users as colleagues in the workplace. This paper demonstrates the importance of allyship to the establishment, implementation and sustainability of expert by experience roles, and highlights critical factors allies have utilized in support of such roles. Nurses and other mental health professional academics have the potential to become allies and support change and innovation. ABSTRACT: Introduction Experts by experience in academia have demonstrated more positive student attitudes towards relationships with service users. Notwithstanding this supportive evidence, academic positions for EBE have not grown substantially. Enhanced understanding of positions that have been implemented is important knowledge for others with similar aspirations. Aim To enrich understanding of the role of allies in identifying and pursuing opportunities to support academic positions for experts by experience. Methods Qualitative exploratory approach, involving In-depth interviews with allies with expertise in supporting academic positions for experts by experience. Results Participants were enthusiastic about creating or taking opportunities to secure expert by experience involvement within their programs. Factors facilitating success included right person, right role, collaboration and coproduction, support and career pathways. Conclusions Significant barriers have prevented proliferation of academic roles for experts by experience. Despite barriers, allies have been successful in supporting the implementation and sustaining of positions, and gained considerable expertise, which may be invaluable to academics with similar aspirations. Implications for practice Realization of policy goals regarding service user involvement in mental health services requires health professionals with the will to embrace partnerships. By creating and taking opportunities, allies have developed expertise to facilitate implementation of positions more widely.


Noninvasive three-dimensional cardiac activation imaging on a rabbit model.
Three-dimensional cardiac activation imaging (3-DCAI) aims at imaging the activation sequence throughout the 3-D myocardium. In the present study, the performance of 3-DCAI was validated through both in vivo animal experiments and computer simulations under a pacing protocol. The non-invasively imaged activation sequence from body surface potential maps (BSPMs) was quantitatively compared with the measured activation sequence obtained from the simultaneous intramural recording using a 3-D intra-cardiac mapping technique in a rabbit model. In addition, computer simulations were conducted to provide further assessment of the performance of the 3-DCAI algorithm in a realistic-geometry rabbit heart-torso model. The encouraging results suggest that 3-DCAI can non-invasively image the activation sequence and localize the origin of activation with good accuracy.


[Teaching perioperative nursing: a comparative study of audiovisual (video) oral resources].
The aim of this study was to compare information on perioperative Nursing regarding audiovisual (video) and oral resources. 104 patients were registered as subjects and divided in two groups, 54 of them in the oral group and 50 in the video group. Authors concluded that the groups were homogeneous and that there was no significant difference between the two resources used. Independent from the resource used, the responses were qualitatively better. However, regarding perioperative informations, authors spent 10 minutes using the video while oral information lasted 45 minutes. The video unabled verbalization that is characterized by the exposition of methods and reduces the time spent with information.


Foot care education and self management behaviors in diverse veterans with diabetes.
The objective of this study was to examine differences in self-reported diabetes foot care education, self management behaviors, and barriers to good foot care among veterans with diabetes by race and ethnicity. Data was collected using the Veterans Health Administration Footcare Survey, a validated tool that assessed demographic, general health, diabetes and foot self-care information, barriers to foot self-care, receipt of professional foot care, and satisfaction with current care. We mailed surveys to a random sample of patients with diabetes from eight VA medical centers. Study participants were 81% White; 13% African American; 4% Asian, and 2% American Indian and Pacific Islanders. The majority of respondents felt that they did not know enough about foot self-care. There were large gaps between self-reported knowledge and actual foot care practices, even among those who reported "knowing enough" on a given topic. There were significant differences in self-reported foot care behaviors and education by race and ethnicity. These findings document the need for culturally-specific self-management education to address unique cultural preferences and barriers to care.


Sleep deprivation alters neutrophil functions and levels of Th1-related chemokines and CD4+ T cells in the blood.
The state of knowledge about the effect of sleep deprivation on the immune system is scarce and conflicting. It would therefore be useful to investigate the consequences of sleep deprivation on the immune system. We have studied the effect of sleep deprivation on the changes in neutrophil functions, and the ex vivo proliferative pattern of CD4+ T lymphocytes in relationship with blood cytokine and chemokine levels due to the crucial role of these cells in mounting potent immune responses. Healthy volunteers were followed for 3 weeks. They had normal sleep in weeks 1 and 3 and they were sleep-deprived on week 2, sleeping < 6 h per 24 h, a pattern similar to sleep behaviors of many chronically sleep-deprived individuals. We assessed the levels of Th1/Th2 and inflammatory cytokines and chemokines, CD4+ T cells, and the NADPH oxidase activation and phagocytic functions in neutrophils. Our results suggest that sleep deprivation leads to a decreased neutrophil capacity to phagocytose bacteria and activate NADPH oxidase (p < 0.05). Sleep deprivation was associated with a potential increase in CXCL9 levels and decrease in CXCL10/CXCL9 and CCL5/CXCL9 ratios (p < 0.05). Furthermore, our results suggest that the decrease in CD4+ T cell due to sleep deprivation was not associated with changes in their proliferation as observed by Ki67 levels, but rather, it correlated with changes in CXCL10/CXCL9 ratio (p < 0.05). Sleep deprivation may lead to a decreased phagocytosis and NADPH oxidase activity in neutrophils and a decrease in the levels of CD4+ T cells which is related to changes in the Th1-related chemokine balance.


Genomic interspecies microarray hybridization: rapid discovery of three thousand genes in the maize endophyte, Klebsiella pneumoniae 342, by microarray hybridization with Escherichia coli K-12 open reading frames.
In an effort to efficiently discover genes in the diazotrophic endophyte of maize, Klebsiella pneumoniae 342, DNA from strain 342 was hybridized to a microarray containing 96% (n = 4,098) of the annotated open reading frames from Escherichia coli K-12. Using a criterion of 55% identity or greater, 3,000 (70%) of the E. coli K-12 open reading frames were also found to be present in strain 342. Approximately 24% (n = 1,030) of the E. coli K-12 open reading frames are absent in strain 342. For 1.6% (n = 68) of the open reading frames, the signal was too low to make a determination regarding the presence or absence of the gene. Genes with high identity between the two organisms are those involved in energy metabolism, amino acid metabolism, fatty acid metabolism, cofactor synthesis, cell division, DNA replication, transcription, translation, transport, and regulatory proteins. Functions that were less highly conserved included carbon compound metabolism, membrane proteins, structural proteins, putative transport proteins, cell processes such as adaptation and protection, and central intermediary metabolism. Open reading frames of E. coli K-12 with little or no identity in strain 342 included putative regulatory proteins, putative chaperones, surface structure proteins, mobility proteins, putative enzymes, hypothetical proteins, and proteins of unknown function, as well as genes presumed to have been acquired by lateral transfer from sources such as phage, plasmids, or transposons. The results were in agreement with the physiological properties of the two strains. Whole genome comparisons by genomic interspecies microarray hybridization are shown to rapidly identify thousands of genes in a previously uncharacterized bacterial genome provided that the genome of a close relative has been fully sequenced. This approach will become increasingly more useful as more full genome sequences become available.


Vitamin D: its role in cancer prevention and treatment.
Vitamin D, the sunshine vitamin, has been recognized for almost 100 years as being essential for bone health. Vitamin D provides an adequate amount of calcium and phosphorus for the normal development and mineralization of a healthy skeleton. Vitamin D made in the skin or ingested in the diet, however, is biologically inactive and requires obligate hydroxylations first in the liver to 25-hydroxyvitamin D, and then in the kidney to 1,25-dihydroxyvitamin D. 25-Hydroxyvitamin D is the major circulating form of vitamin D that is the best indicator of vitamin D status. 1,25-dihydroxyvitamin D is the biologically active form of vitamin D. This lipid-soluble hormone interacts with its specific nuclear receptor in the intestine and bone to regulate calcium metabolism. It is now recognized that the vitamin D receptor is also present in most tissues and cells in the body. 1,25-dihydroxyvitamin D, by interacting with its receptor in non-calcemic tissues, is able to elicit a wide variety of biologic responses. 1,25-dihydroxyvitamin D regulates cellular growth and influences the modulation of the immune system. There is compelling epidemiologic observations that suggest that living at higher latitudes is associated with increased risk of many common deadly cancers. Both prospective and retrospective studies help support the concept that it is vitamin D deficiency that is the driving force for increased risk of common cancers in people living at higher latitudes. Most tissues and cells not only have a vitamin D receptor, but also have the ability to make 1,25-dihydroxyvitamin D. It has been suggested that increasing vitamin D intake or sun exposure increases circulating concentrations of 25-hydroxyvitamin D, which in turn, is metabolized to 1,25-dihydroxyvitamin D(3) in prostate, colon, breast, etc. The local cellular production of 1,25-dihydroxyvitamin D acts in an autocrine fashion to regulate cell growth and decrease the risk of the cells becoming malignant. Therefore, measurement of 25-hydroxyvitamin D is important not only to monitor vitamin D status for bone health, but also for cancer prevention.


Effect of climate change on nature and human health with a special focus on infectious diseases in the Mediterranean region.
In this short review, the effect of climate change on nature and human health with a special focus on infectious diseases in the Mediterranean region is discussed. This research is a part of the Mediterranean Convention of Human Rights project, which is an organizational work on human rights issues that was established in cooperation with civil society and the national authorities of the Mediterranean Region. Previously published data were collected by retrieving published literature from PubMed, Google Scholar, and Web of Science using "climate change", "the Mediterranean region", "infections in Mediterranean Region", "infectious diseases", "biodiversity", and "the Mediterranean Sea" as keywords. The collected data were then evaluated and reviewed. The recommendations and guidelines were analysed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The Mediterranean region presents a typical example witnessing a dramatic change in climate events and their adverse impact on biodiversity, ecosystems and public health are multiple. This negative impact is in part due to the geographical particularities, and sociocultural and geopolitical conflicts that are progressively worsening the burden of climate change. While most of these changes cannot be totally avoided, many of the health risks related to climate change could be monitored. This can be done by establishing health systems with policies to reduce and prevent the risks of infectious diseases and to recover and support the affected areas, which may identify priority and management of high-risk events.


Ab initio molecular dynamics simulation of a medium-sized water cluster anion: from an interior to a surface-located excess electron via a delocalized state.
We present a computational study of the structure and dynamics of an excess electron in a medium-sized water cluster aimed at addressing the question of interior vs exterior solvation. Ab initio Born-Oppenheimer molecular dynamics simulations were performed within the DFT framework, employing a hybrid Gaussian and plane-wave formalism together with the PBE exchange-correlation functional and norm-conserving pseudopotentials. Analysis of a 15-ps trajectory allowed us to reach the following conclusions: (i) the excess electron is predominantly located at the cluster surface (even if it is initially placed in the interior), (ii) the computed electron binding energies correlate with the electron localization rather than with its bulk vs surface location, and (iii) a dynamical interconversion between two different H-bond patterns around the electron occurs. The computed electron binding energies and the most relevant features of the IR spectrum are in a very good agreement with results of previous experimental studies.


CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis.
In addition to responding to environmental entrainment with diurnal variation, metabolism is also tightly controlled by cell-autonomous circadian clock. Extensive studies have revealed key roles of transcription in circadian control. Post-transcriptional regulation for the rhythmic gating of metabolic enzymes remains elusive. Here, we show that arginine biosynthesis and subsequent ureagenesis are collectively regulated by CLOCK (circadian locomotor output cycles kaput) in circadian rhythms. Facilitated by BMAL1 (brain and muscle Arnt-like protein), CLOCK directly acetylates K165 and K176 of argininosuccinate synthase (ASS1) to inactivate ASS1, which catalyzes the rate-limiting step of arginine biosynthesis. ASS1 acetylation by CLOCK exhibits circadian oscillation in human cells and mouse liver, possibly caused by rhythmic interaction between CLOCK and ASS1, leading to the circadian regulation of ASS1 and ureagenesis. Furthermore, we also identified NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 (NDUFA9) and inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as acetylation substrates of CLOCK. Taken together, CLOCK modulates metabolic rhythmicity by acting as a rhythmic acetyl-transferase for metabolic enzymes.


Using insights into Pim1 structure to design new anticancer drugs.
Human Pim1 (proviral integration site for Moloney murine leukemia virus) kinase is a 313-amino acid serine-threonine kinase that possesses several biological functions in cell survival, proliferation and differentiation, and its overexpression has been observed in a number of human cancers. Indeed, this kinase is a proto-oncogene that has been implicated in early transformation and tumor progression, especially in hematopoietic malignancies and prostate carcinoma where it is a marker of a poor prognosis. For these reasons, Pim1 is emerging as an important target in drug discovery, and many Pim1 inhibitors have been reported in the last three years. The challenge of this research is to obtain compounds that specifically inhibit only Pim1 and not Pim2 and Pim3, the other members of the Pim family, with the aim of providing selective inhibitors as potential therapeutic agents and also of studying the different roles of the three enzymes. In this review Pim1 functions and Pim1 role in human cancer are summarized, but the primary focus of the article is on the Pim1 three-dimensional structure that was deeply analyzed by a detailed inspection of the available crystallographic data and all complexes of small molecule inhibitors reported in the literature to this point. Finally, the use of molecular modeling techniques for the identification and optimization of Pim1 inhibitors is extensively discussed. This data collection, which to the best of our knowledge was not previously reviewed in such detail, could offer a useful tool for medicinal chemists working in the field of small molecule kinase inhibitors.


A single pill to treat postmenopausal hypertension? Not yet.
Postmenopausal women make up one of the fastest growing populations in the United States. Women typically have a higher incidence of cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure (BP) increases progressively in women. Also after menopause, the progression of renal disease increases in women compared with aged matched men. However, the mechanism(s) responsible for the post-menopausal increase in BP and renal injury are yet to be elucidated. Moreover the best therapeutic options to treat postmenopausal hypertension in women are not clear. Hypertension in postmenopausal women are usually associated with other cardiovascular risk factors, such as dyslipidemias, visceral obesity and endothelial dysfunction. Recently it became apparent that in a large number of hypertensive postmenopausal women, their BP is not well controlled with conventional antihypertensive medications. A clear understanding of the complex pathogenesis of postmenopausal hypertension is needed in order to offer the best therapeutic options for these women.


Cyclin B2 and p53 control proper timing of centrosome separation.
Cyclins B1 and B2 are frequently elevated in human cancers and are associated with tumour aggressiveness and poor clinical outcome; however, whether and how B-type cyclins drive tumorigenesis is unknown. Here we show that cyclin B1 and B2 transgenic mice are highly prone to tumours, including tumour types where B-type cyclins serve as prognosticators. Cyclins B1 and B2 both induce aneuploidy when overexpressed but through distinct mechanisms, with cyclin B1 inhibiting separase activation, leading to anaphase bridges, and cyclin B2 triggering aurora-A-mediated Plk1 hyperactivation, resulting in accelerated centrosome separation and lagging chromosomes. Complementary experiments revealed that cyclin B2 and p53 act antagonistically to control aurora-A-mediated centrosome splitting and accurate chromosome segregation in normal cells. These data demonstrate a causative link between B-type cyclin overexpression and tumour pathophysiology, and uncover previously unknown functions of cyclin B2 and p53 in centrosome separation that may be perturbed in many human cancers.


The tidal volume challenge improves the reliability of dynamic preload indices during robot-assisted laparoscopic surgery in the Trendelenburg position with lung-protective ventilation.
The reliability of pulse pressure variation (PPV) and stroke volume variation (SVV) is controversial under pneumoperitoneum. In addition, the usefulness of these indices is being called into question with the increasing adoption of lung-protective ventilation using low tidal volume (VT) in surgical patients. A recent study indicated that changes in PPV or SVV obtained by transiently increasing VT (VT challenge) accurately predicted fluid responsiveness even in critically ill patients receiving low VT. We evaluated whether the changes in PPV and SVV induced by a VT challenge predicted fluid responsiveness during pneumoperitoneum. We performed an interventional prospective study in patients undergoing robot-assisted laparoscopic surgery in the Trendelenburg position under lung-protective ventilation. PPV, SVV, and the stroke volume index (SVI) were measured at a VT of 6 mL/kg and 3 min after increasing the VT to 8 mL/kg. The VT was reduced to 6 mL/kg, and measurements were performed before and 5 min after volume expansion (infusing 6% hydroxyethyl starch 6 ml/kg over 10 min). Fluid responsiveness was defined as ≥15% increase in the SVI. Twenty-four of the 38 patients enrolled in the study were responders. In the receiver operating characteristic curve analysis, an increase in PPV > 1% after the VT challenge showed excellent predictive capability for fluid responsiveness, with an area under the curve (AUC) of 0.95 [95% confidence interval (CI), 0.83-0.99, P < 0.0001; sensitivity 92%, specificity 86%]. An increase in SVV > 2% after the VT challenge predicted fluid responsiveness, but showed only fair predictive capability, with an AUC of 0.76 (95% CI, 0.60-0.89, P < 0.0006; sensitivity 46%, specificity 100%). The augmented values of PPV and SVV following VT challenge also showed the improved predictability of fluid responsiveness compared to PPV and SVV values (as measured by VT) of 6 ml/kg. The change in PPV following the VT challenge has excellent reliability in predicting fluid responsiveness in our surgical population. The change in SVV and augmented values of PPV and SVV following this test are also reliable. This trial was registered with Clinicaltrials.gov, NCT03467711 , 10th March 2018.


A novel mutation of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions.
Benign familial neonatal convulsions (BFNC, also named benign familial neonatal seizures, BFNS) is a rare autosomal dominant inherited epilepsy syndrome with clinical and genetic heterogeneity. Two voltage-gated potassium channel subunit genes, KCNQ2 and KCNQ3, have been identified to cause BFNC1 and BFNC2, respectively. To date, only three mutations of KCNQ3, all located within exon 5, have been reported. By limited linkage analysis and mutation analysis of KCNQ3 in a Chinese family with BFNC, we identified a novel missense mutation of KCNQ3, c.988C>T located within exon 6. c.988C>T led to the substitution Cys for Arg in amino acid position 330 (p.R330C) in KCNQ3 potassium channel, which possibly impaired the neuronal M-current and altered neuronal excitability. Seizures of all BFNC patients started from day 2 to 3 after birth and remitted during 1 month, and no recurrence was found. One family member who displayed fever-associated seizures for two times at age 5 years and was diagnosed as febrile seizures, however, did not carry this mutation, which suggests that febrile seizures and BFNC have different pathogenesis. To our knowledge, this is the first report of KCNQ3 mutation in Chinese family with BFNC.


Advances in diastolic heart failure.
More than 50% of people living with congestive heart failure have diastolic heart failure (DHF). Most of them are older than 70 years, and female. The prevalence of DHF has increased with time. DHF is caused by left ventricular (LV) diastolic dysfunction (DD) which is induced by diastolic dyssynchrony. Cardiac and extracardiac factors play important roles in the development of heart failure (HF) symptoms. The diagnosis of DHF is generally based on typical symptoms and signs of HF, preserved or normal LV ejection fraction, DD and no valvular abnormalities on examination, using noninvasive and invasive methodologies. The outcomes with pharmacological therapy in patients with DHF are frequently neutral in clinical trials, and prognosis still remains poor with a 5-year mortality of 42.3% after hospitalization for HF. Further trials are necessary.


Characterization of Der p 21, a new important allergen derived from the gut of house dust mites.
The house dust mite (HDM) Dermatophagoides pteronyssinus is a major allergen source eliciting allergic asthma. The aim of the study was to identify new important HDM allergens associated with allergic asthma. A cDNA coding for a new mite allergen, designated Der p 21, was isolated using immunoglobulin E (IgE) antibodies from patients with allergic asthma out of a D. pteronyssinus expression cDNA library and expressed in Escherichia coli. Circular dichroism analysis of the purified allergen showed that rDer p 21 (14 726 Da) is one of the few mite allergens with an alpha-helical secondary structure. The protein exhibited high thermal stability and refolding capacity, and, as determined by small angle X-ray scattering, formed a dimer consisting of two flat triangles. rDer p 21 bound high levels of patients' IgE antibodies and showed high allergenic activity in basophil activation experiments. Rabbit anti-Der p 21 IgG antibodies inhibited mite-allergic patients' IgE binding and allowed the ultrastructural localization of the allergen in the midgut (epithelium, lumen and faeces) of D. pteronyssinus by immunogold electron microscopy. Der p 21 revealed sequence homology with group 5 mite allergens, but IgE and IgG reactivity data and cross-inhibition studies identified it as a new mite allergen. Der p 21 is a new important mite allergen which is liberated into the environment via faecal particles and hence may be associated with allergic asthma.


Summary of track A: basic science.
To review Track A, which is organized into five broad areas of emphasis. A variety of new virologic tools are allowing researchers to more effectively evaluate many aspects of HIV, from various therapies and vaccine candidates to the recombination and international spread of genotypes. The recent understandings of HIV-1 pathogenesis have led to potential new treatment strategies of early aggressive treatment with combination drugs and the potential for biologic or immunologic therapy directed to blocking viral entry through second receptors. HIV treatment focused on chemical/drug advances and treatment, and immunologic/genetic advances. Some areas of development include optimizing combination therapies using the oncology model; continued work on new preclinical compounds (e.g. integrase and tat/rev inhibitors); evaluation of viral reduction in all compartments; and resistance surveillance and prevention. Biologics, including fusin/CC-CKR5 inhibitors and CD8 HIV-1 suppressor factors, ex vivo expansion of T cells and in vivo expansion of effector CD8 cells continue to be developed as possible future treatments. In order to obtain worldwide control over HIV, we must have a universally effective vaccine. The question remains as to what specifically is required for a protective response. Mechanisms of CD8 suppression, and cellular and antibody correlates of protection were discussed as areas of research that may shed light on the critical protective immune response. GENOTYPES: Discussion of HIV genotypes focused on international subtypes, correlates of diversity, and HIV-1 recombination. Numerous groups have shown an international intermixing of HIV-1 strains. Recombination during transcription was found to lead to extensive genomic shift and increased diversity, which may also increase HIV-1 fitness and enhance transmission. The spread and adaptation of HIV-1 is occurring independently of borders. Therefore, HIV-1 research must be global; vaccine development must be international in concept and application; collaboration in all areas is essential for success in combating HIV; and finally, the challenge for the future will be to actively involve all basic scientists in the science of the international epidemics.


Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotors-only ablation in patients with nonparoxysmal atrial fibrillation.
Focal impulse and rotor modulation (FIRM)-guided ablation targets sites that are thought to sustain atrial fibrillation (AF). The purpose of this study was to evaluate the acute and mid-term outcomes of FIRM-guided only ablation in patients with nonparoxysmal AF. We prospectively enrolled patients with persistent and long-standing persistent (LSP) AF at three centers to undergo FIRM-guided only ablation. We evaluated acute procedural success (defined as AF termination, organization, or ≥10% slowing), safety (incidence of periprocedural complications), and long-term success (single-procedure freedom from atrial tachycardia [AT]/AF off antiarrhythmic drugs [AAD] after a 2-month blanking period). Twenty-nine patients with persistent (N = 20) and LSP (N = 9) AF underwent FIRM mapping. Rotors were presents in all patients, with a mean of 4 ± 1.2 per patient (62% were left atrial); 1 focal impulse was identified. All sources were successfully ablated, and overall acute success rate was 41% (0 AF termination, 2 AF slowing, 10 AF organization). There were no major procedure-related adverse events. After a mean 5.7 months of follow-up, single-procedure freedom from AT/AF without AADs was 17%. In nonparoxysmal AF patients, targeted ablation of FIRM-identified rotors is not effective in obtaining AF termination, organization, or slowing during the procedure. After mid-term follow-up, the strategy of ablating FIRM-identified rotors alone did not prevent recurrence from AT/AF.


Novel method for evaluating the health condition of mice in space through a video downlink.
Clarification of the criteria for managing animal health is essential to increase the reliability of experiments and ensure transparency in animal welfare. For experiments performed in space, there is no consensus on how to care for animals owing to technical issues, launch mass limitation, and human resources. Some biological processes in mammals, such as musculoskeletal or immune processes, are altered in the space environment, and mice in space can be used to simulate morbid states, such as senescence acceleration. Thus, there is a need to establish a novel evaluation method and evaluation criteria to monitor animal health. Here, we report a novel method to evaluate the health of mice in space through a video downlink in a series of space experiments using the Multiple Artificial-gravity Research System (MARS). This method was found to be more useful in evaluating animal health in space than observations and body weight changes of the same live mice following their return to Earth. We also developed criteria to evaluate health status via a video downlink. These criteria, with "Fur condition" and "Respiratory" as key items, provided information on the daily changes in the health status of mice and helped to identify malfunctions at an early stage. Our method and criteria led to the success of our missions, and they will help establish appropriate rules for space experiments in the future.


A novel colorimetric and ratiometric fluorescent probe for sensing SO2 derivatives and their bio-imaging in living cells.
We report a novel fluorescent probe HBN-TCF for the detection of SO2 derivatives. This probe exhibited near-infrared fluorescence emission with an excitation wavelength of 620 nm. After reacting with SO32-, the emission channel at 664 nm decreased, while the new strong emission channel at 482 nm increased (λex = 400 nm), with a large emission distance (Δλ = 182 nm) observed. This probe exhibited the rapid and selective detection of SO2 derivatives compared with other sulfur-containing species and featured a low detection limit (82 nM). This colorimetric and ratiometric fluorescent probe showed high selectivity and sensitivity for detecting SO2 derivatives. The probe was also successfully exploited for the fluorescence imaging of intracellular and exogenous SO2 derivatives in BEL-7402 cells.


Imperfect past and present progressive: beak color reflects early-life and adult exposure to antigen.
Secondary sexual traits may convey information about individual condition. We assessed the capacity for immune challenge with lipopolysaccharide (LPS) or keyhole limpet hemocyanin (KLH) during the prenatal and early postnatal stages to impact beak color development and expression in captive zebra finches. In addition, we tested whether adult immune challenge impacted beak color, and if early-life experience was influential. Immune challenge with KLH early in life slowed development of red beak coloration, and males challenged with KLH as nestlings had reduced red coloration as adults. Following adult KLH challenge, males exhibited a decline in beak redness. Birds challenged with KLH during development produced more anti-KLH antibodies after adult challenge. There was a significant interaction between young treatment and anti-KLH antibody production; for males not challenged with KLH early in life, individuals that mounted a weaker antibody response lost more red coloration after challenge than males mounting a stronger antibody response. Based on models of avian vision, these differences in beak coloration should be detectable to the finches. In contrast to previous studies, we found no effect of early-life or adult challenge with LPS on any aspects of beak coloration. These results provide evidence that beak color reflects developmental and current conditions, and that the signal is linked to critical physiological processes.


CORD: COmparsion of Recommended Doses of ACE inhibitors and angiotensin II receptor blockers.
The CORD trials tested ramipril and losartan in patients with hypertension. CORD IA involving switching from an angiotensin-converting enzyme inhibitor (ACEI) to the angiotensin II receptor blocker (ARB) losartan. 4,016 patients with blood pressure (BP) < 160/100 mm Hg who had been treated with an ACEI for > 3 months were enrolled. The mean age was 62.6 +/- 11.6 years and 53.1% were women. The patients discontinued ACEI and switched to losartan 50 mg once daily. BP, heart rate, biochemistry, blood counts and ECGs were measured at day 1 and months 1, 3, 6 and 12. If the BP was > or = 140/90 mm Hg after 1 month or more, the dose of losartan was increased to 100 mg. After 1 month the BP decreased from 147.4 +/- 14.8/87.7 +/- 9.3 mm Hg to 139.7 +/- 11.8/83.0 +/- 9.3 mm Hg (p < 0.001) and after 1 year to 133.7 +/- 11.3/79.1 +/- 7.06 mm Hg (p < 0.001). The rate of adverse events did not significantly increase and no changes in plasma sodium, potassium, urea or creatinine were observed. CORD IB compared ramipril and losartan. 3,813 patients with BP > or = 140/90 mm Hg who were not being treated with an ACEI or ARB were enrolled. The mean age was 60.5 +/- 12.2 years and 50.5% were women. The patients were randomised to ramipril 5 mg (n = 1,926) or losartan 50 mg (n = 1,887). The dose was doubled if BP after 1 month was > or = 140/90 mm Hg. If the BP after 3 months still was > or = 140/90 mm Hg, another antihypertensive drug was added, typically athiazide diuretic. After 1 yearthe BP decreased in the ramipril group from 155.9 +/- 13.1/93.0 +/- 8.9 mm Hg to 134.1 +/- 11.2/81.5 +/- 6.8 mm Hg (p < 0.001) and in the losartan group from 156.5 +/- 13.1/93.4 +/- 8.8 to 134.55 +/- 11.3/80.16 +/- 6.6 mm Hg (p < 0.001). No significant differences were found between the groups. A slight increase in plasma potassium (0.2 mmol in both groups) and urea (0.3 mmol in both groups) was observed, but no change in plasma creatinine. There was a small, insignificant decrease in plasma uric acid (in the ramipril group from 325.5 to 320.7 micromol/l and in the losartan group from 321.6 to 318.3 micromol/l) and a slight decrease in plasma glucose and triglycerides (0.2 mmol/l in both measures in both groups). No severe adverse events were observed, but dry cough was 8 times more frequently reported in the ramipril group. CORD IA confirmed that switching from an ACEI to losartan is safe and effective. Titrating the dose upwards or adding diuretics leads to good BP control in the majority of patients (2/3). CORD IB showed no differences between ramipril and losartan in lowering BP and both drugs showed a trend to improve metabolic parameters such as glycaemia, triglyceridaemia and uric acid equally. Dry cough was more frequent after ACEI.


Mitochondrial epigenetics in bone remodeling during hyperhomocysteinemia.
Increased levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), is an independent risk factor of various diseases. Clinical studies report that people born with severe HHcy develop skeletal malformations with weaker bone. Studies also report that altered mitochondrial dynamics and altered epigenetics contribute to weaker bones and bone diseases. Although Hcy-induced mitochondrial dysfunction has been shown to affect bone metabolism, the role of mitochondrial epigenetics (mito-epigenetics) has not been studied in bones. The epigenetics in mitochondria is interesting as the mitochondrial genome size is small (16 kb) with fewer CpG, and without histones and introns. Recently, fascinating works on epigenetics along with the discovery of histone-like proteins in mitochondria are giving exciting areas for novel studies on mitochondria epigenetics. There are mutual cause and effect relationships between bone, mitochondria, Hcy, and epigenetics, but unfortunately, studies are lacking that describe the involvement of all these together in bone disease progression. This review describes the reciprocal relationships and mechanisms of Hcy-bone-mitochondria-epigenetics along with a short discussion of techniques which could be employed to assess Hcy-induced anomaly in bone, mediated through alterations in mito-epigenetics.


Cigarette smoking: a modifier of human immunodeficiency virus type 1 infection?
Two hundred and two homosexual men enrolled in a prospective cohort study of AIDS risk were assessed for differences in the occurrence and progression of human immunodeficiency virus type 1 (HIV-1) infection with respect to cigarette smoking. Among subjects who were initially seronegative, smokers were more likely than nonsmokers to become HIV-1 seropositive (p = 0.03). After seroconversion, serum beta 2-microglobulin and CD4+ lymphocyte levels were elevated in cigarette smokers relative to nonsmokers (p = 0.02 for both comparisons), but both of these differences disappeared within 2 years. There was no detectable difference in the risk of AIDS or Pneumocystis carinii pneumonia with respect to smoking. Our data suggest that cigarette smoking may alter the immune response to HIV-1 infection, but it appears to have no marked effect on clinical outcome. They also suggest that cigarette smoking may be a surrogate marker for continued high-risk sexual behavior in homosexual men.


The long noncoding RNA urothelial carcinoma-associated 1 overexpression as a poor prognostic biomarker in clear cell renal cell carcinoma.
Long noncoding RNA urothelial carcinoma-associated 1 has previously played important roles in cancer. However, its role is still unknown in clear cell renal cell carcinoma. We utilized the most recent molecular and clinical data of clear cell renal cell carcinoma from The Cancer Genome Atlas project, and the relationship between urothelial carcinoma-associated 1 expression and the clinicopathological features was analyzed. Our results indicated that urothelial carcinoma-associated 1 overexpression was associated with male ( p = 0.003), wild-type PBRM1 ( p = 0.021), and BAP1 mutation ( p = 0.022) in clear cell renal cell carcinoma, although lower expression was found in tumors compared with normal controls, validated in tumor tissues from The Cancer Genome Atlas and 21 clear cell renal cell carcinoma patients at our hospital. Moreover, urothelial carcinoma-associated 1 overexpression indicated poor prognosis independently (Hazard Ratio [HR]: 1.92, p = 0.000) in clear cell renal cell carcinoma; it might be a potential detrimental gene considered as a predictive biomarker involved in clear cell renal cell carcinoma.


Air contamination following aerosol ventilation in the gamma camera room.
Air contamination levels arising from lung aerosol ventilation studies have previously been monitored [1]. Residence time in the room used for ventilation was perceived to be an important factor in dose received. This study was designed to assess air contamination levels when ventilation and imaging are carried out in the same room. Air samples were taken before, during and after aerosol administration, over 24 studies where a mouthpiece was used. The mean airborne contamination during administration was 4.39 kBq m-3, implying an effective dose equivalent (EDE) to the operator from inhaled activity of 0.004 microSv. Measurements made during studies on three patients where a mask was used gave a mean EDE of 0.065 microSv (the highest EDE was 0.08 microSv). Ten minutes after nebulizing had stopped, the contamination had reduced to background levels in all but two cases; in these cases, the levels were less than 1.1 kBq m-3. Aerosol ventilation in the gamma camera room does not constitute a significant radiation hazard to staff. Patient compliance is an important factor in minimizing doses. Clear instructions and practice are a vital part of the procedure.


Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase II trial.
We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.


Early presentation of pityriasis rubra pilaris.
Pityriasis rubra pilaris (PRP), a disorder of epidermal proliferation and altered keratinization, typically first appears as a scaly, erythematous patch on the upper portion of the body. Its initial appearance is nonspecific and may be confused with other common dermatoses. Subtle clinical findings and histologic changes in the early stage of PRP are helpful in the early diagnosis of this condition. We describe two cases to illustrate the initial manifestations of PRP and review the literature, emphasizing its early presentation and treatment.


Integration of multi-scale defects for optimizing thermoelectric properties of n-type Cu1-xCdxFeS2 (x = 0-0.1).
The performance of thermoelectric (TE) materials is strongly influenced by multi-scale defects. Some defects can improve the TE performance but some are unfavorable. Therefore, the multi-scale defects need to be integrated rationally to enhance the TE properties. Here, the defects including atomic-scale point defects, high-density grain boundaries and nano-precipitates were integrated into CuFeS2, an n-type and Earth-abundant TE material. Primitively, a Cd dopant with high scattering factor was introduced to form point defects in Cu1-xCdxFeS2 (x = 0-0.1) according to the calculated scattering parameters. Furthermore, the processes of quenching, annealing, high-energy ball milling (QAH) and sintering were carried out to integrate the multi-scale defects into Cu1-xCdxFeS2. The results suggested that point defects and antisite defects were achieved and the unfavorable Cd'Fe defects were suppressed effectively, leading to a higher electrical conductivity. Moreover, the CdS nano-precipitates played a vital role in carrier filtering to increase the Seebeck coefficient. Meanwhile, the high-density grain boundaries suppressed the lattice thermal conductivity. As a result, a peak ZT value of 0.39 at 723 K was obtained in Cu0.92Cd0.08FeS2, which is the highest value reported so far in the CuFeS2 family.


Alterations in chromatin structure are implicated in the activation of the steroid hormone response unit of the ovalbumin gene.
Hormone-responsive genes rely on complex regulatory elements known as hormone response units to integrate various regulatory signals. Characterization of the steroid-dependent regulatory element (SDRE) in the check ovalbumin gene (--892 to --796) suggests that it functions as a hormone response unit. Previous studies using gel mobility shift assays and several types of footprinting analyses demonstrated that proteins bind to this entire element in vitro even in the absence of steroid hormones. However, the genomic footprinting experiments described herein indicate that the binding of three different proteins or protein complexes to the SDRE requires estrogen and corticosterone, suggesting that the chromatin structure of this site is restricted in vivo. Transfection experiments using linker scanning and point mutations support the contention that the binding of these three complexes is essential for induction of the ovalbumin gene by steroid hormones. In addition, functional analyses suggest that a fourth complex is also necessary for maximal induction. These and other data suggest that the SDRE functions as a hormone response unit to coordinate signals generated by two steroid hormones.


Sodium-glucose co-transporter 2 inhibitor canagliflozin modulates myocardial metabolism and inflammation in a swine model for chronic myocardial ischemia.
Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia. Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection. Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment. The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways.


Disparity statistics in natural scenes.
Binocular disparity is the input to stereopsis, which is a very strong depth cue in humans. However, the distribution of binocular disparities in natural environments has not been quantitatively measured. In this study, we converted distances from accurate range maps of forest scenes and indoor scenes into the disparities that an observer would encounter, given an eye model and fixation distances (which we measured for the forest environment, and simulated for the indoor environment). We found that the distributions of natural disparities in these two kinds of scenes are centered at zero, have high peaks, and span about 5 deg, which closely matches the macaque MT cells' disparity tuning range. These ranges are fully within the operational range of human stereopsis determined psychophysically. Suprathreshold disparities (>10 arcsec) are common rather than exceptional. There is a prevailing notion that stereopsis only operates within a few meters, but our finding suggests that we should rethink the role of stereopsis at far viewing distances because of the abundance of suprathreshold disparities.


Job satisfaction among Syrian healthcare workers in refugee health centres.
Achieving universal health coverage is subject to the availability, accessibility, acceptability, and quality of health workers. Countries that host refugees and migrants, such as Turkey, must strengthen the capacity of their health systems to increase access to services, especially for refugees and migrants. The Turkish Ministry of Health adapted Syrian refugee healthcare workers in the healthcare services to boost Syrian refugees' access to healthcare. This study aimed to assess job satisfaction and the factors influencing job satisfaction among refugee physicians and nurses working in Refugee Healthcentres (RHCs) in Turkey. A self-administered, cross-sectional survey targeted all Syrian physicians and nurses working in RHCs across Turkey. The short-form Minnesota Satisfaction Questionnaire(MSQ) was used to assess job satisfaction. In total, 555 nurse/midwives and 336 physicians responded, yielding a total response rate of 56.5%. Descriptive analyses and linear regression tests were conducted to determine the level of job satisfaction and to analyze determinant factors. Nurses/midwives reported the highest level of general job satisfaction, followed by specialist physicians and general physicians. Physicians who had worked as specialists in Syria but were now working as general physicians in Turkey had the lowest job satisfaction levels. Multiple regression analysis showed that professional status in Turkey, income, teamwork and team management were significantly associated with job satisfaction. To maintain a high level of job satisfaction in refugee healthcare workers, human resources management should consider matching job placements with training specialization and support good leadership and good teamwork. Remuneration that accounts for the cost of living and non-financial incentives could also play a significant role in job satisfaction.


Detection of anti-vascular endothelial cell antibodies with microcytotoxicity testing.
Antivascular endothelial cell antibodies (anti-VEC) were detected in 20 out of 20 serum samples from post renal transplant nephrectomy patients using a microcytotoxicity (MET) test, but in only 1 of 100 healthy blood donors. Cytotoxicity to VEC could occur in the absence of lymphocytotoxic antibodies. In this paper factors influencing the specificity and sensitivity of microcytotoxicity on vascular endothelial cell (VEC) were studied, including improvements in the preparation of VEC from an umbilical cord vein to get 95% and more of purity and viability; adequate dilution of rabbit sera to reduce its nonspecific VEC cytotoxic effect; and results read by exactly adjusted phase contrast microscopy to reduce the percentage of false negative. The original titers of allotypic and monoclonal antibodies against VEC have been shown to be reproducible in repeated testing during the past two years. The recognition of the weak cytotoxic effects of anti-HLA on VEC makes possible direct application of microcytotoxicity on VEC, to detect anti-VEC and to study VEC antigen classification (through a comparison of the cytotoxic effects of tested sera on VEC and concordant lymphocytes).


Fibroblast dependency during early thymocyte development maps to the CD25+ CD44+ stage and involves interactions with fibroblast matrix molecules.
We have investigated the role of specific components of the thymic stroma during development of CD4-8-T cell precursors by separating and reaggregating precursor subsets with individual or combinations of stromal cells. We show that while the development of CD25+ 44+ precursors is dependent upon a combination of major histocompatibility complex (MHC) class II+ thymic epithelial cells and fibroblasts, their direct descendants, CD25+ 44- precursors, develop to the CD4+ 8+ stage in the presence of MHC class II+ thymic epithelial cells alone. Thus, CD25+ 44+ precursors are the last developmental stage to be dependent upon fibroblast support. In addition, while metabolically inactive, 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide (ECDI)-treated fibroblasts retain the ability to promote T cell development, prior treatment with hyaluronidase abrogates this effect, suggesting that fibroblast-associated extracellular matrix components are the key elements involved. In support of this, we show that fibroblasts are located in cortical regions of the thymus where T cell precursors are known to reside, and that these fibroblasts are associated with an extensive extracellular matrix not found on thymic epithelial cells. Finally, antibodies to alpha 4 integrin and CD44 interfere with the efficiency with which CD4+ 8+ cells are generated from CD25+ 44+ precursors in reaggregate cultures and also reduce the binding of the latter to 3T3 fibroblasts, suggesting these molecules play a role in bringing T cell precursors into contact with fibroblast-associated extracellular matrix.


Efficient Plastid Transformation in Arabidopsis.
Plastid transformation is routine in tobacco (Nicotiana tabacum) but 100-fold less frequent in Arabidopsis (Arabidopsis thaliana), preventing its use in plastid biology. A recent study revealed that null mutations in ACC2, encoding a plastid-targeted acetyl-coenzyme A carboxylase, cause hypersensitivity to spectinomycin. We hypothesized that plastid transformation efficiency should increase in the acc2 background, because when ACC2 is absent, fatty acid biosynthesis becomes dependent on translation of the plastid-encoded ACC β-carboxylase subunit. We bombarded ACC2-defective Arabidopsis leaves with a vector carrying a selectable spectinomycin resistance (aadA) gene and gfp, encoding the green fluorescence protein GFP. Spectinomycin-resistant clones were identified as green cell clusters on a spectinomycin medium. Plastid transformation was confirmed by GFP accumulation from the second open reading frame of a polycistronic messenger RNA, which would not be translated in the cytoplasm. We obtained one to two plastid transformation events per bombarded sample in spectinomycin-hypersensitive Slavice and Columbia acc2 knockout backgrounds, an approximately 100-fold enhanced plastid transformation frequency. Slavice and Columbia are accessions in which plant regeneration is uncharacterized or difficult to obtain. A practical system for Arabidopsis plastid transformation will be obtained by creating an ACC2 null background in a regenerable Arabidopsis accession. The recognition that the duplicated ACCase in Arabidopsis is an impediment to plastid transformation provides a rational template to implement plastid transformation in related recalcitrant crops.


Accuracy of the quantities measured by four vocal dosimeters and its uncertainty.
Although vocal dosimeters are often used for long-term voice monitoring, the uncertainty of the quantities measured by these devices is not always stated. In this study, two common vocal dosimetry quantities, mean vocal sound pressure level and mean vocal fundamental frequency, were measured by four vocal dosimeters (VocaLog2, VoxLog, Voice Care, and APM3200). The expanded uncertainty of the mean error in the estimation of these two quantities as measured by the four dosimeters was performed by simultaneously comparing signals acquired through a reference microphone and the devices themselves. Dosimeters, assigned in random order, were worn by the participants (22 vocally healthy adults), along with a head-mounted microphone, which acted as a reference. For each device, participants produced a sustained /a/ vowel four times and then read a text with three different vocal efforts (relaxed, normal, and raised). The measurement uncertainty was obtained by comparing data from the microphone and the dosimeters. The mean vocal sound pressure level was captured the most accurately by the Voice Care and the VoxLog while the APM3200 was the least accurate. The most accurate mean vocal fundamental frequency was estimated by the Voice Care and the APM3200, while the VoxLog was the least accurate.


Effect of three endodontic materials on the bond strength of two composite core materials to dentin.
This study investigated the effect of dentin treatment with iodine potassium iodide, calcium hydroxide or a biphenol-A- diglycidylether epoxy resin sealer on the dentin bond strength of titanium-reinforced Bis-GMA and urethane dimethacrylate composite materials. Dentin was exposed in four groups of extracted teeth (20 specimens each). Three groups were treated with one of the contaminants and the fourth group was left uncovered and served as the control group. All specimens were stored for 1 week at 37 degrees C and 100% humidity. The dentin surfaces were cleaned with pumice slurry using a prophylaxis rubber cup, rinsed and dried. Then the dentin surfaces were treated using the conditioner and the primer of the GLUMA adhesive system followed by placement of composite core materials. After 20 minutes, debonding of the core materials was accomplished using a shear-peel test. A two-way analysis of variance and Tukey's multiple range test was performed based upon core type and contaminant type (alpha = 0.05). Titanium-reinforced Bis-GMA composite showed significantly greater bond strength values than the urethane dimethacrylate composite material (p < 0.0001). The mean bond strength values in megapascals for the Bis-GMA resin ranged from 8.47 +/-1.52 for the calcium hydroxide group to 9.81 +/-0.94 for the control group. Mean bond strengths for the urethane dimethacrylate resin ranged from 3.35 +/-0.90 for calcium hydroxide to 3.99 +/-0.88 for iodine potassium iodide groups. Within each core group, no difference in bond strengths were noted compared to the uncontaminated control. Pretreatment of the dentin with iodine potassium iodide, calcium hydroxide, or epoxy resin followed by pumicing and using the GLUMA system conditioner and primer had no effect on the bond strength of the two resin composite core materials. However, the titanium reinforced Bis-GMA composite exhibited significantly greater bond strength to dentin than the urethane dimethacrylate based composite.


[Use of nonsteroidal anti-inflammatory drugs in case of ankylosing spondylitis: long and persistently!].
Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used in the treatment of rheumatic diseases to relieve pain and signs of inflammation. However, when treated for ankylosing spondylosis (AS), NSAIDS exert both symptomatic and structure-modifying effects, by slowing down the development of vertebral ankylosis. The effect of these drugs, which underlines the formation of syndesmophytes, may be associated with their anti-inflammatory activity and ability to suppress abnormal bone proliferation. There is convincing evidence to support the capacity of NSAIDs, when long and continuously used, to reduce the rates of X-ray progression of AS. So the continuous use of NSAIDs must be now considered to be a mandatory component of pharmacotherapy for this disease. Their use should be continued even after achieving a marked clinical improvement. At the same time, this situation requires that the development of adverse reactions as structural and functional diseases of the gastrointestinal tract and cardiovascular system be thoroughly controlled in this situation. The danger of these complications determines the need for a physician's attention, obligatory consideration of risk factors, and rational choice of the safest NSAIDs.


[Potential role of the early response gene c-Myc in the loss of differentiation and function of pancreatic beta cells submitted to chronic hyperglycemia].
Chronic hyperglycemia exerts deleterious effects on glucose-induced insulin secretion by pancreatic beta cells. In 90% pancreatectomized rats, chronic hyperglycemia induces beta cell hypertrophy and loss of differentiation associated with increased expression of the early response gene c-Myc. Hyperglycemia also stimulates c-Myc expression in vivo in islets from glucose-infused rats and in vitro in cultured rat islets. This effect requires the elevation of cytosolic Ca2+ concentration produced by glucose. Our results suggest that overstimulation of c-Myc expression by chronic hyperglycemia may be the cause of beta cell hypertrophy and loss of differentiation and function observed in animal models of type 2 diabetes.


Factorial invariance of the Dyadic Adjustment Scale across gender.
The Dyadic Adjustment Scale (DAS; G. B. Spanier, 1976) is the most widely used inventory of relationship satisfaction in the social sciences, yet the question of whether it is measuring the same concept in men and women has never been addressed. In the current study, the authors examined the factor structure of the DAS in a sample of 900 currently married couples who participated in the Minnesota Twin Family Study. Confirmatory factor analysis was applied to a second-order factor solution with Spanier's four factors (Dyadic Consensus, Dyadic Satisfaction, Dyadic Cohesion, Affectional Expression) loading on one higher order factor (Relationship Adjustment), to test for measurement invariance across gender. The second-order solution was relatively invariant across gender, even when taking into account the nonindependent nature of the data. This suggests that the best conceptualization of the DAS is one of a gender-invariant measure of marital adjustment with four distinct subfactors and that differences between men and women on any of these constructs can be interpreted by both clinicians and researchers as true mean differences rather than measurement bias.


Simplifying fuzzy rule-based models using orthogonal transformation methods.
An important issue in fuzzy-rule-based modeling is how to select a set of important fuzzy rules from a given rule base. Even though it is conceivable that removal of redundant or less important fuzzy rules from the rule base can result in a compact fuzzy model with better generalizing ability, the decision as to which rules are redundant or less important is not an easy exercise. In this paper, we introduce several orthogonal transformation-based methods that provide new or alternative tools for rule selection. These methods include an orthogonal least squares (OLS) method, an eigenvalue decomposition (ED) method, a singular value decomposition and QR with column pivoting (SVD-QR) method, a total least squares (TLS) method, and a direct singular value decomposition (D-SVD) method. A common attribute of these methods is that they all work on a firing strength matrix and employ some measure index to detect the rules that should be retained and eliminated. We show the performance of these methods by applying them to solving a nonlinear plant modeling problem. Our conclusions based on analysis and simulation can be used as a guideline for choosing a proper rule selection method for a specific application.


Plasma tissue factor pathway inhibitor levels as a marker for postoperative bleeding after enoxaparin use in deep vein thrombosis prophylaxis in orthopedics and general surgery.
Low-molecular-weight heparins (LMWH) are widely used as antithrombotic prophylactic pharmaceutical agents in orthopedic and general surgery. Their antithrombotic characteristics are expressed by plasma mediators such as anti-Xa, anti-IIa, and increased release of tissue factor pathway inhibitor (TFPI) from vascular endothelium. The purpose of this clinical research is to study the relation between plasma levels of these mediators and postoperative bleeding. Forty-one consecutive patients undergoing hip or knee arthroplasty (n = 36) and colectomy (n = 5) received the standard enoxaparin (a LMWH) dose preoperatively (general surgery) or immediately postoperatively (orthopedic surgery). Major bleeding was defined as a postoperative drop of > or = 5 g/dL) of hemoglobin. The authors observed that there was a linear relationship between an increase in free/total TFPI ratio levels and postoperative bleeding. When that ratio increased by > 60%, the hemoglobin dropped to > 5 g/dL (n = 17). This relationship between free/total TFPI ratio increase and postoperative bleeding was statistically significant (P < 0.001). Those who did not bleed (hemoglobin drop was less than 5 g/dL) (n = 24) had a ratio increase (if any) of less than 50%. However, the authors did not observe any statistical relationship between anti-Xa, anti-IIa, or prothrombin time and postoperative bleeding in patients receiving LMWH for deep vein thrombosis prophylaxis in orthopedic and general surgery patients. The authors recommend a pre- and postoperative ratio level measurement whenever major bleeding is anticipated, as adjustments of LMWH dose or frequency might be necessary.


Human Papillomavirus-Attributable Cancers - United States, 2012-2016.
Human papillomavirus (HPV) causes nearly all cervical cancers and some cancers of the vagina, vulva, penis, anus, and oropharynx (1).* Most HPV infections are asymptomatic and clear spontaneously within 1 to 2 years; however, persistent infection with oncogenic HPV types can lead to development of precancer or cancer (2). In the United States, the 9-valent HPV vaccine (9vHPV) is available to protect against oncogenic HPV types 16, 18, 31, 33, 45, 52, and 58 as well as nononcogenic types 6 and 11 that cause genital warts. CDC analyzed data from the U.S. Cancer Statistics (USCS)† to assess the incidence of HPV-associated cancers and to estimate the annual number of cancers caused by HPV, overall and by state, during 2012-2016 (3,4). An average of 43,999 HPV-associated cancers were reported annually, and an estimated 34,800 (79%) of those cancers were attributable to HPV. Of these 34,800 cancers, an estimated 32,100 (92%) were attributable to the types targeted by 9vHPV, with 19,000 occurring among females and 13,100 among males. The most common were cervical (9,700) and oropharyngeal cancers (12,600). The number of cancers estimated to be attributable to the types targeted by 9vHPV ranged by state from 40 to 3,270 per year. HPV vaccination is an important strategy that could prevent these cancers, but during 2018, only half of adolescents were up to date on HPV vaccination (5). These surveillance data from population-based cancer registries can be used to inform the planning for, and monitor the long-term impact of, HPV vaccination and cancer screening efforts nationally and within states.


Kinetochore-driven formation of kinetochore fibers contributes to spindle assembly during animal mitosis.
It is now clear that a centrosome-independent pathway for mitotic spindle assembly exists even in cells that normally possess centrosomes. The question remains, however, whether this pathway only activates when centrosome activity is compromised, or whether it contributes to spindle morphogenesis during a normal mitosis. Here, we show that many of the kinetochore fibers (K-fibers) in centrosomal Drosophila S2 cells are formed by the kinetochores. Initially, kinetochore-formed K-fibers are not oriented toward a spindle pole but, as they grow, their minus ends are captured by astral microtubules (MTs) and transported poleward through a dynein-dependent mechanism. This poleward transport results in chromosome bi-orientation and congression. Furthermore, when individual K-fibers are severed by laser microsurgery, they regrow from the kinetochore outward via MT plus-end polymerization at the kinetochore. Thus, even in the presence of centrosomes, the formation of some K-fibers is initiated by the kinetochores. However, centrosomes facilitate the proper orientation of K-fibers toward spindle poles by integrating them into a common spindle.


Evolution of poliovirus during an outbreak: sequential type 3 poliovirus isolates from several persons show shifts of neutralization determinants.
An outbreak of poliomyelitis in Finland resulted in the widespread circulation of wild-type 3 poliovirus strains that had antigenic properties distinct from the strains used to produce the attenuated and inactivated vaccines. Considerable variation was observed in the ability of broadly reacting monoclonal antibodies directed against type 3 poliovirus to neutralize the 54 strains examined. Sequential isolates from several persons showed an antigenic drift with these monoclonal antibodies and selected human sera. In addition, some faecal specimens were found to contain more than one antigenic variant. Primer extension sequencing of genomic RNAs of three plaque-purified antigenic variants isolated from one patient showed base substitutions in the region coding for the major antigenic site of poliovirus type 3. The resulting difference in the amino acid sequence in the virion protein VP1 could explain the differences observed in the neutralization of these strains by the monoclonal antibodies. Whether the observed changes in the antigenic characteristics of the sequential isolates represent true antigenic drift under immunological pressure or whether the emergence of the new variants is based on other modes of selection during replication is not known.


Measurements of the hygroscopic and deliquescence properties of organic compounds of different solubilities in water and their relationship with cloud condensation nuclei activities.
The initial phase (solid or aqueous droplet) of aerosol particles prior to activation is among the critical factors in determining their cloud condensation nuclei (CCN) activity. Single-particle levitation in an electrodynamic balance (EDB)was used to measure the phase transitions and hygroscopic properties of aerosol particles of 11 organic compounds with different solubilities (10(-1) to 102 g solute/100 g water). We use these data and other literature data to relate the CCN activity and hygroscopicity of organic compounds with different solubilities. The EDB data show that glyoxylic acid, 4-methylphthalic acid, monosaccharides (fructose and mannose), and disaccharides (maltose and lactose) did not crystallize and existed as metastable droplets at low relative humidity (RH). Hygroscopic data from this work and in the literature support earlier studies showing that the CCN activities of compounds with solubilities down to the order of 10(-1) g solute/100 g water can be predicted by standard Köhler theory with the assumption of complete dissolution of the solute at activation. We also demonstrate the use of evaporation data (or efflorescence data), which provides information on the water contents of metastable solutions below the compound deliquescence RH that can be extrapolated to higher dilutions, to predict the CCN activity of organic particles, particularly for sparingly soluble organic compounds that do not deliquesce at RH achievable in the EDB and in the hygroscopic tandem differential mobility analyzer.


Radioimmunoassay for 11-deoxycortisol using iodine-labeled tracer.
A simple and sensitive radioimmunoassay for 11-deoxycortisol was developed. The antiserum produced in rabbits by immunizing with a complex of 11-deoxycortisol-3-oxime and bovine serum albumin (BSA) has little cross-reactivity with other endogenous steroids. The immunoassay procedure requires only one-step ethanol denaturation of binding proteins in plasma and extraction by an organic solvent can be omitted. Furthermore, use of 125I-labeled tracer significantly simplify the counting procedure. The method is sensitive enough to detect 1 microng/100 ml of 11-deoxycortisol. Plasma 11-deoxycortisol levels measured by this method after the administration of a single dose of metyrapone ranged from 5.0 to 19.2 microng/100 ml, whereas they were 0 to 4.0 microng/100 ml in hypopituitary patients. It is concluded that this simple method is useful for the routine assay of plasma 11-deoxycortisol as a parameter of the metyrapone tests.


Characterization of genome structure of amphotropic and ecotropic wild mouse retroviruses.
We studied the RNA genomes of several wild mouse type C retroviruses by using RNase T1-oligonucleotide fingerprinting. The amphotropic and ecotropic viruses of field strain 1504 produced very similar oligonucleotide fingerprints, but each also had several unique oligonucleotides. All of these unique oligonucleotides were located in the env gene region and were probably responsible for the host range differences between these viruses, as well as the lymphomagenic and paralytogenic properties of the viruses. We obtained similar results with the amphotropic and ecotropic viruses of another field strain (4070), which was isolated from a mouse from a different trapping area. The amphotropic viruses of several field strains (strains 1504, 4070, and 1313) were more closely related than the ecotropic viruses of different strains (strains 1504, 4070, and 4996). These findings suggested that the genetic sequences of the amphotropic viruses are more conserved than those of ecotropic viruses isolated from the same wild mice.


Seasonal dynamics of Diplectanum grouperi parasitism on wild versus cultured groupers, Epinephelus spp., and the linkage between infestation and host species phylogeny.
In this article, we examined the influences of the polycultured potential hosts on monogenean seasonality and the possible linkage between the infestations on different species of hosts and host phylogeny. The seasonality of Diplectanum grouperi , the dominant species, on wild versus cultured groupers, Epinephelus spp., was analyzed in Daya Bay, South China Sea, between April 2008 and January 2009. The prevalence, mean intensity, abundance, and variance/mean ratio were calculated for each species of host under polycultured and wild conditions. Except for the overall prevalence, which was slightly higher in autumn than that in summer under wild conditions, the mean intensity and variance were highest in summer, decreasing slightly in autumn to lowest levels in winter or spring. The infection level (prevalence, mean intensity, and abundance) was correlated with changes in water temperature during the sampling period, with a peak in summer, with the exception of E. awoara in autumn under wild conditions. The prevalence, intensity, and mean intensity of D. grouperi on Epinephelus spp. in the wild were much lower than those in experimental (mixed species) culture ponds. The correlation between the molecular phylogeny of 5 species of Epinephelus and the dendrogram based on the susceptibility to D. grouperi was not significant, which infers that variable susceptibilities of these Epinephelus species cannot be revealed by phylogenetic relationships determined from mitochondrial 16S rDNA and Cyt b gene sequences.


New pertussis vaccination strategies beyond infancy: recommendations by the global pertussis initiative.
The Global Pertussis Initiative, an expert scientific forum, was established to address the ongoing problems associated with pertussis disease worldwide. The group analyzed pertussis disease trends, developed recommendations to improve disease control through expanded vaccination strategies, and proposed solutions to barriers to implementation and support of research activities. Bordetella pertussis infection is endemic and continues to be a serious problem among unvaccinated or incompletely vaccinated infants. In addition, the reported incidence of pertussis disease is increasing in adolescents and adults, who not only experience a considerable health burden themselves but also infect vulnerable infants. Current vaccination strategies need to be reinforced. Expanded vaccination should include adding booster doses to existing childhood schedules (preschool or adolescent) and booster doses for those specific adult subgroups that have the highest risk of transmitting B. pertussis infection to infants (i.e., new parents, other contacts of newborns, and health care workers). More epidemiological studies and studies of disease transmission and the cost-effectiveness of vaccination would be valuable, and surveillance, diagnostic improvements, and educational campaigns are needed for implementation. However, as a prelude to universal adult vaccination, immediate universal adolescent vaccination should be instituted in countries in which it is economically feasible.


A Remarkable Difference That One Fluorine Atom Confers on the Mechanisms of Inactivation of Human Ornithine Aminotransferase by Two Cyclohexene Analogues of γ-Aminobutyric Acid.
Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate-dependent enzyme, plays a critical role in the progression of hepatocellular carcinoma (HCC). Pharmacological selective inhibition of hOAT has been shown to be a potential therapeutic approach for HCC. Inspired by the discovery of the nonselective aminotransferase inactivator (1R,3S,4S)-3-amino-4-fluoro cyclopentane-1-carboxylic acid (1), in this work, we rationally designed, synthesized, and evaluated a novel series of fluorine-substituted cyclohexene analogues, thereby identifying 8 and 9 as novel selective hOAT time-dependent inhibitors. Intact protein mass spectrometry and protein crystallography demonstrated 8 and 9 as covalent inhibitors of hOAT, which exhibit two distinct inactivation mechanisms resulting from the difference of a single fluorine atom. Interestingly, they share a similar turnover mechanism, according to the mass spectrometry-based analysis of metabolites and fluoride ion release experiments. Molecular dynamics (MD) simulations and electrostatic potential (ESP) charge calculations were conducted, which elucidated the significant influence of the one-fluorine difference on the corresponding intermediates, leading to two totally different inactivation pathways. The novel addition-aromatization inactivation mechanism for 9 contributes to its significantly enhanced potency, along with excellent selectivity over other aminotransferases.


Nodopathies of the peripheral nerve: an emerging concept.
Peripheral nerve diseases are traditionally classified as demyelinating or axonal. It has been recently proposed that microstructural changes restricted to the nodal/paranodal region may be the key to understanding the pathophysiology of antiganglioside antibody mediated neuropathies. We reviewed neuropathies with different aetiologies (dysimmune, inflammatory, ischaemic, nutritional, toxic) in which evidence from nerve conductions, excitability studies, pathology and animal models, indicate the involvement of the nodal region in the pathogenesis. For these neuropathies, the classification in demyelinating and axonal is inadequate or even misleading, we therefore propose a new category of nodopathy that has the following features: (1) it is characterised by a pathophysiological continuum from transitory nerve conduction block to axonal degeneration; (2) the conduction block may be due to paranodal myelin detachment, node lengthening, dysfunction or disruption of Na(+) channels, altered homeostasis of water and ions, or abnormal polarisation of the axolemma; (3) the conduction block may be promptly reversible without development of excessive temporal dispersion; (4) axonal degeneration, depending on the specific disorder and its severity, eventually follows the conduction block. The term nodopathy focuses to the site of primary nerve injury, avoids confusion with segmental demyelinating neuropathies and circumvents the apparent paradox that something axonal may be reversible and have a good prognosis.


Presence and location of modified nucleotides in Escherichia coli tmRNA: structural mimicry with tRNA acceptor branches.
Escherichia coli tmRNA functions uniquely as both tRNA and mRNA and possesses structural elements similar to canonical tRNAs. To test whether this mimicry extends to post-transcriptional modification, the technique of combined liquid chromatography/ electrospray ionization mass spectrometry (LC/ESIMS) and sequence data were used to determine the molecular masses of all oligonucleotides produced by RNase T1 hydrolysis with a mean error of 0.1 Da. Thus, this allowed for the detection, chemical characterization and sequence placement of modified nucleotides which produced a change in mass. Also, chemical modifications were used to locate mass-silent modifications. The native E.coli tmRNA contains two modified nucleosides, 5-methyluridine and pseudouridine. Both modifications are located within the proposed tRNA-like domain, in a seven-nucleotide loop mimicking the conserved sequence of T loops in canonical tRNAs. Although tmRNA acceptor branches (acceptor stem and T stem-loop) utilize different architectural rules than those of canonical tRNAs, their conformations in solution may be very similar. A comparative structural and functional analysis of unmodified tmRNA made by in vitro transcription and native E.coli tmRNA suggests that one or both of these post-transcriptional modifications may be required for optimal stability of the acceptor branch which is needed for efficient aminoacylation.


Circadian rhythm disturbances and sleep disorders in shift workers.
Employment which requires frequent shift rotation may lead to the development of specific sleep disorders. Delayed sleep phase (DSP) insomnia, a syndrome identified recently, can greatly impair an individual's circadian rhythm-dependent functions; it can occur when shift work disrupts normal sleep-waking schedules. Disorders of excessive daytime sleepiness, such as narcolepsy, occur in some subjects after they have been subjected to frequently rotating shifts. Understanding the problems associated with circadian rhythm disturbances and their interaction with sleep disorders is particularly important in industrial medicine; any clinician whose patients are subjected to frequent shift rotations should consider the effects of disrupted sleep-waking schedules.


Differential subcellular localization of the regulatory T-cell protein LAG-3 and the coreceptor CD4.
CD4 binds to MHC class II molecules and enhances T-cell activation. The CD4-related transmembrane protein LAG-3 (lymphocyte activation gene-3, CD223) binds to the same ligand but inhibits T-cell proliferation. We have previously shown that LAG-3 cell surface expression is tightly regulated by extracellular cleavage in order to regulate its potent inhibitory activity. Given this observation and the contrasting functions of CD4 and LAG-3, we investigated the cell distribution, location and transport of these related cell surface molecules. As expected, the vast majority of CD4 is expressed at the cell surface with minimal intracellular localization, as determined by flow cytometry, immunoblotting and confocal microscopy. In contrast, nearly half the cellular content of LAG-3 is retained in intracellular compartments. This significant intracellular storage of LAG-3 appears to facilitate its rapid translocation to the cell surface following T-cell activation, which was much faster for LAG-3 than CD4. Increased vesicular pH inhibited translocation of both CD4 and LAG-3 to the plasma membrane. While some colocalization of the microtubule organizing center, early/recycling endosomes and secretory lysosomes was observed with CD4, significantly greater colocalization was observed with LAG-3. Analysis of CD4:LAG-3 chimeras suggested that multiple domains may contribute to intracellular retention of LAG-3. Thus, in contrast with CD4, the substantial intracellular storage of LAG-3 and its close association with the microtubule organizing center and recycling endosomes may facilitate its rapid translocation to the cell surface during T-cell activation and help to mitigate T-cell activation.


Diagnostic Accuracy of History, Physical Examination, Laboratory Tests, and Point-of-care Ultrasound for Pediatric Acute Appendicitis in the Emergency Department: A Systematic Review and Meta-analysis.
Acute appendicitis (AA) is the most common surgical emergency in children. Accurate and timely diagnosis is crucial but challenging due to atypical presentations and the inherent difficulty of obtaining a reliable history and physical examination in younger children. The aim of this study was to determine the utility of history, physical examination, laboratory tests, Pediatric Appendicitis Score (PAS) and Emergency Department Point-of-Care Ultrasound (ED-POCUS) in the diagnosis of AA in ED pediatric patients. We performed a systematic review and meta-analysis and used a test-treatment threshold model to identify diagnostic findings that could rule in/out AA and obviate the need for further imaging studies, specifically computed tomography (CT) scan, magnetic resonance imaging (MRI), and radiology department ultrasound (RUS). We searched PubMed, EMBASE, and SCOPUS up to October 2016 for studies on ED pediatric patients with abdominal pain. Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) was used to evaluate the quality and applicability of included studies. Positive and negative likelihood ratios (LR+ and LR-) for diagnostic modalities were calculated and when appropriate data was pooled using Meta-DiSc. Based on the available literature on the test characteristics of different imaging modalities and applying the Pauker-Kassirer method we developed a test-treatment threshold model. Twenty-one studies were included encompassing 8,605 patients with weighted AA prevalence of 39.2%. Studies had variable quality using the QUADAS-2 tool with most studies at high risk of partial verification bias. We divided studies based on their inclusion criteria into two groups of "undifferentiated abdominal pain" and abdominal pain "suspected of AA." In patients with undifferentiated abdominal pain, history of "pain migration to right lower quadrant (RLQ)" (LR+ = 4.81, 95% confidence interval [CI] = 3.59-6.44) and presence of "cough/hop pain" in the physical examination (LR+ = 7.64, 95% CI = 5.94-9.83) were most strongly associated with AA. In patients suspected of AA none of the history or laboratory findings were strongly associated with AA. Rovsing's sign was the physical examination finding most strongly associated with AA (LR+ = 3.52, 95% CI = 2.65-4.68). Among different PAS cutoff points, PAS ≥ 9 (LR+ = 5.26, 95% CI = 3.34-8.29) was most associated with AA. None of the history, physical examination, laboratory tests findings, or PAS alone could rule in or rule out AA in patients with undifferentiated abdominal pain or those suspected of AA. ED-POCUS had LR+ of 9.24 (95% CI = 6.24-13.28) and LR- of 0.17 (95% CI = 0.09-0.30). Using our test-treatment threshold model, positive ED-POCUS could rule in AA without the use of CT and MRI, but negative ED-POCUS could not rule out AA. Presence of AA is more likely in patients with undifferentiated abdominal pain migrating to the RLQ or when cough/hop pain is present in the physical examination. Once AA is suspected, no single history, physical examination, laboratory finding, or score attained on PAS can eliminate the need for imaging studies. Operating characteristics of ED-POCUS are similar to those reported for RUS in literature for diagnosis of AA. In ED patients suspected of AA, a positive ED-POCUS is diagnostic and obviates the need for CT or MRI while negative ED-POCUS is not enough to rule out AA.


Identifying the Risk Factors of Suicidal Ideation in Patients With Hematologic Malignancies Using a Multidimensional Approach.
Patients with hematologic malignancies have a 3.5-fold higher rate of suicide completion than the noncancer population, and the Hodgkin lymphoma has the highest suicide rate among all cancers. Although the risk factors for suicidal ideation among the cancer population are well-known, the specific risk factors contributing to the high suicide rate among patients with hematologic malignancies are elusive. This study aimed to identify the risk factors for suicidal ideation among patients with hematologic malignancies using a multidimensional approach. This was a cross-sectional, observational study. A total of 163 patients were recruited from the oncology department of a university hospital. We collected data on psychological and physical symptoms, social support, and suicidal ideation using the Memorial Symptom Assessment Scale-Short Form, the Multidimensional Scale of Perceived Social Support, and the Suicidal Ideation Scale. Multiple regression analysis was performed using SPSS (version 26.0) to analyze the clinical data. Among the 163 participants, 96 (58.9%) were male, 57 (35%) were diagnosed with acute leukemia, and 97 (59.5%) received chemotherapy. The mean age was 55.26 ± 15.75. Physical symptoms, psychological symptoms, and willingness to use mental health services accounted for 39.5% of suicidal ideation cases. Assessment of psychological conditions at the beginning of diagnosis, provision of appropriate interventions throughout treatment, and follow-up care to relieve psychological symptoms should be initiated in patients with hematologic malignancies to prevent suicide.


Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells.
Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells.


Generous economic investments after basolateral amygdala damage.
Contemporary economic models hold that instrumental and impulsive behaviors underlie human social decision making. The amygdala is assumed to be involved in social-economic behavior, but its role in human behavior is poorly understood. Rodent research suggests that the basolateral amygdala (BLA) subserves instrumental behaviors and regulates the central-medial amygdala, which subserves impulsive behaviors. The human amygdala, however, typically is investigated as a single unit. If these rodent data could be translated to humans, selective dysfunction of the human BLA might constrain instrumental social-economic decisions and result in more impulsive social-economic choice behavior. Here we show that humans with selective BLA damage and a functional central-medial amygdala invest nearly 100% more money in unfamiliar others in a trust game than do healthy controls. We furthermore show that this generosity is not caused by risk-taking deviations in nonsocial contexts. Moreover, these BLA-damaged subjects do not expect higher returns or perceive people as more trustworthy, implying that their generous investments are not instrumental in nature. These findings suggest that the human BLA is essential for instrumental behaviors in social-economic interactions.


Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene.
Hereditary hemochromatosis in adults is usually characterized by mutations in the HFE gene on the short arm of chromosome 6. Most patients have a substitution of tyrosine for cysteine at position 282 (C282Y). We studied a large family from Italy that includes persons who have a hereditary iron-overload condition indistinguishable from hemochromatosis but without apparent pathogenic mutations in the HFE gene. We performed biochemical, histologic, and genetic studies of 53 living members of the family, including microsatellite analysis of chromosome 6 and direct sequencing of the HFE gene. Of the 53 family members, 15 had abnormal serum ferritin levels, values for transferrin saturation that were higher than 50 percent, or both. Thirteen of the 15 had elevated body iron levels, diagnosed on the basis of the clinical evaluation and liver biopsy, and underwent iron-removal therapy. The other two, both children, did not undergo liver biopsy or iron-removal therapy. None of the 15 members had the C282Y mutation of the HFE gene; 5 of the 15 (as well as 5 healthy relatives) had another mutation of this gene, a substitution of aspartate for histidine at position 63, but none were homozygous for it. No other mutations were found after sequencing of the entire HFE gene for all family members. Microsatellite analysis showed no linkage of the hemochromatosis phenotype with the short arm of chromosome 6, the site of the HFE gene. Hereditary hemochromatosis can occur in adults who do not have pathogenic mutations in the hemochromatosis gene.


Submegabase clusters of unstable tandem repeats unique to the Tla region of mouse t haplotypes.
We describe here the identification and genomic organization of mouse t haplotype-specific elements (TSEs) 7.8 and 5.8 kb in length. The TSEs exist as submegabase-long clusters of tandem repeats localized in the Tla region of the major histocompatibility complex of all t haplotype chromosomes examined. In contrast, no such clusters were detected among 12 inbred strains of Mus musculus and other Mus species; thus, clusters of TSEs represent the first absolutely qualitative difference between t haplotypes and wild-type chromosomes. Pulsed field gel electrophoresis shows that the number of clusters, and the number of repeats in each cluster are extremely variable. Dramatic quantitative differences of TSEs uniquely distinguish every independent t haplotype from any other. The complete nucleotide sequence of one 7.8-kb TSE reveals significant homology to the ETn (a major transcript in the early embryo of the mouse), and some homologies to intracisternal A-particles and the mammary tumor virus env gene. Apart from the diagnostic relevance to t haplotypes, evolutionary and functional significances are discussed with respect to chromosome structure and genetic recombination.