Improved fibrosis staging by elastometry and blood test in chronic hepatitis C.
Our main objective was to improve non-invasive fibrosis staging accuracy by resolving the limits of previous methods via new test combinations. Our secondary objectives were to improve staging precision, by developing a detailed fibrosis classification, and reliability (personalized accuracy) determination. All patients (729) included in the derivation population had chronic hepatitis C, liver biopsy, 6 blood tests and Fibroscan. Validation populations included 1584 patients. The most accurate combination was provided by using most markers of FibroMeter and Fibroscan results targeted for significant fibrosis, i.e. 'E-FibroMeter'. Its classification accuracy (91.7%) and precision (assessed by F difference with Metavir: 0.62 ± 0.57) were better than those of FibroMeter (84.1%, P < 0.001; 0.72 ± 0.57, P < 0.001), Fibroscan (88.2%, P = 0.011; 0.68 ± 0.57, P = 0.020), and a previous CSF-SF classification of FibroMeter + Fibroscan (86.7%, P < 0.001; 0.65 ± 0.57, P = 0.044). The accuracy for fibrosis absence (F0) was increased, e.g. from 16.0% with Fibroscan to 75.0% with E-FibroMeter (P < 0.001). Cirrhosis sensitivity was improved, e.g. E-FibroMeter: 92.7% vs. Fibroscan: 83.3%, P = 0.004. The combination improved reliability by deleting unreliable results (accuracy <50%) observed with a single test (1.2% of patients) and increasing optimal reliability (accuracy ≥85%) from 80.4% of patients with Fibroscan (accuracy: 90.9%) to 94.2% of patients with E-FibroMeter (accuracy: 92.9%), P < 0.001. The patient rate with 100% predictive values for cirrhosis by the best combination was twice (36.2%) that of the best single test (FibroMeter: 16.2%, P < 0.001). The new test combination increased: accuracy, globally and especially in patients without fibrosis, staging precision, cirrhosis prediction, and even reliability, thus offering improved fibrosis staging.


An anatomically-based masking protocol for the assessment of in-shoe plantar pressure measurement of the forefoot.
The area beneath the metatarsal heads is a common location of foot pain, which is often associated with high plantar pressures. Current plantar pressure assessment protocols focus mainly on the gross area of the forefoot with minimal attention paid to specific areas such as the metatarsal heads. The aim of this study was to develop and assess a new anatomically-based masking protocol that is clinically relevant to measure forefoot plantar pressure during shod conditions based on the anatomical positions of the metatarsal heads. Initially, we developed a masking protocol to measure forefoot plantar pressure during shod conditions based on the anatomical positions of the metatarsal heads. This new masking protocol divided the forefoot into three sub-areas (proximal, beneath, and distal to the metatarsal heads) as determined by the position of each metatarsal head. Following development of the new masking protocol, we compared the new protocol against a traditional protocol, which defines the forefoot as between 51 and 81% of the foot length. To compare the two masking protocols, we tested two experimental conditions: (i) a control condition (i.e. no metatarsal pad), and (ii) a metatarsal pad condition. We then compared plantar pressure differences between the two experimental conditions for the two masking protocols. Participants for this component of the study included 36 community dwelling older adults (mean age 75.6 years ±5.4) with a history of forefoot pain. Forefoot plantar pressure data were measured while walking using the pedar®-X in-shoe system. Peak pressure, maximum force and contact area at the time of peak pressure were determined and results were compared between the two masking protocols. The traditional masking protocol showed that the metatarsal pad significantly decreased peak pressure and increased contact area in the forefoot area (i.e. within the entire mask area), but maximum force was not significantly different between the two conditions. In contrast, the newly developed anatomically-based masking protocol indicated that the metatarsal pad decreased peak plantar pressures distal to and beneath the metatarsal heads by increasing force and contact area proximal to the metatarsal heads. An anatomically-based masking protocol that is clinically relevant was developed to assess forefoot plantar pressure during shod conditions based on the anatomical positions of metatarsal heads. We propose that the new forefoot masking protocol will provide greater interpretability of forefoot plantar pressure data, which will aid clinicians and researchers for diagnostic, prognostic and therapeutic purposes.


X-ray absorption resonances near L2,3-edges from real-time propagation of the Dirac-Kohn-Sham density matrix.
The solution of the Liouville-von Neumann equation in the relativistic Dirac-Kohn-Sham density matrix formalism is presented and used to calculate X-ray absorption cross sections. Both dynamical relaxation effects and spin-orbit corrections are included, as demonstrated by calculations of the X-ray absorption of SF6 near the sulfur L2,3-edges. We also propose an analysis facilitating the interpretation of spectral transitions from real-time simulations, and a selective perturbation that eliminates nonphysical excitations that are artifacts of the finite basis representation.


Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function.
Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers from patients with myofibrillar myopathy (MFM) caused by FLNC mutations (MFM-filaminopathy) and limb-girdle muscular dystrophy type-2A due to CAPN3 mutations (LGMD2A), compared to healthy control myofibers. Because the giant protein titin determines myofiber PT, we measured its molecular size and the titin-to-myosin ratio, but found no differences between myopathies and controls. All-titin phosphorylation and site-specific phosphorylation in the PEVK region were reduced in myopathy, which would be predicted to lower PT. Electron microscopy revealed extensive ultrastructural changes in myofibers of various hereditary myopathies and also suggested massive binding of proteins to the sarcomeric I-band region, presumably heat shock proteins (HSPs), which can translocate to elastic titin under stress conditions. Correlative immunofluorescence and immunoelectron microscopy showed that two small HSPs (HSP27 and αB-crystallin) and the ATP-dependent chaperone HSP90 translocated to the titin springs in myopathy. The small HSPs, but not HSP90, were upregulated in myopathic versus control muscles. The titin-binding pattern of chaperones was regularly observed in Duchenne muscular dystrophy (DMD), LGMD2A, MFM-filaminopathy, MFM-myotilinopathy, titinopathy, and inclusion body myopathy due to mutations in valosin-containing protein, but not in acquired sporadic inclusion body myositis. The three HSPs also associated with elastic titin in mouse models of DMD and MFM-filaminopathy. Mechanical measurements on skinned human myofibers incubated with exogenous small HSPs suggested that the elevated PT seen in myopathy is caused, in part, by chaperone-binding to the titin springs. Whereas this interaction may be protective in that it prevents sarcomeric protein aggregation, it also has detrimental effects on sarcomere function. Thus, we identified a novel pathological phenomenon common to many hereditary muscle disorders, which involves sarcomeric alterations.


BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.
BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1+/-) developed one and often several BAP1-/- malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1+/- carriers cause reduction both of IP3R3 levels and of Ca2+ flux, preventing BAP1+/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1+/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.


Identifying the factors for improving quality of oral fluorescein angiography.
To evaluate the quality of oral fluorescein angiography (FA) in relation to food intake. This is an observational, case-crossover study. We collected information from patients undergoing routine oral FA for retinal disease at the Shiley Eye Institute. Eighty patients (160 eyes) were analysed. Fasting and non-fasting images of the same patient were recorded, compared and analysed for different image quality parameters and clinical relevance by experienced retina specialists. When analysing the images, intergrader agreement was moderate to good with a Kappa averaging 0.60 (0.5-0.85). When patients were fasting pre-imaging, better angiography quality scores were achieved when compared with images taken when patients were non-fasting (mean 0.84 vs 0.72, p<0.001). Multivariate analysis showed that non-fasting patients with higher body mass index had the worst scores. Other clinical parameters, such as staining of drusen, staining of disciform scars or central and peripapillary atrophy, were also significantly better during the pre-fasting exam (p<0.001). Oral FA was approximately 22% faster (time to fluorescein dye appearance) under fasting conditions than non-fasting (mean±SD, minutes, 18.7±6.9 vs 25.14±8.1, p<0.001). Fasting oral FA provided significantly better quality images as well as faster optimal imaging times when compared with non-fasting oral FA. By improving its overall quality, oral FA could be a useful adjunctive examination to optical coherence tomography (OCT) and OCT angiography in patients who require FA studies but who have difficult access or refuse an invasive procedure.


Frequent misdirected courtship in a natural community of colorful Habronattus jumping spiders.
Male courtship display is common in many animals; in some cases, males engage in courtship indiscriminately, spending significant time and energy courting heterospecifics with whom they have no chance of mating or producing viable offspring. Due to high costs and few if any benefits, we might expect mechanisms to evolve to reduce such misdirected courtship (or 'reproductive interference'). In Habronattus jumping spiders, males frequently court heterospecifics with whom they do not mate or hybridize; females are larger and are voracious predators, posing a severe risk to males who court indiscriminately. In this study, we examined patterns of misdirected courtship in a natural community of four sympatric Habronattus species (H. clypeatus, H. hallani, H. hirsutus, and H. pyrrithrix). We used direct field observations to weigh support for two hypotheses (differential microhabitat use and species recognition signaling) to explain how these species reduce the costs associated with misdirected courtship. We show that, while the four species of Habronattus do show some differences in microhabitat use, all four species still overlap substantially, and in three of the four species individuals equally encountered heterospecifics and conspecifics. Males courted females at every opportunity, regardless of species, and in some cases, this led to aggression and predation by the female. These results suggest that, while differences in microhabitat use might reduce misdirected courtship to some extent, co-existence of these four species may be possible due to complex communication (i.e. species-specific elements of a male's courtship display). This study is the first to examine misdirected courtship in jumping spiders. Studies of misdirected courtship and its consequences in the field are limited and may broaden our understanding of how biodiversity is maintained within a community.


Energy oversupply to tissues: a single mechanism possibly underlying multiple cancer risk factors.
Several major risk factors for cancer involve vascular oversupply of energy to affected tissues. These include obesity, diabetes and chronic inflammation. Here, we propose a potential mechanistic explanation for the association between energy oversupply and cancer risk, which we call the metabolic cancer suppression hypothesis: We hypothesize that oncogenesis is normally suppressed by organismal physiology that regulates and strictly limits normal energy supply to somatic cells, and that this protection is removed by abnormal oversupply of energy. We evaluate this hypothesis using a computational model of somatic cell evolution to simulate experimental manipulation of the vascular energy supply to a tissue. The model simulates the evolutionary dynamics of somatic cells during oncogenesis. In our simulation experiment, we found that under plausible biological assumptions, elevated energy supply to a tissue led to the evolution of elevated energy uptake by somatic cells, leading to the rapid evolution of both defining traits of cancer cells: hyperproliferation, and tissue invasion. Our results support the hypothesis of metabolic cancer suppression, suggesting that vascular oversupply of energetic resources to somatic cells removes normal energetic limitations on cell proliferation, and that this accelerates cellular evolution toward cancer. Various predictions of this hypothesis are amenable to empirical testing, and have promising implications for translational research toward clinical cancer prevention.


Augmentation of the ascending component of the peristaltic reflex and substance P release by glial cell line-derived neurotrophic factor.
Glial cell line-derived neurotrophic factor (GDNF) is present in adult gut although its role in the mature enteric nervous system is not well defined. The aim of the present study was to examine the role of GDNF as neuromodulator of the ascending phase of the peristaltic reflex. Colonic segments were prepared as flat sheets and placed in compartmented chambers so as to separate the sensory and motor limbs of the reflex. Ascending contraction was measured in the orad compartment and mucosal stroking stimuli (two to eight strokes) were applied in the caudad compartment. GDNF and substance P (SP) release were measured and the effects of GDNF and GDNF antibody on contraction and release were determined. Mice with reduced levels of GDNF (Gdnf(+/-)) and wild type littermates were also examined. GDNF was released in a stimulus-dependent manner into the orad motor but not caudad sensory compartment. Addition of GDNF to the orad motor but not caudad sensory compartment augmented ascending contraction and SP release. Conversely, addition of GDNF antibody to the orad motor but not caudad sensory compartment reduced ascending contraction and SP release. Similarly, the ascending contraction and SP release into the orad motor compartment was reduced in Gdnf(+/-) mice as compared to wild type littermates. The results suggest that endogenous GDNF is released during the ascending contraction component of the peristaltic reflex where it acts as a neuromodulator to augment SP release from motor neurons thereby augmenting contraction of circular muscle orad to the site of stimulation.


Cardiometabolic risk factors among patients with tuberculosis attending tuberculosis treatment centers in Nepal.
The co-morbidity of cardiometabolic diseases in patients with Tuberculosis adds a significant burden in current health systems in developing countries including Nepal. The main objective of this study was to explore cardiometabolic risk factors among patients with Tuberculosis. This was a cross-sectional study conducted among patients with tuberculosis in 12 tuberculosis treatment centers from eight districts of Nepal between May and July 2017. Interviews with participants were conducted using a structured questionnaire and were supplemented by anthropometric measurements and on-site blood glucose tests. Data were analyzed using descriptive and inferential statistics. Among 221 study participants, 138 (62.4%) had new smear-positive pulmonary tuberculosis, 24 (10.9%) had new smear-negative pulmonary tuberculosis and 34 (15.4%) had new extra- pulmonary tuberculosis. Overall, 43.1% of the patients with tuberculosis had at least one cardiometabolic risk factor. The prevalence of at least one cardiometabolic risk factor was more in male than female (47.8% versus 33.8%). Prevalence of tobacco (18.9% versus 4.8%), and alcohol (12.6% versus 6.5%) use was proportionately higher in male compared to female. The prevalence of hypertension (17% vs. 21%) and obesity (11.9% vs. 12.9%) was lower in male compared to females. Female (AOR = 0.47; CI: 0.23-0.94), those from Gandaki Province (AOR = 0.32; CI: 0.13-0.79) and literate (AOR = 0.49; CI: 0.25-0.96) had reduced risk of cardiometabolic disease risk factors. This study highlights the role of gender and socio-demographic characteristics associated with the risk of cardiometabolic diseases in patients with Tuberculosis. The findings from this study can guide medical practitioners and policy makers to consider clinical suspicion, diagnosis and treatment. National treatment guideline can benefit by integrating the management of non-communicable diseases in Tuberculosis treatment centers.


Nanoscale spectroscopic imaging of organic semiconductor films by plasmon-polariton coupling.
Tip-enhanced near-field optical images and correlated topographic images of an organic semiconductor film (diindenoperylene, DIP) on Si have been recorded with high optical contrast and high spatial resolution (17 nm) using a parabolic mirror with a high numerical aperture for tip illumination and signal collection. The DIP molecular domain boundaries being one to four molecular layers (1.5-6 nm) high are resolved topographically by a shear-force scanning tip and optically by simultaneously recording the 6x10{5} times enhanced photoluminescence (PL). The excitation is 4x10{4} times enhanced and the intrinsically weak PL-yield of the DIP-film is 15-fold enhanced by the tip. The Raman spectra indicate an upright orientation of the DIP molecules. The enhanced PL contrast results from the local film morphology via stronger coupling between the tip plasmon and the exciton-polariton in the DIP film.


Genome-wide transcript analysis of inflorescence development in wheat.
The process of inflorescence development is directly related to yield components that determine the final grain yield in most cereal crops. Here, microarray analysis was conducted for four different developmental stages of inflorescence to identify genes expressed specifically during inflorescence development. To select inflorescence-specific expressed genes, we conducted meta-analysis using 1245 Affymetrix GeneChip array sets obtained from various development stages, organs, and tissues of members of Poaceae. The early stage of inflorescence development was accompanied by a significant upregulation of a large number of cell differentiation genes, such as those associated with the cell cycle, cell division, DNA repair, and DNA synthesis. Moreover, key regulatory genes, including the MADS-box gene, KNOTTED-1-like homeobox genes, GROWTH-REGULATING FACTOR 1 gene, and the histone methyltransferase gene, were highly expressed in the early inflorescence development stage. In contrast, fewer genes were expressed in the later stage of inflorescence development, and played roles in hormone biosynthesis and meiosis-associated genes. Our work provides novel information regarding the gene regulatory network of cell division, key genes involved in the differentiation of inflorescence in wheat, and regulation mechanism of inflorescence development that are crucial stages for determining final grain number per spike and the yield potential of wheat.


Magnetic resonance imaging findings in epileptic cats with a normal interictal neurological examination: 188 cases.
Epilepsy is a common neurological condition in dogs and cats. Although an increased likelihood of significant brain lesions with age has been identified in neurologically normal dogs with epileptic seizures, the underlying aetiology of epileptic seizures in cats that present with normal physical and neurological examinations remains unknown. In this cross-sectional study, the authors examined MRI findings in a large population of cats with a normal interictal physical and neurological examination. They hypothesised that age would have an impact on the prevalence of detectable lesions. First, following the guidelines for dogs and in accordance with previous studies, the authors divided the cats into three age groups (aged one year or younger, between one and six, and older than six) and calculated the proportion of cats with a detectable lesion on MRI in these groups. In the first group, 3/32 cats (9.4 per cent) had significant MRI abnormalities that were all consistent with congenital malformation; in the second group, only 5/92 (5.4 per cent) MRI scans were abnormal and in the third group, 15/ 65 (23.1 per cent) cats showed abnormal findings that were predominantly lesions of neoplastic origin. Second, to investigate the impact of age further, data were investigated as a continuous variable using receiver operating characteristic analysis. This indicated an optimal cut-off age of five years, above which MRI abnormalities were more likely, with an increase in the odds of a significant structural lesion increasing by 14 per cent per year.


Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 12: pedicle screw fixation as an adjunct to posterolateral fusion.
The utilization of pedicle screw fixation as an adjunct to posterolateral lumbar fusion (PLF) has become routine, but demonstration of a definitive benefit remains problematic. The medical evidence indicates that the addition of pedicle screw fixation to PLF increases fusion rates when assessed with dynamic radiographs. More recent evidence, since publication of the 2005 Lumbar Fusion Guidelines, suggests a stronger association between radiographic fusion and clinical outcome, although, even now, no clear correlation has been demonstrated. Although several reports suggest that clinical outcomes are improved with the addition of pedicle screw fixation, there are conflicting findings from similarly classified evidence. Furthermore, the largest contemporary, randomized, controlled study on this topic failed to demonstrate a significant clinical benefit with the use of pedicle screw fixation in patients undergoing PLF for chronic low-back pain. This absence of proof should not, however, be interpreted as proof of absence. Several limitations continue to compromise these investigations. For example, in the majority of studies the sample size is insufficient to detect small increments in clinical outcome that may be observed with pedicle screw fixation. Therefore, no definitive statement regarding the efficacy of pedicle screw fixation as a means to improve functional outcomes in patients undergoing PLF for chronic low-back pain can be made. There appears to be consistent evidence suggesting that pedicle screw fixation increases the costs and complication rate of PLF. High-risk patients, including (but not limited to) patients who smoke, patients who are undergoing revision surgery, or patients who suffer from medical conditions that may compromise fusion potential, may appreciate a greater benefit with supplemental pedicle screw fixation. It is recommended, therefore, that the use of pedicle screw fixation as a supplement to PLF be reserved for those patients in whom there is an increased risk of nonunion when treated with only PLF.


Comparative toll-like receptor 4-mediated innate host defense to Bordetella infection.
Bordetella pertussis, B. parapertussis, and B. bronchiseptica are closely related species associated with respiratory disease in humans and other mammals. While B. bronchiseptica has a wide host range, B. pertussis and B. parapertussis evolved separately from a B. bronchiseptica-like progenitor to naturally infect only humans. Despite very different doubling times in vitro, all three establish similar levels of infection in the mouse lung within 72 h. Recent work has revealed separate roles for Toll-like receptor 4 (TLR4) in immunity to B. pertussis and B. bronchiseptica, while no role for TLR4 during B. parapertussis infection has been described. Here we compared the requirement for TLR4 in innate host defense to these organisms using the same mouse infection model. While B. bronchiseptica causes lethal disease in TLR4-deficient mice, B. pertussis and B. parapertussis do not. Correspondingly, TLR4 is critical in limiting B. bronchiseptica but not B. pertussis or B. parapertussis bacterial numbers during the first 72 h. Interestingly, B. bronchiseptica induces a TLR4-dependent cytokine response that is considerably larger than that induced by B. pertussis or B. parapertussis. Analysis of their endotoxins using RAW cells suggests that B. bronchiseptica lipopolysaccharide (LPS) is 10- and 100-fold more stimulatory than B. pertussis or B. parapertussis LPS, respectively. The difference in LPS stimulus is more pronounced when using HEK293 cells expressing human TLR4. Thus, it appears that in adapting to infect humans, B. pertussis and B. parapertussis independently modified their LPS to reduce TLR4-mediated responses, which may compensate for slower growth rates and facilitate host colonization.


Aptamer-targeted gold nanoparticles as molecular-specific contrast agents for reflectance imaging.
Targeted metallic nanoparticles have shown potential as a platform for development of molecular-specific contrast agents. Aptamers have recently been demonstrated as ideal candidates for molecular targeting applications. In this study, we investigated the development of aptamer-based gold nanoparticles as contrast agents, using aptamers as targeting agents and gold nanoparticles as imaging agents. We devised a novel conjugation approach using an extended aptamer design where the extension is complementary to an oligonucleotide sequence attached to the surface of the gold nanoparticles. The chemical and optical properties of the aptamer-gold conjugates were characterized using size measurements and oligonucleotide quantitation assays. We demonstrate this conjugation approach to create a contrast agent designed for detection of prostate-specific membrane antigen (PSMA), obtaining reflectance images of PSMA(+) and PSMA(-) cell lines treated with the anti-PSMA aptamer-gold conjugates. This design strategy can easily be modified to incorporate multifunctional agents as part of a multimodal platform for reflectance imaging applications.


Short-term effects of pharmacologic HIF stabilization on vasoactive and cytotrophic factors in developing mouse brain.
Hypoxia-inducible transcription factors (HIFs) are crucially involved in brain development and cellular adaptation to hypoxia and ischemia. Degradation of HIF is regulated under normoxia by oxygen-dependent hydroxylation of specific prolyl residues on the labile alpha-subunit by HIF prolyl hydroxylases (PHD). Prolyl-4-hydroxylase inhibitors (PHI) have shown protective effects in vitro and in vivo in adult kidney and brain. The aim of the present study was to investigate in vivo short-term effects of a novel low molecular weight PHI, FG-4497, on HIF-regulated cytotrophic and vasoactive factors in developing mouse brain. Neonatal (P7, n=26) C57/BL6 mice were treated with PHI FG-4497 (30-100 mg/kg, i.p., duration 6 h). Gene expression was analyzed by TaqMan RT-PCR in kidney and developing brain in comparison to controls (NaCl 0.9% and non-treated animals). HIF-1alpha protein was quantified by Western blot analysis. Dose-response studies revealed prominent effects of FG-4497 at a dose of 100 mg/kg as assessed by significant up-regulation of mRNA in both kidney and brain of the following HIF-dependent genes: vascular endothelial growth factor, adrenomedullin and erythropoietin. Organ-specific transcriptional regulation was evident from analysis of hexokinase 2, inducible NO synthase and PHD3 mRNA concentrations. In the brain, HIF-1alpha and HIF-2alpha protein markedly accumulated in response to FG-4497. Besides vasoactive factors, PHI significantly increased cerebral chemokine receptor CXCR-4 mRNA levels. In conclusion, the novel PHI FG-4497 activates HIFs at an early stage of brain maturation and modulates neurotrophic processes known to be crucially involved in brain development and hypoxia-induced brain pathology.


Bioimaging of multiple elements by high-resolution LA-ICP-MS reveals altered distribution of mineral elements in the nodes of rice mutants.
Inter-vascular transfer in rice (Oryza sativa) nodes is required for delivering mineral elements to developing tissues, which is mediated by various transporters in the nodes. However, the effect of these transporters on distribution of mineral elements in the nodes at a cellular level is still unknown. Here, we established a protocol for bioimaging of multiple elements at a cellular level in rice node by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), and compared the mineral distribution profile between wild-type (WT) rice and mutants. Both relative comparison of mineral distribution normalized by endogenous 13 C and quantitative analysis using spiked standards combined with soft ablation gave valid results. Overall, macro-nutrients such as K and Mg were accumulated more in the phloem region, while micro-nutrients such as Fe and Zn were highly accumulated at the inter-vascular tissues of the node. In mutants of nodal Zn transporter OsHMA2, Zn localization pattern in the node tissues did not differ from that of WT; however, Zn accumulation in the inter-vascular tissues was lower in uppermost node I but higher in the third upper node III compared with the WT. In contrast, Si deposition in the mutants of three nodal Si transporters Lsi2, Lsi3 and Lsi6 showed different patterns, which are consistent with the localization of these transporters. This improved LA-ICP-MS analysis combined with functional characterization of transporters will provide further insight into mineral element distribution mechanisms in rice and other plant species.


Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation.
The latent plasma carboxypeptidase thrombin-activable fibrinolysis inhibitor (TAFI) is activated by thrombin/thrombomodulin on the endothelial cell surface, and functions in dampening fibrinolysis. In this study, we examined the effect of activated TAFI (TAFIa) in modulating the proinflammatory functions of bradykinin, complement C5a, and thrombin-cleaved osteopontin. Hydrolysis of bradykinin and C5a and thrombin-cleaved osteopontin peptides by TAFIa was as efficient as that of plasmin-cleaved fibrin peptides, indicating that these are also good substrates for TAFIa. Plasma carboxypeptidase N, generally regarded as the physiological regulator of kinins, was much less efficient than TAFIa. TAFIa abrogated C5a-induced neutrophil activation in vitro. Jurkat cell adhesion to osteopontin was markedly enhanced by thrombin cleavage of osteopontin. This was abolished by TAFIa treatment due to the removal of the C-terminal Arg168 by TAFIa from the exposed SVVYGLR alpha 4 beta 1 integrin-binding site in thrombin-cleaved osteopontin. Thus, thrombin cleavage of osteopontin followed by TAFIa treatment may sequentially up- and down-modulate the pro-inflammatory properties of osteopontin. An engineered anticoagulant thrombin, E229K, was able to activate endogenous plasma TAFI in mice, and E229K thrombin infusion effectively blocked bradykinin-induced hypotension in wild-type, but not in TAFI-deficient, mice in vivo. Our data suggest that TAFIa may have a broad anti-inflammatory role, and its function is not restricted to fibrinolysis.


Adverse effects of Δ9-tetrahydrocannabinol on neuronal bioenergetics during postnatal development.
Ongoing societal changes in views on the medical and recreational roles of cannabis increased the use of concentrated plant extracts with a Δ9-tetrahydrocannabinol (THC) content of more than 90%. Even though prenatal THC exposure is widely considered adverse for neuronal development, equivalent experimental data for young age cohorts are largely lacking. Here, we administered plant-derived THC (1 or 5 mg/kg) to mice daily during P5-P16 and P5-P35 and monitored its effects on hippocampal neuronal survival and specification by high-resolution imaging and iTRAQ proteomics, respectively. We found that THC indiscriminately affects pyramidal cells and both cannabinoid receptor 1+ (CB1R)+ and CB1R- interneurons by P16. THC particularly disrupted the expression of mitochondrial proteins (complexes I-IV), a change that had persisted even 4 months after the end of drug exposure. This was reflected by a THC-induced loss of membrane integrity occluding mitochondrial respiration and could be partially or completely rescued by pH stabilization, antioxidants, bypassed glycolysis, and targeting either mitochondrial soluble adenylyl cyclase or the mitochondrial voltage-dependent anion channel. Overall, THC exposure during infancy induces significant and long-lasting reorganization of neuronal circuits through mechanisms that, in large part, render cellular bioenergetics insufficient to sustain key developmental processes in otherwise healthy neurons.


Mouse models of dominant optic atrophy: what do they tell us about the pathophysiology of visual loss?
Dominant optic atrophy (DOA) is the most common inherited optic neuropathy affecting one in every 12,000 people. It presents with bilateral visual loss, central visual fields defects, colour vision disturbance and optic disc pallor. OPA1 has been identified as the responsible gene and its locus mapped to chromosome 3q28-q29. Mutations in this gene are responsible for the clinical phenotype in over 70% of patients with DOA. Histopathological studies in tissues from patients reveal loss of retinal ganglion cells but the paucity of viable human tissue has raised the importance of an animal model to study the pathophysiology of the disease. In the last decade considerable work has gone into the generation of animal, most notably mouse, models of Opa1 DOA. Two murine models of DOA have been published, designated B6;C3-Opa1(Q285STOP) and B6;C3-Opa1(329-355del) and they provide valuable insights with respect to neurological and visual phenotyping, mitochondrial dysfunction, optic nerve and axonal changes, retinal ganglion cell depletion and dendritic atrophy. Here we summarise the current state of knowledge of the mechanisms of disease based on data from these models of Opa1 DOA.


Assessing the Impact of Leveraging Traditional Leadership on Access to Sanitation in Rural Zambia.
Open defecation is practiced by more than one billion people throughout the world and leads to significant public health issues including infectious disease transmission and stunted growth in children. Zambia implemented community-led total sanitation (CLTS) as an intervention to eliminate open defecation in rural areas. To support CLTS and the attainment of open defecation free communities, chiefs were considered key agents of change and were empowered to drive CLTS and improve sanitation for their chiefdom. Chiefs were provided with data on access to sanitation in the chiefdom during chiefdom orientations prior to the initiation of CLTS within each community and encouraged to make goals of universal sanitation access within the community. Using a survival regression, we found that where chiefs were orientated and mobilized in CLTS, the probability that a village would achieve 100% coverage of adequate sanitation increased by 23% (hazard ratio = 1.263, 95% confidence interval = 1.080-1.478, P = 0.003). Using an interrupted time series, we found a 30% increase in the number of individuals with access to adequate sanitation following chiefdom orientations (95% confidence interval = 28.8-32.0%). The mobilization and support of chiefs greatly improved the uptake of CLTS, and empowering them with increased CLTS knowledge and authority of the program in their chiefdom allowed chiefs to closely monitor village sanitation progress and follow-up with their headmen/headwomen. These key agents of change are important facilitators of public health goals such as the elimination of open defecation in Zambia by 2020.


Clinical research at a crossroads: the NIH roadmap.
As a result of the NIH investment in biomedical research, over the past 30 years we have seen many great advances impacting the health of our nation which have been fostered by the effective translation of scientific advances. However, rising costs for both research and health care mean that the NIH must make strategic decisions that maximize the return on its investment. Because treating end-stage disease is so costly, both personally and financially, learning how to pre-empt illness through molecular knowledge and behavioral interventions is the only viable strategy for maintaining the nation's health in the coming years. In order to speed scientific discovery and its efficient translation to patient care, the NIH developed the Roadmap for Biomedical Research. The Roadmap provides an incubator space for funding innovative programs to address a panoply of scientific challenges and has engendered a new culture of cooperation among researchers seeking new avenues for collaboration. An important feature of the Roadmap is the Clinical and Translational Science Awards (CTSA). The program's goals are to eliminate growing barriers between clinical and basic research, to address the increasing complexities involved in conducting clinical research, and to help institutions nationwide create an academic home for clinical and translational science. By adopting a strong strategic vision now, the NIH will be able to stand at the ready as future challenges and opportunities emerge. In keeping with our mission, the NIH's current and future actions will be defined by the requirements of the scientific community and the public health needs of the nation.


Zip3 plays a major role in zinc uptake into mammary epithelial cells and is regulated by prolactin.
During lactation, a substantial amount of Zn(2+) is transferred by the mammary gland from the maternal circulation into milk; thus secretory mammary epithelial cells must tightly regulate Zn(2+) transport to ensure optimal Zn(2+) transfer to the suckling neonate. To date, six Zn(2+) import proteins (Zip1-6) have been identified; however, Zip3 expression is restricted to tissues with unique requirements for Zn(2+), such as the mammary gland, which suggests that it may play a specialized role in this tissue. In the present study, we have used a unique mammary epithelial cell model (HC11) to characterize the role of Zip3 in mammary epithelial cell Zn(2+) transport. Confocal microscopy demonstrated that Zip3 is localized to the cell surface in mammary epithelial cells and transiently relocalized to an intracellular compartment in cells with a secretory phenotype. Total (65)Zn transport was higher in secreting cells, while gene silencing of Zip3 decreased (65)Zn uptake into mammary epithelial cells, particularly in those with a secretory phenotype. Finally, reduced expression of Zip3 ultimately resulted in cell death, indicating that mammary epithelial cells have a unique requirement for Zip3-mediated Zn(2+) import, which may reflect the unique requirement for Zn(2+) of this highly specialized cell type and thus provides a physiological explanation for the restricted tissue distribution of this Zn(2+) importer.


Preparing the ground: contributions of the preclinical years to medical education for care near the end of life. Working Group on the Pre-clinical Years of the National Consensus Conference on Medical Education for Care Near the End of Life.
The preclinical years of medical education have rich potential for preparing medical students to provide optimal end-of-life care. Most of the opportunities and settings for this education already exist in the curricula of most medical schools, although they are underutilized for this purpose. In this report The Working Group on the Pre-clinical Years of the National Consensus Conference on Medical Education for Care Near the End of Life identifies the most promising settings and suggests how they might be used for maximum benefit in end-of-life education. Basic end-of-life care competencies are in five domains: (1) psychological, sociologic, cultural, and spiritual issues; (2) interviewing and communication skills; (3) management of common symptoms; (4) ethical issues; and (5) self-knowledge and self-reflection. A centralized group should oversee educational activities related to end-of-life care at each medical school. This group would identify and facilitate teaching opportunities in the preclinical curriculum: basic science courses; problem-based learning seminars; courses in interviewing, the doctor-patient relationship, and introduction to clinical medicine; courses in ethics, humanities, and the social-behavioral sciences; clinical preceptorships; and longitudinal experiences with patients. The group would also assess the potential impact of the "hidden curriculum."


Text-messaging versus telephone reminders to reduce missed appointments in an academic primary care clinic: a randomized controlled trial.
Telephone or text-message reminders have been shown to significantly reduce the rate of missed appointments in different medical settings. Since text-messaging is less resource-demanding, we tested the hypothesis that text-message reminders would be as effective as telephone reminders in an academic primary care clinic. A randomized controlled non-inferiority trial was conducted in the academic primary care division of the Geneva University Hospitals between November 2010 and April 2011. Patients registered for an appointment at the clinic, and for whom a cell phone number was available, were randomly selected to receive a text-message or a telephone call reminder 24 hours before the planned appointment. Patients were included each time they had an appointment. The main outcome was the rate of unexplained missed appointments. Appointments were not missed if they were cancelled or re-scheduled before or independently from the intervention. We defined non-inferiority as a difference below 2% in the rate of missed appointments and powered the study accordingly. A satisfaction survey was conducted among a random sample of 900 patients (response rate 41%). 6450 patients were included, 3285 in the text-message group and 3165 in the telephone group. The rate of missed appointments was similar in the text-message group (11.7%, 95% CI: 10.6-12.8) and in the telephone group (10.2%, 95% CI: 9.2-11.3 p = 0.07). However, only text message reminders were cost-effective. No patient reported any disturbance by any type of reminder in the satisfaction survey. Three quarters of surveyed patients recommended its regular implementation in the clinic. Text-message reminders are equivalent to telephone reminders in reducing the proportion of missed appointments in an academic primary care clinic and are more cost-effective. Both types of reminders are well accepted by patients.


Does living near heavy industry cause lung cancer in women? A case-control study using life grid interviews.
The incidence of lung cancer among women is high in the highly industrialised area of Teesside in north-east England. Previous research has implicated industrial pollution as a possible cause. A study was undertaken to investigate whether prolonged residence close to heavy industry is associated with lung cancer among women in Teesside. Two hundred and four women aged <80 years with incident primary lung cancer and 339 age matched community controls were recruited to a population based case-control study. Life course residential, occupational, and active and passive smoking histories were obtained using an interviewer administered questionnaire. The age adjusted odds ratio (OR) for lung cancer among people living >25 years v 0 years near (within 0-5 km) heavy industry in Teesside was 2.13 (95% CI 1.34 to 3.38). After adjustment for confounding factors the OR was 1.83 (95% CI 0.82 to 4.08) for >25 years or 1.10 (95% CI 0.96 to 1.26) for an additional 10 years living near industry. ORs were similar after residence near heavy industry outside Teesside was also included, and when latency was allowed for by disregarding residential exposures within the last 20 years. Adjustment for active smoking had the greatest effect on the OR. This population based study using life grid interviews for life course exposure assessment has addressed many deficiencies in the design of previous studies. The findings support those in most of the international literature of a modestly raised risk of lung cancer with prolonged residence close to heavy industry, although the confidence intervals were wide. The effect of air pollution on the incidence of lung cancer merits continued study.


Providing managed care options for a large population: evaluating the CHAMPUS reform initiative. Civilian Health and Medical Program of the Uniformed Services.
To evaluate a managed care demonstration project in CHAMPUS (Civilian Health and Medical Program of the Uniformed Services), the insurance program covering physical and mental health care services for the dependents of active duty military personnel, military retirees, and the retirees' dependents. The demonstration project added a health maintenance organization (HMO) option and a preferred provider organization (PPO) option to the standard CHAMPUS coverage and allowed beneficiaries to select the coverage option they preferred. Utilization, costs, access, and beneficiary satisfaction were measured using data from CHAMPUS claims records, the Defense Enrollment Eligibility Reporting System, the demonstration project contractor's HMO enrollment file, the contractor's list of network hospitals, and two surveys of CHAMPUS beneficiaries. Changes in utilization at 11 demonstration sites were compared with changes in utilization at 11 matched control sites. The effect of the demonstration project on costs was evaluated by estimating the costs for the demonstration sites both with and without the managed care options based on data from the control sites. Access to care and satisfaction were compared between the demonstration sites and control sites based on beneficiary surveys. All claims in both demonstration and control sites were used in estimating utilization changes. Two mailed surveys were sent to a randomly selected sample of active duty and retiree households with CHAMPUS beneficiaries; the sample was stratified by beneficiary type (active duty or retiree) and site. Overall utilization in the CHAMPUS system decreased at the demonstration sites but stayed approximately the same at the control sites. Utilization among the enrollees in the HMO demonstration option, however, increased dramatically. Patient access to care and satisfaction generally remained at the same levels at both demonstration and control sites, but enrollees in the HMO option reported higher satisfaction. Costs to the government at the demonstration areas, based on regression estimates from the control sites, were about the same or slightly higher than what they would have been under the standard CHAMPUS system. Managed care plans for large government-sponsored insurance programs can reduce utilization and maintain patient access and satisfaction. Careful structuring of such plans is needed, however, if they are to reduce costs.


Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study.
Despite convincing evidence in the Mediterranean region, the cardiovascular benefit of the Mediterranean diet is not well established in non-Mediterranean countries and the optimal criteria for defining adherence are unclear. The population attributable fraction (PAF) of adherence to this diet is also unknown. In the UK-based EPIC-Norfolk prospective cohort, we evaluated habitual diets assessed at baseline (1993-1997) and during follow-up (1998-2000) using food-frequency questionnaires (n = 23,902). We estimated a Mediterranean diet score (MDS) using cut-points projected from the Mediterranean dietary pyramid, and also three other pre-existing MDSs. Using multivariable-adjusted Cox regression with repeated measures of MDS and covariates, we examined prospective associations between each MDS with incident cardiovascular diseases (CVD) by 2009 and mortality by 2013, and estimated PAF for each outcome attributable to low MDS. We observed 7606 incident CVD events (2818/100,000 person-years) and 1714 CVD deaths (448/100,000). The MDS based on the Mediterranean dietary pyramid was significantly associated with lower incidence of the cardiovascular outcomes, with hazard ratios (95 % confidence intervals) of 0.95 (0.92-0.97) per one standard deviation for incident CVD and 0.91 (0.87-0.96) for CVD mortality. Associations were similar for composite incident ischaemic heart disease and all-cause mortality. Other pre-existing MDSs showed similar, but more modest associations. PAF due to low dietary pyramid based MDS (<95th percentile) was 3.9 % (1.3-6.5 %) for total incident CVD and 12.5 % (4.5-20.6 %) for CVD mortality. Greater adherence to the Mediterranean diet was associated with lower CVD incidence and mortality in the UK. This diet has an important population health impact for the prevention of CVD.


Thioredoxin-thioredoxin reductase system of Streptomyces clavuligerus: sequences, expression, and organization of the genes.
The genes that encode thioredoxin and thioredoxin reductase of Streptomyces clavuligerus were cloned, and their DNA sequences were determined. Previously, we showed that S. clavuligerus possesses a disulfide reductase with broad substrate specificity that biochemically resembles the thioredoxin oxidoreductase system and may play a role in the biosynthesis of beta-lactam antibiotics. It consists consists of two components, a 70-kDa NADPH-dependent flavoprotein disulfide reductase with two identical subunits and a 12-kDa heat-stable protein general disulfide reductant. In this study, we found, by comparative analysis of their predicted amino acid sequences, that the 35-kDa protein is in fact thioredoxin reductase; it shares 48.7% amino acid sequence identity with Escherichia coli thioredoxin reductase, the 12-kDa protein is thioredoxin, and it shares 28 to 56% amino acid sequence identity with other thioredoxins. The streptomycete thioredoxin reductase has the identical cysteine redox-active region--Cys-Ala-Thr-Cys--and essentially the same flavin adenine dinucleotide- and NADPH dinucleotide-binding sites as E. coli thioredoxin reductase and is partially able to accept E. coli thioredoxin as a substrate. The streptomycete thioredoxin has the same cysteine redox-active segment--Trp-Cys-Gly-Pro-Cys--that is present in virtually all eucaryotic and procaryotic thioredoxins. However, in vivo it is unable to donate electrons to E. coli methionine sulfoxide reductase and does not serve as a substrate in vitro for E. coli thioredoxin reductase. The S. clavuligerus thioredoxin (trxA) and thioredoxin reductase (trxB) genes are organized in a cluster. They are transcribed in the same direction and separated by 33 nucleotides. In contrast, the trxA and trxB genes of E. coli, the only other organism in which both genes have been characterized, are physically widely separated.


Use of and factors associated with self-treatment in China.
When an individual is ill or symptomatic, they have the options of seeking professional health care, self-treating or doing nothing. In China, some studies suggest that the number of individuals opting to self-treat has been rapidly increasing in recent years. Therefore, the aim of this study was to analyze the trends of and factors related to self-treatment in China. Self-treatment was measured based the concept and data of the China National Health Survey (CNHS), which covers 802,454 individuals. We used CNHS data from 1993, 1998, 2003, and 2008, and a Multinomial Logit Selection Model to estimate the factors influencing the decision to self-treat. The prevalences of self-treatment with a recall period of two-weeks were significantly higher in urban compared with rural areas (31.2% vs 14.9% in 1993, 43.5% vs 21.4% in 1998, 47.2% vs 31.4% in 2003, 31.0% vs 25.3% in 2008) in China. Economic (per capita income, TV, sanitary water) and individual (education, profession, family members, exercise) factors, as well as accessibility to drugs had a positive association with the probability of self-treating. Different illness symptoms, severity, and duration show a negative association with the probability of self-treating, showing a degree of rationality in decision-making. Different insurance systems were also found to have an effect on self-treatment decision-making. Self-treatment and professional medical services have shared the incremental medical needs of residents in recent years in China. Self-perceived illness status, economic circumstances, and education play important roles in health care decision-making.


Fostering open collaboration in drug development for paediatric brain tumours.
Brain tumours have become the leading cause of child mortality from cancer. Indeed, aggressive brainstem tumours, such as diffuse intrinsic pontine glioma (DIPG), are nearly uniformly fatal. These tumours display a unique set of driver mutations that distinguish them from adult gliomas and define new opportunity for the development of precision medicines. The specific association of ACVR1 mutations with DIPG tumours suggests a direct link to neurodevelopment and highlights the encoded bone morphogenetic protein receptor kinase ALK2 as a promising drug target. Beneficial effects of ALK2 inhibition have now been observed in two different in vivo models of DIPG. Nonetheless, such tumours present a huge challenge for traditional economic models of drug development due to their small market size, high failure rate, tumour location and paediatric population. Moreover, a toolkit of different investigational drugs may be needed to fully address the heterogeneity of these tumours in clinical trials. One new business model is suggested by M4K Pharma, a recent virtual start up that aims to align diffuse academic and industry research into a collaborative open science drug discovery programme. Fostering scientific collaboration may offer hope in rare conditions of dire unmet clinical need and provide an alternative route to affordable medicines.


Docetaxel and irinotecan in recurrent or metastatic head and neck cancer: a phase 2 trial of the Eastern Cooperative Oncology Group.
Docetaxel and irinotecan have single-agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN. Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m(2) and irinotecan 60 mg/m(2), intravenously, on Days 1 and 8, every 21 days, until disease progression. The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase-2 and VEGF in baseline tumor tissue. Fifty-two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel-exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression-free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085). Docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum-based regimens.


Decanal Protects against UVB-Induced Photoaging in Human Dermal Fibroblasts via the cAMP Pathway.
Solar ultraviolet (UV) radiation is the primary factor of cutaneous aging, resulting in coarse wrinkles and dryness. In this study, we aimed to test whether decanal, an aromatic compound found mainly in citrus fruits, inhibits UVB-mediated photoaging in human dermal fibroblasts and to explore whether its anti-photoaging effect occurs via cyclic adenosine monophosphate (cAMP) signaling. We found that decanal promotes collagen production dose-dependently. Meanwhile, it also increased the intracellular cAMP levels and decreased the number of molecules involved in the mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) pathway, downregulating the collagen genes and upregulating the matrix metalloproteinase (MMP) genes in UVB-exposed dermal fibroblasts. Furthermore, it enhanced hyaluronic acid levels and hyaluronic acid synthase mRNA expression. Notably, the beneficial effects of decanal were lost in the presence of a cAMP inhibitor. Our results revealed the potential of decanal for preventing photoaging and suggested that its effects are cAMP-mediated in human dermal fibroblasts.


Adult Pre-pregnancy Weight Change and Risk of Developing Hypertensive Disorders in Pregnancy.
While the association of pre-pregnancy body mass index (BMI) and hypertensive disorders in pregnancy (HDP) is well documented, little is known about the relationship between pre-pregnancy weight change and HDP. We examined the impact of adult pre-pregnancy weight change on the development of HDP. We included 2914 women, surveyed about every three years since 1996, from the 1973-78 cohort of the Australian Longitudinal Study on Women's Health. Women without hypertension or HDP were followed-up between 2003 and 2012. Generalised estimating equations were used to assess the effect of baseline BMI (mean age 20 years) and pre-pregnancy weight change on the incidence of HDP. Over 9 years of follow up, 301 incident HDP cases (6.3%) were reported from 4813 pregnancies. Overweight and obese women at the baseline survey were 1.67 (95% CI 1.3, 2.2) and 2.15 (95% CI 1.4, 3.3) times more likely to develop HDP than normal weight women, respectively. Compared with stable weight women, women with small (>1.5-2.5%) or moderate/high (>2.5%) annual weight gain had elevated risk of HDP (RR 1.67 95% CI 1.3, 2.2; RR 2.31, 95% CI 1.8, 3.0, respectively). Women who reported annual weight loss (>1.5%) between baseline and the average age of 24 years were 46% (95% CI 0.4, 0.8) less likely to develop HDP. Pre-pregnancy weight gain is associated with an increased risk of HDP, whereas early adult weight loss is associated with lower risk of HDP.


High-resolution modeling of residential outdoor particulate levels in Sweden.
Large-scale exposure assessments that include both between- and within-city differences in air pollution levels are lacking. The objective of this study was to model long-term particle exposure for the whole of Sweden, separating long-range transport from local sources, which were further separated into combustion and road dust. Annual regional, urban and local traffic PM exposure contributions were modeled for 26,000 addresses from a national survey, using a European scale model, an urban model and a local traffic model. Total PM(10) was overall dominated by the regional contribution, ranging from 3.5 μg/m(3) (northernmost) to 13.5 μg/m(3) (southernmost). Local traffic and urban sources contributed nationally on average to 16% of total PM(10), but for urban populations this contribution was larger (for Stockholm around 30%). Generalized to the Swedish adult population, the average residential exposure contributions from regional, urban and local traffic PM(10) were 10.2, 1.3 and 0.2 μg/m(3), respectively. Corresponding exposure to PM(1) was 5.1, 0.5 and 0.03 μg/m(3), respectively. Long-range transport dominates average Swedish residential PM(1) and PM(10) levels, but for urban populations the contributions from urban and local traffic sources are important and may even dominate for residences close to heavily trafficked roads. The study shows the importance of considering both national and city-scale gradients. The approach to exposure modeling at home addresses of a Swedish cohort includes both the regional scale and the urban and local traffic contributions to total PM exposure. With this we can resolve both between- and within-city gradients in national exposure assessments. The within-city exposure is further divided into a submicron (combustion) and a supermicron (road dust generated by studded tires) part. This gives new possibilities to study health impacts of different particles generated in Scandinavian cities.


Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer.
Among patients in whom childhood cancer was diagnosed in the 1970s and 1980s, 18% of those who survived for 5 years died within the subsequent 25 years. In recent decades, cancer treatments have been modified with the goal of reducing life-threatening late effects. We evaluated late mortality among 34,033 patients in the Childhood Cancer Survivor Study cohort who survived at least 5 years after childhood cancer (i.e., cancer diagnosed before the age of 21 years) for which treatment was initiated during the period from 1970 through 1999. The median follow-up was 21 years (range, 5 to 38). We evaluated demographic and disease factors that were associated with death from health-related causes (i.e., conditions that exclude recurrence or progression of the original cancer and external causes but include the late effects of cancer therapy) using cumulative incidence and piecewise exponential models to estimate relative rates and 95% confidence intervals. Of the 3958 deaths that occurred during the study period, 1618 (41%) were attributable to health-related causes, including 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes. A reduction in 15-year mortality was observed for death from any cause (from 12.4% in the early 1970s to 6.0% in the 1990s, P<0.001 for trend) and from health-related causes (from 3.5% to 2.1%, P<0.001 for trend). These reductions were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04). Changes in therapy according to decade included reduced rates of cranial radiotherapy for acute lymphoblastic leukemia (85% in the 1970s, 51% in the 1980s, and 19% in the 1990s), of abdominal radiotherapy for Wilms' tumor (78%, 53%, and 43%, respectively), of chest radiotherapy for Hodgkin's lymphoma (87%, 79%, and 61%, respectively), and of anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among survivors of acute lymphoblastic leukemia and Wilms' tumor. The strategy of lowering therapeutic exposure has contributed to an observed decline in late mortality among 5-year survivors of childhood cancer. (Funded by the National Cancer Institute and the American Lebanese-Syrian Associated Charities.).


NTP Toxicology and Carcinogenesis Studies of Ampicillin Trihydrate (CAS No. 7177-48-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Ampicillin trihydrate is a broad-spectrum semi-synthetic penicillin that is effective in the treatment of gram-positive and gram-negative bacterial infections produced by Streptococcus, Bacillus anthracis, Haemophilus influenzae, Neisseria gonorrhoeae, and Escherichia coli. This antibiotic is used in the treatment of upper respiratory tract infections, genital and urinary tract infections, and otitis media in children. Toxicology and carcinogenesis studies of ampicillin trihydrate (97%-99% pure) were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Male and female rats received doses of 0, 750, or 1,500 mg/kg, and male and female mice received doses of 0, 1,500, or 3,000 mg/kg. Doses selected for the 2-year studies were based on the lack of body weight effects and histopathologic effects at 2,400 mg/kg in the 14-day studies and 3,000 mg/kg in the 13-week studies. Clinical signs in the 13-week studies included diarrhea at 3,000 mg/kg in male and female rats and male mice. Corn oil suspensions containing more than 300 mg ampicillin trihydrate/ml were too viscous to be administered by gavage; therefore, a high dose of 1,500 mg/kg was selected for rats and a high dose of 3,000 mg/kg was selected for mice. During the 2-year studies, mean body weights of male and female rats were similar to or slightly increased over those of the corresponding vehicle control groups. Mean body weights of low dose and high dose male mice were similar to those of the corresponding vehicle group during year 1 of the study but were slightly below those of the vehicle control group during the last half of the study. Mean body weights of low dose and high dose female mice were greater than those of the vehicle controls throughout most of the study. No significant differences in survival were observed in groups of rats or mice of either sex. Clinical signs observed in dosed rats included diarrhea, excessive urination, and chromodacryorrhea and in dosed mice included increased salivation and decreased activity. In male rats, administration of ampicillin trihydrate was associated with an increased incidence of mononuclear cell leukemia (vehicle control, 5/50; low dose, 14/50; high dose, 13/50). Malignant lymphomas were observed in one additional vehicle control male rat and two low dose male rats. Lymphocytic leukemia was seen in one high dose rat. High dose male rats showed increased incidences of pheochromocytomas of the adrenal gland medulla (13/50; 12/50; 23/49). Malignant pheochromocytomas were observed in 1/50 vehicle control, 5/50 low dose, and 1/49 high dose male rats. The incidence of adrenal gland medullary hyperplasia was not increased in male rats (14/50; 10/50; 8/49). There were increased incidences of C-cellhyperplasia of the thyroid gland in low dose male and high dose female rats. High dose male rats showed increased incidences of hyperkeratosis and acanthosis of the forestomach. In male and female mice, ampicillin trihydrate administration was associated with increased incidences of forestomach lesions, including ulcers, inflammation, hyperkeratosis, acanthosis, and evidence of fungal infection. Ampicillin trihydrate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Syrian hamster or male Sprague-Dawley rat liver S9 when tested according to preincubation protocol. Ampicillin trihydrate was not mutagenic in L5178Y mouse lymphoma cells with or without metabolic activation. Ampicillin trihydrate did not cause chromosomal aberrations or sister-chromatid exchanges in Chinese hamster ovary cells with or without metabolic activation. An audit was conducted for these 2-year studies. Animal/carcass identification discrepancies were observed in rats and mice. The most common findings were the failure to clip some toes in rats and opened ear holes in mice. A review of the inlife data (including body weights, clinical observations, and dosing records) indicrecords) indicated that animals had not been interchanged among groups. The data are considered adequate to support the conclusions. Under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenicity of ampicillin trihydrate for male F344/N rats as shown by increased incidences of pheochromocytomas of the adrenal medulla and by marginally increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for female F344/N rats receiving 750 or 1,500 mg/kg or for male and female B6C3F1 mice receiving 1,500 or 3,000 mg/kg per day. Nonneoplastic lesions of the forestomach were seen in male rats and male and female mice. Synonyms and trade names: Acillin; Amcap; Amcill; Aminobenzylpencillin trihydrate; a-Aminobenzylpencillin trihydrate; Amperil; Ampichel; Ampikel; Ampinova; Amplin; Cymbi; Divercillin; Liffampil; Morepen; Pen A; Pensyn; Polycillin; Princillin; Principen; Ro-ampen; Trafarbiot


5-4-3-2-1 go! Coordinating pediatric resident education and community health promotion to address the obesity epidemic in children and youth.
This study investigated the feasibility and effectiveness of training pediatric residents to conduct a brief clinic-based behavioral intervention in coordination with community dissemination of a health promotion message developed by the Consortium for Lowering Obesity in Chicago Children. A total of 113 residents completed a short (<60 minutes) online training program. Some (64) residents distributed interview contact cards to patients they saw in their continuity of care clinics after training; others (45) distributed cards before training. A researcher interviewed 75% of the 509 patients 4 weeks after the visit. More patients of trained residents reported positive changes in behaviors which have been associated with lower obesity rates: increased intake of fruits and vegetables (28% vs 16%, P < .01), increased intake of water (30% vs 19%, P < .01), increased physical activity (40% vs 29%, P < .03), and decreased television time (36% vs 24%, P < .01). Brief training using the 5-4-3-2-1-Go! message seems to be feasible and effective.


Regional electric field induced by electroconvulsive therapy: a finite element simulation study.
The goal of this study is to investigate the regional distribution of the electric field (E-field) strength induced by electroconvulsive therapy (ECT), and to contrast clinically relevant electrode configurations through finite element (FE) analysis. An FE human head model incorporating tissue heterogeneity and white matter anisotropy was generated based on structural magnetic resonance imaging (MRI) and diffusion tensor MRI (DT-MRI) data. We simulated the E-field spatial distributions of three standard ECT electrode placements [bilateral (BL), bifrontal (BF), and right unilateral (RUL)] and an investigational electrode configuration [focal electrically administered seizure therapy (FEAST)]. A quantitative comparison of the E-field strength was subsequently carried out in various brain regions of interests (ROIs) that have putative role in the therapeutic action and/or adverse side effects of ECT. This study illustrates how the realistic FE head model provides quantitative insight in the biophysics of ECT, which may shed light on the differential clinical outcomes seen with various forms of ECT, and may guide the development of novel stimulation paradigms with improved risk/benefit ratio.


Factors affecting ventriculoperitoneal shunt survival in adult patients.
Ventriculoperitoneal (VP) shunt insertion remains the mainstay of treatment for hydrocephalus despite a high rate of complications. The predictors of shunt malfunction have been studied mostly in pediatric patients. In this study, we report our 11-year experience with VP shunts in adult patients with hydrocephalus. We also assess the various factors affecting shunt survival in a developing country setting. A retrospective chart analysis was conducted for all adult patients who had undergone shunt placement between the years 2001 and 2011. Kaplan-Meier curves were used to determine the duration from shunt placement to first malfunction and log-rank (Cox-Mantel) tests were used to determine the factors affecting shunt survival. A total of 227 patients aged 18-85 years (mean: 45.8 years) were included in the study. The top four etiologies of hydrocephalus included post-cranial surgery (23.3%), brain tumor or cyst (22.9%), normal pressure hydrocephalus (15%), and intracranial hemorrhage (13.7%). The overall incidence of shunt malfunction was 15.4% with the median time to first shunt failure being 120 days. Etiology of hydrocephalus (P = 0.030) had a significant association with the development of shunt malfunction. Early shunt failure was associated with age (P < 0.001), duration of hospital stay (P < 0.001), Glasgow Coma Scale (GCS) score less than 13 (P = 0.010), excision of brain tumors (P = 0.008), and placement of extra-ventricular drains (P = 0.033). Patients with increased age, prolonged hospital stay, GCS score of less than 13, extra-ventricular drains in situ, or excision of brain tumors were more likely to experience early shunt malfunction.


GluA4 is indispensable for driving fast neurotransmission across a high-fidelity central synapse.
Fast excitatory synaptic transmission in central synapses is mediated primarily by AMPA receptors (AMPARs), which are heteromeric assemblies of four subunits, GluA1-4. Among these subunits, rapidly gating GluA3/4 appears to be the most abundantly expressed to enable neurotransmission with submillisecond precision at fast rates in subsets of central synapses. However, neither definitive identification of the molecular substrate for native AMPARs in these neurons, nor their hypothesized functional roles in vivo has been unequivocally demonstrated, largely due to lack of specific antagonists. Using GluA3 or GluA4 knockout (KO) mice, we investigated these issues at the calyx of Held synapse, which is known as a high-fidelity synapse involved in sound localization. Patch-clamp recordings from postsynaptic neurons showed that deletion of GluA4 significantly slowed the time course of both evoked and miniature AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), reduced their amplitude, and exacerbated AMPAR desensitization and short-term depression (STD). Surprisingly, presynaptic release probability was also elevated, contributing to severe STD at GluA4-KO synapses. In contrast, only marginal changes in AMPAR-EPSCs were found in GluA3-KO mice. Furthermore, independent of changes in intrinsic excitability of postsynaptic neurons, deletion of GluA4 markedly reduced synaptic drive and increased action potential failures during high-frequency activity, leading to profound deficits in specific components of the auditory brainstem responses associated with synchronized spiking in the calyx of Held synapse and other related neurons in vivo. These observations identify GluA4 as the main determinant for fast synaptic response, indispensable for driving high-fidelity neurotransmission and conveying precise temporal information.


The effect of garlic extract on human metabolism of acetaminophen.
Several studies suggest that the constituents of garlic may inhibit experimentally induced carcinogenesis. To evaluate the chemopreventive properties of garlic in humans, the effects of chronic administration of an aged garlic extract on the disposition of acetaminophen and metabolites were studied. This commonly used drug was chosen because it forms a reactive electrophilic metabolite after oxidative metabolism. Sixteen subjects ingested daily doses of garlic extract (approximately equivalent to six to seven cloves of garlic) for 3 months. Before the course of garlic, at the end of each month and 1 month after termination of garlic administration, a 1-g oral dose of acetaminophen was given to each subject. Plasma and urine were measured for acetaminophen and the glucuronide, sulfate, cysteinyl, mercapturate, and methylthio metabolites. It was found that garlic treatment had no discernible effect on oxidative metabolism but was associated with a slight increase in sulfate conjugation of drug. These findings suggest that garlic extract has limited potential as a chemopreventive agent.


Mining legacy across a wetland landscape: high mercury in Upper Peninsula (Michigan) rivers, lakes, and fish.
A geographic enigma is that present-day atmospheric deposition of mercury in the Upper Peninsula of Michigan is low (48%) and that regional industrial emissions have declined substantially (ca. 81% reduction) relative to downstate. Mercury levels should be declining. However, state (MDEQ) surveys of rivers and lakes revealed elevated total mercury (THg) in Upper Peninsula waters and sediment relative to downstate. Moreover, Western Upper Peninsula (WUP) fish possess higher methyl mercury (MeHg) levels than Northern Lower Peninsula (NLP) fish. A contributing explanation for elevated THg loading is that a century ago the Upper Peninsula was a major industrial region, centered on mining. Many regional ores (silver, copper, zinc, massive sulfides) contain mercury in part per million concentrations. Copper smelters and iron furnace-taconite operations broadcast mercury almost continuously for 140 years, whereas mills discharged tailings and old mine shafts leaked contaminated water. We show that mercury emissions from copper and iron operations were substantial (60-650 kg per year) and dispersed over relatively large areas. Moreover, lake sediments in the vicinity of mining operations have higher THg concentrations. Sediment profiles from the Keweenaw Waterway show that THg accumulation increased 50- to 400-fold above modern-day atmospheric deposition levels during active mining and smelting operations, with lingering MeHg effects. High MeHg concentrations are geographically correlated with low pH and dissolved organic carbon (DOC), a consequence of biogeochemical cycling in wetlands, characteristic of the Upper Peninsula. DOC can mobilize metals and elevate MeHg concentrations. We argue that mercury loading from mining is historically superimposed upon strong regional wetland effects, producing a combined elevation of both THg and MeHg in the Western Upper Peninsula.


Isolation and characterisation of a novel Bohle-like virus from two frog species in the Darwin rural area, Australia.
Twelve captive magnificent tree frogs Litoria splendida and 2 green tree frogs L. caerulea on a property in the Darwin rural area (Northern Territory, Australia) either died or were euthanased after becoming lethargic or developing skin lesions. Samples from both species of frog were submitted for histopathology and virus isolation. An irido-like virus was cultured from tissue samples taken from both species and was characterised using electron microscopy, restriction enzyme digests and nucleic acid amplification and sequencing. The isolates were determined to belong to the genus Ranavirus, were indistinguishable from each other and shared a 98.62% nucleotide similarity and a 97.32% deduced amino acid homology with the Bohle iridovirus over a 1161 bp region of the major capsid gene. This is the first isolation of a ranavirus from amphibians in the Northern Territory and the first report of natural infection in these 2 species of native frog. The virus is tentatively named Mahaffey Road virus (MHRV).


Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats.
Vascular dysfunction is thought to play a major role in the development of diabetic cardiovascular disease. The roles of endothelial dysfunction, oxidative stress, and dyslipidemia will be considered. Melatonin as well as L-carnitine were shown to possess strong antioxidant properties. Diabetes induced with high fat diet (for 8 weeks) and multipl low doses intraperitoneal injection of STZ (twice, 30mg/kg/d i.p). The diabetic animals were randomly assigned to one of the experimental groups as follows: Control group (C), high fat diet (HFD), STZ-induced diabetic group (HFD+STZ) , HFD+STZ diabetic group received melatonin (10mg/kg/d i.p), HFD+STZ diabetic group received L-carnitine (0.6g/kg/d i.p), and HFD+STZ diabetic group received glibenclamide (5mg/kg/d, oral). The serum fasting blood glucose, insulin, total cholesterol, HDL- cholesterol, LDL-cholesterol, triglyceride and malondialdehyde (MDA) levels were tested. Acetylcholine induced endothelium-dependent relaxation and sodium nitroprusside induced endothelium-independent relaxation were measured in aortas for estimating endothelial function. Also, glutathione peroxidase (GPx), superoxide dismutase (SOD) and nitric oxide (NO) levels activities were determined in rat liver. According to our results melatonin and L-carnitine treatment decreased fasting blood glucose, total cholesterol, and LDL levels. MDA levels significantly decreased with the melatonin treatment whereas SOD levels were not significantly changed between the groups. The results suggest that especially melatonin restores the vascular responses and endothelial dysfunction in diabetes.


Automated segmentation of the substantia nigra, subthalamic nucleus and red nucleus in 7T data at young and old age.
With recent developments in MR acquisition at 7T, smaller brainstem structures such as the red nuclei, substantia nigra and subthalamic nuclei can be imaged with good contrast and resolution. These structures have important roles both in the study of the healthy brain and in diseases such as Parkinson's disease, but few methods have been described to automatically segment them. In this paper, we extend a method that we have previously proposed for segmentation of the striatum and globus pallidus to segment these deeper and smaller structures. We modify the method to allow more direct control over segmentation smoothness by using a Markov random field prior. We investigate segmentation performance in three age groups and show that the method produces consistent results that correspond well with manual segmentations. We perform a vertex-based analysis to identify changes with age in the shape of the structures and present results suggesting that the method may be at least as effective as manual delineation in capturing differences between subjects.


PON1 polymorphisms are associated with polycystic ovary syndrome susceptibility, related traits, and PON1 activity in Indian women with the syndrome.
To investigate the association of paraoxonase 1 (PON1) polymorphisms (L55M and Q192R) with polycystic ovary syndrome (PCOS) susceptibility and its related traits in Indian women. Case-control study. Academic research institute, infertility, and endocrinology clinics. Controls (n = 326), women with PCOS (n = 482). None. Genotypic and allelic frequency distribution, genotype-phenotype association, different PON1 activities (lactonase, arylesterase, and paraoxonase). The genotypic and allelic frequency distributions of the L55M polymorphism were significantly different between lean controls and lean women with PCOS, and this polymorphism reduced the risk of PCOS development in lean but not in obese Indian women. Furthermore, this polymorphism was significantly associated with decreased 2-hour glucose, apolipoprotein B, free and bioavailable T, and free androgen index concurrent with increased sex hormone-binding globulin (SHBG) and FSH levels only in lean women with PCOS. However, Q192R polymorphism showed comparable genotypic frequency distribution between controls and women with PCOS. PON1 lactonase and arylesterase activities were significantly decreased in women with PCOS compared with controls. PON1 polymorphisms were shown to influence its activities. Our study showed that L55M, but not Q192R, polymorphism is significantly associated with reduced PCOS susceptibility only in lean women and also impacts glucose metabolism, lipid parameters, and hyperandrogenemia in them. Our study therefore suggests the possibility of differential genetic pathophysiology of PCOS between lean and obese women.


CDP-choline: pharmacological and clinical review.
Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.


Differentiating intraprofessional attitudes toward paradigms in health care delivery among chiropractic factions: results from a randomly sampled survey.
As health care has increased in complexity and health care teams have been offered as a solution, so too is there an increased need for stronger interprofessional collaboration. However the intraprofessional factions that exist within every profession challenge interprofessional communication through contrary paradigms. As a contender in the conservative spinal health care market, factions within chiropractic that result in unorthodox practice behaviours may compromise interprofessional relations and that profession's progress toward institutionalization. The purpose of this investigation was to quantify the professional stratification among Canadian chiropractic practitioners and evaluate the practice perceptions of those factions. A stratified random sample of 740 Canadian chiropractors was surveyed to determine faction membership and how professional stratification could be related to views that could be considered unorthodox to current evidence-based care and guidelines. Stratification in practice behaviours is a stated concern of mainstream medicine when considering interprofessional referrals. Of 740 deliverable questionnaires, 503 were returned for a response rate of 68%. Less than 20% of chiropractors (18.8%) were aligned with a predefined unorthodox perspective of the conditions they treat. Prediction models suggest that unorthodox perceptions of health practice related to treatment choices, x-ray use and vaccinations were strongly associated with unorthodox group membership (X(2) =13.4, p = 0.0002). Chiropractors holding unorthodox views may be identified based on response to specific beliefs that appear to align with unorthodox health practices. Despite continued concerns by mainstream medicine, only a minority of the profession has retained a perspective in contrast to current scientific paradigms. Understanding the profession's factions is important to the anticipation of care delivery when considering interprofessional referral.


Choosing the ideal length of a double-pigtail ureteral stent according to body height: study based on a Chinese population.
We conducted this study to determine the ideal stent length according to body height, as data are limited. A total of 408 patients undergoing ureteroscopic lithotripsy and stent insertion (22, 24 or 26 cm) were enrolled. The appropriateness of the stent length was determined according to the plain films and was further compared among patients with different body heights and stent lengths. In patients <160 cm, the use of a 22-cm stent was significantly more appropriate than a 24- or 26-cm stent (86.5, 51.9 and 46.4%). In patients between 160 and 175 cm, a 22- or 24-cm stent was significantly more appropriate than a 26-cm stent (79.2, 66.7 and 46.3%), while the difference between the use of a 22- and 24-cm stent was not significant. In patients >175 cm, a 24- or 26-cm stent might be more appropriate. Body heights can predict the ideal stent length. Based on a Chinese population, a 22-cm stent length is more appropriate for those <175 cm. A longer, 24- or 26-cm stent may be suitable for those >175 cm.


New molecular targets beyond KIT and PDGFRA in gastrointestinal stromal tumors: present and future.
The biological complexity of gastrointestinal stromal tumors (GISTs) and the concomitant increase in patients' life expectancy have enhanced the need for new therapeutic options to overcome the development of primary and secondary resistance to tyrosine kinase inhibitors. Aided by more sophisticated molecular biology techniques, researchers have recently sought to identify new therapeutic targets with a defined role in GISTs pathogenesis and a potential application in clinical practice. The first aim of this review is to describe new targets and drugs in GISTs, alone or in combination, both in pre-clinical and clinical settings. The second aim is to discuss the criticism in this field, the role of molecular biology, and future perspectives in light of the recent development of more sophisticated whole-genomic technologies. Several targets involved in GIST pathogenesis have been identified and novel biological drugs have recently been developed, offering new treatment options in the scenario of GIST therapy. However, the identification of new therapeutic targets represents a long process and requires a global overview of the problem and a multi-step approach to convert an initial intuition or casual finding into a systematic analytical process.


Randomized, double-blind comparison of ceftazidime and moxalactam in complicated urinary tract infections.
Sixty-seven patients with complicated urinary tract infections were randomized in double-blind fashion to ceftazidime or moxalactam (MOX). A total of 54 patients were evaluable, 27 in each group. Patients received 500 mg of antibiotic intravenously every 12 h, except for those with Pseudomonas aeruginosa randomized to MOX who received 2 g intravenously every 12 h. Toxic effects with ceftazidime were experienced by the following number of patients: pain with infusion, one; posttherapy diarrhea, one; liver function test elevations, two; and neutropenia, one. Toxic effects with MOX were experienced by the following number of patients: liver function test elevations, two; and prolonged prothrombin time, one. All resolved. At 1 week posttherapy, bacteriologic results were 74% cured, 11% relapsed, 15% reinfection with ceftazidime and 52% cured, 33% relapsed, and 19% reinfection with MOX. Ceftazidime was effective for infections caused by MOX-resistant P. aeruginosa. P. aeruginosa resistant to MOX and other beta-lactams was isolated from one patient after MOX therapy. Enterococcal reinfection was common in both groups.


Financial catastrophe, treatment discontinuation and death associated with surgically operable cancer in South-East Asia: Results from the ACTION Study.
This study assessed the extent to which individuals with surgically operable cancer in Southeast Asia experience financially catastrophic out-of-pocket costs, discontinuation of treatment, or death. The ACTION study is a prospective, 8-country, cohort study of adult patients recruited consecutively with an initial diagnosis of cancer from public and private hospitals. Participants were interviewed at baseline and 3 months. In this paper, we identified 4,584 participants in whom surgery was indicated in initial treatment plans and assessed the following competing outcomes: death, financial catastrophe (out-of-pocket costs of >30% of annual household income), treatment discontinuation, and hospitalization without financial catastrophe incurred. We then analyzed a range of predictors using a multinomial regression model. Of the participants, 72% were female and 44% had health insurance at baseline. At 3 months, 31% of participants incurred financial catastrophe, 8% had died, 23% had discontinued treatment, and 38% were hospitalized but avoided financial catastrophe. Health insurance status was found to be associated with lower odds of treatment discontinuation (odds ratio [OR], 0.60; 95% CI, 0.47-0.77) relative to hospitalization without financial catastrophe. Women had greater odds of financial catastrophe than men (OR, 1.35; 95% CI, 1.05-1.74), whereas lower socioeconomic status (range of indicators) was generally found to be associated with higher odds of death, treatment discontinuation, and financial catastrophe. Priority should be given to measures such as programs to extend social health insurance to offset the out-of-pocket costs associated with surgery for cancer faced in particular by women, the uninsured, and individuals of low socioeconomic status in Southeast Asia.


Sociolinguistic awareness and false belief in young Cantonese learners of English.
In this study, we examined whether sociolinguistic awareness and false belief were uniquely related in 3- and 4-year-old Cantonese-speaking children learning English as a second language. The English-use background of these children varied so that they possessed sociolinguistic awareness to different degrees. Results indicated that sociolinguistic awareness predicted false belief uniquely after controlling for age, nonverbal intelligence, English vocabulary, and family income for both the second language learners and the more balanced bilinguals. The group difference in false belief was adequately explained by the corresponding difference in sociolinguistic awareness over and above the other variables. Such findings provide evidence for the claim that false belief understanding is critically related to sociolinguistic awareness, which in turn is influenced by how a second language is learned.


A filamentous distribution for the herpes simplex virus type 2-encoded major DNA-binding protein.
Monoclonal antibodies reacting with the herpes simplex virus (HSV)-encoded major DNA-binding protein defined an intracellular filamentous network. This network was associated predominantly with the infected cell nucleus and occurred in cells infected with HSV type 2. It did not co-distribute with microfilaments, microtubules or intermediate filaments, and DNA synthesis was required for its formation. We suggest explanations for the occurrence and function of this novel filamentous network structure.