A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism.
Mandibuloacral dysplasia (MAD) is an autosomal recessive progeroid disorder associated with type A (partial) or B (generalized) lipodystrophy and is due to mutations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) genes. The objective of the study was to report a novel syndrome with some overlapping features with MAD. We report seven patients with mandibular hypoplasia, deafness, progeroid features (MDP), and associated lipodystrophy. These patients have similar features to MAD patients such as hypoplastic mandible, beaked nose, stiff joints, and sclerodermatous skin. However, the patients did not harbor any disease causing variants in LMNA or ZMPSTE24 and showed distinct characteristics such as sensorineural hearing loss and absence of clavicular hypoplasia and acroosteolysis. All males with MDP had undescended testes and were hypogonadal. One adult female showed lack of breast development. Skinfold thickness, dual-energy X-ray absorptiometry and whole-body magnetic resonance imaging for body fat distribution revealed a lack of lipodystrophy in a prepubertal female but a progressive loss of sc fat presenting with partial lipodystrophy in young adults and generalized lipodystrophy in older patients. Patients with MDP syndrome have a few overlapping but some distinct clinical features as compared with MAD, suggesting that it is a novel syndrome. The molecular basis of MDP syndrome remains to be elucidated.


Analysis of tubulin isotypes and mutations from taxol-resistant cells by combined isoelectrofocusing and mass spectrometry.
Six human alpha-tubulin and seven human beta-tubulin isotypes, each of which can undergo posttranslational modifications, have been detected by the reverse transcriptase-polymerase chain reaction. This repertoire of tubulin isotypes plays a role in development and in the building of specialized microtubule-based structures. In cell lines, the relationship between resistance to microtubule-interacting drugs and altered tubulin isotype expression profiles is often established by quantitation of cDNA and/or Western blot analysis. Tubulin mutations in major isotypes are detected by sequencing cDNA, but more analysis of expression of tubulin mutations at the protein level, to assess their role in drug resistance, is needed. We utilized a Taxol-based purification and high-resolution isoelectrofocusing combined with a mass spectrometry-based analysis of tubulin. This approach has allowed the separation and relative quantitation of tubulin isotypes having a difference in isoelectric point values of 0.01, without the need for two-dimensional gel electrophoresis. The specificity of tubulin isotype antibodies also has been established. In cell lines resistant to microtubule-stabilizing drugs that express heterozygous tubulin mutations, the relative amount of mutant tubulin expression has been determined. In these cell lines, the absence of betaII- and betaIVa-tubulin has been demonstrated, and an increased level of expression of betaIII-tubulin in resistant cells has been confirmed, indicating that this tubulin isotype is a unique marker of resistance.


HIV infection does not alter interferon α/β receptor 2 expression on mucosal immune cells.
The innate immune response induced by type I interferons (IFNs) plays a critical role in the establishment of HIV infection. IFNs are induced early in HIV infection and trigger an antiviral defense program by signaling through the IFNα/β receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. Changes in IFNAR expression in HIV target cells, as well as other immune cells, could therefore have important consequences for initial HIV spread. It was previously reported that IFNAR2 expression is increased in peripheral blood CD4+ CXCR4+ T cells of HIV+ patients compared to HIV uninfected controls, suggesting that HIV infection may alter the IFN responsiveness of target cells. However, the earliest immune cells affected by HIV in vivo reside in the gut-associated lymphoid tissue (GALT). To date, it remains unknown if IFNAR expression is altered in GALT immune cells in the context of HIV infection and exposure to IFNs, including the 12 IFNα subtypes. Here, we analyzed the expression of surface bound and soluble IFNAR2 on Lamina propria mononuclear cells (LPMCs) isolated from the GALT of HIV- individuals and in plasma samples of HIV+ patients. IFNAR2 expression varied between different T cells, B cells and natural killer cells, but was not altered following HIV infection. Furthermore, expression of the soluble IFNAR2a isoform was not changed in HIV+ patients compared to healthy donors, nor in LPMCs after HIV-1 infection ex vivo. Even though the 12 human IFNα subtypes trigger different biological responses and vary in their affinity to both receptor subunits, stimulation of LPMCs with different recombinant IFNα subtypes did not result in any significant changes in IFNAR2 surface expression. Our data suggests that potential changes in the IFN responsiveness of mucosal immune cells during HIV infection are unlikely dictated by changes in IFNAR2 expression.


Matrix metalloproteinase-9 is differentially expressed in nonfunctioning invasive and noninvasive pituitary adenomas and increases invasion in human pituitary adenoma cell line.
The complete resection of pituitary adenomas (PAs) is unlikely when there is an extensive local dural invasion and given that the molecular mechanisms remain primarily unknown. DNA microarray analysis was performed to identify differentially expressed genes between nonfunctioning invasive and noninvasive PAs. Gene clustering revealed a robust eightfold increase in matrix metalloproteinase (MMP)-9 expression in surgically resected human invasive PAs and in the (nonfunctioning) HP75 human pituitary tumor-derived cell line treated with phorbol-12-myristate-13-acetate; these results were confirmed by real-time polymerase chain reaction, gelatin zymography, reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and Northern blot analyses. The activation of protein kinase C (PKC) increased both MMP-9 activity and expression, which were blocked by some PKC inhibitors (Gö6976, bisindolylmaleimide, and Rottlerin), PKC-alpha, and PKC-delta small interfering (si)RNAs but not by hispidin (PKC-beta inhibitor). In a transmembrane invasion assay, phorbol-12-myristate-13-acetate (100 nmol/L) increased the number of invaded HP75 cells, a process that was attenuated by PKC inhibitors, MMP-9 antibody, PKC-alpha siRNA, or PKC-delta siRNA. These results demonstrate that MMP-9 and PKC-alpha or PKC-delta may provide putative therapeutic targets for the control of PA dural invasion.


Surface plasmon-enhanced photoluminescence of DCJTB by using silver nanoparticle arrays.
It is demonstrated that photoluminescence of DCJTB can be enhanced by surface plasmons occurred in silver nanoparticle arrays on glass substrates fabricated by using nanosphere lithography (NSL) combined with reactive ion etching (RIE). By changing the size of the seed polystyrene nanosphere with fixed thickness of SiO(2) film as a buffer layer between silver nanoparticles and fluorescent dye, we systematically studied the interaction between surface plasmons in Ag nanostructures and fluorescent dye by measuring the photoluminescence and time-resolved photoluminescence (TRPL) of the samples. As compared with pure DCJTB, it is observed that PL enhancement as high as 9.4 times and life time shortening from 0.966 ns shortened to 0.63 ns can be achieved with polystyrene nanosphere 430 nm in diameter. The physical origin due to plasmonic excitation has been clarified from 3D finite element simulations, as well as the assistance of UV-visible reflectance spectrum.


Mapping protein-ligand interactions in the gas phase using a functional group replacement strategy. Comparison of CID and BIRD activation methods.
Intermolecular interactions in the gaseous ions of two protein-ligand complexes, a single chain antibody (scFv) and its trisaccharide ligand (α-D-Galp-(1→2)-[α-D-Abep-(1→3)]-α-Manp-OCH3, L1) and streptavidin homotetramer (S4) and biotin (B), were investigated using a collision-induced dissociation (CID)-functional group replacement (FGR) strategy. CID was performed on protonated ions of a series of structurally related complexes based on the (scFv + L1) and (S4 + 4B) complexes, at the +10 and +13 charge states, respectively. Intermolecular interactions were identified from decreases in the collision energy required to dissociate 50% of the reactant ion (Ec50) upon modification of protein residues or ligand functional groups. For the (scFv + L1)(10+) ion, it was found that deoxygenation of L1 (at Gal C3 and C6 and Man C4 and C6) or mutation of His101 (to Ala) resulted in a decrease in Ec50 values. These results suggest that the four hydroxyl groups and His101 participate in intermolecular H-bonds. These findings agree with those obtained using the blackbody infrared radiative dissociation (BIRD)-FGR method. However, the CID-FGR method failed to reveal the relative strengths of the intermolecular interactions or establish Man C4 OH and His101 as an H-bond donor/acceptor pair. The CID-FGR method correctly identified Tyr43, but not Ser27, Trp79, and Trp120, as a stabilizing contact in the (S4 + 4B)(13+) ion. In fact, mutation of Trp79 and Trp120 led to an increase in the Ec50 value. Taken together, these results suggest that the CID-FGR method, as implemented here, does not represent a reliable approach for identifying interactions in the gaseous protein-ligand complexes.


The impact of calcium volume and distribution in aortic root injury related to balloon-expandable transcatheter aortic valve replacement.
A detailed assessment of calcium within the aortic root may provide important additional information regarding the risk of aortic root injury during transcatheter heart valve replacement (TAVR). We sought to delineate the effect of calcium volume and distribution on aortic root injury during TAVR. Thirty-three patients experiencing aortic root injury during TAVR with a balloon-expandable valve were compared with a control group of 153 consecutive TAVR patients without aortic root injury (as assessed by post-TAVR multidetector CT). Using commercial software to analyze contrast-enhanced pre-TAVR CT scans, calcium volume was determined in 3 regions: (1) the overall left ventricular outflow tract (LVOT), extending 10 mm down from the aortic annulus plane; (2) the upper LVOT, extending 2 mm down from the annulus plane; and (3) the aortic valve region. Calcium volumes in the upper LVOT (median, 29 vs 0 mm(3); P < .0001) and overall LVOT (median, 74 vs 3 mm(3); P = .0001) were higher in patients who experienced aortic root injury compared with the control group. Calcium in the aortic valve region did not differ between groups. Upper LVOT calcium volume was more predictive of aortic root injury than overall LVOT calcium volume (area under receiver operating curve [AUC], 0.78; 95% confidence interval, 0.69-0.86 vs AUC, 0.71; 95% confidence interval, 0.62-0.82; P = .010). Upper LVOT calcium below the noncoronary cusp was significantly more predictive of aortic root injury compared to calcium underneath the right coronary cusp or the left coronary cusp (AUC, 0.81 vs 0.68 vs 0.64). Prosthesis oversizing >20% (likelihood ratio test, P = .028) and redilatation (likelihood ratio test, P = .015) improved prediction of aortic root injury by upper LVOT calcium volume. Calcification of the LVOT, especially in the upper LVOT, located below the noncoronary cusp and extending from the annular region, is predictive of aortic root injury during TAVR with a balloon-expandable valve.


Impulsivity as a risk factor for HIV transmission in men who have sex with men: a delay discounting approach.
Delay discounting (DD) is a measure of impulsivity that describes the subjective decline in value of a consequence as the delay to that consequence increases. We sought to assess whether the results of a monetary DD task would be predictive of sexual risk-taking in a group of Internet-using men who have sex with men (MSM). 1402 participants completed an online survey that included questions about the participant's demographics, sexual history and behavior, drug use, sexual compulsivity, and a monetary DD task. High DD was associated with increased odds of reporting >2 UAI partners in the past 12 months [aOR = 1.5 (1.1-2.1)]. Future studies should examine the utility of DD as a predictor of risky sexual behavior, as well as explore the possibility of HIV prevention interventions targeting DD.


Shaping the metaphase chromosome: coordination of cohesion and condensation.
Recent progress in our understanding of mitotic chromosome dynamics has been accelerated by the identification of two essential protein complexes, cohesin and condensin. Cohesin is required for holding sister chromatids (duplicated chromosomes) together from S phase until the metaphase-to-anaphase transition. Condensin is a central player in chromosome condensation, a process that initiates at the onset of mitosis. The main focus of this review is to discuss how the mitotic metaphase chromosome is assembled and shaped by a precise balance between the cohesion and condensation machineries. We argue that, in different eukaryotic organisms, the balance of cohesion and condensation is adjusted in such a way that the size and shape of the resulting chromosomes are best suited for their accurate segregation.


Pain and Self-reported Swollen Joints Are Main Drivers of Patient-reported Flares in Rheumatoid Arthritis: Results from a 12-month Observational Study.
To examine prospectively self-reported flare characteristics and their longitudinal association with disease activity and patient-reported outcomes (PRO) in patients with rheumatoid arthritis (RA). Consecutive RA patients with 28-joint count Disease Activity Score based on C-reactive protein (DAS28-CRP) < 3.2 and no swollen joints were examined at baseline, Month 6, and Month 12. Assessments included joint counts, DAS28-CRP, visual analog scale-evaluator's global assessment (EGA), and PRO. Every third month, patients completed the Flare Assessment in Rheumatoid Arthritis and RA Flare Questionnaire, and disclosed self-management strategies. Flaring and non-flaring patients were compared and longitudinal associations between self-reported flare status (yes/no) and disease activity, PRO, and treatment escalation were explored. Among 80 patients with RA [74% females, mean (SD) age 63 (10) yrs, disease duration 11 (7) yrs, and baseline DAS28-CRP 1.9 (0.6)], 64 (80%) reported flare at least once during 12 months. Fifty-five percent of flares lasted less than 1 week. Common self-management strategies were analgesics (50%) and restricted activities (38%). Patients who reported being in flare had consistently higher disease activity measures and PRO compared to patients without flare. In a partly adjusted model, all flare domains, patient-reported swollen and tender joint counts and disease activity measures were associated with flares. In fully adjusted analyses, present flare was independently associated with pain (OR 1.85, 95% CI 1.34-2.60), patient-reported swollen joints (OR 1.18, 95% CI 1.03-1.36), and higher EGA (OR 1.15, 95% CI 1.04-1.28). Treatment escalation was associated with present flare (p ≤ 0.001). In RA, self-reported flares were frequent, mainly managed by analgesics, substantiated by higher disease activity measures, independently associated with pain and patient-reported swollen joints, and related to treatment escalation.


An ESR and ENDOR study of irradiated 6Li-formate.
Lithium formate ((6)LiOOCH.H(2)O), 95% (6)Li enrichment, combined with an exchange of crystallization water with D(2)O was investigated. The ESR spectrum of the radiation induced free radicals stable at room temperature consists of a singlet with a narrow line width, 0.92mT. (6)Li has smaller magnetic moment and nuclear spin, which resulted in the narrower line width accompanied with an increase in peak amplitude. In comparison with lithium formate with natural isotopic composition, (6)Li (7.5%, I=1) and (7)Li (92.5%, I=3/2), the sensitivity was increased by a factor of two. With optimised spectrometer settings (6)Li formate had seven times higher sensitivity compared to alanine. Therefore this material is proposed as a dosimeter material in a dose range down to 0.1Gy. The g and the (13)C-hyperfine (hf) tensors of the CO(2)(-) radical anion, major paramagnetic products, were evaluated to be g=(2.0037, 1.9975, 2.0017), and A((13)C)=(465.5, 447.5, 581.3) MHz for polycrystalline samples at room temperature. Furthermore, the (1)H-hf and (6)Li-hf tensors observed for the surroundings of CO(2)(-) by ENDOR technique were in fairly good agreement with DFT calculations. The CO(2)(-) radicals are found to be so stable that the formate is applicable to the ESR dosimetry, because of fully relaxing in a fully relaxed geometrical structure of the CO(2)(-) component and remaining tight binding with the surroundings after the H atom detachment from HCO(2)(-).


Influence of Motion Therapy in the Prevention of Lumbar Pain Syndrome Relapse.
Lumbar pain syndrome is one of the most common conditions in clinical practice, more common than 290 other pathological conditions, which affect up to 84% of adults in a certain period of their life. The origin of the lower back pain can be classified as mechanical, neuropathic and secondary due to another illness. Patient education and information, muscle strengthening exercises, maintenance of routine daily physical activity and pain therapy are the basis of acute non-specific pain syndrome therapy. To determine the success of the motion therapy procedure in the prevention of lumbar pain syndrome relapse. The research is prospective, longitudinal, manipulative and controllable. It was conducted in the private practice "Praxis - dr. Pecar" in the period from June 20, 2014 to June 1, 2016, and included 200 respondents with symptoms of lumbar pain syndromes divided into the experimental (n=100) and control (n=100) groups. The presence of lumbar pain syndrome relapse in respondents experimental and control group was recorded in the second and third clinical examination. In the second examination, 4 (4%) of the respondents from experimental group and 37 (37%) of the control group responded had LBS relapse. In the third examination, the number of respondents with recurrent LBS in the experimental group was 4 (4%), while in the control group was 17 (17%). After the study, no statistically significant difference was observed in the mean age of respondents who had LBS relapse compared to respondents without LBS relapse, as well as significant influence of sex structure on relapse in the experimental and control group during the second and third examination. After the second examination, the relapse rate in the experimental group was statistically significantly higher in the respondents withstanding jobs, while there was no statistically significant difference in the control group and both groups after the third examination.


Trans-arterial radio-embolization: a new chance for patients with hepatocellular cancer to access liver transplantation, a world review.
Liver transplantation (LT) for hepatocellular carcinoma (HCC) within the Milan criteria (MC) is nowadays a curative procedure. Yttrium-90 microspheres radioembolization (Y90-RE) has shown to be an effective and safe treatment of primary liver tumors. The aim of this work is to offer a view on the publications which report on the use of Y90-RE as bridge or downstaging prior to LT. Twenty articles have been considered for this world review. About 178 LT in patients were treated with Y90-RE prior to LT. Most of patients had a downstaging strategy. In all series alpha-fetoproteins decreased between Y90-RE and LT. Therefore, Y90-RE may have an important role in the bridge and downstaging treatments.


Cerebrospinal fluid levels of substance P and calcitonin-gene-related peptide: correlation with sural nerve levels and neuropathic signs in sensory diabetic polyneuropathy.
1. Lumbar spinal substance P and calcitonin-gene-related peptide derive from spillage out of the dorsal horns associated with activity of small primary sensory afferents (C- and A delta-fibres). Cerebrospinal fluid and sural nerve levels of substance P and calcitonin-gene-related peptide have been measured in patients with diabetic polyneuropathy to determine whether differences in small primary sensory afferent activity are related to the presence or absence of painful symptoms. 2. Calcitonin-gene-related peptide was undetectable in the cerebrospinal fluid of the majority of diabetic patients (14 out of 22); it was lower overall in diabetic patients as compared with control subjects (P < 0.01), it was lower in those diabetic patients with painless neuropathy (100% undetectable) as compared with those with painful neuropathy (50% undetectable; P < 0.05) and it correlated conversely with warming threshold (r = 0.50; P < 0.01). 3. Substance P showed no overall numerical intergroup differences or correlation with other measured variables, but six diabetic patients as compared with one control subject had undetectable cerebrospinal fluid levels and the proportion of patients with undetectable levels was higher in the group with painless neuropathy than in the group with painful neuropathy (P < 0.05). 4. The levels of each peptide in cerebrospinal fluid correlated with its equivalent in sural nerve (P < 0.01 for calcitonin-gene-related peptide and P < 0.03 for substance P). Calcitonin-gene-related peptide correlated with substance P in the sural nerve (r = 0.84; P < 0.002) and in the cerebrospinal fluid (r = 0.30; P < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)


Non-pharmacological management of behavioural symptoms of dementia.
This article describes a 6-month pilot project in which a community mental health team provided a dementia inreach service into 4 care homes in Birmingham, UK. The project included analysis of the impact of the service at the end of the project as well as a literature review of dementia care in care homes, and especially the issue of antipsychotic medication use and non-pharmacological approaches in managing behavioural and psychological symptoms of dementia (BPSD). The project included training care home staff in the management of BPSD; 2 questionnaires distributed at the beginning of the project found that 65% of care home staff felt a need for education and awareness, practical problem-solving and counselling in managing BPSD. Self-reported knowledge of common mental health problems and dementia increased in care home staff at the end of the project by a margin of 7% and 11% respectively. Reported confidence in managing behavioural problems increased by 9% among care home staff at the end of the project. The project achieved regular monitoring of psychotropic medications, and enabled the discharge of 14 out of 63 existing patients in the selected homes. The project also provided guidance for non-pharmacological techniques for management of BPSD, which included relaxation techniques, distraction techniques, reality orientation, reminiscence work, needs led therapy, music therapy, person-centred approach and behaviour therapy.


Photo-oxidation of proteins and its role in cataractogenesis.
Proteins comprise approximately 68% of the dry weight of cells and tissues and are therefore potentially major targets for photo-oxidation. Two major types of processes can occur with proteins. The first of these involves direct photo-oxidation arising from the absorption of UV radiation by the protein, or bound chromophore groups, thereby generating excited states (singlet or triplets) or radicals via photo-ionisation. The second major process involves indirect oxidation of the protein via the formation and subsequent reactions of singlet oxygen generated by the transfer of energy to ground state (triplet) molecular oxygen by either protein-bound, or other, chromophores. The basic principles behind these mechanisms of photo-oxidation of amino acids, peptides and proteins and the potential selectivity of damage are discussed. Emphasis is placed primarily on the intermediates that are generated on amino acids and proteins, and the subsequent reactions of these species, and not the identity or chemistry of the sensitizer itself, unless the sensitizing group is itself intrinsic to the protein. A particular system is then discussed--the cataractous lens--where UV photo-oxidation may play a role in the aetiology of the disease, and tryptophan-derived metabolites act as UV filters.


Free radicals and low-level photon emission in human pathogenesis: state of the art.
Convincing evidence supports a role for oxidative stress in the pathogenesis of many chronic diseases. The model includes the formation of radical oxygen species (ROS) and the misassembly and aggregation of proteins when three tiers of cellular defence are insufficient: (a) direct antioxidative systems, (b) molecular damage repairing systems, and (c) compensatory chaperone synthesis. The aim of the present overview is to introduce (a) the basics of free radical and antioxidant metabolism, (b) the role of the protein quality control system in protecting cells from free radical damage and its relation to chronic diseases, (c) the basics of the ultraweak luminescence as marker of the oxidant status of biological systems, and (d) the research in human photon emission as a non-invasive marker of oxidant status in relation to chronic diseases. In considering the role of free radicals in disease, both their generation and their control by the antioxidant system are part of the story. Excessive free radical production leads to the production of heat shock proteins and chaperone proteins as a second line of protection against damage. Chaperones at the molecular level facilitate stress regulation vis-à-vis protein quali y control mechanisms. The manifestation of misfolded proteins and aggregates is a hallmark of a range of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amylotrophic lateral sclerosis, polyglutamine (polyQ) diseases, diabetes and many others. Each of these disorders exhibits aging-dependent onset and a progressive, usually fatal clinical course. The second part reviews the current status of human photon emission techniques and protocols for recording the human oxidative status. Sensitive photomultiplier tubes may provide a tool for non-invasive and continuous monitoring of oxidative metabolism. In that respect, recording ultraweak luminescence has been favored compared to other indirect assays. Several biological models have been used to illustrate the technique in cell cultures and organs in vivo. This initiated practical applications addressing specific human pathological issues. Systematic studies on human emission have presented information on: (a) procedures for reliable measurements, and spectral analysis, (b) anatomic intensity of emission and left-right symmetries, (c) biological rhythms in emission, (d) physical and psychological influences on emission, (e) novel physical characteristics of emission, and (f) the identification of ultraweak photon emission with the staging of ROS-related damage and disease. It is concluded that both patterns and physical properties of ultraweak photon emission hold considerable promise as measure for the oxidative status.


Radiotherapy plus concurrent or sequential temozolomide for glioblastoma in the elderly: a meta-analysis.
Many physicians are reluctant to treat elderly glioblastoma (GBM) patients as aggressively as younger patients, which is not evidence based due to the absence of validated data from primary studies. We conducted a meta-analysis to provide valid evidence for the use of the aggressive combination of radiotherapy (RT) and temozolomide (TMZ) in elderly GBM patients. A systematic literature search was conducted using the PubMed, EMBASE and Cochrane databases. Studies comparing combined RT/TMZ with RT alone in elderly patients (≥65 years) with newly diagnosed GBM were eligible for inclusion. No eligible randomized trials were identified. Alternatively, a meta-analysis of nonrandomized studies (NRSs) was performed, with 16 studies eligible for overall survival (OS) analysis and nine for progression-free survival (PFS) analysis. Combined RT/TMZ was shown to reduce the risk of death and progression in elderly GBM patients compared with RT alone (OS hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.48-0.72; PFS: HR 0.58, 95% CI 0.41-0.84). Evaluable patients were reported to tolerate combined treatment but certain toxicities, and especially hematological toxicities, were more frequently observed. Limited data on O6-methylguanine-DNA methyltransferase (MGMT) promoter status and quality of life were reported. The meta-analysis of NRSs provided level 2a evidence (Oxford Centre for Evidence-Based Medicine) that combined RT/TMZ conferred a clear survival benefit on a selection of elderly GBM patients who had a favorable prognosis (e.g., extensive resection, favorable KPS). Toxicities were more frequent but acceptable. Future randomized trials are warranted to justify a definitive conclusion.


Effect evaluation of a heated ambulance mattress-prototype on thermal comfort and patients' temperatures in prehospital emergency care--an intervention study.
The ambulance milieu does not offer good thermal comfort to patients during the cold Swedish winters. Patients' exposure to cold temperatures combined with a cold ambulance mattress seems to be the major factor leading to an overall sensation of discomfort. There is little research on the effect of active heat delivered from underneath in ambulance care. Therefore, the aim of this study was to evaluate the effect of an electrically heated ambulance mattress-prototype on thermal comfort and patients' temperatures in the prehospital emergency care. A quantitative intervention study on ambulance care was conducted in the north of Sweden. The ambulance used for the intervention group (n=30) was equipped with an electrically heated mattress on the regular ambulance stretcher whereas for the control group (n=30) no active heat was provided on the stretcher. Outcome variables were measured as thermal comfort on the Cold Discomfort Scale (CDS), subjective comments on cold experiences, and finger, ear and air temperatures. Thermal comfort, measured by CDS, improved during the ambulance transport to the emergency department in the intervention group (p=0.001) but decreased in the control group (p=0.014). A significant higher proportion (57%) of the control group rated the stretcher as cold to lie down compared to the intervention group (3%, p<0.001). At arrival, finger, ear and compartment air temperature showed no statistical significant difference between groups. Mean transport time was approximately 15 minutes. The use of active heat from underneath increases the patients' thermal comfort and may prevent the negative consequences of cold stress.


Cloning, characterization, and expression of the macrophage migration inhibitory factor gene from the Pacific white shrimp Litopenaeus vannamei (Penaeidae).
The macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine that mediates both innate and adaptive immune responses. In this study, we identified a homolog of MIF in the Pacific white shrimp Litopenaeus vannamei. The MIF cDNA contained a 363-bp open reading frame encoding a 120-amino acid protein with a calculated molecular mass of 13.442 kDa and a theoretical isoelectric point of 6.57. The L. vannamei MIF shared high amino acid identity with MIFs of other invertebrates. Tissue distribution analysis by quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the L. vannamei MIF was abundantly expressed in the blood, heart, and hepatopancreas, was moderately expressed in the gill, and was weakly expressed in the muscle and intestine. Furthermore, in order to gain a basic understanding of the role of MIF in the shrimp immune response against viral infection, its mRNA expression was determined in the hepatopancreas of L. vannamei at different stages after white spot syndrome virus (WSSV) challenge using qRT-PCR. The result indicated that the expression of MIF was significantly upregulated after WSSV injection, suggesting that MIF may be involved in the response to viral infection in shrimp.


Systematically evaluating the impact of diagnosis-related groups (DRGs) on health care delivery: a matrix of ethical implications.
Swiss hospitals were required to implement a prospective payment system for reimbursement using a diagnosis-related groups (DRGs) classification system by the beginning of 2012. Reforms to a health care system should be assessed for their impact, including their impact on ethically relevant factors. Over a number of years and in a number of countries, questions have been raised in the literature about the ethical implications of the implementation of DRGs. However, despite this, researchers have not attempted to identify the major ethical issues associated with DRGs systematically. To address this gap in the literature, we have developed a matrix for identifying the ethical implications of the implementation of DRGs. It was developed using a literature review, and empirical studies on DRGs, as well as a review and analysis of existing ethics frameworks. The matrix consists of the ethically relevant parameters of health care systems on which DRGs are likely to have an impact; the ethical values underlying these parameters; and examples of specific research questions associated with DRGs to illustrate how the matrix can be applied. While the matrix has been developed in light of the Swiss health care reform, it could be used as a basis for identifying the ethical implications of DRG-based systems worldwide and for highlighting the ethical implications of other kinds of provider payment systems (PPS).


Development of a harmonized method for the profiling of amphetamines. II. Stability of impurities in organic solvents.
The present study focused on the stability of 22 amphetamine impurities dissolved in six organic solvents: isooctane, toluene, ethanol, dichloromethane, ethyl acetate, and diethyl ether. The aim was to find the most inert, and thereby most suitable, solvent for amphetamine profiling. Mixtures of the impurities were prepared in the different solvents, and changes in the concentrations of the individual compounds over-time were monitored by gas chromatographic analysis after 0, 4, 12, 24, 48, and 96 h. Isooctane and toluene provided the most inert conditions, although, a few of the impurities were insufficiently stable in these two solvents. The present experiments were performed as a part of the development of a harmonized method for profiling of amphetamine. The results can be used to support the choice of organic solvents for sample preparation. They also provide information about the stability of the impurities that are found in profiles of illicit amphetamine. This is essential due to the fact, that unstable compounds can have a negative influence on the comparison of profiles.


Vaccinia virus-encoded ribonucleotide reductase subunits are differentially required for replication and pathogenesis.
Ribonucleotide reductases (RRs) are evolutionarily-conserved enzymes that catalyze the rate-limiting step during dNTP synthesis in mammals. RR consists of both large (R1) and small (R2) subunits, which are both required for catalysis by the R1(2)R2(2) heterotetrameric complex. Poxviruses also encode RR proteins, but while the Orthopoxviruses infecting humans [e.g. vaccinia (VACV), variola, cowpox, and monkeypox viruses] encode both R1 and R2 subunits, the vast majority of Chordopoxviruses encode only R2 subunits. Using plaque morphology, growth curve, and mouse model studies, we investigated the requirement of VACV R1 (I4) and R2 (F4) subunits for replication and pathogenesis using a panel of mutant viruses in which one or more viral RR genes had been inactivated. Surprisingly, VACV F4, but not I4, was required for efficient replication in culture and virulence in mice. The growth defects of VACV strains lacking F4 could be complemented by genes encoding other Chordopoxvirus R2 subunits, suggesting conservation of function between poxvirus R2 proteins. Expression of F4 proteins encoding a point mutation predicted to inactivate RR activity but still allow for interaction with R1 subunits, caused a dominant negative phenotype in growth experiments in the presence or absence of I4. Co-immunoprecipitation studies showed that F4 (as well as other Chordopoxvirus R2 subunits) form hybrid complexes with cellular R1 subunits. Mutant F4 proteins that are unable to interact with host R1 subunits failed to rescue the replication defect of strains lacking F4, suggesting that F4-host R1 complex formation is critical for VACV replication. Our results suggest that poxvirus R2 subunits form functional complexes with host R1 subunits to provide sufficient dNTPs for viral replication. Our results also suggest that R2-deficient poxviruses may be selective oncolytic agents and our bioinformatic analyses provide insights into how poxvirus nucleotide metabolism proteins may have influenced the base composition of these pathogens.


In search of genes associated with risk for psychopathic tendencies in children: a two-stage genome-wide association study of pooled DNA.
Quantitative genetic data from our group indicates that antisocial behaviour (AB) is strongly heritable when coupled with psychopathic, callous-unemotional (CU) personality traits. We have also demonstrated that the genetic influences for AB and CU overlap considerably. We conducted a genome-wide association scan that capitalises on these findings in an attempt to identify quantitative trait loci (QTLs) that may increase risk for psychopathic tendencies (AB+/CU+). Teacher ratings at age 7 were used to screen 8374 twins with available DNA samples for individuals that were high vs. low on both AB and CU. In Stage 1, we screened for allele frequency differences in 642,432 autosomal single-nucleotide polymorphisms (SNPs) using the Affymetrix 6.0 GeneChip with pooled DNA for high-scoring (AB+/CU+) versus low-scoring children (N = approximately 300/group). In Stage 2, we tested the 3000 most strongly associated SNPs from Stage 1 for association in the same direction in a second sample of high- versus low-scoring children from the same twin study (18% co-twins). Using allele frequencies estimated from pooled DNA, we found suggestive evidence for enrichment of association in the second stage of our two-stage genome-wide association design and focus on reporting the 30 top-ranking SNPs nominally associated with psychopathic tendencies. These SNPs include neurodevelopmental genes such as ROBO2. Although none of the SNPs reached genome-wide statistical significance we have generated a list of SNPs that are potentially associated with psychopathic tendencies, which we believe warrant verification and replication in large independent and clinical samples.


Who needs laboratories and who needs statins?: comparative and cost-effectiveness analyses of non-laboratory-based, laboratory-based, and staged primary cardiovascular disease screening guidelines.
Early detection and treatment of cardiovascular disease (CVD) risk factors produces significant clinical benefits, but no consensus exists on optimal screening algorithms. This study aimed to evaluate the comparative and cost-effectiveness of staged laboratory-based and non-laboratory-based total CVD risk assessment. We used receiver operating characteristic curve and cost-effectiveness modeling methods to compare strategies with and without laboratory components and used single-stage and multistage algorithms, including approaches based on Framingham risk scores (laboratory-based assessments for all individuals). Analyses were conducted using data from 5998 adults in the Third National Health and Nutrition Examination Survey without history of CVD using 10-year CVD death as the main outcome. A microsimulation model projected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios for 60 Framingham-based, non-laboratory-based, and staged screening approaches. Across strategies, the area under the receiver operating characteristic curve was 0.774 to 0.780 in men and 0.812 to 0.834 in women. There were no statistically significant differences in area under the receiver operating characteristic curve between multistage and Framingham-based approaches. In cost-effectiveness analyses, multistage strategies had incremental cost-effectiveness ratios of $52,000/QALY and $83,000/QALY for men and women, respectively. Single-stage/Framingham-based strategies were dominated (higher cost and lower QALYs) or had unattractive incremental cost-effectiveness ratios (>$300,000/QALY) compared with single-stage/non-laboratory-based and multistage approaches. Non-laboratory-based CVD risk assessment can be useful in primary CVD prevention as a substitute for laboratory-based assessments or as the initial component of a multistage approach. Cost-effective multistage screening strategies could avoid 25% to 75% of laboratory testing used in CVD risk screening with predictive power comparable with Framingham risks.


Erythrocytosis in a patient on hemodialysis for thirteen years.
Most hemodialysis patients exhibit renal anemia mainly due to erythropoietin deficiency as a result of impaired erythropoetin production in the kidney. However, erythrocytosis in patients with renal failure requiring hemodialysis is extremely rare. We report the development of erythrocytosis in a patient with a polycystic kidney disease on hemodialysis for 13 years. She had erythrocytosis with increased serum erythropoietin levels despite severe secondary hyperparathyroidism, which is known to depress erythrocytosis. Since neither renal disease (renal cell carcinoma) nor extrarenal diseases (hypoxia, hepatoma, cerebellar diseases) linked with erythropoietin production could be proven, this case might be one with inappropriate idiopathic erythropoietin production after 13 years of hemodialysis, the longest duration of dialysis in the literature before erythrocytosis was observed.


Seasonal changes in amount and patterns of physical activity in women.
Environmental factors including seasonal changes are important to guide physical activity (PA) programs to achieve or sustain weight loss. The goal was to determine seasonal variability in the amount and patterns of free-living PA in women. PA was measured in 57 healthy women from metropolitan Nashville, TN, and surrounding counties (age: 20 to 54 years, body mass index: 17 to 48 kg/m2) using an accelerometer for 7 consecutive days during 3 seasons within 1 year. PA counts and energy expenditure (EE) were measured in a whole-room indirect calorimeter and used to model accelerometer output and to calculate daily EE and intensity of PA expressed as metabolic equivalents (METs). PA was lower in winter than in summer (131+/-45 vs. 144+/-54x10(3) counts/d; P=.025) and in spring/fall (143+/-48x10(3) counts/d; P=.027). On weekends, PA was lower in winter than in summer by 22,652 counts/d (P=.008). In winter, women spent more time in sedentary activities than in summer (difference 35 min/d; P=.007) and less time in light activities (difference -29 min/d, P=.018) and moderate or vigorous activities (difference -6 min/d, P=.051). Women living in the southeastern United States had lower PA levels in winter compared with summer and spring/fall, and the magnitude of this effect was greater on weekends than weekdays.


A new anti-inflammatory flavonol glycoside from Alchornea floribunda leaves.
Alchornea floribunda leaves are widely used in African ethnomedicine for the management of acute and chronic inflammatory disorders. In the present study, bioactivity-guided fractionation of the ethyl acetate fraction of the methanol leaf extract of the plant material led to the isolation of a new flavonol glycoside (AFF1). The anti-inflammatory activity of this novel compound was evaluated using egg albumen-induced rat paw oedema as a model of inflammation. AFF1 showed significant inhibition of the rat paw oedema in a dose-dependent manner. The activity of AFF1 (50 mg kg(-1)) was higher than that of the standard anti-inflammatory drug, aspirin (100 mg kg(-1)). The compound also significantly (p < 0.001) inhibited heat-induced haemolysis of human erythrocytes in vitro. The structure of AFF1 was elucidated as 3,5,7,3'-tetrahydroxyflavone-3-O-alpha-L-rhamnoside, using a combination of UV, IR, 1D and 2D (COSY) 1H-NMR spectroscopy. This compound, in part, accounts for the anti-inflammatory effect of A. floribunda leaves.


Patients' willingness to pay for anti-emetic treatment.
Post-operative nausea and vomiting (PONV) is a common complication of anaesthesia. This study was conducted in 100 German and 100 Turkish patients scheduled for elective surgery under general anaesthesia to assess the amount patients were willing to pay for an anti-emetic that completely prevented PONV. Post-operatively, using Dixon's up and down method, patients completed an interactive computer questionnaire with a random starting point to determine how much of their own money they were willing to pay for a totally effective anti-emetic treatment. On average, participants were willing to pay 65 euro in Germany and 68 euro in Turkey to avoid PONV. However, patients who actually experienced PONV were willing to pay larger amounts: 96 euro in Germany and 99 euro in Turkey. The amount patients were willing to pay was related to female sex, history of motion sickness, non-smoking status and better education. Despite differences in political and cultural origin, health care system and financial background, the amount patients were willing to pay for an effective anti-emetic was similar in both Germany and Turkey to that reported previously for the USA.


Molecular characterization of a novel UDP-galactose:fucoside alpha3-galactosyltransferase that modifies Skp1 in the cytoplasm of Dictyostelium.
Skp1 is a nucleocytoplasmic protein that is post-translationally modified by a pentasaccharide, Gal alpha1,Gal alpha1,3Fuc alpha1,2Gal-beta1,3GlcNAc alpha1O-, at a 4-hydroxylated derivative of Pro-143 in the amebazoan Dictyostelium discoideum. An enzymatic activity that catalyzes formation of the Gal alpha1,3Fuc linkage by transfer of Gal from UDP-alphaGal to Fuc alpha1,2Gal beta1,3GlcNAc alpha1O-benzyl, or the corresponding glycoform of Skp1, was described previously in cytosolic extracts of Dictyostelium. A protein GT78 associated with this activity has been purified to chromatographic homogeneity. In-gel tryptic digestion followed by nano-liquid chromatography-mass spectrometry on a quadrupole time-of-flight geometry instrument with data-dependent tandem mass spectrometry acquisition yielded a number of peptide fragmentation spectra, nine of which were manually de novo sequenced and found to map onto a predicted 3-exon gene of unknown function on chromosome 4. GT78 is predicted to comprise 648 amino acids with an N-terminal glycosyltransferase and a C-terminal beta-propeller domain. Overexpression of GT78 with a His6-tag resulted in a 120-fold increase in GalT-activity in cytosolic extracts, and purified His6-GT78 exhibited alpha3GalT-activity toward a synthetic acceptor substrate. Expression of the truncated N-terminal region confirmed the predicted catalytic activity of this domain. Disruption of the GT78 gene led to a loss of enzyme activity in extracts and accumulation of the non-galactosylated isoform of Skp1 in cells. GT78 therefore represents the Skp1 alpha3GalT, and its mechanism conforms to the sequential model of Skp1 glycosylation in the cytoplasm shown for earlier enzymes in the pathway. Informatics studies suggest that related catalytic domains are expressed in the Golgi or cytoplasm of plants, other protozoans, and animals.


Closed incision negative pressure wound therapy versus standard dressings in obese women undergoing caesarean section: multicentre parallel group randomised controlled trial.
To determine the effectiveness of closed incision negative pressure wound therapy (NPWT) compared with standard dressings in preventing surgical site infection (SSI) in obese women undergoing caesarean section. Multicentre, pragmatic, randomised, controlled, parallel group, superiority trial. Four Australian tertiary hospitals between October 2015 and November 2019. Eligible women had a pre-pregnancy body mass index of 30 or greater and gave birth by elective or semi-urgent caesarean section. 2035 consenting women were randomised before the caesarean procedure to closed incision NPWT (n=1017) or standard dressing (n=1018). Allocation was concealed until skin closure. The primary outcome was cumulative incidence of SSI. Secondary outcomes included depth of SSI (superficial, deep, or organ/body space), rates of wound complications (dehiscence, haematoma, seroma, bleeding, bruising), length of stay in hospital, and rates of dressing related adverse events. Women and clinicians were not masked, but the outcome assessors and statistician were blinded to treatment allocation. The pre-specified primary intention to treat analysis was based on a conservative assumption of no SSI for a minority of women (n=28) with missing outcome data. Post hoc sensitivity analyses included best case analysis and complete case analysis. In the primary intention to treat analysis, SSI occurred in 75 (7.4%) women treated with closed incision NPWT and in 99 (9.7%) women with a standard dressing (risk ratio 0.76, 95% confidence interval 0.57 to 1.01; P=0.06). Post hoc sensitivity analyses to explore the effect of missing data found the same direction of effect (closed incision NPWT reducing SSI), with statistical significance. Blistering occurred in 40/996 (4.0%) women who received closed incision NPWT and in 23/983 (2.3%) who received the standard dressing (risk ratio 1.72, 1.04 to 2.85; P=0.03). Prophylactic closed incision NPWT for obese women after caesarean section resulted in a 24% reduction in the risk of SSI (3% reduction in absolute risk) compared with standard dressings. This difference was close to statistical significance, but it likely underestimates the effectiveness of closed incision NPWT in this population. The results of the conservative primary analysis, multivariable adjusted model, and post hoc sensitivity analysis need to be considered alongside the growing body of evidence of the benefit of closed incision NPWT and given the number of obese women undergoing caesarean section globally. The decision to use closed incision NPWT must also be weighed against the increases in skin blistering and economic considerations and should be based on shared decision making with patients. ANZCTR identifier 12615000286549.


Overland flow computations in urban and industrial catchments from direct precipitation data using a two-dimensional shallow water model.
This paper presents the experimental validation and the application to a real industrial catchment of a two-dimensional depth-averaged shallow water model used for the computation of rainfall-runoff transformation from direct precipitation data. Instead of using the common approach in flood inundation modelling, which consists in computing the water depth and velocity fields given the water discharge, in this study the rainfall intensity is imposed directly in the model, the surface runoff being generated automatically. The model considers infiltration losses simultaneously with flow simulation. Gullies are also included in the model, although the coupling between the surface runoff and the sewer network is not considered. Experimental validation of the model is presented in several simplified laboratory configurations of urban catchments, in which the surface runoff has been measured for different hyetographs. The application to a real industrial catchment includes a sewer network flow component, which is solved with the SWMM model. The numerical predictions of the discharge hydrograph generated by a 12 hours storm event are compared with field measurements, providing encouraging results.


Helicobacter pylori infection is an independent risk factor for Runx3 methylation in gastric cancer.
Runx3, a member of the human runt-related transcription factor family, is known as a possible tumor suppressor gene for gastric cancer. Runx 3 expression is frequently suppressed by the promoter hypermethylation in gastric cancer cell lines and tissues. However, the precise mechanism of the induction of Runx3 methylation, which is considered to be a critical step in gastric carcinogenesis, remains to be elucidated. In the present study, we evaluated runx3 gene methylation in 57 resected early gastric cancer specimens. Then, we correlated Runx3 methylation in the cancer tissue specimens with clinicopathological factors as well as the mucosal backgrounds, such as intestinal metaplasia surrounding the cancer cells and Helicobacter pylori (H. pylori) infection. Runx3 methylation was observed in 30 of the 57 (52.6%) cancer specimens, whereas methylation was detected in 10 of the 57 (17.5%) corresponding non-cancerous mucosae. In comparison to the clinicopathological factors, Runx3 methylation was significantly correlated with both age and tumor location. A multivariate analysis demonstrated that age and tumor location as well as H. pylori infection were independent risk factors for Runx3 methylation. We demonstrated for the first time that H. pylori infection contributes to Runx3 methylation in gastric cancer tissues. When a persistent infection by H. pylori continues in the middle/lower stomach for a long period, Runx3 methylation may be induced and the subsequent loss of Runx3 expression may therefore affect gastric carcinogenesis.


Hemin exerts multiple protective mechanisms and attenuates dextran sulfate sodium-induced colitis.
Inflammatory bowel disease (IBD) is characterized by recurrent and severe gastrointestinal inflammation. Activation of inflammatory cells, such as TH17 lymphocytes, and/or deficiency of regulatory T cells (Treg) are responsible for the pathogenesis of IBD. As an acute phase reactant, heme oxygenase-1 (HO-1) has been shown to play an anti-inflammatory and immunomodulatory role in many disease processes. In this study, we used a dextran sulfate sodium (DSS)-induced murine colitis model to investigate the effect of upregulating HO-1 by hemin on the development of colonic inflammation. The mice were enterically challenged with 4% DSS. In addition, some mice were intraperitoneally administered with hemin or Sn-protoporphyrin (SnPP) on days 0, 1, and 6 after DSS treatment. The severity of colitis was evaluated by daily monitoring of weight change and diarrhea. At the end of the experiment, the colon, spleen, and mesenteric lymph nodes were harvested for histology and various immunological assays. Compared to control groups, DSS challenge markedly induced HO-1 expression in the colon epithelium. Upregulation of HO-1 by hemin was further correlated with attenuation of DSS-induced colitis. In contrast, inhibition of endogenous HO-1 by SnPP aggravated the colitis. To further assess the anti-inflammatory mechanisms, we examined whether hemin enhanced the proliferation of Treg cells and suppressed the production of interleukin (IL)-17. Flow cytometry analysis revealed that hemin markedly expanded the CD4 + CD25 + Foxp3+ Treg population. Moreover, hemin attenuated IL-17 and TH17-related cytokines. This inhibition coincided with the attenuation of DSS-induced colitis. Finally, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling assay showed that hemin treatment markedly reduced programmed cell death of colonic epithelium, indicating that hemin exerts a modulatory effect on the induction of Treg, IL-17, and apoptosis. These results demonstrate that upregulation of HO-1 by hemin ameliorated experimental colitis. Moreover, our study suggests a broader protective mechanism of hemin.


Repeatability and contingency in the evolution of a key innovation in phage lambda.
The processes responsible for the evolution of key innovations, whereby lineages acquire qualitatively new functions that expand their ecological opportunities, remain poorly understood. We examined how a virus, bacteriophage λ, evolved to infect its host, Escherichia coli, through a novel pathway. Natural selection promoted the fixation of mutations in the virus's host-recognition protein, J, that improved fitness on the original receptor, LamB, and set the stage for other mutations that allowed infection through a new receptor, OmpF. These viral mutations arose after the host evolved reduced expression of LamB, whereas certain other host mutations prevented the phage from evolving the new function. This study shows the complex interplay between genomic processes and ecological conditions that favor the emergence of evolutionary innovations.


A theory-driven approach to encourage physical activity in pediatric cancer survivors: a pilot study.
The present study examined the efficacy of a theory-based intervention designed to positively influence physical activity (PA) behavior in a group of pediatric cancer survivors. Ten survivors participated in a 16-week PA intervention that targeted the main theoretical tenets of the theory of planned behavior (TPB). Survivors were followed over a course of 1 year and completed measures of attitudes, subjective norms, perceived control, intentions for PA, and self-reported PA behavior at five different times. While the magnitude of change varied across the key theoretical constructs, it appears that the intervention had a small yet meaningful impact, particularly for overall behavioral intentions. Overall, this study provides preliminary data to suggest that the TPB may be a viable framework from which to build interventions for pediatric cancer survivors. Future research will be required to further identify and target the key elements and theoretical constructs within a behavioral intervention.


Growth behavior of titanium dioxide thin films at different precursor temperatures.
The hydrophilic TiO2 films were successfully deposited on slide glass substrates using titanium tetraisopropoxide as a single precursor without carriers or bubbling gases by a metal-organic chemical vapor deposition method. The TiO2 films were employed by scanning electron microscopy, Fourier transform infrared spectrometry, UV-Visible [UV-Vis] spectroscopy, X-ray diffraction, contact angle measurement, and atomic force microscopy. The temperature of the substrate was 500°C, and the temperatures of the precursor were kept at 75°C (sample A) and 60°C (sample B) during the TiO2 film growth. The TiO2 films were characterized by contact angle measurement and UV-Vis spectroscopy. Sample B has a very low contact angle of almost zero due to a superhydrophilic TiO2 surface, and transmittance is 76.85% at the range of 400 to 700 nm, so this condition is very optimal for hydrophilic TiO2 film deposition. However, when the temperature of the precursor is lower than 50°C or higher than 75°C, TiO2 could not be deposited on the substrate and a cloudy TiO2 film was formed due to the increase of surface roughness, respectively.


Absence of Decussation in Optic Pathway Inflammation in Neuromyelitis Optica and Its Implications for Astrocyte Localization.
A 39-year-old woman presented with acute visual loss in her right eye. Brain and orbit MRI demonstrated T2 hyperintensity along a long section of her right optic nerve, chiasm, and tract with no evidence of decussation of the inflammation. Subsequent seropositivity for the aquaporin 4 antibody confirmed a diagnosis of neuromyelitis optica. Posterior pathway involvement is typical in neuromyelitis optica and supports the hypothesis that the condition is an astrocytopathy. Furthermore, the absence of decussation in the condition may be a function of astrocyte localization within the chiasm.


Atomic-scale dynamic process of deformation-induced stacking fault tetrahedra in gold nanocrystals.
Stacking fault tetrahedra, the three-dimensional crystalline defects bounded by stacking faults and stair-rod dislocations, are often observed in quenched or irradiated face-centred cubic metals and alloys. All of the stacking fault tetrahedra experimentally observed to date are believed to originate from vacancies. Here we report, in contrast to the classical vacancy-originated ones, a new kind of stacking fault tetrahedra formed via the interaction and cross-slip of partial dislocations in gold nanocrystals. The complete atomic-scale processes of nucleation, migration and annihilation of the dislocation-originated stacking fault tetrahedra are revealed by in situ high-resolution observations and molecular dynamics simulations. The dislocation-originated stacking fault tetrahedra can undergo migration and annihilation due to mechanical loading in a manner that is not expected in bulk samples. These results uncover a unique deformation mechanism via dislocation interaction inside the confined volume of nanocrystals and have important implications regarding the size effect on the mechanical behaviour of small-volume materials.


Muscle-specific (CArG) and serum-responsive (SRE) promoter elements are functionally interchangeable in Xenopus embryos and mouse fibroblasts.
The Xenopus cardiac actin gene contains four copies of a promoter element, the CArG box, which is conserved amongst striated muscle actin genes and is essential for tissue-specific expression in the developing Xenopus embryo. Our aim is to identify embryo and muscle proteins that interact with the CArG box as a step towards understanding the molecular basis of this developmentally regulated gene expression. The CArG box shares some sequence similarity with the Serum Response Element (SRE), which mediates the transcriptional activation by serum of genes such as c-fos and cytoskeletal actin. We show here that the most proximal cardiac actin CArG box is recognized by the same binding activity as the cytoskeletal actin SRE in nuclear extracts from both Xenopus embryos and mammalian muscle cells. This activity is indistinguishable from the previously characterized HeLa cell SRE-binding activity, Serum Response Factor (SRF). Importantly, we extend these in vitro studies to demonstrate that the CArG box and SRE are functionally interchangeable, both in Xenopus embryos and mouse fibroblasts. This implies that the CArG box and SRE can bind the same protein in vivo, as well as in vitro. Our results identify an SRF-like protein as a CArG box-binding factor and we discuss the implication that a common mechanism may be utilized in both muscle-specific gene expression and serum-responsive transcription.


Anorectal Function and Quality of Life in IBD Patients With A Perianal Complaint.
Anorectal function of inflammatory bowel disease (IBD) patients is still poorly understood, with contradictory results. This prospective observational study aimed to analyze the effect of perianal disease on anorectal function and quality of life in IBD patients. Methods: Patient assessment included full clinical examination, validated scores, anorectal manometry, three-dimensional endoanal ultrasonography, and endoscopy. The Inflammatory Bowel Disease Questionnaire was adopted to evaluate patients' quality of life. Results: From January to November 2016, 37 consecutive IBD patients (30 Crohn's disease, 7 ulcerative colitis) and 20 controls were enrolled in the study. Twenty-five patients had a history of perianal fistula, 9 reported fecal incontinence, and 2 had anal fissure. Fecal incontinent patients were older, had a longer disease duration, and higher bowel movement number than continent patients. Endoanal ultrasound findings were normal in all volunteers, while pathological features were found in 31/37 patients. Rectal sensory testing and anal pressure did not differ between the IBD patients and controls. However, the rectoanal inhibitory reflex was normally elicited in all controls vs. 32/37 (86%) IBD patients; 25/37 (68%) IBD patients showed manometric features of dyssynergic defecation. Rectal inflammation and incontinence were associated with low maximum anal resting pressure. The quality of life score was lower in ulcerative colitis patients than in Crohn's patients and significantly lower in fecal incontinent patients. Conclusions: Anorectal function is impaired in IBD patients with perianal disease. Fecal incontinence correlates with poorer quality of life. Anorectal manometry and ultrasonography are useful tools for evaluating IBD patients.


Carbon mass balance methodology to characterize the growth of pigmented marine bacteria under conditions of light cycling.
A carbon mass balance methodology employing minimal measurements was applied to heterotrophic and photoheterotrophic marine bacteria grown under constant dilution and exposed to 12-h intervals of light or darkness. Carbon mass balance calculations using measurements taken every 3 h closed to within 93-103% using dissolved organic carbon, biomass carbon and CO2 production data only, indicating that background interference from dissolved inorganic carbon variations in the amended seawater medium was not significant. Neither strain was observed to sustain a net CO2 fixation using paramagnetic measurement of oxygen uptake rates (OUR), indicating a need for more sensitive on-line measurement techniques for OUR. Photoheterotrophic growth demonstrated lower carbon-mole biomass yields (0.41+/-0.026 vs. 0.64+/-0.013 mol mol(-1)) despite higher specific glucose uptake rates (0.025 vs. 0.02 mol mol(-1) h(-1)), suggesting that bioreactor-based study of marine bacteria can present growth modes that are different from those encountered in the marine environment.


Age and sex relationship with flow-mediated dilation in healthy children and adolescents.
Flow-mediated dilation (FMD) is a noninvasive technique used to measure conduit artery vascular function. Limited information is available on normative FMD values in healthy children and adolescents. The objective of this study was to assess relationships between age and sex with FMD across childhood and adolescence. Nine hundred and seventy-eight asymptomatic children (12 ± 3 yr, range 6-18 yr, 530 male) underwent ultrasonic brachial artery assessment before and after 5 min of forearm ischemia. Sex differences in FMD and baseline artery diameter were assessed using mixed linear models. Baseline artery diameter was smaller in females than males [2.96 mm (95% CI: 2.92-3.00) vs. 3.24 mm (3.19-3.28), P < 0.001] and increased with age across the cohort (P < 0.001). Diameter increased between ages 6 and 17 yr in males [from 2.81 mm (2.63, 3.00) to 3.91 mm (3.68, 4.14)] but plateaued at age 12 yr in females. Males had a lower FMD [7.62% (7.33-7.91) vs. 8.31% (7.95-8.66), P = 0.024], specifically at ages 17 and 18 yr. There was a significant effect of age on FMD (P = 0.023), with a reduction in FMD apparent postpuberty in males. In conclusion, the brachial artery increases structurally with age in both sexes; however, there are sex differences in the timing and rate of growth, in line with typical sex-specific adolescent growth patterns. Males have a lower FMD than females, and FMD appears to decline with age; however, these findings are driven by reductions in FMD as males near maturity. The use of age- and sex-specific FMD data may therefore not be pertinent in childhood and adolescence.


From Handcrafted to Deep Features for Pedestrian Detection: A Survey.
Pedestrian detection is an important but challenging problem in computer vision, especially in human-centric tasks. Over the past decade, significant improvement has been witnessed with the help of handcrafted features and deep features. Here we present a comprehensive survey on recent advances in pedestrian detection. First, we provide a detailed review of single-spectral pedestrian detection that includes handcrafted features based methods and deep features based approaches. For handcrafted features based methods, we present an extensive review of approaches and find that handcrafted features with large freedom degrees in shape and space have better performance. In the case of deep features based approaches, we split them into pure CNN based methods and those employing both handcrafted and CNN based features. We give the statistical analysis and tendency of these methods, where feature enhanced, part-aware, and post-processing methods have attracted main attention. In addition to single-spectral pedestrian detection, we also review multi-spectral pedestrian detection, which provides more robust features for illumination variance. Furthermore, we introduce some related datasets and evaluation metrics, and a deep experimental analysis. We conclude this survey by emphasizing open problems that need to be addressed and highlighting various future directions. Researchers can track an up-to-date list at https://github.com/JialeCao001/PedSurvey.


Lessons from the foot and mouth disease outbreak in The Netherlands in 2001.
The Netherlands had recently developed a new strategy for the eradication of foot and mouth disease (FMD). When FMD was confirmed in Great Britain and France, recent imports of susceptible animals from these countries were traced and preventive measures were taken. On 21 March 2001, FMD was confirmed in The Netherlands. The disease was introduced by calves which became infected at a staging post in Mayenne, France, where infected sheep from Great Britain were present. A total of 26 farms were infected. Emergency vaccination of all susceptible animals was applied. Suppressive vaccination was chosen, implying that all vaccinated animals had to be slaughtered. Ring vaccination of all susceptible animals within 2 km of an infected herd was the standard procedure. However, in the 'Noord Veluwe', vaccination had to be applied to a larger area. The last affected farm was confirmed on 22 April 2001. Emergency vaccination contained the FMD infection rapidly. The last vaccinated animal was slaughtered on 25 May 2001. Many farmers were not convinced that the killing of their healthy, vaccinated animals was justified and tried to prevent the culling, but without success. Politicians and the public at large are now strongly opposed to the large-scale slaughter of vaccinated animals should a future outbreak of FMD occur. The Office International des Epizooties (OIE: World organisation for animal health) should incorporate control of vaccinated animals with non-structural protein (NSP) tests in the chapter on FMD in the International Animal Health Code.


Endovascular repair of descending thoracic aortic aneurysm: an evidence-based analysis.
To conduct an assessment on endovascular repair of descending thoracic aortic aneurysm (TAA). Aneurysm is the most common condition of the thoracic aorta requiring surgery. Aortic aneurysm is defined as a localized dilatation of the aorta. Most aneurysms of the thoracic aorta are asymptomatic and incidentally discovered. However, TAA tends to enlarge progressively and compress surrounding structures causing symptoms such as chest or back pain, dysphagia (difficulty swallowing), dyspnea (shortness of breath), cough, stridor (a harsh, high-pitched breath sound), and hoarseness. Significant aortic regurgitation causes symptoms of congestive heart failure. Embolization of the thrombus to the distal arterial circulation may occur and cause related symptoms. The aneurysm may eventually rupture and create a life-threatening condition. The overall incidence rate of TAA is about 10 per 100,000 person-years. The descending aorta is involved in about 30% to 40% of these cases. The prognosis of large untreated TAAs is poor, with a 3-year survival rate as low as 25%. Intervention is strongly recommended for any symptomatic TAA or any TAA that exceeds twice the diameter of a normal aorta or is 6 cm or larger. Open surgical treatment of TAA involves left thoracotomy and aortic graft replacement. Surgical treatment has been found to improve survival when compared with medical therapy. However, despite dramatic advances in surgical techniques for performing such complex operations, operative mortality from centres of excellence are between 8% and 20% for elective cases, and up to 50% in patients requiring emergency operations. In addition, survivors of open surgical repair of TAAs may suffer from severe complications. Postoperative or postprocedural complications of descending TAA repair include paraplegia, myocardial infarction, stroke, respiratory failure, renal failure, and intestinal ischemia. Endovascular aortic aneurysm repair (EVAR) using a stent graft, a procedure called endovascular stent-graft (ESG) placement, is a new alternative to the traditional surgical approach. It is less invasive, and initial results from several studies suggest that it may reduce mortality and morbidity associated with the repair of descending TAAs. The goal in endovascular repair is to exclude the aneurysm from the systemic circulation and prevent it from rupturing, which is life-threatening. The endovascular placement of a stent graft eliminates the systemic pressure acting on the weakened wall of the aneurysm that may lead to the rupture. However, ESG placement has some specific complications, including endovascular leak (endoleak), graft migration, stent fracture, and mechanical damage to the access artery and aortic wall. The Talent stent graft (manufactured by Medtronic Inc., Minneapolis, MN) is licensed in Canada for the treatment of patients with TAA (Class 4; licence 36552). The design of this device has evolved since its clinical introduction. The current version has a more flexible delivery catheter than did the original system. The prosthesis is composed of nitinol stents between thin layers of polyester graft material. Each stent is secured with oversewn sutures to prevent migration. Objectives To compare the effectiveness and cost-effectiveness of ESG placement in the treatment of TAAs with a conventional surgical approachTo summarize the safety profile and effectiveness of ESG placement in the treatment of descending TAAsMeasures of Effectiveness Primary Outcome Mortality rates (30-day and longer term)Secondary Outcomes Technical success rate of introducing a stent graft and exclusion of the aneurysm sac from systemic circulationRate of reintervention (through surgical or endovascular approach)Measures of Safety Complications were categorized into 2 classes: Those specific to the ESG procedure, including rates of aneurysm rupture, endoleak, graft migration, stent fracture, and kinking; andThose due to the intervention, either surgical or endovascular. These include paraplegia, stroke, cardiovascular events, respiratory failure, real insufficiency, and intestinal ischemia.Inclusion Criteria Studies comparing the clinical outcomes of ESG treatment with surgical approachesStudies reporting on the safety and effectiveness of the ESG procedure for the treatment of descending TAAsExclusion Criteria Studies investigating the clinical effectiveness of ESG placement for other conditions such as aortic dissection, aortic ulcer, and traumatic injuries of the thoracic aortaStudies investigating the aneurysms of the ascending and the arch of the aortaStudies using custom-made graftsLiterature Search The Medical Advisory Secretariat searched The International Network of Agencies for Health Technology Assessment and the Cochrane Database of Systematic Reviews for health technology assessments. It also searched MEDLINE, EMBASE, Medline In-Process & Other Non-Indexed Citations, and Cochrane CENTRAL from January 1, 2000 to July 11, 2005 for studies on ESG procedures. The search was limited to English-language articles and human studies. One health technology assessment from the United Kingdom was identified. This systematic review included all pathologies of the thoracic aorta; therefore, it did not match the inclusion criteria. The search yielded 435 citations; of these, 9 studies met inclusion criteria. Mortality The results of a comparative study found that in-hospital mortality was not significantly different between ESG placement and surgery patients (2 [4.8%] for ESG vs. 6 [11.3%] for surgery).Pooled data from case series with a mean follow-up ranging from 12 to 38 months showed a 30-day mortality and late mortality rate of 3.9% and 5.5%, respectively. These rates are lower than are those reported in the literature for surgical repair of TAA.Case series showed that the most common cause of early death in patients undergoing endovascular repair is aortic rupture, and the most common causes of late death are cardiac events and aortoesophageal or aortobronchial fistula.Technical Success Rate Technical success rates reported by case series are 55% to 100% (100% and 94.4% in 2 studies with all elective cases, 89% in a study with 5% emergent cases, and 55% in a study with 42% emergent cases).Surgical Reintervention In the comparative study, 3 (7.1%) patients in the ESG group and 14 (26.5%) patients in the surgery group required surgical reintervention. In the ESG group, the reasons for surgical intervention were postoperative bleeding at the access site, paraplegia, and type 1 endoleak. In the surgical group, the reasons for surgery were duodenal perforation, persistent thoracic duct leakage, false aneurysm, and 11 cases of postoperative bleeding.Pooled data from case series show that 9 (2.6%) patients required surgical intervention. The reasons for surgical intervention were endoleak (3 cases), aneurysm enlargement and suspected infection (1 case), aortic dissection (1 case), pseudoaneurysm of common femoral artery (1 case), evacuation of hematoma (1 case), graft migration (1 case), and injury to the access site (1 case).Endovascular Revision In the comparative study, 3 (7.1%) patients required endovascular revision due to persistent endoleak.Pooled data from case series show that 19 (5.3%) patients required endovascular revision due to persistent endoleak.Graft Migration Two case series reported graft migration. In one study, 3 proximal and 4 component migrations were noted at 2-year follow-up (total of 5%). Another study reported 1 (3.7%) case of graft migration. Overall, the incidence of graft migration was 2.6%.Aortic Rupture In the comparative study, aortic rupture due to bare stent occurred in 1 case (2%). The pooled incidence of aortic rupture or dissection reported by case series was 1.4%.Postprocedural Complications In the comparative study, there were no statistically significant differences between the ESG and surgery groups in postprocedural complications, except for pneumonia. The rate of pneumonia was 9% for those who received an ESG and 28% for those who had surgery (P = .02). There were no cases of paraplegia in either group. The rate of other complications for ESG and surgery including stroke, cardiac, respiratory, and intestinal ischemia were all 5.1% for ESG placement and 10% for surgery. The rate for mild renal failure was 16% in the ESG group and 30% in the surgery group. The rate for severe renal failure was 11% for ESG placement and 10% for surgery.POOLED DATA FROM CASE SERIES SHOW THE FOLLOWING POSTPROCEDURAL COMPLICATION RATES IN THE ESG PLACEMENT GROUP: paraplegia (2.2%), stroke (3.9%), cardiac (2.9%), respiratory (8.7%), renal failure (2.8%), and intestinal ischemia (1%).Time-Related Outcomes The results of the comparative study show statistically significant differences between the ESG and surgery group for mean operative time (ESG, 2.7 hours; surgery, 5 hours), mean duration of intensive care unit stay (ESG, 11 days; surgery, 14 days), and mean length of hospital stay (ESG, 10 days; surgery, 30 days).The mean duration of intensive care unit stay and hospital stay derived from case series is 1.6 and 7.8 days, respectively. ONTARIO-BASED ECONOMIC ANALYSIS: In Ontario, the annual treatment figures for fiscal year 2004 include 17 cases of descending TAA repair procedures (source: Provincial Health Planning Database). Fourteen of these have been identified as "not ruptured" with a mean hospital length of stay of 9.23 days, and 3 cases have been identified as "ruptured," with a mean hospital length of stay of 28 days. However, because one Canadian Classification of Health Interventions code was used for both procedures, it is not possible to determine how many were repaired with an EVAR procedure or with an open surgical procedure. (ABSTRACT TRUNCATED)


[Pesticides use by flower companies associated with the Colombian Association of Flower Exporters].
In Colombia, pesticide exposure has became a public health problem, as the use of these substances continues to increase. The current study accumulated information concerning pesticides used by flower companies in Bogotá and Rionegro (Antioquia) that were associated with Asociación Colombiana de Exportadores de Flores (Asocolflores) in Colombia. Eighty-four companies were stratified by geographic location and size. Company and worker information was collected, and for each company, the process of pesticide application and maintenance of the cultivated flowers was carefully observed. Univariate and bivariate, and correlation analyses were applied for data analysis. Sex of workers was 39.4% male and 60.6% female. Pesticides were grouped into 4 toxicity classes: 14.3% were class I, 14.4% class II, 52.0% class III, and 19.2% class IV. Dithiocarbamates was the group of pesticides more commonly used (11.7%). The equipment most frequently used for pesticide application was the "bomba móvil" (92.8%), and the "lanza" (92.9%). Cholinesterase activity measured by the Michel-Aldrige method was the biological marker for exposure to pesticides used in 85.9% of the companies. Recommendations for improvements in their use and for measures to further reduce exposure of workers are made.


Absolute qPCR for measuring telomere length in bone marrow samples of plasma cell disorders.
Telomere length (TL) is currently used as an emerging biomarker in understanding the development/progression of hematological malignancies. The absolute quantitative PCR (qPCR) methodology has allowed the study of TL from a variety of mammalian tissues, but it has not been tested for bone marrow (BM) samples. In this study, we have examined the relationship between TL data generated by absolute qPCR versus those obtained by terminal restriction fragments (TRF) in 102 BM samples from patients with plasma cell disorders. A significant linear correlation between both methodologies was observed (p < 0.0001; r (2) = 0.70). Results were also analyzed in relation to clinical characteristics and significant associations between telomere shortening and parameters of adverse prognosis were observed. Furthermore, another set of 47 BM samples from patients with low quantity of DNA for TRF assay were suitably analyzed by qPCR, indicating the usefulness of the absolute qPCR methodology for the inclusion of patients with scarce material to the study. Taken together, these findings are of interest considering the importance of telomere dysfunction in the pathogenesis of cancer and give a new alternative to measure TL in hematologic disorders with substantial time and cost savings.


An application of kernel methods to variety identification based on SSR markers genetic fingerprinting.
In crop production systems, genetic markers are increasingly used to distinguish individuals within a larger population based on their genetic make-up. Supervised approaches cannot be applied directly to genotyping data due to the specific nature of those data which are neither continuous, nor nominal, nor ordinal but only partially ordered. Therefore, a strategy is needed to encode the polymorphism between samples such that known supervised approaches can be applied. Moreover, finding a minimal set of molecular markers that have optimal ability to discriminate, for example, between given groups of varieties, is important as the genotyping process can be costly in terms of laboratory consumables, labor, and time. This feature selection problem also needs special care due to the specific nature of the data used. An approach encoding SSR polymorphisms in a positive definite kernel is presented, which then allows the usage of any kernel supervised method. The polymorphism between the samples is encoded through the Nei-Li genetic distance, which is shown to define a positive definite kernel between the genotyped samples. Additionally, a greedy feature selection algorithm for selecting SSR marker kits is presented to build economical and efficient prediction models for discrimination. The algorithm is a filter method and outperforms other filter methods adapted to this setting. When combined with kernel linear discriminant analysis or kernel principal component analysis followed by linear discriminant analysis, the approach leads to very satisfactory prediction models. The main advantage of the approach is to benefit from a flexible way to encode polymorphisms in a kernel and when combined with a feature selection algorithm resulting in a few specific markers, it leads to accurate and economical identification models based on SSR genotyping.


Potentiation of Acetylcholine-Induced Relaxation of Aorta in Male UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rats: Sex-Specific Responses.
Previous reports suggest that diabetes may differentially affect the vascular beds of females and males. The objectives of this study were to examine whether there were (1) sex differences in aortic function and (2) alterations in the relative contribution of endothelium-derived relaxing factors in modulating aortic reactivity in UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine (ACh) was measured in aortic rings before and after exposure to pharmacological inhibitors. Relaxation responses to sodium nitroprusside were assessed in endothelium-denuded rings. Moreover, contractile responses to phenylephrine (PE) were measured before and after incubation of aortic rings with a nitric oxide synthase (NOS) inhibitor in the presence of indomethacin. Metabolic parameters and expression of molecules associated with vascular and insulin signaling as well as reactive oxygen species generation were determined. Diabetes slightly but significantly impaired EDV in response to ACh in aortas from females but potentiated the relaxation response in males. The potentiation of EDV in diabetic male aortas was accompanied by a traces of nitric oxide (NO)- and prostanoid-independent relaxation and elevated aortic expression of small- and intermediate conductance Ca2+-activated K+ channels in this group. The smooth muscle sensitivity to NO was not altered, whereas the responsiveness to PE was significantly enhanced in aortas of diabetic groups in both sexes. Endothelium-derived NO during smooth muscle contraction, as assessed by the potentiation of the response to PE after NOS inhibition, was reduced in aortas of diabetic rats regardless of sex. Accordingly, decreases in pAkt and peNOS were observed in aortas from diabetic rats in both sexes compared with controls. Our data suggest that a decrease in insulin sensitivity via pAkt-peNOS-dependent signaling and an increase in oxidative stress may contribute to the elevated contractile responses observed in diabetic aortas in both sexes. This study demonstrates that aortic function in UCD-T2DM rats is altered in both sexes. Here, we provide the first evidence of sexual dimorphism in aortic relaxation in UCD-T2DM rats.


Phytomedicines (medicines derived from plants) for sickle cell disease.
Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. There has been little systematic appraisal of their benefits. This is an update of a Cochrane Review first published in 2010 and updated in 2013. To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International Standard Randomised Controlled Trial Number Register (ISRCTN) and the Allied and Complimentary Medicine Database (AMED).Dates of most recent searches: Haemoglobinopathies Trials Register: 13 October 2014; 17 January 2015; AMED: 20 January 2015. Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. Both authors independently assessed trial quality and extracted data. Two trials (182 participants) and two phytomedicines Niprisan(®) (also known as Nicosan(®)) and Ciklavit(®) were included. The Phase IIB (pivotal) trial suggests that Niprisan(®) was effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period. It did not affect the risk of severe complications or the level of anaemia. No serious adverse effects were reported. The single trial of Cajanus cajan (Ciklavit(®)) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia. While Niprisan(®) appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in the management of people with sickle cell disease and the results of its multicentre trials are awaited. Currently no conclusions can be made regarding the efficacy of Ciklavit(®). Based on the published results for Niprisan(®) and in view of the limitations in data collection and analysis of both trials, phytomedicines may have a potential beneficial effect in reducing painful crises in sickle cell disease. This needs to be further validated in future trials. More trials are required on the safety and efficacy of phytomedicines used in managing sickle cell disease.


'They shouldn't be coming to the ED, should they?' A qualitative study of why patients with palliative care needs present to the emergency department.
Across the developed world, there are concerns about 'inappropriate' use of the emergency department (ED). Patients with palliative care needs frequently attend the ED. Previous studies define the 'reason' for presentation as the 'presenting symptom', which ignores the perspectives of service users. This paper addresses an acknowledged gap in the literature, which fails to examine the decision-making process that brings patients to the ED. In-depth narrative interviews were conducted with 7 patients (known to a specialist palliative care service and presenting to the ED during a 10-week period) and 2 informal caregivers. Analysis drew on 'Burden of Treatment Theory' to examine the meaning attributed by participants to their experience of serious acute illness, their capacity for action and the work required to access emergency care. 5 themes were identified about how and why emergency services were accessed: capacity for action, making sense of local services, making decisions to access emergency services, experience of emergency care and coping with change. All narratives captured concerns surrounding the complexity of services. Participants struggled to piece together the jigsaw of services, and were subsequently more likely to attend the ED. Differences between the ways that patients with chronic obstructive pulmonary disease and cancer accessed the ED were prominent. Further work is needed to understand and respond to decisions leading patients with palliative care needs to the ED, particularly in the context of locally fragmented services, poor signposting and confusion about available healthcare. The perspectives of service users are essential in shaping emergency care.


The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure.
The coxsackie and adenovirus receptor (CAR) is identified as a high-affinity receptor for adenovirus type 5. We observed that invasive bladder cancer specimens had significantly reduced CAR mRNA levels compared with superficial bladder cancer specimens, which suggests that CAR may play a role in the progression of bladder cancer. Elevated CAR expression in the T24 cell line (CAR-negative cells) increased its sensitivity to adenovirus infection and significantly inhibited its in vitro growth, accompanied by p21 and hypophosphorylated retinoblastoma accumulation. Conversely, decreased CAR levels in both RT4 and 253J cell lines (CAR-positive cells) promoted their in vitro growth. To unveil the mechanism of action of CAR, we showed that the extracellular domain of CAR facilitated intercellular adhesion. Furthermore, interrupting intercellular adhesion of CAR by a specific antibody alleviates the growth-inhibitory effect of CAR. We also demonstrated that both the transmembrane and intracellular domains of CAR were critical for its growth-inhibitory activity. These data indicate that the cell-cell contact initiated by membrane-bound CAR can elicit a negative signal cascade to modulate cell cycle regulators inside the nucleus of bladder cancer cells. Therefore, the presence of CAR cannot only facilitate viral uptake of adenovirus but also inhibit cell growth. These results can be integrated to formulate a new strategy for bladder cancer therapy.


Huntington's disease: changes in saccades and hand-tapping over 3 years.
Saccades and hand-tapping are both potential biomarkers in patients with Huntington's disease (HD). While it is well known that patients with manifest Huntington's disease display abnormalities in both of these tasks, less is known about how these abnormalities progress over time, or to what extent premanifest patients are affected. This study was designed to address these issues. We examined premanifest and manifest Huntington's cohorts, together with a group of controls, over a 3-year period. Data were collected using a portable head-mounted saccadometer and a computerised hand-tapping device. Both premanifest and manifest Huntington's disease patients display significant and systematic changes from year to year in the parameters describing saccadic latency, while controls remain unchanged. By contrast, although hand-tapping was abnormal in HD patients, annual changes were much smaller. Measuring the rate of progression of saccadic abnormalities in manifest HD patients may provide a way to track disease progression, and thus help to evaluate novel therapies to modify the disease. The clear-cut progression in saccadic abnormalities in the premanifest group may prove useful in the future as a predictor of time to disease onset.


Dysregulated microRNAs in the pathogenesis and progression of cervical neoplasm.
MicroRNAs (miRNAs) play an important role in a variety of physiological as well as pathophysiological processes, including carcinogenesis. The aim of this study is to identify a distinct miRNA expression signature for cervical intraepithelial neoplasia (CIN) and to unveil individual miRNAs that may be involved in the development of cervical carcinoma. Expression profiling using quantitative real-time RT-PCR of 202 miRNAs was performed on micro-dissected high-grade CIN (CIN 2/3) tissues and compared to normal cervical epithelium. Unsupervised hierarchical clustering of the miRNA expression pattern displayed a distinct separation between the CIN and normal cervical epithelium samples. Supervised analysis identified 12 highly differentially regulated miRNAs, including miR-518a, miR-34b, miR-34c, miR-20b, miR-338, miR-9, miR-512-5p, miR-424, miR-345, miR-10a, miR-193b and miR-203, which distinguished the high-grade CIN specimens from normal cervical epithelium. This miRNA signature was further validated by an independent set of high-grade CIN cases. The same characteristic signature can also be used to distinguish cervical squamous cell carcinoma from normal controls. Target prediction analysis revealed that these dysregulated miRNAs mainly control apoptosis signaling pathways and cell cycle regulation. These findings contribute to understanding the role of microRNAs in the pathogenesis and progression of cervical neoplasm at the molecular level.