Research review: gene-environment interaction research in youth depression - a systematic review with recommendations for future research.
Depression is a major public health problem among youth, currently estimated to affect as many as 9% of US children and adolescents. The recognition that both genes (nature) and environments (nurture) are important for understanding the etiology of depression has led to a rapid growth in research exploring gene-environment interactions (GxE). However, there has been no systematic review of GxE in youth depression to date. The goal of this article was to systematically review evidence on the contribution of GxE to the risk of child and adolescent depression. Through a search of PubMed and PsycINFO databases to 1 April 2010, we identified 20 candidate gene-environment interaction studies focused on depression in youth (up to age 26) and compared each study in terms of the following characteristics: research design and sample studied; measure of depression and environment used; genes explored; and GxE findings in relation to these factors. In total, 80% of studies (n = 16) found at least one significant GxE association. However, there was wide variation in methods and analyses adopted across studies, especially with respect to environmental measures used and tests conducted to estimate GxE. This heterogeneity made it difficult to compare findings and evaluate the strength of the evidence for GxE. The existing body of GxE research on depression in youth contains studies that are conceptually and methodologically quite different, which contributes to mixed findings and makes it difficult to assess the current state of the evidence. To decrease this heterogeneity, we offer 20 recommendations that are focused on: (a) reporting GxE research; (b) testing and reporting GxE effects; (c) conceptualizing, measuring and analyzing depression; (d) conceptualizing, measuring and analyzing environment; (e) increasing power to test for GxE; and (f) improving the quality of genetic data used. Although targeted to GxE research on depression, these recommendations can be adopted by GxE researchers focusing on other mental health outcomes.


Making vaccines "on demand": a potential solution for emerging pathogens and biodefense?
The integrated US Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) has made great strides in strategic preparedness and response capabilities. There have been numerous advances in planning, biothreat countermeasure development, licensure, manufacturing, stockpiling and deployment. Increased biodefense surveillance capability has dramatically improved, while new tools and increased awareness have fostered rapid identification of new potential public health pathogens. Unfortunately, structural delays in vaccine design, development, manufacture, clinical testing and licensure processes remain significant obstacles to an effective national biodefense rapid response capability. This is particularly true for the very real threat of "novel pathogens" such as the avian-origin influenzas H7N9 and H5N1, and new coronaviruses such as hCoV-EMC. Conventional approaches to vaccine development, production, clinical testing and licensure are incompatible with the prompt deployment needed for an effective public health response. An alternative approach, proposed here, is to apply computational vaccine design tools and rapid production technologies that now make it possible to engineer vaccines for novel emerging pathogen and WMD biowarfare agent countermeasures in record time. These new tools have the potential to significantly reduce the time needed to design string-of-epitope vaccines for previously unknown pathogens. The design process-from genome to gene sequence, ready to insert in a DNA plasmid-can now be accomplished in less than 24 h. While these vaccines are by no means "standard," the need for innovation in the vaccine design and production process is great. Should such vaccines be developed, their 60-d start-to-finish timeline would represent a 2-fold faster response than the current standard.


Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009.
In April 2009, CDC reported the first two cases in the United States of human infection with a novel influenza A (H1N1) virus. As of July 6, a total of 122 countries had reported 94,512 cases of novel influenza A (H1N1) virus infection, 429 of which were fatal; in the United States, a total of 33,902 cases were reported, 170 of which were fatal. Cases of novel influenza A (H1N1) virus infection have included rapidly progressive lower respiratory tract disease resulting in respiratory failure, development of acute respiratory distress syndrome (ARDS), and prolonged intensive care unit (ICU) admission. Since April 26, communitywide transmission of novel influenza A (H1N1) virus has occurred in Michigan, with 655 probable and confirmed cases reported as of June 18 (Michigan Department of Community Health [MDCH], unpublished data, 2009). This report summarizes the clinical characteristics of a series of 10 patients with novel influenza A (H1N1) virus infection and ARDS at a tertiary-care ICU in Michigan. Of the 10 patients, nine were obese (body mass index [BMI] >or=30), including seven who were extremely obese (BMI =40); five had pulmonary emboli; and nine had multiorgan dysfunction syndrome (MODS). Three patients died. Clinicians should be aware of the potential for severe complications of novel influenza A (H1N1) virus infection, particularly in extremely obese patients.


The endocrine disrupting effect of municipal effluent on the zebra mussel (Dreissena polymorpha).
Municipal effluents have been shown to contain a cocktail of endocrine disrupting chemicals (EDCs). The estrogenic effect of these effluents has been demonstrated on both vertebrate and invertebrate species by the feminisation of the exposed males. This effect was investigated on the freshwater zebra mussel (Dreissena polymorpha) after exposure to tertiary treated effluent from a municipal sewage treatment works (STW). Mussels were exposed to the effluent in situ for 112 days during gametogenesis (December to mid-March). Levels of vitellin (Vn)-like proteins (the major protein found in oocytes) were measured indirectly using the alkali-labile phosphate (ALP) technique and confirmed by gel electrophoresis. Significant increases (P < 0.05) in Vn-like proteins were found in both male and female mussels after exposure to the effluent, indicating that endocrine disruption (ED) had occurred. Using High-performance thin layer chromatography (HPTLC) levels of the mussels main steroid, cholesterol were found to more than double after effluent exposure. General physiological (survival, condition, etc.) and histological effects were also investigated. Histological effects observed included a large increase in interstitial tissue between the seminiferous tubules of the gonad in male mussels exposed to effluent. Effluent samples were tested for estrogenic compounds using the toxicity identification and evaluation method (TIE). A complex mixture of compounds with estrogenic activity was found with 17beta-estradiol, 17alpha-ethynlestradiol and bisphenol A accounting for the majority of the effluents estrogenic activity. Results indicate that the zebra mussel is a suitable bioindicator of endocrine disruption in freshwater environments.


Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.
Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.


Postoperative stabilization of the strabismic angle in intermittent exotropia.
To analyze the postoperative strabismic angle for five years or more and to investigate when the angle stabilized in intermittent exotropia. We retrospectively reviewed the clinical records of 89 patients who had undergone surgery for intermittent exotropia. The postoperative strabismic angles measured were analyzed at one-year intervals up to five years postoperatively. We divided them into two groups according to their age at the time of surgery. Group 1 was less than 5 years of age, while Group 2 participants were 5 years of age or older. For our 89 total patients, average exo-angles were 7.8 ± 7.26, 7.9 ± 7.51, 9.5 ± 7.05, 10.1 ± 6.87, and 9.4 ± 6.90 prism diopters at one, two, three, four, and five years postoperatively, respectively. Average exo-angles between postoperative year one and year three, as well as between postoperative year two and year three, were statistically significant (p = 0.015, 0.022). However, the angles were not statistically significant between postoperative year three and year four or between years three and five, respectively (p = 0.707, p = 0.948). The stabilization characteristics of the angle were somewhat different according to age group. In Group 1, the average exo-angle in postoperative years one and three were statistically significant (p = 0.016), but the angle in the same period was not statistically significant in Group 2 (p = 0.203). There was no significant interval change after three years postoperatively in intermittent exotropia, but if the patient's age at surgery was 5 years or higher, no significant change of exo-angle was found following postoperative year one in this study.


The dynein gene family in Chlamydomonas reinhardtii.
To correlate dynein heavy chain (Dhc) genes with flagellar mutations and gain insight into the function of specific dynein isoforms, we placed eight members of the Dhc gene family on the genetic map of Chlamydomonas. Using a PCR-based strategy, we cloned 11 Dhc genes from Chlamydomonas. Comparisons with other Dhc genes indicate that two clones correspond to genes encoding the alpha and beta heavy chains of the outer dynein arm. Alignment of the predicted amino acid sequences spanning the nucleotide binding site indicates that the remaining nine clones can be subdivided into three groups that are likely to include representatives of the inner-arm Dhc isoforms. Gene-specific probes reveal that each clone represents a single-copy gene that is expressed as a transcript of the appropriate size (> 13 kb) sufficient to encode a high molecular weight Dhc polypeptide. The expression of all nine genes is upregulated in response to deflagellation, suggesting a role in axoneme assembly or motility. Restriction fragment length polymorphisms between divergent C. reinhardtii strains have been used to place each Dhc gene on the genetic map of Chlamydomonas. These studies lay the groundwork for correlating defects in different Dhc genes with specific flagellar mutations.


The Effect of a Digital Behavioral Weight Loss Intervention on Adherence to the Dietary Approaches to Stop Hypertension (DASH) Dietary Pattern in Medically Vulnerable Primary Care Patients: Results from a Randomized Controlled Trial.
Obesity treatment focuses primarily on reducing overall caloric intake with limited focus on improving diet quality. The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is effective in managing hypertension and other chronic conditions, yet it is not clear whether behavioral weight control interventions improve DASH adherence. We conducted a post hoc analysis of a behavioral weight loss intervention that did not emphasize diet quality and examined whether the intervention impacted DASH adherence in medically vulnerable community health center patients. Participants (n=306) were enrolled in Track, a randomized controlled weight loss intervention for patients with elevated cardiovascular risk. The trial compared usual care to an intervention with weekly self-monitoring, tailored feedback on diet and exercise goals, and dietitian and provider counseling in community health centers. Dietary intake was measured using the Block Food Frequency Questionnaires collected at baseline and 12 months. DASH adherence was determined using previously validated scoring indices that assessed adherence based on recommended nutrient or food group targets. Total scores for both indices ranged from 0 to 9, with higher scores indicating greater DASH adherence. The mean (and standard deviation [SD]) age of participants was 51.1 (SD=8.8) years and the mean body mass index was 35.9 (SD=3.9). Most were female (69%) and black (51%); 13% were Hispanic. Half (51%) had an annual income <$25,000 and 33% had both diabetes and hypertension. At baseline, the mean DASH nutrient score was 1.81 (SD=1.42) with 6% achieving at least a score of 4.5. Similar scores were seen for the DASH foods index. The intervention group saw significantly greater, albeit small, improvements in mean DASH nutrient score (intervention: 1.28 [SD=1.5] vs control: 0.20 [SD=1.3]; P<0.001), and there was no difference in DASH food score between study arms. There were no significant predictors of change in DASH score and no association between DASH adherence and changes in blood pressure. Within the intervention arm, improvements in DASH nutrient score were associated with greater weight loss (r=-0.28; P=0.003). Although the intervention was not designed to increase adoption of DASH, the Track intervention produced significant weight loss and small improvements in DASH adherence. Despite these small improvements, overall adoption of DASH was poor among the medically vulnerable patients enrolled in Track. To further reduce chronic disease burden, weight loss interventions should include a focus on both caloric restriction and increasing diet quality.


Reforming pathology teaching in medical college by peer-assisted learning and student-oriented interest building activities: A pilot study.
Peer-assisted learning (PAL) is a teaching-learning method in which students act as peer teachers and help other students to learn while also themselves learning by teaching. PAL through modified interest building activities (MIBAs) is seldom tried in teaching pathology in medical colleges. This study aimed to evaluate the usefulness of peer teaching using MIBA, obtain feedback from students, and compare different activities with each other and with traditional teaching-learning methods. An interventional pilot study was conducted in 2 months on the 2nd MBBS undergraduates learning pathology at a medical college in North India. Students acted as peer teachers and performed different MIBAs including role plays, demonstration of pathogenesis through props, student-led seminars such as PowerPoint teaching, blackboard teaching, multiple choice question seminars, case-based learning (CBL) exercises, and quizzes before teaching sessions. Feedback was obtained through structured questionnaires on a 5-point Likert scale. Paired t-test was used to compare traditional teaching with MIBAs, and Friedman test was used to compare among different MIBAs. Students found ease of understanding and the interaction and involvement of students as the most important benefits of PAL. MIBAs increased voluntary participation, coordination, teamwork, shared responsibility, and group dynamics among students. Quiz sessions followed by PowerPoint seminars and prop demonstrations received highest mean scores from students on most of the parameters. Quizzes, blackboard teaching, prop activities, and CBL helped students understand topics better and generated interest. Learners advocated for making MIBAs and PAL compulsory for future students. PAL complemented by MIBAs may be adopted to make teaching-learning more interesting and effective through the active involvement and participation of students.


Adherence to surgical antimicrobial prophylaxis: "checking-the-box" is not enough.
The purpose of this paper is to review surgical antimicrobial prophylaxis administration practices in a small cohort and assess compliance with national guidelines. Patients that developed surgical site infections (SSI) in a tertiary care academic medical center over a two-year period were identified. Their electronic medical records were reviewed for compliance with national guidelines with respect to surgical antibiotic prophylaxis. Over a two-year period, 283 SSI patients were identified. An appropriate antibiotic was chosen in 80 percent, an appropriate dose was administered in 45 percent and timing complied in 89 percent. The antibiotics were appropriately re-dosed in only 9.2 percent in whom the requirement was met. The prescribing guidelines were adhered to in entirety in only 54 patients (23.8 percent). Timely and appropriate antibiotic administration prior to surgery is essential to prevent SSI. Proper diligence is required to accomplish this task effectively. Based on the findings, it appears that merely, "checking a box" for antibiotic administration during surgery is not enough, and a multidisciplinary approach should be followed to ensure "appropriate" antibiotic administration.


First Report of Lily Blight and Wilt Caused by Fusarium tricinctum in China.
Lily (Lilium spp.) is one of the most well-known horticultural crops, and plays an important economic role in China. In September 2011, wilted plants were observed on Lilium oriental hybrid cultivar 'Sorbonne' growing in Longde County, Ningxia Hui Autonomous Region, China. Disease symptoms included wilting, stem and root rot, brown spots of bulbs and then bulbs rotting and spalling from the basal disc, plus a progressive yellowing and defoliation of the leaves from the base. Diseased plants were sampled from fields. Small pieces of symptomatic bulbs, stems, and roots from 10 different plants were surface disinfected with 75% ethanol for 30 s, 3% sodium hypochlorite for 5 min, and then washed three times in sterilize distilled water. The tissues were placed onto Martin Agar (2) at 25°C for 7 days. Nine isolates with morphology similar to Fusarium were obtained from the diseased tissues. Isolates were transferred to potato dextrose agar (PDA) and carnation leaf agar (CLA) and incubated at 25°C. Seven were identified as Fusarium oxysporum and one was F. solani, which have been reported as pathogens of lily in China (1). The other isolate, when grown on PDA, rapidly produced dense, white aerial mycelium that became pink with age and formed red pigments in the medium. On CLA, macroconidia with three to five septate were abundant, relatively slender, and curved to lunate. Microconidia were abundant, oval or pyriform, and one to two celled. Chlamydospores were in chains with smooth exine. The rDNA internal transcribed spacer (ITS) region and a portion of the translation elongation factor 1-alpha (EF-1α) gene of the fungus were amplified, with universal primers ITS1/ITS4 and EF1/EF2 primers respectively (3) and sequenced. In addition, the β-tubulin gene (β-tub) of the fungus was amplified with modified primers Btu-F-F01 (5'-CAGACMGGTCAGTGCGTAA-3') and Btu-F-R01 (5'-TCTTGGGGTCGAACATCTG-3') (4). BLASTn analysis showed that the ITS sequences of the isolate (GenBank Accession No. JX989827) had 98.9% similarity with those of F. tricinctum (EF611092, JF776665, and HM776425) and the EF-1α sequences of the isolate (JX989828) had 98.1% similarity with those of F. tricinctum (EU744837 and JX397850). The β-tub sequences of the isolate (JX989829) had 99.0% similarity with those of F. tricinctum (EU490236 and AB587077). The isolate was tested for pathogenicity. Two-month-old 'Sorbonne' seedlings were inoculated by placing 5 ml of conidial suspension (about 106 conidia per ml) over the roots of plants in each pot. Control plants were treated with sterile water in the same way. Plants were placed in a greenhouse at 22 to 25°C with a 15-h photoperiod. There were eight plants per pot and three replicates for each treatment. After 3 weeks, 87.5% of the inoculated plants exhibited browning of the root tips, root rot, and yellowing of the leaves, while control plants were symptomless. The pathogen was reisolated from the infected roots and identified as F. tricinctum, thus fulfilling Koch's postulates. To our knowledge, this is the first report of Fusarium wilt of lily caused by F. tricinctum. This information will provide guidance for the control of lily wilt disease and add information useful for the production of lilies. References: (1) C. Li and J. J. Li. Acta Phytopathol. Sin. (in Chinese) 26:192, 1995. (2) J. P. Martin. Soil Sci. 38:215, 1950. (3) K. O'Donnell et al. Proc. Nat. Acad. Sci. U. S. A. 95:2044, 1998. (4) M. Watanabe et al. BMC Evol. Biol. 11:322. 2011.


Geographic variation in body form of prehistoric Jomon males in the Japanese archipelago: its ecogeographic implications.
Diversity of human body size and shape is often biogeographically interpreted in association with climatic conditions. According to Bergmann's and Allen's rules, populations in regions with a cold climate are expected to display an overall larger body and smaller/shorter extremities than those in warm/hot environments. In the present study, the skeletal limb size and proportions of prehistoric Jomon hunter-gatherers, who extensively inhabited subarctic to subtropical areas in the ancient Japanese archipelago, were examined to evaluate whether or not the inter-regional differences follow such ecogeographic patterns. Results showed that the Jomon intralimb proportions including relative distal limb lengths did not differ significantly among five regions from northern Hokkaido to the southern Okinawa Islands. This suggests a limited co-variability of the intralimb proportions with climate, particularly within genealogically close populations. In contrast, femoral head breadth (associated with body mass) and skeletal limb lengths were found to be significantly and positively correlated with latitude, suggesting a north-south geographical cline in the body size. This gradient therefore comprehensively conforms to Bergmann's rule, and may stem from multiple potential factors such as phylogenetic constraints, microevolutionary adaptation to climatic/geographic conditions during the Jomon period, and nutritional and physiological response during ontogeny. Specifically, the remarkably small-bodied Jomon in the Okinawa Islands can also be explained as an adjustment to subtropical and insular environments. Thus, the findings obtained in this study indicate that Jomon people, while maintaining fundamental intralimb proportions, displayed body size variation in concert with ambient surroundings.


Excess weight and physical health-related quality of life in postmenopausal women of diverse racial/ethnic backgrounds.
Studies of weight and health-related quality of life (HRQOL) generally focus on white populations. This analysis examines the association between clinical weight categories and physical HRQOL in five racial/ethnic groups of older women and determines the extent to which emotional/psychological (social support, caregiver burden) and physical health (diabetes, osteoarthritis) factors modify this relationship. The cross-sectional analysis, completed in 2007, used baseline data from postmenopausal women enrolled in the Women's Health Initiative (WHI) during the 5-year recruitment period (1993-1998). Of 161,393 women, 83% were non-Hispanic white, 9% were African American, 4% were Hispanic/Latina, 3% were Asian/Pacific Islander, and <1% were American Indian/Alaska Native. Obesity (body mass index [BMI] > or =30 kg/m(2)) was most common in non-Asian minority groups. Regression modeling showed higher odds of poor physical HRQOL with increasing weight category in all groups. In the total sample, these odds were at least 6 times as high in women with class 3 obesity as in women of normal weight and were only mildly attenuated after the analysis adjusted for emotional/psychological factors. Further adjustment for physical health factors made odds ratio (OR) estimates drop from 2.36 to 1.59 for class 1 obesity and from 6.96 to 3.71 for class 3 obesity. This pattern generally persisted within each racial/ethnic group. Heavier weight negatively affects physical HRQOL in postmenopausal women across diverse racial/ethnic backgrounds. Weight-relevant physical health factors have a greater impact on this weight-HRQOL association than do emotional/psychological factors.


The burden of cancer at work: estimation as the first step to prevention.
Work-related cancers are largely preventable. The overall aim of this project is to estimate the current burden of cancer in Great Britain attributable to occupational factors, and identify carcinogenic agents, industries and occupations for targeting risk prevention. Attributable fractions and numbers were estimated for mortality and incidence for bladder, lung, non-melanoma skin, and sinonasal cancers, leukaemia and mesothelioma for agents and occupations classified as International Agency for Research on Cancer (IARC) Group 1 and 2A carcinogens with "strong" or "suggestive" evidence for carcinogenicity at the specific cancer site in humans. Risk estimates were obtained from published literature and national data sources used for estimating proportions exposed. In 2004, 78,237 men and 71,666 women died from cancer in Great Britain. Of these, 7317 (4.9%) deaths (men: 6259 (8%); women: 1058 (1.5%)) were estimated to be attributable to work-related carcinogens for the six cancers assessed. Incidence estimates were 13,338 (4.0%) registrations (men: 11,284 (6.7%); women 2054 (1.2%)). Asbestos contributed over half the occupational attributable deaths, followed by silica, diesel engine exhaust, radon, work as a painter, mineral oils in metal workers and in the printing industry, environmental tobacco smoke (non-smokers), work as a welder and dioxins. Occupational exposure to solar radiation, mineral oils and coal tars/pitches contributed 2557, 1867 and 550 skin cancer registrations, respectively. Industries/occupations with large numbers of deaths and/or registrations include construction, metal working, personal and household services, mining (not metals), land transport and services allied to transport, roofing, road repair/construction, printing, farming, the Armed Forces, some other service industry sectors and manufacture of transport equipment, fabricated metal products, machinery, non-ferrous metals and metal products, and chemicals. Estimates for all but leukaemia are greater than those currently used in UK health and safety strategy planning and contrast with small numbers (200-240 annually) from occupational accidents. Sources of uncertainty in the estimates arise principally from approximate data and methodological issues. On balance, the estimates are likely to be a conservative estimate of the true risk. Long latency means that past high exposures will continue to give substantial numbers in the near future. Although levels of many exposures have reduced, recent measurements of others, such as wood dust and respirable quartz, show continuing high levels.


High-speed motility originates from cooperatively pushing and pulling flagella bundles in bilophotrichous bacteria.
Bacteria propel and change direction by rotating long, helical filaments, called flagella. The number of flagella, their arrangement on the cell body and their sense of rotation hypothetically determine the locomotion characteristics of a species. The movement of the most rapid microorganisms has in particular remained unexplored because of additional experimental limitations. We show that magnetotactic cocci with two flagella bundles on one pole swim faster than 500 µm·s-1 along a double helical path, making them one of the fastest natural microswimmers. We additionally reveal that the cells reorient in less than 5 ms, an order of magnitude faster than reported so far for any other bacteria. Using hydrodynamic modeling, we demonstrate that a mode where a pushing and a pulling bundle cooperate is the only possibility to enable both helical tracks and fast reorientations. The advantage of sheathed flagella bundles is the high rigidity, making high swimming speeds possible.


Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos.
We have isolated two mouse genes, Mox-1 and Mox-2 that, by sequence, genomic structure and expression pattern, define a novel homeobox gene family probably involved in mesodermal regionalization and somitic differentiation. Mox-1 is genetically linked to the keratin and Hox-2 genes of chromosome 11, while Mox-2 maps to chromosome 12. At primitive streak stages (approximately 7.0 days post coitum), Mox-1 is expressed in mesoderm lying posterior of the future primordial head and heart. It is not expressed in neural tissue, ectoderm, or endoderm. Mox-1 expression may therefore define an extensive 'posterior' domain of embryonic mesoderm before, or at the earliest stages of, patterning of the mesoderm and neuroectoderm by the Hox cluster genes. Between 7.5 and 9.5 days post coitum, Mox-1 is expressed in presomitic mesoderm, epithelial and differentiating somites (dermatome, myotome and sclerotome) and in lateral plate mesoderm. In the body of midgestation embryos, Mox-1 signal is restricted to loose undifferentiated mesenchyme. Mox-1 signal is also prominent over the mesenchyme of the heart cushions and truncus arteriosus, which arises from epithelial-mesenchymal transformation and over a limited number of craniofacial foci of neural crest-derived mesenchyme that are associated with muscle attachment sites. The expression profile of Mox-2 is similar to, but different from, that of Mox-1. For example, Mox-2 is apparently not expressed before somites form, is then expressed over the entire epithelial somite, but during somitic differentiation, Mox-2 signal rapidly becomes restricted to sclerotomal derivatives. The expression patterns of these genes suggest regulatory roles for Mox-1 and Mox-2 in the initial anterior-posterior regionalization of vertebrate embryonic mesoderm and, in addition, in somite specification and differentiation.


Glyphosate (Pesticides).
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of glyphosate (CAS No. 1071-83-6), an amino acid herbicide, based on results from various studies. Major adverse effects of glyphosate were observed on reduced gain of body weight, GI tract (diarrhea, increased cecum weight, bowel dilatation, thickening of intestinal mucosa), and liver (increased alkaline phosphatase (ALP), hepatocellular hypertrophy). Glyphosate had no neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity, and genotoxicity. As the whole, the lowest value among no-observed-adverse-effect levels (NOAELs) was 100 mg/kg bw/day obtained in the 90-days and one-year toxicity studies in dogs, and in the developmental toxicity studies of rabbits. FSCJ thus established an acceptable daily intake (ADI) for glyphosate at 1 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects elicited by a single oral administration of glyphosate was 1,000 mg/kg bw observed in an acute toxicity studies in rats and mice. It is thus unnecessary to specify an acute reference dose (ARfD), due to the exceeding of the cut off level (500 mg/kg bw).


Development of the Short Form Endometriosis Health Profile Questionnaire: the EHP-5.
To develop and validate a short form version of the Endometriosis Health Profile-30 questionnaire which consists of a 30-item core questionnaire and a 23 item modular questionnaire. Three studies were carried out to develop the Endometriosis Health Profile-5. Study 1: a short form version of the Endometriosis Health Profile-30 core questionnaire was developed. Study 2: the results were verified in a new data set. Study 3: a short form version of the 23 item modular questionnaire was produced. The modular questionnaire contains six dimensions which may not be applicable to every woman with endometriosis and is used to supplement the five scales on the core questionnaire when required. The final instrument contained 11 items: five items from the core questionnaire and six items from the modular questionnaire. The 95% confidence intervals for Study 1 indicated that the scale scores overlapped with each item score and were confirmed in the second analysis (study 2). Each item was most highly correlated to its parent scale and less with the remaining four core questionnaire scales which was verified in study 2. In both studies all correlations were significant at the 0.01 level (two tailed test). The Endometriosis Health Profile-5 is a reliable and valid short form questionnaire which can also be supplemented with a short form version of the modular questionnaire when required. It will be especially useful in clinical settings where a short and economical endometriosis health status measure is required.


Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen.
One of the challenges in drug development today is that many new drug candidates are poorly water-soluble, and one of the approaches to overcome this problem is to transfer a crystalline drug into its amorphous form, thus increasing dissolution rate and apparent solubility of the compound. In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and γ-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined at 277.15 and 298.15 K under dry conditions (phosphorus pentoxide) and analyzed with X-ray powder diffraction (XRPD). Intrinsic dissolution testing was carried out to identify dissolution advantages of the coamorphous form over its crystalline counterparts or amorphous indomethacin. Fourier transform infrared spectroscopy (FTIR) was used for analyses at the molecular level to detect potential molecular interactions. Differential scanning calorimetry (DSC) thermograms were employed to assess the glass transition temperatures (T(g)), and the results were compared with predicted T(g)s from the Gordon-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore, samples at the 1:2 and 2:1 ratios showed recrystallization of the excess drug upon storage whereas the 1:1 ratio samples remained amorphous. Intrinsic dissolution testing showed increased dissolution rate of both drugs in the coamorphous form as well as a synchronized release for the 1:1 coamorphous blend. All T(g)s displayed negative deviations from the Gordon-Taylor equation with the 1:1 ratio showing the largest deviation. In a novel approach of predicting the glass transition temperature, the 1:1 drug ratio was inserted as an individual component in the Gordon-Taylor equation with the excess drug representing the second compound. This approach resulted in a good fit to the experimentally determined T(g)s.


Management of myocardial infarction in children with Kawasaki disease.
Kawasaki disease is an acute, systemic vasculitis of unknown cause affecting mainly neonates (infants) and young children. Despite treatment during the acute phase with intravenous immunoglobulin and aspirin, up to 5% of those affected will develop coronary aneurysms, predisposing them to thrombotic complications that could result in myocardial infarction and/or death. There are treatment protocols in place for the management of myocardial infarction in adults, but the practical nature of medication is unclear in children. To date, there are no clinical trials or specific recommendations on the dosing of thrombolytic therapy for the treatment of myocardial infarction in Kawasaki pediatric patients. However, there are reports of the use of thrombolytic agents, including streptokinase, urokinase and tissue plasminogen activator, as well as the monoclonal platelet glycoprotein (GP)IIb/IIIa receptor inhibitor, abciximab, that have been used to treat myocardial infarction in children with Kawasaki disease. The outcomes in these reports are varied. This review provides a summary of the available data on the management of children with Kawasaki disease suffering from myocardial infarction or thrombotic complications that can potentially lead to myocardial infarction.


Lactosomes: structural and compositional classification of unique nanometer-sized protein lipid particles of human milk.
Milk fat globules (MFGs) are accepted primarily as triacylglycerol delivery systems. The identification of nanometer-sized lipid-protein particles termed "lactosomes" that do not contain triacylglycerol raises the question of their possible functions. MFGs were isolated by slow centrifugation, and lactosomes were isolated by ultracentrifugation at a density equivalent to plasma high-density lipoproteins (HDL) (d > 1.063 g/mL) from human milk obtained from six volunteers at different lactation stages. Isolated lactosomes were analyzed and compared with MFGs for their size distribution, lipidome, proteome, and functional activity. Lactosomes from early milk, day 8, were found to be similar in size as those from mature milk >28 days, averaging ∼ 25 nm in diameter. In total, 97 nonredundant proteins were identified in the MFG and lactosome fractions, 46 of which were unique to the MFG fraction and 29 of which were unique to the lactosome fraction. The proteins identified in the lactosome and MFG fractions were enriched with proteins identified with immunomodulatory pathways. Unlike MFGs and GM1-laden reconstituted HDL that served as a positive control, lactosomal binding capacity to cholera toxin was weak. Lipidomic analyses found that lactosomes were devoid of triacylglycerol and gangliosides, unlike MFGs, but rich in a variety of phospholipid species. The data found differences in structure, composition, and function between lactosomes and MFG, suggesting that these two particles are derived from different biosynthetic and/or secretory pathways. The results reveal a bioactive lipid-protein, nanometer-length scale particle that is secreted into milk not to supply energy to the infant but to play unique, protective, and regulatory roles.


Translating the evidence-based NICU COPE program for parents of premature infants into clinical practice: impact on nurses' evidence-based practice and lessons learned.
Many interventions that have been supported as efficacious through research never make it to clinical practice to improve care and patient outcomes. Therefore, the purposes of this dissemination-implementation study were to determine (a) the impact of translating the evidence-based Creating Opportunities for Personal Empowerment (COPE) program for parents of premature infants into clinical practice on nurses' EBP (evidence-based practice) beliefs and implementation; (b) the best strategy for disseminating COPE into the neonatal intensive care unit (NICU), including evaluating the use of a COPE EBP mentor; and (c) barriers and facilitators to successful implementation of the COPE program. The subjects for this study were 81 (45%) out of 180 nurses from a 55-bed NICU of a large children's hospital located in the Southwest region of the United States. The nurses completed the EBP beliefs and EBP implementation scales at baseline and 6 months after a full-day workshop on COPE and EBP and introduction of the COPE program into the unit. Evaluations from the nurses assisted in the identification of barriers and facilitators that fostered implementation of COPE in the NICU. Nurses in the 2 pods in which COPE was being implemented reported higher EBP beliefs and greater EBP implementation than did nurses in the non-COPE pods. The EBP mentor was instrumental in routine delivery of COPE to the parents. Strategies to accelerate the translation of efficacious interventions into clinical practice and to create cultures to support evidence-based care in healthcare systems are urgently needed.


Characterization of human rheumatoid factors with seven antiidiotypes induced by synthetic hypervariable region peptides.
Recently, we have used synthetic peptides corresponding to the complementarity-determining regions (CDR) of Ig molecules to induce antiidiotypic antisera. Peptide PSH3, representing the third CDR of the IgM rheumatoid factor (RF) Sie heavy (H) chain, induced a private antiidiotype that reacted with only one out of five IgM-RF. Peptide PSL2, corresponding to the second CDR of Sie light (L) chain, induced an antibody against a crossreactive idiotype (CRI), expressed by 10 out of 12 human IgM-RF analyzed. Herein, we report that five additional antiidiotypic antibodies were generated by immunization with synthetic peptides identical to the third L chain CDR of IgM-RF Sie (PSL3), the second and third H chain CDR of IgM-RF Wol, and the second and third CDR of IgM-RF Pom. As analyzed by immunoblot assay, both anti-PSL3 and anti-PSL2 reacted with the majority of 16 IgM-RF. In contrast, all five antiidiotypes induced by the H chain peptides reacted only with the parent proteins, except anti-PSH3, which reacted weakly with one additional RF. These results suggest that one (or very few) VL gene(s), but a larger number of VH genes, are used to encode IgM-RF autoantibodies.


Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region.
On the basis of 2093 meioses analyzed in two separate intraspecific backcrosses, the location of the mouse Lpsd mutation was circumscribed to a genetic interval 0.9 cM in size. A total of 19 genetic markers that lie in close proximity to the mutation were examined in mapping. Most of these were previously unpublished polymorphic microsatellites, identified by fragmentation of YAC and BAC clones spanning the region of interest. Lpsd was found to be inseparable from the microsatellite marker D4MIT178, and from three novel polymorphic microsatellites identified near D4MIT178. The mutation was confined between two novel microsatellite markers, herein designated "B" and "83.3." B lies centromeric to the mutation, and was separated by four crossovers in a panel of 1600 mice; 83.3 lies distal to the mutation and was separated by three crossovers in a panel of 493 mice. 66 BAC clones and one YAC clone were assembled to cover > 95% of the critical region. Estimates based on pulsed field gel electrophoresis and fluorescence in situ hybridization indicate that the The B-->83.3 interval is about 3.2 Mb in length. A minimal area of zero recombinational distance from Lpsd was also assigned, and found to occupy approximately 1.2 Mb of physical size. To identify gene candidates, nearly 40,000 sequencing runs were performed across the critical region. Selective hybridization and exon trapping were also employed to identify genes throughout the "zero" region. Only a single intact gene was identified within the entire critical region. This gene encodes the Toll-4 receptor, a member of the IL-1 receptor family.


Eye-specific segregation requires neural activity in three-eyed Rana pipiens.
The addition of a third eye primordium to the forebrain region of a Rana pipiens embryo invariably results in the development of a series of periodic, mutually exclusive eye-specific bands in tectal lobes dually innervated by the host and supernumerary fibers. A number of investigators have proposed that such source-specific segregation arises as a compromise between two mechanisms that are normally involved in retinotectal map formation: one which is dependent on cell surface affinities to align the map and produce a rough retinotopy and a second that "fine tunes" the map by stabilizing adjacent terminals from neighboring retinal ganglion cell bodies at the expense of terminals from non-neighboring cells. In this study we have tested the idea that this second "fine-tuning" mechanism is dependent on neural activity by blocking impulse activity in the optic nerves of three-eyed tadpoles. To assess the requirement for activity on the formation of bands, both normal optic nerves of 17 three-eyed tadpoles were crushed intraorbitally. Two weeks after this operation, the supernumerary retinal projection had debanded and spread to cover the entire tectum in a continuous fashion. By 4 weeks, however, the host optic fibers regenerated back to the tecta and began to form segregated stripes with the fibers from the third eye. Six to 7 weeks after the optic nerve crush the periodic pattern of eye-specific segregation characteristic of dually innervated tecta was again pronounced. When activity in all three optic nerves was eliminated with tetrodotoxin (TTX; embedded in a slow release plastic) during the last 3 weeks of this process, the fibers from the two competing eyes failed to segregate and, instead, formed two completely overlapping, continuous projections across the tectal surface. To test for the requirement of activity in the maintenance of segregation, we also subjected three-eyed tadpoles without optic nerve crush to TTX blockade for 2, 3, and 4 weeks. Animals sacrificed at 2 weeks show overlap of the projections in the rostral tectum but distinct interdigitating stripes in other regions of these lobes. After 3 weeks of blockade, segregation of the projections was less distinct in the central tectum as well. After 4 weeks of TTX blockade the terminals from both eyes spread to form continuous overlapping projections throughout the tectum. Examination of well isolated, individual retinal ganglion cell terminal arbors during this period reveals that they occupy a significantly greater area of tectum following the TTX treatment.(ABSTRACT TRUNCATED AT 400 WORDS)


Hip impingement: identifying and treating a common cause of hip pain.
Femoroacetabular impingement, also known as hip impingement, is the abutment of the acetabular rim and the proximal femur. Hip impingement is increasingly recognized as a common etiology of hip pain in athletes, adolescents, and adults. It injures the labrum and articular cartilage, and can lead to osteoarthritis of the hip if left untreated. Patients with hip impingement often report anterolateral hip pain. Common aggravating activities include prolonged sitting, leaning forward, getting in or out of a car, and pivoting in sports. The use of flexion, adduction, and internal rotation of the supine hip typically reproduces the pain. Radiography, magnetic resonance arthrography, and injection of local anesthetic into the hip joint confirm the diagnosis. Pain may improve with physical therapy. Treatment often requires arthroscopy, which typically allows patients to resume premorbid physical activities. An important goal of arthroscopy is preservation of the hip joint. Whether arthroscopic treatment prevents or delays osteoarthritis of the hip is unknown.


Local avian density influences risk of mortality from window strikes.
Up to a billion birds die per year in North America as a result of striking windows. Both transparent and reflective glass panes are a cause for concern, misleading birds by either acting as invisible, impenetrable barriers to desired resources, or reflecting those resources over a large surface area. A high number of window strikes occur during migration, but little is known about the factors of susceptibility, or whether particular avian taxa are more vulnerable than others. We report on a study of window strikes and mist-netting data at the Virginia Zoological Park (Norfolk, Virginia, USA), conducted in the autumn of 2013 and 2014. We focused on three factors likely to contribute to an individual's predisposition to collide with windows: (i) taxonomic classification, (ii) age, and (iii) migrant vs. resident status. Thrushes, dominated by the partial migrant American Robin (Turdus migratorius), were significantly less likely to strike glass than be sampled in mist nets (χ(2) = 9.21, p = 0.002), while wood-warblers (Parulidae) were more likely to strike than expected (χ(2) = 13.55, p < 0.001). The proportion of juveniles striking windows (45.4%) was not significantly different (χ(2) = 0.05, p = 0.827) than the population of juvenile birds naturally occurring at the zoo (48.8%). Migrants, however, were significantly more susceptible to window strikes than residents (χ(2) = 6.35, p = 0.012). Our results suggest that resident birds are able to learn to avoid and thus reduce their likelihood of striking windows; this intrinsic risk factor may help explain the apparent susceptibility of certain taxa to window strikes.


Amygdala lesions disrupt modulation of functional MRI activity evoked by facial expression in the monkey inferior temporal cortex.
We previously showed that facial expressions modulate functional MRI activity in the face-processing regions of the macaque monkey's amygdala and inferior temporal (IT) cortex. Specifically, we showed that faces expressing emotion yield greater activation than neutral faces; we term this difference the "valence effect." We hypothesized that amygdala lesions would disrupt the valence effect by eliminating the modulatory feedback from the amygdala to the IT cortex. We compared the valence effects within the IT cortex in monkeys with excitotoxic amygdala lesions (n = 3) with those in intact control animals (n = 3) using contrast agent-based functional MRI at 3 T. Images of four distinct monkey facial expressions--neutral, aggressive (open mouth threat), fearful (fear grin), and appeasing (lip smack)--were presented to the subjects in a blocked design. Our results showed that in monkeys with amygdala lesions the valence effects were strongly disrupted within the IT cortex, whereas face responsivity (neutral faces > scrambled faces) and face selectivity (neutral faces > non-face objects) were unaffected. Furthermore, sparing of the anterior amygdala led to intact valence effects in the anterior IT cortex (which included the anterior face-selective regions), whereas sparing of the posterior amygdala led to intact valence effects in the posterior IT cortex (which included the posterior face-selective regions). Overall, our data demonstrate that the feedback projections from the amygdala to the IT cortex mediate the valence effect found there. Moreover, these modulatory effects are consistent with an anterior-to-posterior gradient of projections, as suggested by classical tracer studies.


Direct observation of the transfer of orbital angular momentum to metal particles from a focused circularly polarized Gaussian beam.
It is well known that a circularly polarized Gaussian beam carries spin angular momentum, but not orbital angular momentum. This paper demonstrates that focusing a beam carrying spin angular momentum can induce an orbital angular momentum which we used to drive the orbital motion of a micron-sized metal particle that is trapped off the beam axis. The direction of the orbital motion is controlled by the handedness of the circular polarization. The orbiting dynamics of the trapped particle, which acted as an optical micro-detector, were quantitatively measured and found to be in excellent agreement with the theoretical predictions.


Systematic review and meta-analysis of effectiveness of preoperative embolization in surgery for metastatic spine disease.
Preoperative embolization (PE) may decrease intraoperative blood loss (IBL) in decompressive surgery of hypervascular spinal metastases. However, no consensus has been found in other metastases and no meta-analysis which reviewed the benefit of PE in spinal metastases has been conducted. To assess IBL in spinal metastases surgery in a randomized controlled trial (RCT) and cohort studies comparing PE and a control group of non-embolized patients. A systematic search of relevant publications in PubMed and EMBASE was undertaken. Inclusion criteria were RCTs and observational studies in patients with spinal metastases who underwent spine surgery and reported IBL. Meta-analysis was performed using standardized mean difference (SMD) and mean difference (MD) of IBL. Heterogeneity was assessed using the I2 statistic. A total of 265 abstracts (126 from PubMed and 139 from Embase) were identified through database searching. The reviewers selected six studies for qualitative synthesis and meta-analysis. The pooled SMD of the included studies was 0.58 (95% CI -0.10 to 1.25, p=0.09). Sensitivity analysis revealed that, if the study by Rehak et al was omitted, the pooled SMD was significantly changed to 0.88 (95% CI 0.39 to 1.36, p<0.001) and PE reduced the IBL significantly. The pooled MD was 708.3 mL (95% CI -224.4 to 1640.9 mL, p=0.14). If the results of the Rehak et al study were omitted, the pooled MD was significantly changed to 1226.9 mL (95% CI 345.8 to 2108.1 mL, p=0.006). PE can be effective in reducing IBL in spinal metastases surgery in both renal cell carcinoma and mixed primary tumor groups.


Complete genome sequence of Bacillus sp. HBCD-sjtu, an efficient HBCD-degrading bacterium.
Environmental pollution caused by the release of industrial chemicals is currently one of the most important environmental harms. Manufacturing chemicals can be biodegraded, and valuable intermediates can be used as pharmacophores in drug targeting and have several other useful purposes. Hexabromocyclododecane (HBCD), a non-aromatic brominated flame retardant, is a toxic compound that consists of a cycloaliphatic ring of 12 carbon atoms to which six bromine atoms are attached. It is formed by bromination of cis-trans-trans-1,5,9-cyclododecatriene, but its use is now restricted in several countries, because it is an environmental pollutant. Little is known about whether bacteria can degrade HBCD. A bacterial strain that degrades HBCD was recently isolated using enrichment culture techniques. Based on morphological, biochemical and phylogenetic analysis this isolate was categorized as Bacillus cereus and named strain HBCD-sjtu. Maximum growth and HBCD-degrading activity were observed when this strain was grown at 30 °C, pH 7.0 and 200 RPM in mineral salt medium containing 0.5 mm HBCD. The genome of strain HBCD-sjtu, which consists of only one circular chromosome, was sequenced. This whole genome sequence will be crucial for illuminating the molecular mechanisms of HBCD degradation.


Pathogenicity of Treponema denticola Wild-Type and Mutant Strain Tested by an Active Mode of Periodontal Infection Using Microinjection.
The available passive mode of periodontal infections in mice requires high efficiency of bacterial attachment and invasiveness and is not always suitable to test the pathogenicity of genetically engineered mutant strains. We developed an active mode of oral infection, using microinjection in the marginal gingiva of mice, to test the pathogenicity of a genetically engineered Treponema denticola mutant strain deficient in intermediate-like filaments, compared to the wild-type strain. This targeted mode of infection inoculates the bacterial strain to be tested directly at a lesion site (needle entry point) located at the future periodontal lesion site. The efficiency of T. denticola wild-type strain to elicit bone loss contrasted with the lack of pathogenicity of the intermediate-like filament deficient mutant strain in comparison to the sham infection. The periodontal microinjection oral model in mice can be used for a variety of applications complementary to the passive mode of periodontal infection in context of pathogenicity testing.


Right ventricular responses to CPAP therapy in obstructive sleep apnea: CMR analysis of the MOSAIC randomized trial.
Effects of continuous positive airway pressure (CPAP) on right ventricular (RV) function in patients with untreated mild-to-moderate obstructive sleep apnea (OSA) are unclear. In this exploratory analysis of cardiac magnetic resonance (CMR)-derived indices of RV function in patients with minimally symptomatic OSA from the MOSAIC randomized control trial we found no effect of CPAP on RV CMR parameters. In those with lower RV ejection fraction and higher RV end-diastolic volume (EDV) at baseline, CPAP treatment appeared to improve RV function with a significant reduction in both RV EDV and RV end-systolic volume although between-group effects were not observed. These data suggest potential merit in a larger randomized study of CPAP in patients with mild-to-moderate OSA and a greater breadth of RV dysfunction.


Causes and consequences of telomere lengthening in a wild vertebrate population.
Telomeres have been advocated to be important markers of biological age in evolutionary and ecological studies. Telomeres usually shorten with age and shortening is frequently associated with environmental stressors and increased subsequent mortality. Telomere lengthening - an apparent increase in telomere length between repeated samples from the same individual - also occurs. However, the exact circumstances, and consequences, of telomere lengthening are poorly understood. Using longitudinal data from the Seychelles warbler (Acrocephalus sechellensis), we tested whether telomere lengthening - which occurs in adults of this species - is associated with specific stressors (reproductive effort, food availability, malarial infection and cooperative breeding) and predicts subsequent survival. In females, telomere shortening was observed under greater stress (i.e., low food availability, malaria infection), while telomere lengthening was observed in females experiencing lower stress (i.e., high food availability, assisted by helpers, without malaria). The telomere dynamics of males were not associated with the key stressors tested. These results indicate that, at least for females, telomere lengthening occurs in circumstances more conducive to self-maintenance. Importantly, both females and males with lengthened telomeres had improved subsequent survival relative to individuals that displayed unchanged, or shortened, telomeres - indicating that telomere lengthening is associated with individual fitness. These results demonstrate that telomere dynamics are bidirectionally responsive to the level of stress that an individual faces, but may poorly reflect the accumulation of stress over an individuals lifetime.


First Report of Tomato chlorosis virus in China.
In October 2012, a severe yellowing disease was found on greenhouse and plastic house tomato (Solanum lycopersicum) plants in Beijing, China. The disease incidence varied from 5 to 80% in each of six fields across Haidian and Daxing districts. The lower leaves showed symptoms of interveinal chlorosis, leaf brittleness, and limited brown necrotic flecks, similar to symptoms induced by Tomato chlorosis virus (ToCV) and Tomato infectious chlorosis virus (TICV) (two members of genus Crinivirus, family Closteroviridae) (4). A large number of whiteflies (Bemisia tabaci) were also observed. Leaf samples were taken from eight symptomatic and two asymptomatic tomato plants in two plastic houses in the Haidian district and total RNA was isolated from the 10 samples using TRIzol reagent (Tiangen, Beijing, China). Nested reverse transcription (RT)-PCR was performed to test the presence of ToCV and TICV with degenerate primers HS-11 and HS-12 and specific primers ToC-5/ToC-6 or TIC-3/TIC-4 for ToCV or TICV, respectively (1). With ToCV primers, a 463-bp specific fragment was amplified from eight symptomatic samples but not from two asymptomatic samples, and there was no amplification with TICV primers from any sample. Sequence analysis of the amplified fragment showed 99% nucleotide sequence identity with the heat shock protein 70 homolog (HSP70h) gene of ToCV isolates from Japan (GenBank Accession No. AB513442), Spain (DQ136146), Florida (AY903448), and Greece (EU284744). The presence of ToCV was confirmed by amplification of a 848-bp fragment covering the coat protein (CP) gene of ToCV with primers CP-F (5'-GAATCTTTTAGAAGCTTTGGTTTAAGG-3') and CP-R (5'-GATCCTCTTGATCCTCATAGATTTC-3') (3). The CP had 97 to 99% amino acid sequence identity to the above-mentioned four ToCV isolates. A sequence of the CP gene obtained from one isolate was deposited at GenBank (KC311375). Additionally, virions were isolated from 25 g of symptomatic samples followed Klaassen's method (2) and their lengths were estimated to be about 800 to 850 nm by transmission electronic microscopy To our knowledge, this is the first report of ToCV on tomato in mainland China. Tomato is one of the most widely cultivated crops in China and the spread of ToCV in China may cause significant economic losses. Further information on the prevalence and incidence of ToCV is required to assess the potential impact of this virus. References: (1) C. I. Dovas et al. Plant Dis. 86:1345, 2002. (2) V. A. Klaassen et al. J. Gen. Virol. 75:1525, 1994. (3) H. Tomoki et al. J. Gen. Plant Pathol. 76:168, 2010. (4) G. C. Wisler et al. Phytopathology 88:402, 1998.


Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo.
Although many synapse-organizing molecules have been identified in vitro, their functions in mature neurons in vivo have been mostly unexplored. Cbln1, which belongs to the C1q/tumor necrosis factor superfamily, is the most recently identified protein involved in synapse formation in the mammalian CNS. In the cerebellum, Cbln1 is predominantly produced and secreted from granule cells; cbln1-null mice show ataxia and a severe reduction in the number of synapses between Purkinje cells and parallel fibers (PFs), the axon bundle of granule cells. Here, we show that application of recombinant Cbln1 specifically and reversibly induced PF synapse formation in dissociated cbln1-null Purkinje cells in culture. Cbln1 also rapidly induced electrophysiologically functional and ultrastructurally normal PF synapses in acutely prepared cbln1-null cerebellar slices. Furthermore, a single injection of recombinant Cbln1 rescued severe ataxia in adult cbln1-null mice in vivo by completely, but transiently, restoring PF synapses. Therefore, Cbln1 is a unique synapse organizer that is required not only for the normal development of PF-Purkinje cell synapses but also for their maintenance in the mature cerebellum both in vitro and in vivo. Furthermore, our results indicate that Cbln1 can also rapidly organize new synapses in adult cerebellum, implying its therapeutic potential for cerebellar ataxic disorders.


European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full supplement publication.
Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010. They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of Endoscopy. The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.


Exact solution of the dimer model on the generalized finite checkerboard lattice.
We present the exact closed-form expression for the partition function of a dimer model on a generalized finite checkerboard rectangular lattice under periodic boundary conditions. We investigate three different sets of dimer weights, each with different critical behaviors. We then consider different limits for the model on the three lattices. In one limit, the model for each of the three lattices is reduced to the dimer model on a rectangular lattice, which belongs to the c=-2 universality class. In another limit, two of the lattices reduce to the anisotropic Kasteleyn model on a honeycomb lattice, the universality class of which is given by c=1. The result that the dimer model on a generalized checkerboard rectangular lattice can manifest different critical behaviors is consistent with early studies in the thermodynamic limit and also provides insight into corrections to scaling arising from the finite-size versions of the model.


Pediatric lung transplantation: indications and outcomes.
Lung transplantation (LTx) is a treatment option for infants and children with untreatable and otherwise fatal pulmonary diseases. To date, over 1,800 lung transplants have been performed, most frequently in children over the age of five years. The most common indications for transplantation in children overall are cystic fibrosis (CF) and idiopathic pulmonary hypertension (PH). The surfactant protein deficiencies, other interstitial lung diseases (ILDs), and congenital heart disease are important indications among young children and infants. Re-transplantation is an option for selected recipients with chronic allograft rejection. Overall survival following pediatric LTx is similar to that encountered in adult patients, with recent registry data indicating a median survival of 4.9 years. Other outcomes such as the incidence of bronchiolitis obliterans (BO) and the presence of key post-transplant co-morbid conditions are also similar to the experience in adult lung transplant recipients.


Resistance to 1-beta-D-arabinofuranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene.
We have recently identified a complementary DNA clone which encodes the complete amino acid sequence for 2'-deoxycytidine kinase (dCK), the enzyme required for the initial phosphorylation of several deoxyribonucleosides and their analogues that are widely used as chemotherapeutic and antiviral agents. In order to identify the molecular basis for dCK deficiency in two clonal T-lymphoblast cell lines generated by virtue of their resistance to 1-beta-D-arabinofuranosylcytosine (ara-C-8D) or to 2',3'-dideoxycytidine (ddC50), we have cloned and sequenced their dCK complementary DNAs. The ara-C-8D cell line contained two identifiable mutations: (a) a 115-base pair deletion within the coding region, corresponding to the fifth exon of the gene and presumably resulting from a splice site mutation; and (b) a G to A point mutation that substitutes glutamic acid for glycine within the ATP-binding domain of the protein. Expression of each protein in Escherichia coli demonstrated a complete loss of catalytic activity and, in the case of the deletion, a proteolytic degradation product of the altered protein. The substitution of a negatively charged amino acid within the ATP-binding domain resulted in loss of enzyme activity with all nucleoside triphosphates tested. The ddC50 cell line contained a single identifiable structural gene mutation in all clones sequenced resulting in the substitution of arginine for glutamine at amino acid 156 of the protein. This mutation markedly diminished the catalytic activity of the expressed protein with the three substrates, deoxycytosine, deoxyadenosine, and deoxyguanosine. On the basis of the presence of a single point mutation and a marked reduction in dCK mRNA in this cell line, we postulate that the second allele either is not expressed or is expressed at extremely low levels. We conclude that cellular resistance to the toxicity of 1-beta-D-arabinofuranosylcytosine and dideoxycytidine in these cell lines is mediated by specific mutations within the dCK gene. Further elucidation of structural genes alterations in dCK-deficient cells will facilitate a more detailed understanding of the functional domains of this complex enzyme.


Chronic granulocytic leukaemia: effect of elective splenectomy on the course of disease.
Conventional treatment by drugs or irradiation produces little prolongation of life in patients with chronic granulocytic leukaemia (C.G.L.) because the onset of metamorphosis of the disease from a chronic to an acute or subacute leukaemic process is not substantially postponed. Isolated clinical observations as well as both cytogenetic and cytokinetic evidence suggest that the spleen may play a special though not exclusive role in the development of undifferentiated cell clones which lead to metamorphosis of C.G.L. The results of a study of elective splenectomy during the chronic phase of the disease are reported. Twenty-six patients with C.G.L. underwent splenectomy during clinical remission of their disease, and there were no deaths after the operation. Twenty-one patients were alive at the time of writing, two of them eight years after splenectomy. Five cases of metamorphosis of C.G.L. to a refractory phase occurred whereas 10 would have been expected, a significant difference. After the onset of metamorphosis the quality of life was better in splenectomized than in non-splenectomized patients. These results show that splenectomy is a reasonable and safe procedure in C.G.L., and its apparently beneficial effects on prognosis justify a larger controlled clinical trial.


Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial.
Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir. Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg. Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.


[Malignant pheochromocytoma. A case report and comments on a rare pathology].
Pheochromocytomas and functioning paragangliomas are rare tumors arising from the primitive neural crest, and found in the adrenal medulla or elsewhere within the sympathetic paraganglion axis. Clinical symptoms are related to catecholamine production or less frequently to dopamine or other neuropeptides secretion. Malignant pheochromocytomas are very rare tumors comprising between 5-35%, but this value is uncertain because the usual criteria for malignancy, such as mitotic activity, nuclear pleomorphism, are not suitable to discern benign from malignant pheochromocytomas. A specific diagnosis of malignancy requires evidence of invasion of the adjacent organs and the occurrence of metastases. Personal experience is presented with 92 patients affected by: adrenal pheochromocytomas (51 cases), cervical paragangliomas (32 cases), and extra-adrenal paragangliomas (9 cases). Malignant forms were observed in a 23-year-old young woman affected by malignant pheochromocytoma with lymphatic para-aortic metastases (1.9%), and in 2 patients affected by cervical paragangliomas (1 CBT, 1 VBT) with lymph nodal metastases. Careful follow-up of all patients with measurement of the urinary catecholamine is necessary to detect metachronous neoplasm and later metastases, identified with RMN and 131I-MIBG scintiscan.


Broad tuning of whispering-gallery modes in silicon microdisks.
Silicon microdisks with dynamically-tunable resonance spectra are achieved with nanoscale, in-plane silicon electrical contacts in a single lithographic step. Electrical current is passed through the devices to enable thermal tuning via joule heating. A 14nm wavelength shift is demonstrated with 1.6mW power consumption in devices with >20nm free spectral ranges and quality factors exceeding 20,000. Spectral shifts equal to a full width at half maximum can be achieved with approximately 10microW tuning power for a mode with quality factor of 20,000.


Developmental Bias and Evolution: A Regulatory Network Perspective.
Phenotypic variation is generated by the processes of development, with some variants arising more readily than others-a phenomenon known as "developmental bias." Developmental bias and natural selection have often been portrayed as alternative explanations, but this is a false dichotomy: developmental bias can evolve through natural selection, and bias and selection jointly influence phenotypic evolution. Here, we briefly review the evidence for developmental bias and illustrate how it is studied empirically. We describe recent theory on regulatory networks that explains why the influence of genetic and environmental perturbation on phenotypes is typically not uniform, and may even be biased toward adaptive phenotypic variation. We show how bias produced by developmental processes constitutes an evolving property able to impose direction on adaptive evolution and influence patterns of taxonomic and phenotypic diversity. Taking these considerations together, we argue that it is not sufficient to accommodate developmental bias into evolutionary theory merely as a constraint on evolutionary adaptation. The influence of natural selection in shaping developmental bias, and conversely, the influence of developmental bias in shaping subsequent opportunities for adaptation, requires mechanistic models of development to be expanded and incorporated into evolutionary theory. A regulatory network perspective on phenotypic evolution thus helps to integrate the generation of phenotypic variation with natural selection, leaving evolutionary biology better placed to explain how organisms adapt and diversify.


Intervention classifications for nursing practice and the ICNP: cultural considerations for Korean nurses.
There are several intervention classifications for nursing practice. Yet, their relevancy and clarity for international use has not been evaluated. Thus, the paper presents a review of 4 major nursing intervention classifications (Saba's Home Health Care Classifications, Omaha's Intervention Scheme, Grobe's Nursing Intervention Lexicon & Taxonomy, and the International Classification for Nursing Practice) for Korean nursing practice. A simple comparison procedure utilized to determine the relevancy and clarity of each overall scheme and specific elements. The findings showed that general concepts for the top level of all the classifications were both relevant and clear. However, specific elements of lower levels became less clear and relevant because of the lack of definitions and cultural differences. In particular, interventions related to psycho-social and environmental components appeared to be either unclear or non-relevant for Korean nursing practice while interventions related to physiological components were found to be very relevant and clear. In conclusion, multiple levels of hierarchical intervention schemes and the absence of definitions impede clarity of intervention classifications. In addition, for international use, an intervention classification needs to be sensitive to cultural relevancy in its elements.


Multi-morbidity, disability and adaptation strategies among community-dwelling adults aged 75 years and older.
The impact of multi-morbidity and disability on the use of adaptation strategies in older adults has not been well researched. This study investigated categories of adaptation strategies that community-dwelling older adults use to complete their daily activities, identified factors that are associated with the use of behavioral adaptations, and examined the relationship among multi-morbidity, disability and adaptation strategies in this population. A mixed methods research design was used. 105 community-dwelling older adults with ages ranging from 75 to 94 years completed a questionnaire and semi-structured interview on types of chronic illnesses (multi-morbidity), amount of difficulty in completing daily activities (degree of disability), and types of behavioral efforts made to complete daily activities that are challenging (adaptation strategies). The model of selective optimization with compensation (SOC) was used to categorize these strategies. The findings revealed that older adults use a wide range of adaptations with compensation and selection the most (40.4%) and least (16.5%) frequently reported respectively. Degree of disability was uniquely associated with the frequency of using SOC strategies while controlling for other factors. Furthermore, degree of disability was a mediator for multi-morbidity in predicting frequency of using SOC strategies. The findings support that older adults using behavioral adaptations to cope with functional decline is prevalent. Knowing the types of adaptation that older adults employed and the indirect relationship between multi-morbidity and frequency of using SOC strategies, with degree of disability as the mediator will be helpful in planning interventions and prevention programs for educating older adults.


Increased Expression of Several Collagen Genes is Associated with Drug Resistance in Ovarian Cancer Cell Lines.
Ovarian cancer is the most lethal gynaecological cancer. The main reason for the high mortality among ovarian cancer patients is the development of drug resistance. The expression of collagen genes by cancer cells can increase drug resistance by inhibiting the penetration of the drug into the cancer tissue as well as increase apoptosis resistance. In this study, we present data that shows differential expression levels of collagen genes and proteins in cisplatin- (CIS), paclitaxel- (PAC), doxorubicin- (DOX), topotecan- (TOP), vincristine- (VIN) and methotrexate- (MTX) resistant ovarian cancer cell lines. Quantitative real-time polymerase chain reactions were performed to determine the mRNA levels. Protein expression was detected using Western blot and immunocytochemistry assays. In the drug resistant cell lines, we observed the upregulation of eight collagen genes at the mRNA level and based on these expression levels, we divided the collagen genes into the following three groups: 1. Genes with less than a 50-fold increase in expression: COL1A1, COL5A2, COL12A1 and COL17A1. 2. Genes with greater than a 50-fold increase in expression: COL1A2, COL15A1 and COL21A1. 3. Gene with a very high level of expression: COL3A1. Expression of collagen (COL) proteins from groups 2 and 3 were also confirmed using immunocytochemistry. Western blot analysis showed very high expression levels of COL3A1 protein, and immunocytochemistry analysis showed the presence of extracellular COL3A1 in the W1TR cell line. The cells mainly responsible for the extracellular COL3A1 production are aldehyde dehydrogenase-1A1 (ALDH1A1) positive cells. All correlations between the types of cytostatic drugs and the expression levels of different COL genes were studied, and our results suggest that the expression of fibrillar collagens may be involved in the TOP and PAC resistance of the ovarian cancer cells. The expression pattern of COL genes provide a preliminary view into the role of these proteins in cytostatic drug resistance of cancer cells. The exact role of these COL genes in drug resistance requires further investigation.


Delivery of lethal dsRNAs in insect diets by branched amphiphilic peptide capsules.
Development of new and specific insect pest management methods is critical for overcoming pesticide resistance and collateral off-target killings. Gene silencing by feeding dsRNA to insects shows promise in this area. Here we described the use of a peptide nano-material, branched amphiphilic peptide capsules (BAPCs), that facilitates cellular uptake of dsRNA by insects through feeding. The insect diets included dsRNA with and without complexation with BAPCs. The selected insect species come from two different orders with different feeding mechanisms: Tribolium castaneum and Acyrthosiphon pisum. The gene transcripts tested (BiP and Armet) are part of the unfolded protein response (UPR) and suppressing their translation resulted in lethality. For Acyrthosiphon pisum, ingestion of BiP-dsRNA associated with BAPCs led to the premature death of the aphids (t1/2=4-5days) compared to ingestion of the same amounts of free BiP-dsRNA (t1/2=11-12days). Tribolium castaneum was effectively killed using a combination of BiP-dsRNA and Armet-dsRNA complexed with BAPCs; most dying as larvae or during eclosion (~75%). Feeding dsRNA alone resulted in fewer deaths (~30%). The results show that complexation of dsRNA with BAPCs enhanced the oral delivery of dsRNA over dsRNA alone.


Genetic polymorphism of platelet glycoprotein Ib.
Platelet glycoprotein (GP) Ib from 131 healthy Japanese was analyzed using SDS-polyacrylamide gel electrophoresis and specific staining with peroxidase-coupled wheat germ agglutinin after it was transferred to nitrocellulose membranes. Four slightly different species of GPIb were observed and designated as A, B, C, and D for glycoproteins with molecular weights of 168,000, 162,000, 159,000, and 153,000 daltons, respectively. The respective gene frequencies were calculated to be .073, .011, .561, and .355 for A-, B-, C-, D-type GPIb. Portions from each type of GPIb molecule (alpha-chain and glycocalicin) showed heterogeneity with the same molecular weight difference, indicating that the variance would be derived from the polypeptide portion that is exposed to the outer medium. The different types of GPIb were the same with respect to their accessibility to lactoperoxidase, reactivity to lectins, and affinity to TLCK-thrombin. Although Bolin et al reported patients with a bleeding tendency whose platelets have double GPIb bands, here we found that platelets with different GPIb phenotypes showed no significant differences in aggregating activity and platelet retention. Analysis of GPIb phenotype should be important for structural and physiologic studies on GPIb and glycocalicin.


A new dinuclear ruthenium complex as an efficient water oxidation catalyst.
A dinuclear ruthenium complex, which acts as a molecular catalyst for water oxidation, has been synthesized and characterized. The electronic and electrochemical properties were studied by UV-vis spectroscopy and cyclic voltammetry. The oxidation potentials of the complex are significantly lowered by introducing a negatively charged carboxylate ligand, in comparison with those of the reported complexes that have neutral ligands. The catalytic activity of the complex toward water oxidation using Ce(NH(4))(2)(NO(3))(6) as a chemical oxidant was investigated by means of an oxygen electrode and mass spectrometry. The turnover number of this catalyst with Ce(IV) as the chemical oxidant was found to be ca. 1700. The mass spectroscopic analysis of the isotopomer distribution in oxygen evolved from (18)O-labeled water indicates that O atoms in the evolved oxygen originate from water.


Control of Meloidogyne javanica by Formulations of Inula viscosa Leaf Extracts.
Inula viscosa is a perennial plant that is widely distributed in Mediterranean countries. Formulations of I. viscosa extracts were tested for their effectiveness in control of Meloidogyne javanica in laboratory, growth chamber, microplot, and field experiments. Oily pastes were obtained by extraction of dry leaves with a mixture of acetone and n-hexane or n-hexane alone, followed by evaporation of the solvents. Emulsifiable concentrate formulations of the pastes killed M. javanica juveniles in sand at a concentration of 0.01% (paste, w/w) or greater and reduced the galling index of cucumber seedlings as well as the galling index and numbers of nematode eggs on tomato plants in growth chamber experiments. In microplot experiments, the hexane-extract formulation at 26 g paste/m(2) reduced nematode infection on tomato plants in one of two experiments. In a field experiment, a reduction of 40% in root galling index by one of two formulations was observed on lettuce plants. The plant extracts have potential as a natural nematicide, although the formulations need improvement.


Predictors, demographics and frequency of sustained remission and low disease activity in anti-tumour necrosis factor-treated rheumatoid arthritis patients.
To investigate the frequency and predictors of sustained 28-joint DAS (DAS28) remission and low disease activity (LDA) in patients receiving anti-TNF therapy and changes in responses over a 12 year period. Data from the British Society for Rheumatology Biologics Registry for Rheumatoid Arthritis were used. Sustained remission and LDA were defined according to DAS28-ESR thresholds sustained for 6 months. The dataset was dichotomized into sequential chronological subgroups (2001-2010 and 2010-2013). Predictive variables were identified from a previous systematic review and modelled using multivariable logistic regression. Overall, 2144 (14.9%) and 3802 (26.3%) patients achieved sustained remission or LDA, respectively. Positive predictors of sustained remission/LDA included adalimumab (vs etanercept), greater patient global assessment, never- and ex-smoker status (vs current smoking), greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription (except in the 2010-2013 subgroup). Negative predictors of sustained remission and LDA included poor baseline functional status (HAQ), female gender, older age at starting anti-TNF, infliximab use (vs etanercept), increasing BMI and greater baseline ESR. Increasing tender joint count was negatively associated with sustained LDA only. The overall proportion of patients achieving sustained remission and LDA has increased significantly over time. Sustained remission/LDA on anti-TNF treatment remains uncommon. Adalimumab use, greater patient global assessment, never- and ex-smoker status, greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription are associated with achievement of sustained remission/LDA. However, co-prescription of MTX was not associated with an increased likelihood of achieving sustained remission or LDA in the analysis of more recent anti-TNF responses.


Precision medicine for long-term depression outcomes using the Personalized Advantage Index approach: cognitive therapy or interpersonal psychotherapy?
Psychotherapies for depression are equally effective on average, but individual responses vary widely. Outcomes can be improved by optimizing treatment selection using multivariate prediction models. A promising approach is the Personalized Advantage Index (PAI) that predicts the optimal treatment for a given individual and the magnitude of the advantage. The current study aimed to extend the PAI to long-term depression outcomes after acute-phase psychotherapy. Data come from a randomized trial comparing cognitive therapy (CT, n = 76) and interpersonal psychotherapy (IPT, n = 75) for major depressive disorder (MDD). Primary outcome was depression severity, as assessed by the BDI-II, during 17-month follow-up. First, predictors and moderators were selected from 38 pre-treatment variables using a two-step machine learning approach. Second, predictors and moderators were combined into a final model, from which PAI predictions were computed with cross-validation. Long-term PAI predictions were then compared to actual follow-up outcomes and post-treatment PAI predictions. One predictor (parental alcohol abuse) and two moderators (recent life events; childhood maltreatment) were identified. Individuals assigned to their PAI-indicated treatment had lower follow-up depression severity compared to those assigned to their PAI-non-indicated treatment. This difference was significant in two subsets of the overall sample: those whose PAI score was in the upper 60%, and those whose PAI indicated CT, irrespective of magnitude. Long-term predictions did not overlap substantially with predictions for acute benefit. If replicated, long-term PAI predictions could enhance precision medicine by selecting the optimal treatment for a given depressed individual over the long term.


Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells.
Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers.


Label free process monitoring of 3D bioprinted engineered constructs via dielectric impedance spectroscopy.
Biofabrication processes can affect biological quality attributes of encapsulated cells within constructs. Currently, assessment of the fabricated constructs is performed offline by subjecting the constructs to destructive assays that require staining and sectioning. This drawback limits the translation of biofabrication processes to industrial practice. In this work, we investigate the dielectric response of viable cells encapsulated in bioprinted 3D hydrogel constructs to an applied alternating electric field as a label-free non-destructive monitoring approach. The relationship between β-dispersion parameters (permittivity change-Δε, Cole-Cole slope factor-α, critical polarization frequency-f c ) over the frequency spectrum and critical cellular quality attributes are investigated. Results show that alginate constructs containing a higher number of viable cells (human adipose derived stem cells-hASC and osteosarcoma cell line-MG63) were characterized by significantly higher Δε and α (both p < 0.05). When extended to bioprinting, results showed that changes in hASC proliferation and viability in response to changes in critical bioprinting parameters (extrusion pressure, temperature, processing time) significantly affected ∆ε, α, and f c . We also demonstrated monitoring of hASC distribution after bioprinting and changes in proliferation over time across the cross-section of a bioprinted medial knee meniscus construct. The trends in ∆ε over time were in agreement with the alamarBlue assay results for the whole construct, but this measurement approach provided a localized readout on the status of encapsulated cells. The findings of this study support the use of dielectric impedance spectroscopy as a label-free and non-destructive method to characterize the critical quality attributes of bioprinted constructs.


Adversarial Confidence Learning for Medical Image Segmentation and Synthesis.
Generative adversarial networks (GAN) are widely used in medical image analysis tasks, such as medical image segmentation and synthesis. In these works, adversarial learning is directly applied to the original supervised segmentation (synthesis) networks. The usage of adversarial learning is effective in improving visual perception performance since adversarial learning works as realistic regularization for supervised generators. However, the quantitative performance often cannot improve as much as the qualitative performance, and it can even become worse in some cases. In this paper, we explore how we can take better advantage of adversarial learning in supervised segmentation (synthesis) models and propose an adversarial confidence learning framework to better model these problems. We analyze the roles of discriminator in the classic GANs and compare them with those in supervised adversarial systems. Based on this analysis, we propose adversarial confidence learning, i.e., besides the adversarial learning for emphasizing visual perception, we use the confidence information provided by the adversarial network to enhance the design of supervised segmentation (synthesis) network. In particular, we propose using a fully convolutional adversarial network for confidence learning to provide voxel-wise and region-wise confidence information for the segmentation (synthesis) network. With these settings, we propose a difficulty-aware attention mechanism to properly handle hard samples or regions by taking structural information into consideration so that we can better deal with the irregular distribution of medical data. Furthermore, we investigate the loss functions of various GANs and propose using the binary cross entropy loss to train the proposed adversarial system so that we can retain the unlimited modeling capacity of the discriminator. Experimental results on clinical and challenge datasets show that our proposed network can achieve state-of-the-art segmentation (synthesis) accuracy. Further analysis also indicates that adversarial confidence learning can both improve the visual perception performance and the quantitative performance.