Natural history of uncomplicated urinary tract infection without antibiotics: a systematic review.
Although uncomplicated urinary tract infection (UTI) is commonly treated with antibiotics, the duration of symptoms without their use is not established; this hampers informed decision making about antibiotic use. To determine the natural history of uncomplicated UTI in adults. Systematic review. PubMed was searched for articles published until November 2019, along with reference lists of articles identified in the search. Eligible studies were those involving adults with UTIs in either the placebo group of randomised trials or in single-group prognostic studies that did not use antibiotics and measured symptom duration. A modified version of a risk of bias assessment for prognostic studies was used. Outcomes were the percentage of patients who, at any time point, were symptom free, had symptom improvement, or had worsening symptoms (failed to improve). Adverse event data were also extracted. Three randomised trials (346 placebo group participants) were identified, all of which specified women only in their inclusion criteria. The risk of bias was generally low, but incomplete reporting of some details limited assessment. Over the first 9 days, the percentage of participants who were symptom free or reported improved symptoms was reported as rising to 42%. At 6 weeks, the percentage of such participants was 36%; up to 39% of participants failed to improve by 6 weeks. The rate of adverse effects was low and, in two trials, progression to pyelonephritis was reported in one placebo participant. Although some uncertainty around the natural history of uncomplicated UTIs remains, some women appear to improve or become symptom free spontaneously, and most improvement occurs in the first 9 days. Other women either failed to improve or became worse over a variable timespan, although the rate of serious complications was low.


Cyberknife radiotherapy for vestibular schwannoma.
Stereotactic radiosurgery is a well-established treatment modality for vestibular schwannoma. Initial reports using single-stage radiosurgery have demonstrated excellent tumor control rates. Many patients now elect to undergo radiosurgery given the potential for tumor control while avoiding the morbidity associated with microsurgical resection. In attempt to improve hearing preservation rates of single-state radiosurgery, staged frame-based radiotherapy using a 12-hour interfraction interval was used at the authors' institution and has shown a hearing preservation rate of 77% at 2 years of follow-up. With the arrival of the Cyberknife, a frameless, image-guided radiotherapy system, staged stereotactic radiotherapy for vestibular schwannoma became more practical. This article outlines the rationale and treatment protocols developed at Stanford University (California) and reports the authors' initial experience using the Cyberknife to treat vestibular schwannoma.


NUAK2: an emerging acral melanoma oncogene.
Recent technological advances in cancer genomics make it possible to dissect complicated genomic aberrations of melanomas. In particular, several specific genomic aberrations including 11q13 amplification and KIT aberrations have been identified in acral melanomas. We recently identified NUAK2 at 1q32 as a promising oncogene in acral melanomas and reported its significant roles in tumorigenesis in melanoma cells using both in vitro and in vivo analyses. NUAK2 as a member of the AMPK family has several intriguing aspects both as an oncogene and as a tumor suppressor gene. Here we review genomic aberrations of melanomas focusing on acral melanomas to emphasize the possible roles of NUAK2 in tumorigenesis in general and suggest that NUAK2 has pivotal roles in acral melanomagenesis.


Mutational analysis of the Drosophila tolloid gene, a human BMP-1 homolog.
Seven zygotically active genes have been identified in Drosophila that determine the fate of dorsal cells in the developing embryo. decapentaplegic (dpp), a member of the transforming growth factor-beta (TGF-beta) family, appears to play the central role in dorsal ectoderm formation, as mutations in this gene confer the most severe mutant phenotype of this group of genes. dpp's activity is modulated by tolloid, which also has a role in the determination of dorsal cell fate. tolloid encodes a protein that contains a metalloprotease domain and regulatory domains consisting of two EGF motifs and five C1r/s repeats. We have generated several mutant tolloid alleles and have examined their interaction with a graded set of dpp point alleles. Some tolloid alleles act as dominant enhancers of dpp in a trans heterozygote, and are therefore antimorphic alleles. However, a tolloid deficiency shows no such genetic interaction. To characterize the nature of the tolloid mutations, we have sequenced eighteen tolloid alleles. We find that five of the seven alleles that act as dominant enhancers of dpp are missense mutations in the protease domain. We also find that most tolloid alleles that do not interact with dpp are missense mutations in the C-terminal EGF and C1r/s repeats, or encode truncated proteins that delete these repeats. Based on these data, we propose a model in which the tolloid protein functions by forming a complex containing DPP via protein-interacting EGF and C1r/s domains, and that the protease activity of TOLLOID is necessary, either directly or indirectly, for the activation of the DPP complex.(ABSTRACT TRUNCATED AT 250 WORDS)


Childhood family income, adolescent violent criminality and substance misuse: quasi-experimental total population study.
Low socioeconomic status in childhood is a well-known predictor of subsequent criminal and substance misuse behaviours but the causal mechanisms are questioned. Aims To investigate whether childhood family income predicts subsequent violent criminality and substance misuse and whether the associations are in turn explained by unobserved familial risk factors. Nationwide Swedish quasi-experimental, family-based study following cohorts born 1989-1993 (n(total) = 526 167, n(cousins) = 262 267, n(siblings) = 216 424) between the ages of 15 and 21 years. Children of parents in the lowest income quintile experienced a seven-fold increased hazard rate (HR) of being convicted of violent criminality compared with peers in the highest quintile (HR = 6.78, 95% CI 6.23-7.38). This association was entirely accounted for by unobserved familial risk factors (HR = 0.95, 95% CI 0.44-2.03). Similar pattern of effects was found for substance misuse. There were no associations between childhood family income and subsequent violent criminality and substance misuse once we had adjusted for unobserved familial risk factors.


Leptin potentiates the anti-obesity effects of rimonabant.
We hypothesized that a combination of low doses of rimonabant and leptin would markedly reduce body weight through the modulation of neuronal activity within the hypothalamus. To this end, high fat diet-induced obese rats were randomized to receive either leptin (0.5mg/kg subcutaneously), rimonabant (3mg/kg), the combination of both, or vehicle, daily for a duration of 2 weeks. A subset of rats was pair-fed to the combination-treated animals and received either vehicle or leptin. At the end of the weight loss phase, leptin treatment was maintained for 7 days while rimonabant was discontinued to assess changes in body weight during the rebound phase. The combination of rimonabant and leptin resulted in a marked inhibition of food intake and a profound reduction in body weight that was greater than achieved with either leptin or rimonabant alone. Treatment with leptin during the rebound phase inhibited compensatory increases in body weight associated with restitution of ad libitum feeding in previously pair-fed rats. Moreover, leptin partially blunted the rebound in food intake and body weight associated with cessation of rimonabant therapy.To investigate the effect of the combination on neuronal firing in the rat hypothalamus, single unit activity was recorded from brain slices containing the ventromedial and arcuate nuclei. The combination of rimonabant and leptin synergistically increased and decreased neuronal firing in the ventromedial and arcuate nuclei, respectively. Overall, these data demonstrate profound anti-obesity effects of combining cannabinoid type 1 receptor antagonists and leptin.


Foliar temperature-respiration response functions for broad-leaved tree species in the southern Appalachians.
We measured leaf respiration in 18 eastern deciduous forest tree species to determine if there were differences in temperature-respiration response functions among species or among canopy positions. Leaf respiration rates were measured in situ and on detached branches for Acer pensylvanicum L., A. rubrum L., Betula spp. (B. alleghaniensis Britt. and B. lenta L.), Carya glabra (Mill.) Sweet, Cornus florida L., Fraxinus spp. (primarily F. americana L.), Liriodendron tulipifera L., Magnolia fraseri Walt., Nyssa sylvatica Marsh., Oxydendrum arboreum L., Platanus occidentalis L., Quercus alba L., Q. coccinea Muenchh., Q. prinus L., Q. rubra L., Rhododendron maximum L., Robinia psuedoacacia L., and Tilia americana L. in the southern Appalachian Mountains, USA. Dark respiration was measured on fully expanded leaves at 10, 15, 20, 25, and 30 degrees C with an infrared gas analyzer equipped with a temperature-controlled cuvette. Temperature-respiration response functions were fit for each leaf. There were significant differences in response functions among species and by canopy position within species. These differences were observed when respiration was expressed on a mass, nitrogen, or area basis. Cumulative nighttime leaf respiration was calculated and averaged over ten randomly selected nights for each leaf. Differences in mean cumulative nighttime respiration were statistically significant among canopy positions and species. We conclude that effects of canopy position and species on temperature-respiration response functions may need to be considered when making estimates of whole-tree or canopy respiration.


H beta 58, an insertional mutation affecting early postimplantation development of the mouse embryo.
The generation and analysis of insertional mutations affecting mouse embryogenesis provides a powerful method to identify new genes that function in early development. In this paper, we describe an insertional mutation that interferes with postimplantation mouse development beginning at the time of gastrulation. Embryos homozygous for the H beta 58 transgenic insertion developed normally through the early postimplantation, egg cylinder stage (day 6.5 of development). At the primitive streak stage (day 7.5), however, they began to display characteristic abnormalities, including a retardation in the growth of the embryonic ectoderm (the earliest identifiable defect), and in some cases abnormalities of the amnion and chorion. Homozygotes continued to develop for 2-3 more days, reaching the size of a normal 8.5 day embryo, and formed tissues representative of all three germ layers, including several differentiated cell types. The site of insertion was mapped, by a combination of cytogenetic and genetic methods, to chromosome 10, and it appeared to define a new genetic locus. The inserted transgene provided a probe to clone and characterize the mutant locus, as well as the corresponding wild-type locus. In addition to an insertion of 10-20 copies of the transgene, the mutant locus contained a deletion of 2-3 kb of DNA found at the wild-type locus, and possibly an insertion of mouse repetitive DNA. However, genomic sequences on both sides of the insertion site remained co-linear in the wild-type and mutant genomes, and no chromosomal abnormalities could be detected. Five single copy DNA probes spanning the insertion site were tested for their ability to hybridize to RNA from 8.5 day embryos; one of the probes (located within the region deleted from the mutant chromosome) hybridized to a 2.7 kb mRNA encoded at the H beta 58 locus, thus identifying a gene whose disruption appears to be responsible for the mutant phenotype.


Fine mapping and molecular cloning of mutations in the herpes simplex virus DNA polymerase locus.
Mutations in five phenotypically distinct mutants derived from herpes simplex virus type 1 strain KOS which lie in or near the herpes simplex virus DNA polymerase (pol) locus have been fine mapped with the aid of cloned fragments of mutant and wild-type viral DNAs to distinct restriction fragments of 1.1 kilobase pairs (kbp) or less. DNA sequences containing a mutation or mutations conferring resistance to the antiviral drugs phosphonoacetic acid, acyclovir, and arabinosyladenine of pol mutant PAAr5 have been cloned as a 27-kbp Bg+II fragment in Escherichia coli. These drug resistance markers have been mapped more finely in marker transfer experiments to a 1.1-kbp fragment (coordinates 0.427 to 0.434). In intratypic marker rescue experiments, temperature-sensitive (ts), phosphonoacetic acid resistance, and acyclovir resistance markers of pol mutant tsD9 were mapped to a 0.8-kbp fragment at the left end of the EcoRI M fragment (coordinates 0.422 to 0.427). The ts mutation of pol mutant tsC4 maps within a 0.3-kbp sequence (coordinates 0.420 to 0.422), whereas that of tsC7 lies within the 1.1-kbp fragment immediately to the left (coordinates 0.413 to 0.420). tsC4 displays the novel phenotype of hypersensitivity to phosphonoacetic acid; however, the phosphonoacetic acid hypersensitivity phenotype is almost certainly not due to the mutation(s) conferring temperature sensitivity. The ts mutation of mutant tsN20--which does not affect DNA polymerase activity--maps to a 0.5-kbp fragment at the right-hand end of the EcoRI M fragment (coordinates 0.445 to 0.448). The mapping of the mutations in these five mutants further defines the limits of the pol locus and separates mutations differentially affecting catalytic functions of the polymerase.


EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.
Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.


Can the TLR-4-mediated signaling pathway be "a key inflammatory promoter for sporadic TAA"?
Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA (OR = 14.4, P = 0.0008) and it represents, together with rs1799752 ACE, rs3918242 MMP-9, and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA. Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing. Thus, TLR4 pathway should seem to have a key role in sporadic TAA. It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.


Foot strike patterns and collision forces in habitually barefoot versus shod runners.
Humans have engaged in endurance running for millions of years, but the modern running shoe was not invented until the 1970s. For most of human evolutionary history, runners were either barefoot or wore minimal footwear such as sandals or moccasins with smaller heels and little cushioning relative to modern running shoes. We wondered how runners coped with the impact caused by the foot colliding with the ground before the invention of the modern shoe. Here we show that habitually barefoot endurance runners often land on the fore-foot (fore-foot strike) before bringing down the heel, but they sometimes land with a flat foot (mid-foot strike) or, less often, on the heel (rear-foot strike). In contrast, habitually shod runners mostly rear-foot strike, facilitated by the elevated and cushioned heel of the modern running shoe. Kinematic and kinetic analyses show that even on hard surfaces, barefoot runners who fore-foot strike generate smaller collision forces than shod rear-foot strikers. This difference results primarily from a more plantarflexed foot at landing and more ankle compliance during impact, decreasing the effective mass of the body that collides with the ground. Fore-foot- and mid-foot-strike gaits were probably more common when humans ran barefoot or in minimal shoes, and may protect the feet and lower limbs from some of the impact-related injuries now experienced by a high percentage of runners.


Structural changes of Bombyx mori fibroin from silk gland to fiber as evidenced by Terahertz spectroscopy and other methods.
Here we investigated the structural changes of silk fibroin during Bombyx mori silkworm spinning and reconstitution process. X-ray diffraction, Fourier transform infrared spectroscopy, polarized optical microscopy, and terahertz (THz) spectroscopy were applied to monitor the structural features of silk fibroin from posterior, middle silk glands, to cocoons, and then to reconstituted silk. Results show that from silk gland to cocoon, fibroin experiences a significant transformation in crystal structure from a typical silk I, to a silk I-rich mixed structure, and finally to a typical silk II state, accompanied with a change in secondary structure from α-helix and random coil structures to preferential orientation β-sheets. Compared with natural silk fibroins, the reconstituted silk fibroin lacks β-sheet conformation and orientation crystallization. Terahertz spectroscopy readily follows these silk fibroin structural changes. Two characteristic peaks for silk fibroin is observed in 2-10 THz. Their strength ratio is strongly correlated with the β-sheet conformation. The absorbance properties in 0.2-2.0THz also significantly change as a function of changing their crystal structures caused by diverse sources. All of these observations will help in the study of overall structure in silk fibroin to understand more completely the fibroin assembly process in natural spinning and reconstitution process.


Immigrant generation and physical activity among Mexican, Chinese & Filipino adults in the U.S.
Migrant studies of physical activity (PA) can provide insight into the prevention of chronic disease. It is unclear, however, whether PA increases or decreases the longer migrants live in their host country. In the US, studies on immigrants' length of residence in the US and PA are inconclusive and many studies do not adequately consider the role of socioeconomic status (SES). Using California data, we examine relationships between immigrant generation and physical activity (PA) among Mexican, Chinese and Filipino adults, who represent the three largest immigrant groups in the US, and the extent to which the relationships are confounded by SES. Data from the 2000 US Census was linked with data on adults 18 years and older from the 2005 California Health Interview Survey. PA was measured in three different domains: leisure time (LTPA), non-leisure time (NLTPA) and any PA. Logistic regression was used to examine whether a wide range of SES factors, measured at the respondent and neighborhood levels, influenced the relationship between immigrant generation and PA in all domains and in different ethnic origin groups. Generation was significantly associated with LTPA among Mexican and Chinese adults and with NLTPA among all 3 ethnic origin groups; however the nature of the relationships varied. After adjusting for individual and neighborhood SES factors, a positive association between generation and LTPA remained among Mexican adults, and negative association between generation and NLTPA remained among Chinese and Filipino adults. These results underscore the importance of comparative studies of immigrant generation and PA and consideration of SES factors to identify pathways linking generation to PA. In the context of increasing rates of chronic disease, the study of transitions in PA among immigrants will continue to be critical to promoting the public health of diverse populations in countries such as the US.


Sleep patterns of offshore day-workers in relation to overtime work and age.
In addition to long contractual hours during offshore weeks (14 × 12 h shifts), many personnel on North Sea oil/gas installations also work overtime, but little is known about the implications of overtime for sleep patterns offshore. In this study, the additive and interactive effects of overtime and age were analysed as predictors of sleep duration and sleep quality among offshore day-workers (N = 551), 54% of whom reported overtime. Sleep duration and quality were impaired among personnel who worked overtime, relative to those who worked only standard shifts; there was also an inverse dose-response relationship between overtime hours and sleep duration. Although the sleep measures were more favourable during shore leave than during offshore weeks, there was little evidence of compensatory sleep patterns. These findings are discussed with reference to known performance and health effects of short sleep hours; formal guidance on overtime work offshore is noted; and methodological issues are considered.


Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.
The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis. We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/- SD], 7.01 +/- 0.83 mmol per liter), markedly increased levels of HDL cholesterol (4.24 +/- 1.01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-density lipoprotein cholesterol (1.99 +/- 0.80 mmol per liter) and apolipoprotein B. Members heterozygous for the deficiency (n = 20), whose CETP levels were in the lower part of the normal range, had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3, as compared with unaffected family members (1.5 +/- 0.8 vs. 0.7 +/- 0.4). CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States. CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect. The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2. There was no evidence of premature atherosclerosis in the families with CETP deficiency. In fact, the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.


Cancer and metastasis: prevention and treatment by green tea.
Metastasis is the most deadly aspect of cancer and results from several interconnected processes including cell proliferation, angiogenesis, cell adhesion, migration, and invasion into the surrounding tissue. The appearance of metastases in organs distant from the primary tumor is the most destructive feature of cancer. Metastasis remains the principal cause of the deaths of cancer patients despite decades of research aimed at restricting tumor growth. Therefore, inhibition of metastasis is one of the most important issues in cancer research. Several in vitro, in vivo, and epidemiological studies have reported that the consumption of green tea may decrease cancer risk. (-)-Epigallocatechin-3-gallate, major component of green tea, has been shown to inhibit tumor invasion and angiogenesis which are essential for tumor growth and metastasis. This article summarizes the effect of green tea and its major polyphenolic compounds on cancer and metastasis against most commonly diagnosed cancer sites.


Development of sentinel node biopsy, ROLL and IART in early breast cancer at the European Institute of Oncology, Milan (IEO).
The problem of unnecessary axillary clearance in many patients with early breast cancer was certainly a major issue at IEO when we started working with Prof. Umberto Veronesi in 1994. At that time, axillary dissection in EBC was offered to all patients and this procedure was often hotly debated during our multidisciplinary breast cancer meetings. The question as to whether we could avoid axillary dissection by using PET scans or other nuclear medicine methods was frequently asked by Veronesi. This eventually prompted us to investigate whether, as for melanoma patients, the sentinel node biopsy (SNB) approach could reliably be applied to breast cancer. In December 1995, we proposed a new lymphoscintigraphy protocol to detect the SN in early breast cancer patients to our Ethic Committee, and it was approved. The pilot study was published in 1997 and after only 6 years, the first randomised trial comparing SNB and axillary clearance in breast cancer patients was published. During the pilot study, we optimised the lymphoscintigraphy technique by comparing different radiotracers and different injection modalities. Following the observation that the majority of the radiocolloids injected into the tumour did not migrate to lymph nodes, a new method called ROLL or Radio-guided Occult Lesion Localisation was developed for the localisation of non-palpable breast lesions. This technique was introduced into clinical practice at the European Institute of Oncology in 1996. Several studies showed that the ROLL procedure enabled the surgeon to remove non-palpable breast lesions easily and accurately, overcoming some disadvantages of other methods such as wire-guided localisation (WGL). In addition to SNB and ROLL, other protocols such as the IART (intraoperative avidination for radionuclide therapy)-ARTHE (avidinated radiotherapy) procedure were developed at the IEO Nuclear Medicine Division during the period 1994-2013. I remember that time as the most professionally productive of my career and it would not have been possible without the help, suggestions and encouragement given to me by Umberto Veronesi.


Contextualizing the use of oncologic imaging within treatment phases: imaging trends and modality preferences, 2000-2014.
In the present study, we retrospectively evaluated the use of tomographic imaging in adult cancer patients to clarify how recent growth plateaus in the use of tomographic imaging in the United States might have affected oncologic imaging during the same period. At a U.S. academic cancer centre, 12,059 patients with dates of death from January 2000 through December 2014 were identified. Imaging was restricted to brain and body computed tomography (ct), brain and body magnetic resonance (mr), and body positron-emission tomography (pet) with and without superimposed ct. Trends during the staging (1 year after diagnosis), monitoring (18-6 months before death), and end-of-life (final 6 months before death) phases were analyzed. Comparing the 2005-2009 with the 2010-2014 period, mean intensity of pet imaging increased 21% during staging (p = 0.0000) and 27% during end of life (p = 0.0019). In the monitoring phase, mean intensity for ct brain, ct body, and mr body imaging decreased by 26% (p = 0.0133), 11% (p = 0.0118), and 26% (p = 0.0008), respectively. Aggregate mean intensity of imaging increased in the 13%-27% range every 3 months from 18 months before death to death, reaching 1.43 images in the final 3 months of life. Patients diagnosed in the final 18 months of life had an average of 1 additional image during both the 3 months after diagnosis (p = 0.0000) and the final 3 months before death (p = 0.0000). Imaging increased as temporal proximity to death decreased, and patients diagnosed near death received more staging imaging, suggesting that imaging guidelines should consider imaging intensity within the context of treatment phase. Despite the development, by multiple organizations, of appropriateness criteria to reduce imaging utilization, aggregate per-patient imaging showed insignificant changes. Simultaneous fluctuations in the intensity of imaging by modality suggest recent changes in the modalities preferred by providers.


Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability.
Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next-generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.


State-Level Point-of-Sale Tobacco News Coverage and Policy Progression Over a 2-Year Period.
Mass media content may play an important role in policy change. However, the empirical relationship between media advocacy efforts and tobacco control policy success has rarely been studied. We examined the extent to which newspaper content characteristics (volume, slant, frame, source, use of evidence, and degree of localization) that have been identified as important in past descriptive studies were associated with policy progression over a 2-year period in the context of point-of-sale (POS) tobacco control. We used regression analyses to test the relationships between newspaper content and policy progression from 2012 to 2014. The dependent variable was the level of implementation of state-level POS tobacco control policies at Time 2. Independent variables were newspaper article characteristics (volume, slant, frame, source, use of evidence, and degree of localization) and were collected via content analysis of the articles. State-level policy environment contextual variables were examined as confounders. Positive, significant bivariate relationships exist between characteristics of news content (e.g., high overall volume, public health source present, local quote and local angle present, and pro-tobacco control slant present) and Time 2 POS score. However, in a multivariate model controlling for other factors, significant relationships did not hold. Newspaper coverage can be a marker of POS policy progression. Whether media can influence policy implementation remains an important question. Future work should continue to tease out and confirm the unique characteristics of media content that are most associated with subsequent policy progression, in order to inform media advocacy efforts.


Assessing the underwater acoustics of the world's largest vibration hammer (OCTA-KONG) and its potential effects on the Indo-Pacific humpbacked dolphin (Sousa chinensis).
Anthropogenic noise in aquatic environments is a worldwide concern due to its potential adverse effects on the environment and aquatic life. The Hongkong-Zhuhai-Macao Bridge is currently under construction in the Pearl River Estuary, a hot spot for the Indo-Pacific humpbacked dolphin (Sousa chinensis) in China. The OCTA-KONG, the world's largest vibration hammer, is being used during this construction project to drive or extract steel shell piles 22 m in diameter. This activity poses a substantial threat to marine mammals, and an environmental assessment is critically needed. The underwater acoustic properties of the OCTA-KONG were analyzed, and the potential impacts of the underwater acoustic energy on Sousa, including auditory masking and physiological impacts, were assessed. The fundamental frequency of the OCTA-KONG vibration ranged from 15 Hz to 16 Hz, and the noise increments were below 20 kHz, with a dominant frequency and energy below 10 kHz. The resulting sounds are most likely detectable by Sousa over distances of up to 3.5 km from the source. Although Sousa clicks do not appear to be adversely affected, Sousa whistles are susceptible to auditory masking, which may negatively impact this species' social life. Therefore, a safety zone with a radius of 500 m is proposed. Although the zero-to-peak source level (SL) of the OCTA-KONG was lower than the physiological damage level, the maximum root-mean-square SL exceeded the cetacean safety exposure level on several occasions. Moreover, the majority of the unweighted cumulative source sound exposure levels (SSELs) and the cetacean auditory weighted cumulative SSELs exceeded the acoustic threshold levels for the onset of temporary threshold shift, a type of potentially recoverable auditory damage resulting from prolonged sound exposure. These findings may aid in the identification and design of appropriate mitigation methods, such as the use of air bubble curtains, "soft start" and "power down" techniques.


Skeletal muscle metabolism in heart failure: a 31P nuclear magnetic resonance spectroscopy study of leg muscle.
1. The gastrocnemius muscle of seven patients with mild to moderate chronic heart failure and of five healthy control subjects was studied using 31P nuclear magnetic resonance spectroscopy. Spectra were collected at rest and during an incremental, symptom-limited, exercise protocol. Blood flow was measured in the same study during brief interruptions to exercise. 2. The phosphocreatine/(phosphocreatine plus inorganic phosphate) ratio was lower in patients with heart failure than in control subjects at an exercise rate of 1.5 W, although intracellular pH and blood flow were similar. 3. The cytosolic free adenosine 5'-diphosphate concentration was markedly increased in patients with heart failure exercising at 1.5 W compared with control subjects exercising at the same workload. 4. Although the maximum workload achieved by patients with heart failure was less than half of that reached by control subjects, the pH and the phosphocreatine/(phosphocreatine plus inorganic phosphate) ratio were lower in patients with heart failure at maximal load. Blood flow was less at maximal exercise in patients with heart failure than in control subjects in keeping with the reduced work load. 5. The phosphocreatine depletion induced in the gastrocnemius muscle by exercise was more severe than previously described in the forearm of patients with heart failure. 6. Metabolic abnormalities in skeletal muscle may contribute to exercise intolerance in heart failure, particularly during submaximal exercise.


Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3.
The pregnane X receptor is a ligand-activated transcription factor that is abundantly expressed in hepatocytes. Numerous drugs are pregnane X receptor ligands. To bind to their receptor they must cross the sinusoidal membrane. Organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are polyspecific transporters expressed at the sinusoidal membrane of human hepatocytes. They mediate transport of a variety of drugs including the pregnane X receptor ligands rifampicin and dexamethasone. To test whether additional pregnane X receptor ligands interact with OATP1B1- and 1B3-mediated transport, we developed Chinese Hamster Ovary (CHO) cell lines stably expressing OATP1B1 or 1B3 at high levels. OATP1B1- and 1B3-mediated estradiol-17beta-glucuronide uptake was inhibited by several pregnane X receptor ligands in a concentration dependent way. IC(50) values for rifampicin, paclitaxel, mifepristone, and troglitazone were within their respective pharmacological free plasma concentrations. Kinetic analysis revealed that clotrimazole inhibits OATP1B1-mediated estradiol-17beta-glucuronide transport with a K(i) of 7.7+/-0.3 microM in a competitive way. However, uptake of OATP1B3-mediated estradiol-17beta-glucuronide was stimulated and this stimulation was due to an increased apparent affinity. Transport of estrone-3-sulfate was hardly affected while all other substrates tested were inhibited. Additional azoles like fluconazole, ketoconazole and miconazole did not stimulate OATP1B3-mediated estradiol-17beta-glucuronide transport. In summary, these results demonstrate that pregnane X receptor ligands, by inhibiting or stimulating OATP-mediated uptake, can lead to drug-drug interactions at the transporter level.


The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors.
Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)- dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy.


Electronic Surveillance System for the Early Notification of Community-Based Epidemics (ESSENCE): Overview, Components, and Public Health Applications.
The Electronic Surveillance System for the Early Notification of Community-Based Epidemics (ESSENCE) is a secure web-based tool that enables health care practitioners to monitor health indicators of public health importance for the detection and tracking of disease outbreaks, consequences of severe weather, and other events of concern. The ESSENCE concept began in an internally funded project at the Johns Hopkins University Applied Physics Laboratory, advanced with funding from the State of Maryland, and broadened in 1999 as a collaboration with the Walter Reed Army Institute for Research. Versions of the system have been further developed by Johns Hopkins University Applied Physics Laboratory in multiple military and civilian programs for the timely detection and tracking of health threats. This study aims to describe the components and development of a biosurveillance system increasingly coordinating all-hazards health surveillance and infectious disease monitoring among large and small health departments, to list the key features and lessons learned in the growth of this system, and to describe the range of initiatives and accomplishments of local epidemiologists using it. The features of ESSENCE include spatial and temporal statistical alerting, custom querying, user-defined alert notifications, geographical mapping, remote data capture, and event communications. To expedite visualization, configurable and interactive modes of data stratification and filtering, graphical and tabular customization, user preference management, and sharing features allow users to query data and view geographic representations, time series and data details pages, and reports. These features allow ESSENCE users to gather and organize the resulting wealth of information into a coherent view of population health status and communicate findings among users. The resulting broad utility, applicability, and adaptability of this system led to the adoption of ESSENCE by the Centers for Disease Control and Prevention, numerous state and local health departments, and the Department of Defense, both nationally and globally. The open-source version of Suite for Automated Global Electronic bioSurveillance is available for global, resource-limited settings. Resourceful users of the US National Syndromic Surveillance Program ESSENCE have applied it to the surveillance of infectious diseases, severe weather and natural disaster events, mass gatherings, chronic diseases and mental health, and injury and substance abuse. With emerging high-consequence communicable diseases and other health conditions, the continued user requirement-driven enhancements of ESSENCE demonstrate an adaptable disease surveillance capability focused on the everyday needs of public health. The challenge of a live system for widely distributed users with multiple different data sources and high throughput requirements has driven a novel, evolving architecture design.


Treatment rationale for dogs poisoned with aldicarb (carbamate pesticide).
The treatment rationale for dogs poisoned by aldicarb is reviewed from a pharmacological perspective. The illegal use of aldicarb to maliciously poison dogs is a major problem in some parts of the world. In South Africa, it is probably the most common canine poisoning treated by companion animal veterinarians. Aldicarb poisoning is an emergency and veterinarians need to be able to diagnose it and start with effective treatment immediately to ensure a reasonable prognosis. Successful treatment depends on the timely use of an anti-muscarinic drug (e.g. atropine). Additional supportive treatment options, including fluid therapy, diphenhydramine, benzodiazepines and the prevention of further absorption (activated charcoal) should also be considered. Possible complications after treatment are also briefly discussed.


Robotically assisted prostate brachytherapy with transrectal ultrasound guidance--Phantom experiments.
To report the preliminary experimental results obtained with a robot-assisted transrectal ultrasound (TRUS)-guided prostate brachytherapy system. The system consists of a TRUS unit, a spatially coregistered needle insertion robot, and an FDA-approved treatment planning and image-registered implant system. The robot receives each entry/target coordinate pair of the implant plan, inserts a preloaded needle, and then the seeds are deposited. The needles/sources are tracked in TRUS, thus allowing the plan to be updated as the procedure progresses. The first insertion attempt was recorded for each needle, without adjustment. All clinically relevant locations were reached in a prostate phantom. Nonparallel and parallel needle trajectories were demonstrated. Based on TRUS, the average transverse placement error was 2 mm (worst case 2.5 mm, 80% less than 2 mm), and the average sagittal error was 2.5 mm (worst case 5.0 mm, 70% less than 2.5 mm). The concept and technical viability of robot-assisted brachytherapy were demonstrated in phantoms. The kinematically decoupled robotic assistant device is inherently safe. Overall performance was promising, but further optimization is necessary to prove the possibility of improved dosimetry.


High tibial osteotomy: closed wedge versus combined wedge osteotomy.
High tibial osteotomy is a common procedure to treat symptomatic osteoarthritis of the medial compartment of the knee with varus alignment. This is achieved by overcorrecting the varus alignment to 2-6° of valgus. Various high tibial osteotomy techniques are currently used to this end. Common procedures are medial opening wedge and lateral closing wedge tibial osteotomies. The lateral closing wedge technique is a primary stable correction with a high rate of consolidation, but has the disadvantage of bone loss and change in tibial condylar offset. The medial opening wedge technique does not result in any bone loss but needs to be fixated with a plate and may cause tibial slope and medial collateral ligament tightening. A relatively new technique, the combined valgus high tibial osteotomy, claims to include the advantages of both techniques without bone loss. Aim of this prospective randomized trial is to compare the lateral closing wedge with the combined wedge osteotomy in patients with symptomatic varus osteoarthritis of the knee. A group of 110 patients with osteoarthritis of the medial compartment of the knee with 6-12° varus malalignment over 18 years of age are recruited to participate a randomized controlled trial. Patients are randomized to undergo a high tibial osteotomy, with either a lateral closing wedge technique or a combined wedge osteotomy technique. Primary outcome measure is achievement of an overcorrection of 4° valgus after one year of surgery, assessed by measuring the hip-knee-ankle angle. Secondary objectives are radiological scores and anatomical changes after high tibial osteotomy; pain, functional scores and quality of life will also be compared. Combined high tibial osteotomy modification avoids metaphyseal tibial bone loss, decreasing transposition of the tibial condyle and shortening of the patellar tendon after osteotomy, even in case of great correction. The clinical results of the combined wedge osteotomy technique are very promising. Hypothesis is that the combined wedge osteotomy technique will achieve more accurate overcorrection of varus malalignment with fewer anatomical changes of the proximal tibia after one year. Dutch Trial Registry (Netherlands trial register): NTR3898.


Instruments used to measure the effectiveness of palliative care education initiatives at the undergraduate level: a critical literature review.
The increase in the numbers of patients with palliative care needs has resulted in growing pressures on the small number of specialist palliative care providers within the New Zealand context. These pressures can potentially be eased by ensuring an adequately trained workforce, beginning with undergraduate training in the healthcare field. The goal of the present review is to ascertain what tools exist to measure the effectiveness of undergraduate palliative care education initiatives. A systematic review of qualitative and quantitative literature was undertaken. Searches within ERIC, CINAHL Plus, Medline and Medline in Progress, and Google Scholar databases were conducted for the period 1990-2011. A checklist adapted from Hawker et al was used to select and assess data. 14 of the 112 articles met the inclusion criteria. Overall inconsistencies in the amount of validation information provided and a narrow focus on aspects of palliative care competence was apparent. No universally applicable validated questionnaire to assess the effectiveness of undergraduate palliative care education could be identified. The increased focus by educational institutions on instilling palliative care skills in healthcare students necessitates the development of comprehensive and validated tools to evaluate the effectiveness of education initiatives.


WE-C-217BCD-09: Compressed Sensing in PET Imaging with Partial Detector Rings.
Investigate the possibility of reducing the number of PET detector elements per ring (introduce gaps) while maintaining image quality by employing compressed sensing techniques. A uniform Ge-68 phantom was imaged on a D-RX PET/CT scanner twice; once with all detectors operational (baseline) and once with 8 equidistant detector blocks turned off (partially sampled [PS], 11% detectors off. The resulting PS sinogram was then decomposed in two different components, each sparsely represented in a specific transform domain. An iterative optimization technique was then used to recover the PS sinogram based on the solution of a combination of underdetermined system of equations and block- coordinated relaxations. In addition, the total variation is minimized for the first component to direct it into a piece-wise smooth model. Finally the two components were summed to obtain the sinogram which was used to compare with the original PS sinogram. Comparison was done only for existing sinogram pixel values. This process was repeated iteratively until a RMS error of 5% or a total of 100 iterations were reached. For each iteration update, the values of the pixels corresponding to the missing detectors were obtained from the previous iteration while the remaining pixel values were extracted from the baseline sinogram. The resultant corrected sinograms where then reconstructed using OSEM and FBP and the corresponding images for full and PS sinograms were compared using mean and max activity concentration in a ROI placed centrally over the phantom. For OSEM (FBP) reconstruction, the mean and max activity concentration difference were -0.06% (-0.02%) and 3.7% (5.5%) respectively when compared to baseline. Compressed sensing seems to have the ability to recover PS PET data. Such an approach can potentially be used to generate PET images with accurate quantitation while reducing number of detectors/ring.


p90 ribosomal S6 kinase: a potential therapeutic target in lung cancer.
A global survey of cancer has shown that lung cancer is the most common cause of the new cancer cases and cancer deaths in men worldwide. The mortality from lung cancer is more than the combined mortality from breast, prostate and colorectal cancers. The two major histological types of lung cancer are non-small cell lung cancer (NSCLC) accounting for about 85 % of cases and small cell lung cancer accounting for 15 % of cases. NSCLC, the more prevalent form of lung cancer, is often diagnosed at an advanced stage and has a very poor prognosis. Many factors have been shown to contribute to the development of lung cancer in humans including tobacco smoking, exposure to environmental carcinogens (asbestos, or radon) and genetic factors. Despite the advances in treatment, lung cancer remains one of the leading causes of cancer death worldwide. Interestingly, the overall 5 year survival from lung cancer has not changed appreciably in the past 25 years. For this reason, novel and more effective treatments and strategies for NSCLC are critically needed. p90 ribosomal S6 kinase (RSK), a serine threonine kinase that lies downstream of the Ras-MAPK (mitogen activated protein kinase) cascade, has been demonstrated to be involved in the regulation of cell proliferation in various malignancies through indirect (e.g., modulation of transcription factors) or direct effects on the cell-cycle machinery. Increased expression of RSK has been demonstrated in various cancers, including lung cancer. This review focuses on the role of RSK in lung cancer and its potential therapeutic application.


Naprapathic manual therapy or evidence-based care for back and neck pain: a randomized, controlled trial.
To compare naprapathic manual therapy with evidence-based care for back or neck pain regarding pain, disability, and perceived recovery. Naprapathy that is common in the Nordic countries and in some states in the United States is characterized by manual manipulations with a focus on soft and connective tissues, aiming to decrease pain and disability in the musculoskeletal system. Four hundred and nine patients with pain and disability in the back or neck lasting for at least 2 weeks, recruited at 2 large public companies in Sweden in 2005, were included in this randomized controlled trial. The 2 interventions were naprapathy, including spinal manipulation/mobilization, massage, and stretching (Index Group) and support and advice to stay active and how to cope with pain, according to the best scientific evidence available, provided by a physician (Control Group). Pain, disability, and perceived recovery were measured by questionnaires at baseline and after 3, 7, and 12 weeks. At 7-week and 12-week follow-ups, statistically significant differences between the groups were found in all outcomes favoring the Index Group. At 12-week follow-up, a higher proportion in the naprapathy group had improved regarding pain [risk difference (RD)=27%, 95% confidence interval (CI): 17-37], disability (RD=18%, 95% CI: 7-28), and perceived recovery (RD=44%, 95% CI: 35-53). Separate analysis of neck pain and back pain patients showed similar results. This trial suggests that combined manual therapy, like naprapathy, might be an alternative to consider for back and neck pain patients.


Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography.
L-[18F] fluorodopa was administered in trace amounts intravenously to healthy control subjects and to patients with Parkinson's disease. Striatal uptake of radioactivity was measured using positron emission tomography. The capacity of the striatum to retain tracer was severely impaired in patients compared to controls. This may reflect a reduction of striatal dopamine storage in Parkinson's disease. Patients showing the "on/off" phenomenon had an even greater decrease of striatal storage capacity.


Nurse-physician collaboration: a meta-analytical investigation of survey scores.
This meta-analysis investigated differences between nurses and physicians in interprofessional collaboration (IPC) ratings. Fifty-one surveys, representing a total of 18 782 professionals and students (13 132 nurses and nursing students, and 5650 physicians and medical students), were meta-analyzed, considering several moderating variables. Overall, nurses scored higher on IPC than physicians. Sensitivity analysis revealed that while physicians perceived more existing collaboration than nurses, nurses had a more positive attitude toward collaboration than physicians. Moreover, IPC ratings of nursing and medical students did not differ from those of practitioners. Finally, it appeared that interprofessional education interventions were able to reduce the difference in IPC between nurses and physicians.


Cigarette and waterpipe smoking associated knowledge and behaviour among medical students in Lebanon.
As future physicians capable of controlling tobacco dependence in the population, medical students are considered a main target for tobacco control interventions. This cross-sectional study reported on the prevalence of tobacco use (cigarettes and waterpipes) and associated knowledge and behaviour among 6th-year medical students in 2009-2010 from 6 medical schools in Lebanon. The self-administered questionnaire based on the Global Health Professional Survey (GHPSS) core questions also enquired about training in tobacco cessation approaches. All enrolled students were asked to participate; the response rate was 191/354 (54.3%). The prevalence of tobacco use was 26.3% for cigarettes and 29.5% for waterpipes. Smoking waterpipes was the only significant predictor for cigarette smoking and there was no difference by sex and socioeconomic status. A minority reported ever receiving any formal training in treatment approaches for tobacco dependence. Medical schools should include tobacco dependence treatment training programmes in their curriculum and discourage tobacco use.


Clinical, Biochemical, and Histopathology Features of Patients With Glycogenic Hepatopathy.
Glycogenic hepatopathy, a syndrome characterized by hepatomegaly and increased liver transaminases in patients with type 1 diabetes, has not been well characterized in adults. We describe the clinical, biochemical, and histopathology profile of a cohort of patients with glycogenic hepatopathy. We also examined differences between patients with type 1 diabetes with versus without glycogenic hepatopathy. We performed a case-control study of patients with type 1 diabetes diagnosed with glycogenic hepatopathy and patients with type 1 diabetes without glycogenic hepatopathy (control subjects). Cases were identified in the database of electronic medical records at Mayo Clinic, Rochester from January 1, 1998, through January 1, 2014. Age- and sex-matched control subjects were identified from a Mayo Clinic registry of patients with type 1 diabetes who had normal levels of liver enzymes. Demographic, clinical, laboratory, and histopathology data were collected and compared between cases and control subjects. The primary outcome was difference in frequency of diabetic ketoacidosis episodes and hemoglobin (Hb) A1c levels between cases and control subjects. Among the 36 patients diagnosed with glycogenic hepatopathy, 20 had undergone liver biopsy analysis. Most cases were female (n = 28; 77.8%). Abdominal pain was the most common symptom (n = 23; 63.9%); 28 patients (77.8%) had hepatomegaly. All patients had poor control of diabetes (mean HbA1c level, 11.2 ± 2.4%). A higher proportion of cases had recurrent episodes of diabetic ketoacidosis (61%) than control subjects (9%) (P = .009), and cases had a higher mean level of HbA1c (11.2 ± 2.4% vs 9.0 ± 2.2% in control subjects; P = .0004). Adult cases had higher levels of aspartate transaminase (312.5 IU/L; range, 245.5-775 IU/L) than pediatric cases (157; range, 104-267 IU/L; P = .02) and lower serum levels of albumin (3.7 ± 0.5 g/dL vs 4.3 ± 0.4 g/dL for pediatric cases; P = .008). Only 16.7% of pediatric patients with glycogenic hepatopathy had growth retardation. Levels of liver transaminases were normalized at follow-up examinations of 18 of 21 adult or pediatric patients with glycogenic hepatopathy. More than half of patients with glycogenic hepatopathy and type 1 diabetes have recurrent episodes of diabetic ketoacidosis, and these patients have higher levels of HbA1c than patients with type 1 diabetes without glycogenic hepatopathy. We observed growth retardation in only about 17% of pediatric patients with glycogenic hepatopathy.


Maternal bisphenol A oral dosing relates to the acceleration of neurogenesis in the developing neocortex of mouse fetuses.
Bisphenol A (BPA), an endocrine-disruptor, is widely used in the production of plastics and resins. Human perinatal exposure to this chemical has been proposed to be a potential risk to public health. Animal studies indicate that postnatal exposure to BPA may affect neocortex development in embryos by accelerated neurogenesis and causing neuronal migration defects. The detailed phenotypes and pathogenetic mechanisms, especially with regard to the proliferation and differentiation of neural stem/progenitor cells, however, have not been clarified. C57BL/6J pregnant mice were orally administered BPA at 200μg/kg from embryonic day (E) 8.5 to 13.5, and the fetuses were observed histologically at E14.5. To clarify the histological changes, especially in terms of neurogenesis, proliferation and cell cycle, we performed histological analysis using specific markers of neurons/neural stem cells and cell cycle-specific labeling experiments using thymidine-analog substances. Cortical plate was hyperplastic and the number of neural stem/progenitor cells was decreased after the exposure to BPA. In particular, the maternal BPA oral dosing related to the effects on intermediate progenitor cells (IPCs, neural progenitor cells) in the subventricular zone (SVZ) of dorsal telencephalon. Exposure to BPA associated the promotion of the cell cycle exit in radial glial cells (RGCs, neural stem cells) and IPCs, and decreased the proliferation resulting from the prolong cell cycle length of IPCs in the SVZ. Our data show that maternal oral exposure to BPA related to the disruption of the cell cycle in IPCs and the effects of neurogenesis in the developing neocortex.


Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial.
Coronary artery disease (CAD) is a major cause of cardiovascular morbidity and mortality in patients with diabetes mellitus, yet CAD often is asymptomatic prior to myocardial infarction (MI) and coronary death. To assess whether routine screening for CAD by coronary computed tomography angiography (CCTA) in patients with type 1 or type 2 diabetes deemed to be at high cardiac risk followed by CCTA-directed therapy would reduce the risk of death and nonfatal coronary outcomes. The FACTOR-64 study was a randomized clinical trial in which 900 patients with type 1 or type 2 diabetes of at least 3 to 5 years' duration and without symptoms of CAD were recruited from 45 clinics and practices of a single health system (Intermountain Healthcare, Utah), enrolled at a single-site coordinating center, and randomly assigned to CAD screening with CCTA (n = 452) or to standard national guidelines-based optimal diabetes care (n = 448) (targets: glycated hemoglobin level <7.0%, low-density lipoprotein cholesterol level <100 mg/dL, systolic blood pressure <130 mm Hg). All CCTA imaging was performed at the coordinating center. Standard therapy or aggressive therapy (targets: glycated hemoglobin level <6.0%, low-density lipoprotein cholesterol level <70 mg/dL, high-density lipoprotein cholesterol level >50 mg/dL [women] or >40 mg/dL [men], triglycerides level <150 mg/dL, systolic blood pressure <120 mm Hg), or aggressive therapy with invasive coronary angiography, was recommended based on CCTA findings. Enrollment occurred between July 2007 and May 2013, and follow-up extended to August 2014. The primary outcome was a composite of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization; the secondary outcome was ischemic major adverse cardiovascular events (composite of CAD death, nonfatal MI, or unstable angina). At a mean follow-up time of 4.0 (SD, 1.7) years, the primary outcome event rates were not significantly different between the CCTA and the control groups (6.2% [28 events] vs 7.6% [34 events]; hazard ratio, 0.80 [95% CI, 0.49-1.32]; P = .38). The incidence of the composite secondary end point of ischemic major adverse cardiovascular events also did not differ between groups (4.4% [20 events] vs 3.8% [17 events]; hazard ratio, 1.15 [95% CI, 0.60-2.19]; P = .68). Among asymptomatic patients with type 1 or type 2 diabetes, use of CCTA to screen for CAD did not reduce the composite rate of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization at 4 years. These findings do not support CCTA screening in this population. clinicaltrials.gov Identifier: NCT00488033.


Fall prevention intervention technologies: A conceptual framework and survey of the state of the art.
In recent years, an ever increasing range of technology-based applications have been developed with the goal of assisting in the delivery of more effective and efficient fall prevention interventions. Whilst there have been a number of studies that have surveyed technologies for a particular sub-domain of fall prevention, there is no existing research which surveys the full spectrum of falls prevention interventions and characterises the range of technologies that have augmented this landscape. This study presents a conceptual framework and survey of the state of the art of technology-based fall prevention systems which is derived from a systematic template analysis of studies presented in contemporary research literature. The framework proposes four broad categories of fall prevention intervention system: Pre-fall prevention; Post-fall prevention; Fall injury prevention; Cross-fall prevention. Other categories include, Application type, Technology deployment platform, Information sources, Deployment environment, User interface type, and Collaborative function. After presenting the conceptual framework, a detailed survey of the state of the art is presented as a function of the proposed framework. A number of research challenges emerge as a result of surveying the research literature, which include a need for: new systems that focus on overcoming extrinsic falls risk factors; systems that support the environmental risk assessment process; systems that enable patients and practitioners to develop more collaborative relationships and engage in shared decision making during falls risk assessment and prevention activities. In response to these challenges, recommendations and future research directions are proposed to overcome each respective challenge.


Electrophysiological correlates of the interplay between low-level visual features and emotional content during word reading.
Processing affectively charged visual stimuli typically results in increased amplitude of specific event-related potential (ERP) components. Low-level features similarly modulate electrophysiological responses, with amplitude changes proportional to variations in stimulus size and contrast. However, it remains unclear whether emotion-related amplifications during visual word processing are necessarily intertwined with changes in specific low-level features or, instead, may act independently. In this pre-registered electrophysiological study, we varied font size and contrast of neutral and negative words while participants were monitoring their semantic content. We examined ERP responses associated with early sensory and attentional processes as well as later stages of stimulus processing. Results showed amplitude modulations by low-level visual features early on following stimulus onset - i.e., P1 and N1 components -, while the LPP was independently modulated by these visual features. Independent effects of size and emotion were observed only at the level of the EPN. Here, larger EPN amplitudes for negative were observed only for small high contrast and large low contrast words. These results suggest that early increase in sensory processing at the EPN level for negative words is not automatic, but bound to specific combinations of low-level features, occurring presumably via attentional control processes.


The Gene Encoding Dihydroflavonol 4-Reductase Is a Candidate for the anthocyaninless Locus of Rapid Cycling Brassica rapa (Fast Plants Type).
Rapid cycling Brassica rapa, also known as Wisconsin Fast Plants, are a widely used organism in both K-12 and college science education. They are an excellent system for genetics laboratory instruction because it is very easy to conduct genetic crosses with this organism, there are numerous seed stocks with variation in both Mendelian and quantitative traits, they have a short generation time, and there is a wealth of educational materials for instructors using them. Their main deficiency for genetics education is that none of the genetic variation in RCBr has yet been characterized at the molecular level. Here we present the first molecular characterization of a gene responsible for a trait in Fast Plants. The trait under study is purple/nonpurple variation due to the anthocyaninless locus, which is one of the Mendelian traits most frequently used for genetics education with this organism. We present evidence that the DFR gene, which encodes dihyroflavonol 4-reductase, is the candidate gene for the anthocyaninless (ANL) locus in RCBr. DFR shows complete linkage with ANL in genetic crosses with a total of 948 informative chromosomes, and strains with the recessive nonpurple phenotype have a transposon-related insertion in the DFR which is predicted to disrupt gene function.


New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?
Anti-epidermal growth factor receptor therapy with the monoclonal antibodies cetuximab and panitumumab is the main targeted treatment to combine with standard chemotherapy for metastatic colorectal cancer. Many clinical studies have shown the benefit of the addition of these agents for patients without mutations in the EGFR pathway. Many biomarkers, including KRAS and NRAS mutations, BRAF mutations, PIK3CA mutations, PTEN loss, AREG and EREG expression, and HER-2 amplification have already been identified to select responders to anti-EGFR agents. Among these alterations KRAS and NRAS mutations are currently recognized as the best predictive factors for primary resistance. Liquid biopsy, which helps to isolate circulating tumor DNA, is an innovative method to study both primary and acquired resistance to anti-EGFR monoclonal antibodies. However, high-sensitivity techniques should be used to enable the identification of a wide set of gene mutations related to resistance.


Hairless is required for the development of adult sensory organ precursor cells in Drosophila.
Reduction of the wild-type activity of the gene Hairless (H) results in two major phenotypic effects on the mechanosensory bristles of adult Drosophila. Bristles are either 'lost' (i.e. the shaft and socket fail to appear) or they exhibit a 'double socket' phenotype, in which the shaft is apparently transformed into a second socket. Analysis of the phenotypes conferred by a series of H mutant genotypes demonstrates (1) that different sensilla exhibit different patterns of response to decreasing levels of H+ function, and (2) that the 'bristle loss' phenotype results from greater loss of H+ function than the 'double socket' phenotype. The systematic study of H allelic combinations enabled us to identify genotypes that reliably produce specific mutant defects in particular positions on the bodies of adult flies. This permitted us to investigate the cellular development of sensilla in these same positions in larvae and pupae and thereby establish the developmental basis for the mutant phenotypes. We have found that H is required for at least two steps of adult sensillum development. In positions where 'double socket' microchaetes appear on the notum of H mutant flies, sensillum precursor cells are present in the developing pupa and divide normally, but their progeny adopt an aberrant spatial arrangement and fail to differentiate correctly. In regions of the notum exhibiting 'bristle loss' in adult H mutants, we were unable at the appropriate stages of development to detect sensillum-specific cell types, the precursor cell divisions that generate them, or the primary precursor cells themselves. Thus, the H 'bristle loss' phenotype appears to reflect a very early defect in sensillum development, namely the failure to specify and/or execute the sensory organ precursor cell fate. This finding indicates that H is one of a small number of identified genes for which the loss-of-function phenotype is the failure of sensillum precursor cell development.


A Biochemical/Biophysical Assay Dyad for HTS-Compatible Triaging of Inhibitors of the HIV-1 Nef/Hck SH3 Interaction.
The current treatment regimens for HIV include over 20 anti-retrovirals. However, adverse drug effects and the emergence of drug resistance necessitates the continued improvement of the existing drug classes as well as the development of novel drugs that target as yet therapeutically unexploited viral and cellular pathways. Here we demonstrate a strategy for the discovery of protein-protein interaction inhibitors of the viral pathogenicity factor HIV-1 Nef and its interaction with the host factor SH3. A combination of a time-resolved fluorescence resonance energy resonance energy transfer-based assay and a label-free resonant waveguide grating-based assay was optimized for high-throughput screening formats.


Microhardness and gloss of a new CAD-CAM hybrid material following accelerated aging and coffee immersion.
To evaluate and compare the effect of accelerated aging and coffee immersion on the microhardness and gloss of a new CAD/CAM hybrid material (Crystal Ultra) to those of contemporary restorative materials. A total of 160 specimens (12 x 14 x 1 mm ± 0.05 mm) were obtained from (IPS e.max [IPS], VITA Enamic [VE], Crystal Ultra [CU], Lava Ultimate [LU], and CeraSmart [CS]) high-translucency CAD/CAM blocks. The Vickers microhardness and gloss of the specimens were determined following thermocycling and coffee immersion. Data analysis was performed using SPSS (α = .05). IPS and CS specimens exhibited the highest (572.66 ± 11.30) and lowest (61.92 ± 3.91) microhardness, respectively. The highest gloss was observed with IPS specimens (3.31 ± 0.32), and LU specimens showed the lowest gloss (2.33 ± 0.06). A significant difference in gloss was observed between the materials at all measurement intervals (P < .01), except at T0 (P = .43). IPS specimens showed no significant changes in either group at any measurement interval. The microhardness and gloss of the new CU material were comparable to those of the tested contemporary hybrid restorative materials. Glass-ceramic showed superior hardness and gloss compared to hybrid restorative materials. Accelerated aging by thermocycling and staining significantly affected the microhardness and gloss of all the tested CAD/CAM materials.


Thermal inkjet printing in tissue engineering and regenerative medicine.
With the advantages of high throughput, digital control, and highly accurate placement of cells and biomaterial scaffold to the desired 2D and 3D locations, bioprinting has great potential to develop promising approaches in translational medicine and organ replacement. The most recent advances in organ and tissue bioprinting based on the thermal inkjet printing technology are described in this review. Bioprinting has no or little side effect to the printed mammalian cells and it can conveniently combine with gene transfection or drug delivery to the ejected living systems during the precise placement for tissue construction. With layer-by-layer assembly, 3D tissues with complex structures can be printed using scanned CT or MRI images. Vascular or nerve systems can be enabled simultaneously during the organ construction with digital control. Therefore, bioprinting is the only solution to solve this critical issue in thick and complex tissues fabrication with vascular system. Collectively, bioprinting based on thermal inkjet has great potential and broad applications in tissue engineering and regenerative medicine. This review article introduces some important patents related to bioprinting of living systems and the applications of bioprinting in tissue engineering field.


Hemoglobin F as a predictor of health-related quality of life in children with sickle cell anemia.
As treatment options for children with sickle cell anemia (SCA) continue to expand survival, evaluation of factors associated with health-related quality of life (HRQoL) is becoming an important aspect for further improving clinical management. Although the general features of SCA are similar, factors influencing HRQoL within a country may differ from those of other countries, therefore this study aimed to explore factors affecting HRQoL in children with SCA living in the Sultanate of Oman. This was a cross-sectional study in which the PedsQL™ Sickle Cell Disease Module was used to evaluate the overall HRQoL in children with SCA. The socio-demographic data, clinical, and treatment outcomes were collected. Univariate and multivariate linear regression analyses were used to identify predictors of HRQoL. A total of 123 children with SCA, aged from 2 to 16 years were enrolled. The mean total HRQoL score was 52 ± 15% (9-94), where Worry II scale recorded the highest score. The multiple regression analysis revealed that the only predictors of total HRQoL score were hemoglobin F (B = 0.64, 95% confidence interval [CI] 0.149-1.118, P = 0.009) and to a lesser degree white blood cell count (B = - 0.99, 95% CI - 1.761 to - 0.198, P = 0.01), independently of other study parameters such as age, gender, spleen status, and hydroxyurea therapy. Collectively, these findings indicated that hemoglobin F out-weighted white blood cell count in predicting HRQoL in Omani children with SCA. Recognition of these factors could help health professionals to develop effective strategies to improve the overall HRQoL in these young patients.


Risk for reduced sperm quality among metal workers, with special reference to welders.
The purpose of this study was to investigate whether men employed in the metal industry have sperm of poorer quality than men in other types of work. A postal questionnaire was sent to men employed in the metal industry, certain other types of nonmetal industries, and other types of employment in which the factors suspected to influence sperm quality were not present. By means of this questionnaire survey, it was hoped to define the possible influences of the work environment on sperm quality. Out of the total of 3,119 men included in the investigation, 2,517 (81%) filled out the questionnaire satisfactorily. Semen analysis was performed for all 3,119 men. There was a greater risk for poor sperm quality among welders than among men not employed in welding. The risk for poor sperm quality was increased for those welders who worked with stainless steel. Welding in general, and specifically with stainless steel, is connected with a risk of reduced sperm quality.


Structural basis for binding of RNA and cofactor by a KsgA methyltransferase.
Among methyltransferases, KsgA and the reaction it catalyzes are conserved throughout evolution. However, the specifics of substrate recognition by the enzyme remain unknown. Here we report structures of Aquifex aeolicus KsgA, in its ligand-free form, in complex with RNA, and in complex with both RNA and S-adenosylhomocysteine (SAH, reaction product of cofactor S-adenosylmethionine), revealing critical structural information on KsgA-RNA and KsgA-SAH interactions. Moreover, the structures show how conformational changes that occur upon RNA binding create the cofactor-binding site. There are nine conserved functional motifs (motifs I-VIII and X) in KsgA. Prior to RNA binding, motifs I and VIII are flexible, each exhibiting two distinct conformations. Upon RNA binding, the two motifs become stabilized in one of these conformations, which is compatible with the binding of SAH. Motif X, which is also stabilized upon RNA binding, is directly involved in the binding of SAH.


The social and behavioural determinants of health in Europe: findings from the European Social Survey (2014) special module on the social determinants of health.
Previous studies comparing the social and behavioural determinants of health in Europe have largely focused on individual countries or combined data from various national surveys. In this article, we present the findings from the new rotating module on social determinants of health in the European Social Survey (ESS) (2014) to obtain the first comprehensive comparison of estimates on the prevalence of the following social and behavioural determinants of health: working conditions, access to healthcare, housing quality, unpaid care, childhood conditions and health behaviours. We used the 7th round of the ESS. We present separate results for men and women. All estimates were age-standardized in each separate country using a consistent metric. We show country-specific results as well as pooled estimates for the combined cross-national sample. We found that social and behavioural factors that have a clear impact on physical and mental health, such as lack of healthcare access, risk behaviour and poor working conditions, are reported by substantial numbers of people in most European countries. Furthermore, our results highlight considerable cross-national variation in social and behavioural determinants of health across European countries. Substantial numbers of Europeans are exposed to social and behavioural determinants of health problems. Moreover, the extent to which people experience these social and behavioural factors varies cross-nationally. Future research should examine in more detail how these factors are associated with physical and mental health outcomes, and how these associations vary across countries.


Urotensin-II peptidomimetic incorporating a non-reducible 1,5-triazole disulfide bond reveals a pseudo-irreversible covalent binding mechanism to the urotensin G-protein coupled receptor.
The urotensin-II receptor (UTR) is a class A GPCR that predominantly binds to the pleiotropic cyclic peptide urotensin-II (U-II). U-II is constrained by a disulfide bridge that induces a β-turn structure and binds pseudo-irreversibly to UTR and is believed to result in a structural rearrangement of the receptor. However, it is not well understood how U-II binds pseudo-irreversibly and the nature of the reorganization of the receptor that results in G-protein activation. Here we describe a series of U-II peptidomimetics incorporating a non-reducible disulfide bond structural surrogate to investigate the feasibility that native U-II binds to the G protein-coupled receptor through disulfide bond shuffling as a mechanism of covalent interaction. Disubstituted 1,2,3-triazoles were designed with the aid of computational modeling as a non-reducible mimic of the disulfide bridge (Cys5-Cys10) in U-II. Solid phase synthesis using CuAAC or RuAAC as the key macrocyclisation step provided four analogues of U-II(4-11) incorporating either a 1,5-triazole bridge (5, 6) or 1,4-triazole bridge (9, 10). Biological evaluation of compounds 5, 6, 9 and 10 was achieved using in vitro [125I]UII binding and [Ca2+]i assays at recombinant human UTR. Compounds 5 and 6 demonstrated high affinity (KD ∼ 10 nM) for the UTR and were also shown to bind reversibly as predicted and activate the UTR to increase [Ca2+]i. Importantly, our results provide new insight into the mechanism of covalent binding of U-II with the UTR.


The mitochondrial genomes of sponges provide evidence for multiple invasions by Repetitive Hairpin-forming Elements (RHE).
The mitochondrial (mt) genomes of sponges possess a variety of features, which appear to be intermediate between those of Eumetazoa and non-metazoan opisthokonts. Among these features is the presence of long intergenic regions, which are common in other eukaryotes, but generally absent in Eumetazoa. Here we analyse poriferan mitochondrial intergenic regions, paying particular attention to repetitive sequences within them. In this context we introduce the mitochondrial genome of Ircinia strobilina (Lamarck, 1816; Demospongiae: Dictyoceratida) and compare it with mtDNA of other sponges. Mt genomes of dictyoceratid sponges are identical in gene order and content but display major differences in size and organization of intergenic regions. An even higher degree of diversity in the structure of intergenic regions was found among different orders of demosponges. One interesting observation made from such comparisons was of what appears to be recurrent invasions of sponge mitochondrial genomes by repetitive hairpin-forming elements, which cause large genome size differences even among closely related taxa. These repetitive hairpin-forming elements are structurally and compositionally divergent and display a scattered distribution throughout various groups of demosponges. Large intergenic regions of poriferan mt genomes are targets for insertions of repetitive hairpin- forming elements, similar to the ones found in non-metazoan opisthokonts. Such elements were likely present in some lineages early in animal mitochondrial genome evolution but were subsequently lost during the reduction of intergenic regions, which occurred in the Eumetazoa lineage after the split of Porifera. Porifera acquired their elements in several independent events. Patterns of their intra-genomic dispersal can be seen in the mt genome of Vaceletia sp.


The Circulating Treg/Th17 Cell Ratio Is Correlated with Relapse and Treatment Response in Pulmonary Sarcoidosis Patients after Corticosteroid Withdrawal.
Pulmonary sarcoidosis is an immune-mediated disease, and some patients can be effectively treated with corticosteroids. However, nearly half of all sarcoidosis patients relapse after corticosteroid withdrawal. Different subsets of CD4+ helper T cells participate in the immunopathogenesis of sarcoidosis. Thus, the aims of our study were to investigate whether the circulating subsets of CD4+ helper T cells were associated with sarcoidosis relapse and with its remission after retreatment. Additionally, we identified a useful biomarker for predicting the relapse and remission of sarcoidosis patients. Forty-two patients were enrolled in the present study who had previously been diagnosed with pulmonary sarcoidosis and treated with corticosteroids. The patients were allocated into either a stable group if they exhibited sustained remission (n = 22) or a relapse group if they experienced clinical or radiological recurrence after treatment withdrawal (n = 20). Peripheral blood cells were collected from these patients and analyzed to determine the frequencies of subsets of circulating CD4+ helper T cells by flow cytometry. The patients in the relapse group were retreated with corticosteroids and immunosuppressive agents and were then reevaluated to determine the frequencies of dynamic subsets of circulating CD4+ helper T cells after remission. The frequencies of circulating Tregs were significantly increased concomitant with a decrease in the circulating Th17 cell frequency in the relapsed patients compared with the stable patients. The Treg/Th17 ratio was negatively correlated with sarcoidosis activity and was sensitive to retreatment. In addition, the percentage of isolated CD45RO+Ki67+ Tregs was higher in the patients who were stable and in those who recovered after retreatment than in those who relapsed. An imbalance between Tregs and Th17 cells is associated with pulmonary sarcoidosis relapse after corticosteroid withdrawal. The circulating Treg/Th17 ratio could serve as an alternative marker for monitoring pulmonary sarcoidosis relapse after the end of corticosteroid treatment and for rapidly predicting the response to retreatment.


Vision: efficient adaptive coding.
Recent studies show that perception is driven not only by the stimuli currently impinging on our senses, but also by the immediate past history. The influence of recent perceptual history on the present reflects the action of efficient mechanisms that exploit temporal redundancies in natural scenes.


Adipose and muscle tissue gene expression of two genes (NCAPG and LCORL) located in a chromosomal region associated with cattle feed intake and gain.
A region on bovine chromosome 6 has been implicated in cattle birth weight, growth, and length. Non-SMC conodensin I complex subunit G (NCAPG) and ligand dependent nuclear receptor corepressor-like protein (LCORL) are positional candidate genes within this region. Previously identified genetic markers in both genes were associated with average daily gain (ADG) and average daily feed intake (ADFI) in a crossbred population of beef steers. These markers were also associated with hot carcass weight, ribeye area and adjusted fat thickness suggesting that they may have a role in lean muscle growth and/or fat deposition. The purpose of this study was to determine whether the transcript abundance of either of these genes in cattle adipose and muscle tissue was associated with variation in feed intake and average daily gain phenotypes. Transcript abundance for NCAPG and LCORL in adipose and muscle tissue was measured in heifers (adipose only), cows and steers using real-time polymerase chain reaction. In the adipose tissue from cows and heifers, a negative correlation between LCORL transcript abundance and ADFI were detected (P = 0.05). In the muscle tissue from cows, transcript abundance of NCAPG was associated with ADG (r = 0.26; P = 0.009). A positive correlation between LCORL transcript abundance from muscle tissue of steers and ADFI was detected (P = 0.04). LCORL protein levels in the muscle of steers were investigated and were associated with ADFI (P = 0.01). These data support our earlier genetic associations with ADFI and ADG within this region and represent the potential for biological activity of these genes in the muscle and adipose tissues of beef cattle; however, they also suggest that sex, age and/or nutrition-specific interactions may affect the expression of NCAPG and LCORL in these tissues.


Pharmacogenomics: the promise of personalized medicine for CNS disorders.
This review focuses first on the concept of pharmacogenomics and its related concepts (biomarkers and personalized prescription). Next, the first generation of five DNA pharmacogenomic tests used in the clinical practice of psychiatry is briefly reviewed. Then the possible involvement of these pharmacogenomic tests in the exploration of early clinical proof of mechanism is described by using two of the tests and one example from the pharmaceutical industry (iloperidone clinical trials). The initial attempts to use other microarray tests (measuring RNA expression) as peripheral biomarkers for CNS disorders are briefly described. Then the challenge of taking pharmacogenomic tests (compared to drugs) into clinical practice is explained by focusing on regulatory oversight, the methodological/scientific issues concerning diagnostic tests, and cost-effectiveness issues. Current information on medicine-based evidence and cost-effectiveness usually focuses on average patients and not the outliers who are most likely to benefit from personalized prescription. Finally, future research directions are suggested. The future of 'personalized prescription' in psychiatry requires consideration of pharmacogenomic testing and environmental and personal variables that influence pharmacokinetic and pharmacodynamic drug response for each individual drug used by each patient.


A Rare Case of Vertebral Osteomyelitis and Bilateral Psoas Abscess From an Unknown Source.
We present a case of a 31-year-old Filipino man with vertebral osteomyelitis and bilateral psoas abscesses. Vertebral osteomyelitis is a rare infection of the bone and bone marrow that affects the vertebral column. The patient's initial presentation included a 1-week history of cough, fatigue, diarrhea, fevers, and a 40-pound weight loss. An extensive workup including a computed tomography (CT) scan of the abdomen and pelvis demonstrated bilateral psoas abscesses with subcutaneous air tracking into the right flank. Blood cultures revealed Escherichia coli, Streptococcus anginosus, and Bacteroides. However, with an unclear primary source of infection, the most likely causative factor we believed to be due to immobility.


Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling.
Ongoing efforts to model P2Y receptors for extracellular nucleotides, i.e., endogenous ADP, ATP, UDP, UTP, and UDP-glucose, were summarized and correlated for the eight known subtypes. The rhodopsin-based homology modeling of the P2Y receptors is supported by a growing body of site-directed mutagenesis data, mainly for P2Y(1) receptors. By comparing molecular models of the P2Y receptors, it was concluded that nucleotide binding could occur in the upper part of the helical bundle, with the ribose moiety accommodated between transmembrane domain (TM) 3 and TM7. The nucleobase was oriented towards TM1, TM2, and TM7, in the direction of the extracellular side of the receptor. The phosphate chain was oriented towards TM6, in the direction of the extracellular loops (ELs), and was coordinated by three critical cationic residues. In particular, in the P2Y(1), P2Y(2), P2Y(4), and P2Y(6) receptors the nucleotide ligands had very similar positions. ADP in the P2Y(12) receptor was located deeper inside the receptor in comparison to other subtypes, and the uridine moiety of UDP-glucose in the P2Y(14) receptor was located even deeper and shifted toward TM7. In general, these findings are in agreement with the proposed binding site of small molecules to other class A GPCRs.


Exploring separable components of institutional confidence.
Despite its contemporary and theoretical importance in numerous social scientific disciplines, institutional confidence research is limited by a lack of consensus regarding the distinctions and relationships among related constructs (e.g., trust, confidence, legitimacy, distrust, etc.). This study examined four confidence-related constructs that have been used in studies of trust/confidence in the courts: dispositional trust, trust in institutions, obligation to obey the law, and cynicism. First, the separability of the four constructs was examined by exploratory factor analyses. Relationships among the constructs were also assessed. Next, multiple regression analyses were used to explore each construct's independent contribution to confidence in the courts. Finally, a second study replicated the first study and also examined the stability of the institutional confidence constructs over time. Results supported the hypothesized separability of, and correlations among, the four confidence-related constructs. The extent to which the constructs independently explained the observed variance in confidence in the courts differed as a function of the specific operationalization of confidence in the courts and the individual predictor measures. Implications for measuring institutional confidence and future research directions are discussed.


Fluorescence-based endoscopic imaging of Thomsen-Friedenreich antigen to improve early detection of colorectal cancer.
Thomsen-Friedenreich (TF) antigen belongs to the mucin-type tumor-associated carbohydrate antigen. Notably, TF antigen is overexpressed in colorectal cancer (CRC) but is rarely expressed in normal colonic tissue. Increased TF antigen expression is associated with tumor invasion and metastasis. In this study, we sought to validate a novel nanobeacon for imaging TF-associated CRC in a preclinical animal model. We developed and characterized the nanobeacon for use with fluorescence colonoscopy. In vivo imaging was performed on an orthotopic rat model of CRC. Both white light and fluorescence colonoscopy methods were utilized to establish the ratio-imaging index for the probe. The nanobeacon exhibited specificity for TF-associated cancer. Fluorescence colonoscopy using the probe can detect lesions at the stage which is not readily confirmed by conventional visualization methods. Further, the probe can report the dynamic change of TF expression as tumor regresses during chemotherapy. Data from this study suggests that fluorescence colonoscopy can improve early CRC detection. Supplemented by the established ratio-imaging index, the probe can be used not only for early detection, but also for reporting tumor response during chemotherapy. Furthermore, since the data obtained through in vivo imaging confirmed that the probe was not absorbed by the colonic mucosa, no registered toxicity is associated with this nanobeacon. Taken together, these data demonstrate the potential of this novel probe for imaging TF antigen as a biomarker for the early detection and prediction of the progression of CRC at the molecular level.