Comparative transcriptome analysis of diurnal alterations of liver glycogen structure: A pilot study.
Molecular mechanisms behind structural alterations between fragile and stable glycogen α particles in liver are not clear yet. In this pilot study, we re-examined the diurnal alterations of glycogen structure from the perspective of liver tissue transcriptome. By comparing the structures of liver glycogen from mice at 12 am, 8 am, 12 pm, and 8 pm (light-on: 6 am; light-off: 6 pm), we re-confirmed that the liver glycogen was fragile at 12 am and 8 am and stable at 12 pm and 8 pm as previously reported. The structural differences of glycogen particles at 12 am and 12 pm were thoroughly compared via transcriptomics. Differentially expressed genes (DEGs) with statistical significance were identified, while expression level of the gene ppp1r3g (log2Fold_Change = -6.368, P-value = 2.89E-04) that encoded PPP1R3G with glycogen binding domain was most significantly changed, which provided preliminary clues to the structural alterations of glycogen α particles during the diurnal cycle.


Antiatherosclerotic effects of the novel angiotensin receptor antagonist Fimasartan on plaque progression and stability in a rabbit model: a double-blind placebo-controlled trial.
To evaluate the effect of the novel angiotensin receptor blocker Fimasartan on the development of atherosclerosis and plaque stabilization in an animal model. Twenty-four rabbits received an aortic balloon injury from 30 cm to a level just above the aortic valve to the iliac bifurcation using 3 Fr Fogarty catheters on third day of the experiment, followed by a 1% cholesterol diet for 8 weeks. The rabbits were randomized to receive placebo or 3 or 6 mg · kg⁻¹ · d⁻¹ Fimasartan. The study was double blinded. The rabbits started receiving their medications 2 days before the aortic balloon injury and treatment continued. Atherosclerosis burden was determined by calculating the intima-media ratio of the infrarenal portion of the aorta because the bulk of the atherosclerotic burden was limited to the infrarenal region. The frequency of plaque disruption with thrombosis and the proportions of the plaques that were occupied by macrophages, smooth muscle cells, and collagen were determined. Relative to the placebo group, the Fimasartan-treated rabbits had less atherosclerosis [intima-media ratio (mean ± SEM) of 1.14 ± 0.21 vs. 1.51 ± 0.26, P = 0.005], fewer disrupted plaques with thrombi (3 of 16 vs. 5 of 8, P = 0.047), lower proportion of macrophages (17.5% ± 2.5% vs. 26% ± 3.5%, P = 0.03), higher proportion of smooth muscle cells (43.5% ± 8.3% vs. 11.9% ± 2.1%, P = 0.001), and higher proportion of collagen (34.3% ± 6.4% vs. 19.7% ± 2.1%, P = 0.02). These results show that the newly developed angiotensin receptor blocker, Fimasartan, attenuated atherosclerosis progression and reduced macrophage accumulation in the rabbit aortic plaques.


Auditory potentials of cochlear nerve and brain stem in multiple sclerosis.
Auditory evoked potentials of the cochlear nerve and the brain stem were recorded in ten patients with multiple sclerosis (MS) and four patients thought to possibly have MS. A characteristic pattern materialized, with a prolonged N1-P4 conduction time and absent or small N2 and/or N5 waves. We discuss possible clinical implications.


The effects of amantadine, rimantadine and levodopa on the frequency of fibrillation potentials in denervated muscle.
Right mid-thigh sciatic denervation was performed in 59 rats. Eleven days later they were assigned into 4 groups: a control group that was injected intraperitoneally with normal saline, and 3 test groups that were injected intraperitoneally with amantadine, rimantadine or levodopa (50 mg/kg each), for 3 consecutive days. On the fourteenth day, 2 h after the third injection, electromyography of the soleus-gastrocnemius muscles was performed under pentothal anesthesia. Fibrillation potentials were counted. The statistical analysis showed significant reduction of fibrillations secondary to levodopa and to amantadine injections. Rimantadine did not change the frequency of fibrillations. A stabilizing effect of levodopa and amantadine on the denervated plasmalemma is postulated.


AMP-deaminase from goldfish white muscle: regulatory properties and redistribution under exposure to high environmental oxygen level.
AMP-deaminase was partially purified from white skeletal muscle of goldfish, Carassius auratus. The enzyme was highly stable, showing virtually no change in activity at 1 month following the purification process when stored in 1 M KCl at 2-4 degrees C. The specific activity of the purified enzyme was 130-150 U/mg protein, with a pH optimum of about pH 6.5. AMP-aminohydrolase (AMPD) showed non-Michaelis-Menten kinetics, with a S(0.5) (half saturation by the substrate) for AMP of 0.73 +/- 0.03 mM, a Hill coefficient of 2.01 +/- 0.26, and a V(max) (maximum velocity) of 176 +/- 46 U/mg protein. Both sodium and potassium ions activated goldfish AMPD at low concentrations, with maximal activation at about 80 mM of each chloride salt, whereas higher concentrations became inhibitory. Magnesium and calcium ions also inhibited goldfish muscle AMPD, as did phosphate and fluoride; at a concentration of 8 mM, each anion reduced activity by about 66%. ADP and ATP were strong activators and both demonstrated concentration-dependent activation, with maximal effects at 0.5-1.5 mM. Fish exposure to a high concentration of oxygen (18-20 mg/l against 5-6 mg/l in the control) and recovery to the initial level induced a redistribution of AMPD between free and bound forms in goldfish white muscle and brain in a tissue-dependent manner. A spatial-temporal redistribution may be among the mechanisms regulating enzyme operation in vivo. Possible regulatory mechanisms of AMP-deaminase function in fish muscle are discussed.


Involuntary orientation of attention to unattended deviant nociceptive stimuli is modulated by concomitant visual task difficulty. Evidence from laser evoked potentials.
Recent laser evoked potential (LEP) studies showed that unattended rare intensity-deviant nociceptive stimuli enhance the LEP vertex positivity P2 ('P400 effect'). It was hypothesized to reflect an involuntary switch of attention to nociceptive events. If true the P400 effect (1) should be produced when attention is focused on a task in another sensory modality (primary task), and (2) should be modulated by the primary task difficulty. Subjects had to count the number of visual symbols presented on a screen. In a difficult condition, symbols were digits 1-4 (interference between amount and meaning). In an easy condition, symbols were letters X (no interference). Nociceptive CO2 laser stimuli were simultaneously delivered on the left hand. Occasional stronger deviant stimuli (16%) were presented at random. In additional sessions, the strong stimuli were presented alone in homogenous series (100%). LEP amplitude at about 400 ms was larger for rare deviant than for homogenous stimuli. Visual task difficulty decreased LEP amplitude at this latency. Deviant stimuli seemed also to interfere with performance in the visual task. The results give evidence for considering the P400 effect as reflecting an involuntary attentional shift to nociceptive events. The study provides electrophysiological evidences for an intrusive capacity of pain to attract attention and to decrease behavioural performance in concurrent processes. In turn, such an attentional shift is tampered if attention is very engaged in a concomitant task.


The use of N-terminal immobilization of PTH(1-34) on PLGA to enhance bioactivity.
The objective of this work was to control the orientation of bioactive molecules immobilized on a biodegradable substrate to improve their accessibility for binding to cell surface receptors and, therefore, to increase bioactivity. The osteotropic peptide, parathyroid hormone (1-34) (PTH(1-34)), was used to demonstrate the approach. To this end, the intrinsic N-terminal serine residue was oxidized to create an aldehyde group that specifically bound to hydrazide-derivatized poly(lactide-co-glycolide) under neutral conditions to form a hydrazone bond. Use of dihydrazide spacers significantly increased the amount of peptide immobilized compared to simple adsorption or direct, random attachment. In probing accessibility of immobilized PTH(1-34), attachment using longer dihydrazide spacers enhanced binding of an antibody against an epitope in the N-terminal region of the peptide. The longest spacer also increased binding of a C-terminal antibody. Furthermore, substrates with peptide tethered via spacers stimulated intracellular synthesis of cAMP, with activity increasing with dihydrazide length. PTH(1-34) immobilized using the longest spacer was significantly more effective than both random binding and adsorption. Site-directed binding of bioactive peptides to surfaces presents biomolecules for binding with cells so as to enhance interaction with receptors, and therefore the approach may be useful for obtaining preferred localized tissue responses.


[Distribution of heat production in the tissues of the lower extremities during capacitative heating by a UHF field].
The authors described methods developed by them for measuring heat production in autopsy sections by taking pulse thermograms during local capacitative healing of tissues using special electrode devices filled in with liquid dielectric. Thermograms of heat production distribution on limb sections were shown. Qualitative peculiarities of heat production distribution determined by tissue topological structure, were analysed.


Asymmetrical Obstacles Enable Unilateral Inertial Focusing and Separation in Sinusoidal Microchannel.
Inertial microfluidics uses the intrinsic fluid inertia in confined channels to manipulate the particles and cells in a simple, high-throughput, and precise manner. Inertial focusing in a straight channel results in several equilibrium positions within the cross sections. Introducing channel curvature and adjusting the cross-sectional aspect ratio and shape can modify inertial focusing positions and can reduce the number of equilibrium positions. In this work, we introduce an innovative way to adjust the inertial focusing and reduce equilibrium positions by embedding asymmetrical obstacle microstructures. We demonstrated that asymmetrical concave obstacles could break the symmetry of original inertial focusing positions, resulting in unilateral focusing. In addition, we characterized the influence of obstacle size and 3 asymmetrical obstacle patterns on unilateral inertial focusing. Finally, we applied differential unilateral focusing on the separation of 10- and 15-μm particles and isolation of brain cancer cells (U87MG) from white blood cells (WBCs), respectively. The results indicated an excellent cancer cell recovery of 96.4% and WBC rejection ratio of 98.81%. After single processing, the purity of the cancer cells was dramatically enhanced from 1.01% to 90.13%, with an 89.24-fold enrichment. We believe that embedding asymmetric concave micro-obstacles is a new strategy to achieve unilateral inertial focusing and separation in curved channels.


The prevalence and related factors of restless leg syndrome in the community dwelling elderly; in Kayseri, Turkey: A cross-sectional study.
The aim of this study is to determine the prevalence and related factors of restless leg syndrome (RLS) in the community-dwelling elderly living in Kayseri. This is a cross-sectional population based study in 960 community-dwelling elderly living in an urban area. We sampled 1/100 of elderly people aged 60 years and older. The diagnosis of RLS was made according to the criteria of the International RLS Study Group. The demographic data were collected by face-to-face interviews. Additionally, the Mini-Mental State Examination, Geriatric Depression Scale and anthropometric measurements were used. Logistic regression analyses were performed to define risk factors for RLS. We excluded elderly people with cognitive impairment (295). One hundred and five (15.8%) of the remaining 665 elderly subjects met the criteria to diagnose RLS. There was female predominance (3/1). Gender, length of education, employment status, smoking, hypertension, diabetes mellitus, depressive mood, high body mass index, and high waist circumferences, sleep quality, sleep duration, and difficulty in falling asleep in the first 30min were all detected as risk factors for RLS. However in logistic regression analysis, being a housewife, sleeping less than 6h a day and having diabetes was found as significantly related risk factors for RLS. This is the first epidemiologic study of RLS conducted in the Turkish community-dwelling elderly in an urban area. RLS is a common but underestimated disease in the elderly. Although RLS is prevalent we found very few risk factors for RLS.


The Genetics Underlying Natural Variation in the Biotic Interactions of Arabidopsis thaliana: The Challenges of Linking Evolutionary Genetics and Community Ecology.
In the context of global change, predicting the responses of plant communities in an ever-changing biotic environment calls for a multipronged approach at the interface of evolutionary genetics and community ecology. However, our understanding of the genetic basis of natural variation involved in mediating biotic interactions, and associated adaptive dynamics of focal plants in their natural communities, is still in its infancy. Here, we review the genetic and molecular bases of natural variation in the response to biotic interactions (viruses, bacteria, fungi, oomycetes, herbivores, and plants) in the model plant Arabidopsis thaliana as well as the adaptive value of these bases. Among the 60 identified genes are a number that encode nucleotide-binding site leucine-rich repeat (NBS-LRR)-type proteins, consistent with early examples of plant defense genes. However, recent studies have revealed an extensive diversity in the molecular mechanisms of defense. Many types of genetic variants associate with phenotypic variation in biotic interactions, even among the genes of large effect that tend to be identified. In general, we found that (i) balancing selection rather than directional selection explains the observed patterns of genetic diversity within A. thaliana and (ii) the cost/benefit tradeoffs of adaptive alleles can be strongly dependent on both genomic and environmental contexts. Finally, because A. thaliana rarely interacts with only one biotic partner in nature, we highlight the benefit of exploring diffuse biotic interactions rather than tightly associated host-enemy pairs. This challenge would help to improve our understanding of coevolutionary quantitative genetics within the context of realistic community complexity.


Determination of maternal serum acetylcholinesterase in pregnancies with fetal neural tube defects.
We have investigated the occurrence of acetylcholinesterase (AChE) (E.C. 188.8.131.52) in fetal serum, amniotic fluid and maternal serum using an immuno-chemical assay-technique employing both polyclonal and monoclonal antibodies. Fetal serum had increased amounts of AChE, which is due to an increase in the 10.5S form of the enzyme. This form was also found in amniotic fluids of pregnancies with a fetal neural tube defect (NTD), but not in normal amniotic fluid. The increase in amniotic fluid AChE was however, not reflected in the maternal serum.


Access to Cesarean Section Will Reduce Maternal Mortality in Low-Income Countries: A Mathematical Model.
Despite global efforts to reduce the maternal mortality ratio (MMR) through the World Health Organization's (WHO) Millennium Development Goal 5 (MDG5), MMR remains unacceptably high in low-income countries (LICs). Maternal death and disability from hemorrhage, infection, and obstructed labor may be averted by timely cesarean section (CS). Most LICs have CS rates less than that recommended by the WHO. Without access to timely CS, it is unlikely that MMR in LICs will be further reduced. Our purpose was to measure the MMR gap between the current MMR in LICs and the MMR if LICs were to raise their CS rates to the WHO recommended levels (10-15 %). This model makes the assumption that increasing the CS rates to the recommended rates of 10-15 % will similarly decrease the MMR in these LICs. WHO health statistics were used to generate estimated MMRs for countries with CS rates between 10 and 15 % (N = 14). A weighted MMR average was determined for these countries. This MMR was subtracted from the MMR of each LIC to determine the MMR gap. The percent decrease in MMR due to increasing CS rate was calculated and averaged across the LICs. We found an average 62.75 %, 95 %CI [56.38, 69.11 %] reduction in MMR when LICs increase their CS rates to WHO recommended levels (10-15 %). Maternal mortality is unacceptably high in LICs. Increasing CS rates to WHO recommended rates will decrease the maternal mortality in these countries, significantly decreasing the mortality ratio toward the projected MDG5.


Gastric emptying in infants with gastroesophageal reflux. Measurement with a technetium-99m-labeled semisolid meal.
It is well established that liquid emptying occurs in the absence of motor activity of the stomach. In contrast, solid-phase emptying is controlled in part by antral peristalsis and is, therefore, a more precise indicator of gastric motility. We developed a semisolid, radionuclide gastric emptying test using rice cereal and technetium-99m-sulfur colloid to assess antral physiology in infants with vomiting. Computer-programmed mathematical models were used to determine the shape of a line that best fit our emptying data points. Linear, simple exponential [f = 2-(t/t1/2)], and power exponential [f = 2(t/t1/2)beta] patterns of emptying were calculated, where f is the fraction of the meal remaining in the stomach at time t, and t1/2 is the time when 50% of the meal has emptied and is a determinant of the shape of the curve. In infants with simple regurgitation (chalasia) and those with vomiting and failure to gain weight, we made statistical comparisons between gastric emptying patterns after analysis of the mean percentage of retained radionuclide at 120 min, calculated t1/2, and area under the curve. The coefficient of determination, R2, was calculated as an index of whether a curve provided goodness of fit to the data. Differences between groups of patients were statistically significant for all parameters of each mathematical model. However, higher coefficients of determination were noted in the power exponential model. The data suggest that the power exponential mathematical model provides the best analysis of the gastric emptying patterns for infants with chalasia and those with vomiting and failure to gain weight.(ABSTRACT TRUNCATED AT 250 WORDS)


Proximal weakness of the extremities as main feature of amyloid myopathy.
Two patients with muscle weakness caused by amyloid myopathy are described. Characteristic features such as pseudohypertrophy and abnormal firmness, and tumours of muscles were absent. It is suggested that muscle weakness in amyloid myopathy is caused by layers of amyloid covering muscle fibres. In middle aged or elderly patients with proximal muscle weakness the diagnosis of amyloid myopathy should be considered.


Less-Invasive Endovascular Treatment of Arch Aneurysm With Aberrant Right Subclavian Artery.
We report a patient with an arch aneurysm with an aberrant right subclavian artery who underwent successful endovascular treatment with the chimney technique and bilateral carotid artery-to-subclavian artery bypasses. We used a chimney graft in the left carotid artery to preserve its flow. The bilateral carotid-to-subclavian artery bypasses preserved perfusion of the bilateral vertebral arteries. A thoracic stent graft was subsequently deployed in the aortic arch over the chimney graft of the left carotid artery. There have been few reports about less-invasive treatment for arch aneurysm with aberrant right subclavian artery. This technique was an effective strategy to avoid a high-risk open operation.


Water distribution and moisture-absorption in egg-white derived peptides: Effects on their physicochemical, conformational, thermostable, and self-assembled properties.
Three egg-white derived peptides (DHTKE, MPDAHL, and FFGFN) were characterized with hydrophilia and water distributions. The effect of moisture exposure on their properties at 75% relative humidity for 30 h were further investigated. LF-NMR tests revealed that strong bound-water (relaxation time < 10 ms) accounted for more than 80% of total water in peptides after moisture-absorption. The absorbed water led to the pH of three peptides increase, antioxidant activities in vitro decrease, and diverse changes in their functional group vibrations, molecular hydrophobicity, and phase transformation properties. Compared to dried samples, the hydrated-DHTKE was pyrolyzed and hydrated-MPDAHL was oxidized over 160 °C, while the glass transition, melting, and crosslink temperatures of FFGFN all decreased after moisture-absorption. Moreover, the results indicated that moisture-absorption in FFGFN powder enhanced the surface-hydrophobicity of FFGFN-hydrogel and accelerated its self-organizations. This study provides a comprehensive understanding of moisture-absorption effects on peptides, with these changes potentially impacting storage recommendations and scientific interpretations.


Biflavonoids from Ginkgo biloba leaves as a novel anti-atherosclerotic candidate: Inhibition potency and mechanistic analysis.
Ginkgo biloba L. is one of the oldest trees on earth, and its leaves have been used since ages as herbal medicine to treat cerebrovascular disorders. It is worth noting that in addition to the widely concerned flavonoids and terpenoids, it also contains various thus far neglected biflavonoids. In fact, biflavonoids are flavonoids consisting of apigenin or its derivatives as monomeric scaffold, and are linked via C-C or C-O-C bond. Based on the structural similarity of flavonoids, we hypothesized that biflavonoids may play a potential role in the treatment of cerebrovascular diseases. Here, we describe the effectiveness and underlying mechanisms for prevention and treatment of atherosclerosis (AS) by biflavonoids. Four main biflavonoids in Ginkgo biloba leaves were screened by oleic acid-induced lipid production in HepG2 cells. The non-covalent effects of biflavonoids on the potential targets of atherosclerosis were screened by reverse targeting and molecular dynamics simulation. The interactions between biflavonoids and potential targets were evaluated by an exogenous cell model, which verified the consistency of the simulation results. Among all four biflavonoids, ginkgetin significantly inhibited oleic acid-induced lipid production in HepG2 cells and reduced total cholesterol and triglyceride levels. The interaction of ginkgetin with CDK2 through π-alkyl and hydrogen bonds increased the binding of molecules and proteins. Ginkgetin arrested the cells in the G1-S phase, which significantly inhibited abnormal cell growth which closely related to the occurrence and development of atherosclerosis. Biflavonoids could be a promising natural medicine for the treatment of atherosclerosis.


Adverse events in meditation practices and meditation-based therapies: a systematic review.
Meditation techniques are widely used as therapy and wellbeing practices, but there are growing concerns about its potential for harm. The aim of the present study is to systematically review meditation adverse events (MAEs), investigating its major clinical categories and its prevalence. We searched PubMed, PsycINFO, Scopus, Embase and AMED up to October 2019. Eligible studies included original reports of meditation practices (excluding related physical practices such as Yoga postures) with adult samples across experimental, observational and case studies. We identified a total of 6742 citations, 83 of which met the inclusion criteria for MAEs with a total of 6703 participants who undertook meditation practice. Of the 83 studies analysed, 55 (65%) included reports of at least one type of MAE. The total prevalence of adverse events was 8.3% (95% CI 0.05-0.12), though this varied considerably across types of studies - 3.7% (95% CI 0.02-0.05) for experimental and 33.2% (95% CI 0.25-0.41) for observational studies. The most common AEs were anxiety (33%, 18), depression (27%, 15) and cognitive anomalies (25%, 14); gastrointestinal problems and suicidal behaviours (both 11%, 6) were the least frequent. We found that the occurrence of AEs during or after meditation practices is not uncommon, and may occur in individuals with no previous history of mental health problems. These results are relevant both for practitioners and clinicians, and contribute to a balanced perspective of meditation as a practice that may lead to both positive and negative outcomes.


Intravenous paracetamol and dipyrone for postoperative analgesia after day-case tonsillectomy in children: a prospective, randomized, double blind, placebo controlled study.
Tonsillectomy is associated with severe postoperative pain for which, several drugs are employed for management. In this double-blind, placebo-controlled study we aimed to evaluate the efficacy of intravenous paracetamol and dipyrone when used for post-tonsillectomy analgesia in children. 120 children aged 3-6 yr, undergoing tonsillectomy with or without adenoidectomy and/or ventilation tube insertion were randomized to receive intraoperative infusions of paracetamol (15 mg/kg), dipyrone (15 mg/kg) or placebo (0.9% NaCl). Evaluation was carried out at 0.25, 0.50, 1, 2, 4, 6h postoperatively. Pethidine 0.25 mg/kg was utilized as rescue analgesic. Cumulative pethidine requirement was the primary outcome. Pain intensity measurement, pain relief, sedation level, nausea and vomiting, postoperative bleeding and any other adverse effects were noted. No significant difference was found in pethidine requirement between paracetamol and dipyrone groups. Cumulative pethidine requirement was significantly less in paracetamol and dipyrone groups vs. placebo. No significant difference was observed between groups in postoperative pain intensity scores throughout the study. Intravenous paracetamol is found to have a similar analgesic efficacy as intravenous dipyrone and they both help to reduce the opioid requirement for postoperative analgesia in pediatric day-case tonsillectomy.


Biometry measurements using a new large-coherence-length swept-source optical coherence tomographer.
To evaluate the repeatability and reproducibility of the measurements obtained with the Argos, a new biometer with swept-source optical coherence tomography (SS-OCT), and to compare them with the results obtained with the IOLMaster 500 (partial-coherence interferometry [PCI]) and the Lenstar LS 900 (optical low-coherence reflectometry [OLCR]) biometers. Private practice, Lynwood, California, USA. Prospective observational study. All measurements were performed with the SS-OCT tomographer, the PCI biometer, and the OLCR biometer. Eyes (n = 107) were measured to evaluate the axial length (AL), central corneal thickness (CCT), aqueous depth, anterior chamber depth (ACD), lens thickness, pupil size, corneal diameter, and anterior corneal radius of curvature (RAV). Repeatability and reproducibility of the SS-OCT measurements showed comparable values and a low variation rate, with an interset mean difference of 0.01 mm for AL, 0.01 mm for CCT, 0.01 mm for aqueous depth and ACD, 0.03 mm for lens thickness, 0.10 mm for pupil size, 0.14 mm for corneal diameter, and 0.02 mm for RAV. The SS-OCT device correctly measured the AL in 96% of the cases compared with 79% for the OLCR device and 77% for the PCI device. Comparisons between the PCI device and SS-OCT device were -0.01 ± 0.05 mm for AL, -0.17 ± 0.20 mm for ACD, and -0.01 ± 0.05 mm for RAV. Comparison between the OLCR device and the SS-OCT device was 0.01 ± 0.06 mm for AL, 0.08 ± 0.15 mm for ACD, 0.00 ± 0.05 mm for RAV, 0.00 ± 0.01 mm for CCT, 0.07 ± 0.14 mm for aqueous depth, -0.23 ± 0.22 mm for lens thickness, -0.29 ± 0.53 mm for pupil size, and -0.34 ± 0.76 mm for corneal diameter. Axial length measurements with the new SS-OCT biometer were comparable to the PCI and OLCR measurements with a higher AL acquisition rate. Dr. Shammas is a consultant to Movu, Inc. Drs. Ortiz, Kim, and Chong have proprietary interest in the new technology.


Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML.
Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity.


Filipin-sterol complexes at Schmidt-Lanterman incisures.
Employing the freeze-fracture technique, the distribution of filipin-sterol complexes was determined for membranes of peripheral nerve myelin. A heterogeneous distribution of complexes was observed with the greatest abundance on membranes associated with the cytoplasmic channels of Schmidt-Lanterman and longitudinal incisures. In addition there was an irregular network of well-labelled membrane bands in compact myelin. The results are related to a possible role for these channels and bands in the biochemical turnover of cholesterol in myelin.


Effects of CO2 enrichment, nutrient addition, and fungal endophyte-infection on the growth of two grasses.
Increasing atmospheric carbon dioxide (CO2) concentration is expected to increase plant productivity and alter plant/plant interactions, but little is known about its effects on symbiotic interactions with microorganisms. Interactions between perennial ryegrass, Lolium perenne (a C3 plant), and purpletop grass, Tridens flavus (a C4 plant), and their clavicipitaceous fungal endophytes (Acremonium lolii and Balansia epichloe, respectively) were investigated by growing the grasses under 350 and 650 μl l- 1 CO2 at two nutrient levels. Infected and uninfected perennial ryegrass responded with increased growth to both CO2 enrichment and nutrient addition. Biomass and leaf area of infected and uninfected plants responded similarly to CO2 enrichment. When growth analysis parameters were calculated, there were significant increases in relative growth rate and net assimilation rate of infected plants compared to uninfected plants, although the differences remained constant across CO2 and nutrient treatments. Growth of purpletop grass did not increase with CO2 enrichment or nutrient addition and there were no significant differences between infected and uninfected plants. CO2 enrichment did not alter the interactions between these two host grasses and their endophytic-fungal symbionts.


Cross-cultural comparison of neurobehavioral performance in Asian workers.
Widely-used neurobehavioral tests have been developed and standardized on Western populations, but studies on subject factors for Asian populations have been very limited. For the effective application and interpretation of neurobehavioral tests in Asian populations, an evaluation of the effects of subject factors, including cultural background, is necessary. A cross-cultural study was conducted to evaluate the effects of cultural background and the interaction between cultural background and education on neurobehavioral tests in Asian populations. The Korean version of the Swedish Performance Evaluation System (Simple Reaction Time, Symbol Digit, and Finger Tapping Speed) and a pegboard test were administered to 537 workers who were not exposed to chemicals at work from Fareast (Korea and Chinese), Central (Uzbekistan and Tajikistan), and South Asia (Sri Lanka and Indonesia). The Fareast Asian group exhibited better performance in adjusted test scores than other Asian groups, achieving significance for Symbol Digit and Finger Tapping Speed in both genders. The magnitude of the effect of cultural background on Symbol Digit was comparable to the effect of about 10 years of education. Cultural background did not modify the relation between years of education and Symbol Digit in either males or females. This study may provide the first evidence that cultural background has a large impact on neurobehavioral test performance, even within Asian populations, and suggests that cultural background is a critical confounding factor that must be controlled in epidemiologic studies which include Asian populations in the sample.


Methane emissions in growing heifers while eating from a feed bin compared with 24-hour emissions and relationship with feeding behavior.
The objective of the current study was to determine the relationship of daily CH4 emissions estimated during mealtime compared with measured daily CH4 emissions, and determine the relationship with feeding behavior, in growing heifers fed alfalfa silage in respiration chambers. Data from 8 growing cattle (Hereford × Holstein-Friesian) individually housed in 4 respiration chambers and fed ad libitum alfalfa silage delivered in Insentec feed-bins to record feeding behavior and intake were used. The 4 chambers are linked to 1 analyzer, which measures CH4 in each chamber approximately every 3 min. Each 3-min measurement was expressed as grams per day and averaged per 24 h or per time during a meal. A strong correlation (r = 0.88; determined using Deming regression) was observed between CH4 emissions (g/d) during mealtime (276 ± 22.7 g/d) and measured over 24 h (262 ± 24.0 g/d), without apparent systematic bias. Feeding behavior parameters that were correlated with CH4 yield (g/kg dry matter intake) in the current study were a negative correlation with the number of visits to the feed bin (r = -0.45), average meal size (r = -0.57), and average daily eating rate (r = -0.48). In summary, CH4 measured during meals was similar to 24-h measured CH4 output in growing heifers fed ad libitum alfalfa silage in respiration chambers, and some feeding behavior parameters, based on feed bin visits, explained some of the variation in CH4 yield between animals.


Correlation between hepatic oxidative damage and clinical severity and mitochondrial gene sequencing results in biliary atresia.
To assess the level of hepatic oxidative damage and its correlation with clinical severity in biliary atresia (BA), and to understand BA mitochondrial gene sequencing. Forty-eight BA patients and 28 control subjects (20 hepatoblastoma and 8 cholestasis patients) were enrolled. Hepatic oxidative damage was assessed by the expression of oxidation and antioxidant genes, and the correlation between oxidative damage and BA incidence, liver inflammation, and fibrosis was evaluated. Moreover, 8-hydroxyguanine (8-OHdG), mitochondrial DNA (mtDNA) copy number, and mitochondrial gene sequences were determined to evaluate oxidative mtDNA damage in BA. The expression of oxidation gene cytochrome b-245 beta chain (CYBB) in BA was significantly increased and patients with a higher CYBB expression had the higher risk of BA incidence, liver inflammation, and cirrhosis. However, the expression of antioxidant genes was significantly decreased, and glutathione S-transferase alpha 1 (GSTA1) negatively correlated with BA incidence and cirrhosis. When GSTA1 mRNA expression was <0.5487, the sensitivity was 80.85% and the specificity was 80% for BA diagnosis. Moreover, 8-OHdG was increased, whereas mtDNA copy number was significantly decreased in BA. Using mitochondrial gene sequencing, 10 mutation sites were identified, and one family showed a maternal inheritance in genetic loci 15 326. In BA, oxidative damage positively correlated with BA incidence, liver inflammation, and cirrhosis. GSTA1 could be a novel diagnostic indicator. Genetic loci 15 326 could be a maternal genetic mutation site. Taken together, antioxidation therapy after Kasai surgery might have great potential in relieving liver inflammation and fibrosis in BA patients.


Quantitative analysis of normal tissue effects in the clinic (QUANTEC) guideline validation using quality of life questionnaire datasets for parotid gland constraints to avoid causing xerostomia during head-and-neck radiotherapy.
To perform a validation test of the quantitative analysis of normal tissue effects in the clinic (QUANTEC) guidelines against quality of life (QoL) questionnaire datasets collected prospectively from patients with head and neck (HN) cancers, including HN squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC). QoL questionnaire datasets from 95 patients with NPC and 142 with HNSCC were analyzed separately. The European Organization for Research and Treatment of Cancer H&N35 QoL questionnaire was used as the endpoint evaluation. The primary endpoint (grade 3(+) xerostomia) was defined as moderate to severe xerostomia 3 and 12 months after the completion of RT, and excluded patients with grade 3(+) xerostomia at the baseline. The Lyman-Kutcher-Burman normal tissue complication probability (NTCP) model was used to describe the incidence of xerostomia. Negative predictive values (NPVs) were used to determine the rate of correctly predicting the lack of complications. NTCP fitted parameters were TD₅₀=37.8 Gy (CI: 29.1-46.9 Gy), m=0.59 (CI: 0.48-0.80) and TD50=43.9 Gy (CI: 33.2-52.8 Gy), m=0.48 (CI: 0.37-0.76) at the 3-month and 12-month time points, respectively. For QUANTEC validation, HN and HNSCC data validation gave similar results at 3 months; at mean doses to the spared parotid of ≤20 and ≤25 Gy, the QoL dataset showed approximately 22% and 28% rates of xerostomia, respectively. At 12 months, the rates of xerostomia were approximately 13% and 19%, respectively. For NPC cases, the dataset showed approximately 0% and 33% (∼67% NPV) rates of xerostomia at 3 months. At 12 months, both rates of xerostomia were approximately 0% (∼100% NPV), which differed significantly from the results for the HNSCC cohort. The QoL datasets validated the QUANTEC guidelines and suggested that the modified QUANTEC 20/20-Gy spared-gland guideline is suitable for clinical use in HNSCC cohorts to effectively avoid xerostomia, and the QUANTEC 25-Gy guideline is justified for NPC cohorts.


DSP: database of disease susceptibility genes in plants.
Host-pathogen interaction is the most crucial factor that evokes the host immune system to fight against pathogens. In contrast to specialized immune cells present in humans and animals, plants have disease resistance (R-) and disease susceptibility (S-) genes. R-genes confer disease resistance and are generally introgressed from wild crop relatives to cultivated crops. S-genes, on the other hand, assist pathogens in establishing contact, displaying counter-defense measures, and spreading the infection. To achieve resistance in a variety of crops, researchers are now focusing on the identification, silencing, editing, or elimination of crucial S-genes. To aid in this field, we created the first curated database of disease susceptibility genes in plants (DSP), with the simple and advanced search tool that allows researchers to restrict the query and mining of specified hits. SSR marker identification and primer designing could be performed with the help of MISA and Primer3 software, respectively. The DSP database is available at http://184.108.40.206/bic/sgenos/ and http://188.8.131.52/sgenos/ .


Ca2+-gramicidin A interactions and blocking effects on the ionic channel.
From spectroscopic data (infrared, CD and 13C-NMR) it is shown that Ca2+ interacts with gramicidin A and that a head-to-head gramicidin A dimer can have two Ca2+-binding sites located near the COOH termini. On the basis of this result, we can propose an explanation for the blocking effect of Ca2+ on the transport of alkali metal ions (Cs+ and K+) through gramicidin channels. The binding of Ca2+ is competitive with the alkali metal ion binding; Ca2+ cannot cross the gramicidin channel and its binding in the channel is voltage dependent. From the proposed model, it is possible to account for the influence of the addition of Ca2+ on the single-channel limiting conductance and on the variation of the single-channel current as a function of the voltage in the presence of Cs+ or K+.


Fragility fractures: proposal of the best practice through the fracture coordination units: the experience of Mexico.
Fragility fractures represent a health problem in Mexico and in the world. This paper reviews and puts forward the implementation of Fracture Liaison Services (FLS) as a feasible and cost-effective alternative in health institutions in our country through the identification, treatment, and follow-up of this type of fractures.


Reproduction at an advanced maternal age and maternal health.
Advanced age is a risk factor for female infertility, pregnancy loss, fetal anomalies, stillbirth, and obstetric complications. These concerns are based on centuries-old observations, yet women are delaying childbearing to pursue educational and career goals in greater numbers than ever before. As a result, reproductive medicine specialists are treating more patients with age-related infertility and recurrent pregnancy loss, while obstetricians are faced with managing pregnancies often complicated by both age and comorbidities. The media portrayal of a youthful but older woman, able to schedule her reproductive needs and balance family and job, has fueled the myth that "you can have it all," rarely characterizing the perils inherent to advanced-age reproduction. Reproductive medicine specialists and obstetrician/gynecologists should promote more realistic views of the evidence-based realities of advanced maternal age pregnancy, including its high-risk nature and often compromised outcomes. Doctors should also actively educate both patients and the public that there is a real danger of childlessness if individuals choose to delay reproduction.


Reaching high-risk Black adults for diabetes prevention programming during a pandemic: The design of Fit & Faithful a randomized controlled community trial.
Obesity is a key risk factor for Type 2 diabetes (T2D). Alarmingly, 87% of US adults have overweight or obesity, with non-Hispanic black adults having higher obesity and T2D prevalence than non-Hispanic white. The Diabetes Prevention Program (DPP) demonstrated the clinical benefits of lifestyle intervention (LI). While the DPP LI is effective, some participants don't achieve clinically significant weight loss in the current group-based translation paradigm. Black adults have the lowest adjusted weight loss (3.2%) among all racial/ethnic groups. Early intervention nonresponse defined as ≤1% weight loss at intervention week 4 is linked to lower probability of achieving weight loss goals. This paper describes the design and methods of a cluster randomized controlled trial among black weight loss nonresponders nested in 20 community sites (primarily churches). Descriptions of the adaptations made to transition the program to virtual format during the COVID-19 pandemic are also included. Trained community health workers deliver a group-based, 6-month long DPP over 18 sessions via Zoom. Additionally, nonresponders in the enhanced group receive weekly telephone support to provide individual-level intervention to help overcome weight loss barriers. Outcomes include weight, physical activity level, blood pressure, and dietary behaviors; these are compared between nonresponders in the enhanced intervention group and nonresponders in the active control group. Cost, mediators, and moderators are explored. If found to efficacious, these enhanced strategies could be standardized as a supplement for use with DPP nonresponders.


A study of the interactions between glutamate and aspartate at the lobster neuromuscular junction.
The depolarization produced by bath-applied or iontophoretically applied glutamate and aspartate were recorded from lobster muscle fibres by means of intracellular microelectrodes. 2 Bath-applied glutamate or aspartate evoked reversible, membrane depolarizations; however, responses to repeated applications of aspartate decreased progressively in amplitude until a plateau level was attained. Repeated applications of glutamate, kainate, domoate or quisqualate did not produce a similar effect. 3 After a dose of glutamate, responses to bath-applied aspartate were enhanced. Responses to other depolarizing agonists were little affected by previous administration of glutamate. Aspartate dose-depolarization curves were therefore constructed after initial aspartate responses had stabilized. The log-log transforms of the aspartate and glutamate curves had limiting slopes of 0.8 and 2.1 respectively. 4 Iontophoretic application of aspartate to single glutamate-sensitive sites produced small depolarizations with slow time course, compared with the glutamate potentials. When aspartate and glutamate were pulsed simultaneously from a twin-barrelled pipette, the resultant glutamate potential was enhanced. It is suggested that this potentiation was due to summation of agonist concentrations in the receptor region interacting with a second-order dose-response relationship. 5 Bath-applied aspartate increased the amplitude and prolonged the half-decay time of the glutamate potential. This effect was particularly noticeable when the glutamate potential was of slow time course. 6 It is proposed that bath-applied aspartate has an agonist effect whose magnitude is possibly exaggerated by concomitant release of glutamate and/or inhibition by glutamate of aspartate uptake. This agonist action of aspartate is thought to be exerted mainly on extrajunctional areas of the glutamate-sensitive sites.


Prenatal distress during the COVID-19 pandemic: clinical and research implications.
The objective of this study was to identify risk and protective factors related to general prenatal distress and COVID-19-specific prenatal distress to inform intervention targets among women pregnant during the COVID-19 pandemic. The study relied on data obtained from U.S. pregnant women (N = 701) who participated in the Perinatal Experiences and COVID-19 Effects (PEACE) Study from May 21 to October 3, 2020. The present cross-sectional study examined the potential risk and protective factors associated with different features of prenatal distress among U.S. pregnant women during the COVID-19 pandemic. Approximately two-thirds of expectant mothers indicated being more stressed about going to the hospital because of COVID-19. Generalized anxiety and PTSD were associated with higher levels of general and COVID-19-specific prenatal distress. Depression symptoms were associated with higher general prenatal distress. Higher levels of distress tolerance were associated with lower levels of general prenatal distress (B = - 0.192, p < .001) and COVID-19-specific prenatal distress (B = - 0.089, p < .05). Higher levels of instrumental social support were marginally associated with lower COVID-19-specific prenatal distress (B = - 0.140, p < 0.1). Findings draw attention to prenatal distress experiences during the COVID-19 pandemic, including new types of distress arising from the pandemic itself. Women might benefit from the introduction of interventions such as mindfulness-based or relaxation therapy. Coverage of responsibilities and financial assistance is particularly needed during the COVID-19 pandemic. Limitations include a majority White and high socioeconomic sample. These findings provide specificity regarding potential targets for addressing prenatal distress.


Clinical outcome after microfracture of the knee: a meta-analysis of before/after-data of controlled studies.
The aims of this study were to systematically review the medical literature, in order to find controlled studies about microfracture in the treatment of patients with full-thickness cartilage lesions of the knee, to statistically combine these studies in order to determine a best estimate of the average treatment effect, and to gather information to detect cartilage-specific and patient-specific factors that might have an influence on the clinical outcome. We searched four electronic databases for controlled clinical trials or controlled prospective observational studies. We pooled before/after-data of study arms using the term microfracture. We calculated an overall best estimate of 1.106, with [0.566; 1.646] as 95% confidence interval of the mean standardized treatment effect for a representative patient population. Our meta-analysis revealed a clinically relevant improvement of the postoperative clinical status as compared to the preoperative status. An increase of 22 overall KOOS points may provide a rough estimate for the mean expected treatment effect achieved by microfracturing.


Activity of the epipodophyllotoxin VP-16 in the treatment of combination chemotherapy-resistant non-Hodgkin lymphoma.
Twenty patients with several histologic subtypes of non-Hodgkin lymphoma who had become resistant to combination chemotherapy were treated with a five-day course of the epipodophyllotixin VP-16. Of 19 evaluable patients, 8 (42%) responded to treatment with 1 complete response and 7 partial responses. The median duration of response was 5.5 months. Seven of the responders had a diffuse lymphoma and 1 had a nodular lymphoma. Of the responders who had diffuse histiocytic lymphoma (DHL), diffuse mixed lymphoma (DML), and diffuse undifferentiated lymphoma (DUL)--the more aggressive histologies in the Rappaport classification--6 of 13 (46%) evaluable patients responded to therapy. Responses were seen in node-dominant, skin-dominant, and marrow-dominant disease. Toxicity was mainly hematopoietic, 53% of patients experiencing leukopenia ( less than 2,000 cells per cu mm) and 68% of patients experiencing thrombocytopenian 2,000 cells per cu mm) and 68% of patients experiencing thrombocytopenia ( less than 100,000 platelets per cu mm). There were two deaths attributable to profound leukopenia with sepsis. The activity of VP-16 in patients who have previously been extensively treated with multiple drugs including vincristine supports its activity in the lymphomas and suggests its lack of cross-resistance with vincristine. The inclusion of VP-16 in primary treatment protocols in the diffuse lymphomas should be considered.


Real-time health monitoring through urine metabolomics.
Current healthcare practices are reactive and based on limited physiological information collected months or years apart. By enabling patients and healthy consumers access to continuous measurements of health, wearable devices and digital medicine stand to realize highly personalized and preventative care. However, most current digital technologies provide information on a limited set of physiological traits, such as heart rate and step count, which alone offer little insight into the etiology of most diseases. Here we propose to integrate data from biohealth smartphone applications with continuous metabolic phenotypes derived from urine metabolites. This combination of molecular phenotypes with quantitative measurements of lifestyle reflect the biological consequences of human behavior in real time. We present data from an observational study involving two healthy subjects and discuss the challenges, opportunities, and implications of integrating this new layer of physiological information into digital medicine. Though our dataset is limited to two subjects, our analysis (also available through an interactive web-based visualization tool) provides an initial framework to monitor lifestyle factors, such as nutrition, drug metabolism, exercise, and sleep using urine metabolites.


The Societal Cost of Schizophrenia: An Updated Systematic Review of Cost-of-Illness Studies.
Schizophrenia imposes a substantial economic burden on society. This updated systematic review aims to collate the latest societal cost of schizophrenia across countries by reviewing recent cost-of-illness (COI) studies. An electronic search was conducted across several databases (MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, Health Management Information Consortium, and System for Information on Grey Literature) to identify COI studies published from 2016 to 2022. Two independent reviewers selected studies for inclusion. The cost components and estimates reported by included studies were descriptively summarised. All costs were converted to US dollars (2022 values). Study quality was assessed using a checklist adapted from Larg & Moss. Twenty-four studies were included (5 from the update review and 19 from the original review), of which only two were conducted for low- and middle-income countries (LMICs). Widespread methodological heterogeneity among included studies was observed. The annual societal cost per person varied from US$819 in Nigeria to US$94,587 in Norway. Productivity losses accounted for 32-83% of the overall societal cost, whilst direct healthcare cost made up 11-87%. The reporting quality of included studies varied. This review highlights the substantial economic burden of schizophrenia and a lack of COI studies for LMICs. Recommendations on future research, and good practices on improving the methodological and reporting quality of COI research for schizophrenia are provided.


Human bone marrow-derived mesenchymal stem cells play a role as a vascular pericyte in the reconstruction of human BBB on the angiogenesis microfluidic chip.
A blood-brain barrier (BBB) on a chip similar to the in vivo BBB is important for evaluating the efficacy of reparative cell therapeutics for ischemic stroke in vitro. In this study, we established human BBB-like microvasculature on an angiogenesis microfluidic chip and analyzed the role of human pericytes (hPCs) and human astrocytes (hACs) on the architecture of human brain microvascular endothelial cells (hBMEC)-derived microvasculature on a chip. We found that human bone marrow mesenchymal stem cells (hBM-MSCs) play a role as perivascular pericytes in tight BBB reformation with a better vessel-constrictive capacity than that of hPCs, providing evidence of reparative stem cells on BBB repair rather than a paracrine effect. We also demonstrated that pericytes play an important role in vessel constriction, and astrocytes may induce the maturation of a capillary network. Higher expression of VEGF, SDF-1α, PDGFRβ, N-cadherin, and α-SMA in hBM-MSCs than in hPCs and their subsequent downregulation with hBMEC co-culture suggest that hBM-MSCs may be better recruited and engaged in the BBB-microvasculature than hPCs. Collectively, the human BBB on a chip may be adopted as an alternative to evaluate in vitro cellular behavior and the engagement of cell therapeutics in BBB regeneration and may also be used for studying stroke.


Fractional-order Darwinian PSO-based feature selection for media-adventitia border detection in intravascular ultrasound images.
Media-adventitia (MA) border delineates the outer appearance of arterial wall in intravascular ultrasound (IVUS) image. The detection of MA border is a challenging topic due to many difficulties such as complicated intravascular structures, intrinsic artifacts and image noises. We propose a classification-based MA border detection method with an embedded feature selection technique. The feature selection technique is based on Fractional-order Darwinian particle swarm optimization (FODPSO) algorithm. By employing feature selection, 293-dimension features including multi-scale features, gray-scale features and morphological feature are reducing to 37-dimension. The border detection method with feature selection is tested on a public dataset extracted from in-vivo pullbacks of human coronary arteries, which contains 77 IVUS images. Three indicators, Jaccard (JACC), Hausdorff Distance (HD) and Percentage of Area Difference (PAD), are measured for quantitative evaluation. Detection with 293-dimension features obtains JACC 0.79, HD 1.41 and PAD 0.16, while detection with 37-dimension features obtains JACC 0.83, HD 1.27 and PAD 0.12, indicating that the FODPSO-based feature selection method improves MA border detection by JACC 0.04, HD 0.14 and PAD 0.04. Furthermore, the proposed border detection method acquires better performances compared with two other automatic methods conducted on the same dataset available in literature.


Favorable efficacy of daclatasvir plus asunaprevir in treatment of elderly Japanese patients infected with HCV genotype 1b aged 70 and older.
The combination of daclatasvir and asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (<20%), pretreatment (failure of treatment except for triple therapy with simeprevir, or treatment naive), and level of viremia (<6.0 log IU/ml) as independent predictors of SVR. Direct sequencing showed a significantly higher rate of NS3-D168 mutation at baseline in non-responders to triple therapy with simeprevir (44%) than others (2%). Alfa-fetoprotein (AFP) level and liver stiffness were significantly lower after end of treatment than at baseline, in both the SVR and non-SVR groups. In conclusion, daclatasvir-asunaprevir combination achieved high SVR in HCV genotype 1b patients, including elderly patients. Viral factors negatively influenced the response to treatment. Treatment improved AFP level and liver stiffness (surrogate markers of hepatocellular carcinoma), regardless of treatment efficacy. J. Med. Virol. 89:91-98, 2017. © 2016 Wiley Periodicals, Inc.


Ticarcillin-clavulanate therapy for infections with ticarcillin-resistant microorganisms.
In a prospective study, 46 episodes of serious infection with ticarcillin-resistant microorganisms were treated with the combination ticarcillin disodium and clavulanate potassium (Timentin). Clinical cure was achieved in 35 of the 46 episodes (76%), and microbiologic eradication was achieved in 30 (65%). We found no development of resistance to ticarcillin-clavulanate and observed no serious side effects.


Assessing the crash risk of mixed traffic on multilane rural highways using a proactive safety approach.
The crash risk assessment of mixed traffic has been understudied due to a lack of pertinent data. In recent years, proactive methods have gained significant attention in transportation safety analysis because of their numerous advantages. In this study, we model and evaluate the effect of speed difference on the sideswipe crash risk of mixed traffic using a novel proactive safety indicator called Anticipated Collision Time (ACT). For analysis, detailed trajectory data were collected using an unmanned aerial vehicle from four-lane and six-lane rural highways. The crash risk was derived from the observed conflict risk and then used to assess the highway system's safety performance under study. Using the Extreme Value Theory (EVT), the conflict risk was mapped to the crash risk. The extreme events were identified using the Block Maxima (BM) approach. Later, the Generalized Extreme Value Distribution (GEV) models were developed for each location by extracting the sideswipe conflicts from the vehicle trajectories. The findings suggest that sideswipe conflicts are more of a safety concern than rear-end conflicts due to the frequent nature of lane changes or passing operations. Also, significant speed difference exists among different vehicle modes present in mixed traffic, and the sideswipe crash risk increases with the increase in the maximum speed difference. The analyses of speed differences also indicate that compared to the four-lane highway, the available safety margin is limited on a six-lane highway due to the higher maximum speed difference. Hence, any driver error may lead to sideswipe crashes. In light of the findings of this study, we strongly suggest the need to provide speed control strategies and restrict the frequent risky lane-changing or passing operations that mainly give rise to sideswipe conflicts on a six-lane highway. Further, this study found that the sideswipe crash risk decreases with the increase in vehicle size on both four-lane and six-lane highways. Hence, we suggest developing separate crash risk models for different vehicle modes in mixed traffic on multilane rural highways. Otherwise, the crash risk mitigation strategies may not be appropriate for mixed traffic conditions.


New EORTC guidelines for the treatment of anaemia in patients with cancer: implications for nursing practice.
Anaemia and associated fatigue are common problems in patients with cancer, and fatigue is considered by patients with cancer to be their most limiting symptom. The introduction of erythropoiesis-stimulating proteins (ESPs) has greatly improved the management of anaemia; however, many European patients with cancer-related anaemia are untreated because of a lack of awareness among healthcare professionals of the benefits of anaemia treatment to patients, or because of regional differences in treatment practices. Recently, the European Organisation for Research and Treatment of Cancer (EORTC) developed the first European evidence-based guidelines for the use of ESPs in cancer-related anaemia in order to facilitate and standardize the assessment and management of the condition. These guidelines, and the implications for oncology nurses in implementing them in practice, are discussed.


The learning needs and clinical requirements of post graduate critical care nursing students in rural and regional contexts: A scoping review.
The objective of this review was to establish the learning needs and clinical requirements of postgraduate critical care nursing students preparing for clinical practice in rural and regional contexts. Scoping review. Published and unpublished empirical studies. A scoping review based on database searches (CINAHL and Medline) using Aromataris and Munn's four-step search strategy, plus subsequent forward reference search strategy was undertaken, applying predetermined selection criteria. The review aligned to the Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Review. Studies were uploaded into Endnote 20© for storage and into Covidence 2.0© for data extraction. Screening was undertaken by a primary reviewer, with a secondary reviewer evaluating the studies identified as relevant by the first reviewer. Qualitative codes were derived, and reflexive thematic analysis synthesised the results of the review, using Braun and Clarke's six-phase process. Nine foundational learning needs for critical care nursing students were extracted from the literature. The nine established foundational learning needs were: behavioural attributes/personal base; critical thinking and analysis; ethical practice; identification of risk; leadership, collaboration, and management; professional practice; provision and coordination of clinical care; research knowledge, standards of care, and policy development; and the health consumer experience. Discerning learning needs specific to rural and regional critical care nursing students was difficult. Only one study that met the inclusion criteria was identified. This study identified some instances of interest in relation to rural and regional learning needs. These instances were related to preparation of rural students for low-volume, high-stake situations; transfer of critically ill patients; stabilisation and preparation of critically ill patients; and care of specific patient groups such as, critically ill, bariatric, paediatric, obstetric, trauma, and patients with behavioural issues. Limited literature exists within the rural and regional critical care nursing educational context, making it difficult to determine the unique learning needs of students within this group. This scoping review lays the groundwork for further research into the needs of critical care nursing students situated within the rural and regional context.


Laparoscopic versus open surgery for extraperitoneal rectal cancer: a prospective comparative study.
The role of laparoscopic resection (LR) in the management of extraperitoneal rectal cancer still is unclear. This study aimed to compare perioperative and long-term results of laparoscopic and open resection (OR) for low and midrectal cancer. A prospective nonrandomized trial comparing patients submitted to OR or LR for low and midrectal cancer at a single institution was conducted. The study included 191 consecutive patients: 98 patients who underwent LR and 93 who underwent OR. The mean follow-up period was 46.3 months for LR and 49.7 months for OR. The conversion rate for LR was 18.4%. With the use of LR, the mean time for complete patient mobilization was shorter (1.7 vs 3.3 days; p < 0.001) and patients were earlier in passing flatus (2.6 vs 3.9 days; p < 0.001) and stools (3.8 vs 4.7 days; p < 0.01), and in resuming oral intake (3.4 vs 4.8 days; p < 0.001). The mean hospital stay was shorter for LR, but the difference did not reach significance (11.4 vs 13 days). Morbidity and mortality rates were similar: LR (24.4% and 1%) and OR (23.6% and 2.2%). Laparoscopic patients presented a higher rate of anastomotic fistulas (13.5% vs 5.1%) and reoperations (6.1% vs 3.2%) but the difference was statistically nonsignificant. Laparoscopic resection presented a significantly lower local recurrence rate (3.2% vs 12.6%; p < 0.05). The cumulative survival and disease-free rates at 5 years were, respectively, 80% and 65.4% after LR and 68.9% and 58.9% after OR (nonsignificant difference). Stage-by-stage comparison showed prolonged cumulative survival for stages III and IV cancer in LR (82.5% vs 40.5%; p = 0.006 and 15.8% vs 0%; p = 0.013, respectively) and a reduced rate of cancer-related death for stage III in LR (11.4% vs 51.9%; p = 0.001). As compared with conventional open surgery, LR for low and midrectal cancer is characterized by a faster recovery and similar overall morbidity (but a higher rate of anastomotic leakages), and does not present any adverse oncologic effect.


Epigenetic suppression of neprilysin regulates breast cancer invasion.
In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer, and epigenetic suppression of neprilysin in invasive breast cancer cells enables invasion. Together, this implicates neprilysin as an important regulator of breast cancer invasion and clarifies its utility as a potential biomarker for invasive breast cancer.


Enzyme-linked immunosorbent assay (ELISA) for steroid hormones with polyclonal and monoclonal antibodies: an assay for urinary aldosterone.
The development of non-competitive microtitre plate enzyme-linked immunosorbent assays for steroids was investigated using immobilised steroid as immunosorbent and enzyme-labelled second antibodies. An assay for testosterone with polyclonal anti-testosterone immunoglobulins was optimised with respect to a number of parameters but remained unsatisfactory for clinical assays. The results were applied to developing an aldosterone assay using monoclonal anti-aldosterone immunoglobulins. The latter method was used for the determination of urinary aldosterone and the results are compared with those obtained by a classical radioimmunoassay. Problems concerned with the use of sulphur-containing proteins and with the presence of low affinity antibodies in polyclonal preparations are discussed.


Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses.
Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.


Intermittent living; the use of ancient challenges as a vaccine against the deleterious effects of modern life - A hypothesis.
Chronic non-communicable diseases (CNCD) are the leading cause of mortality in developed countries. They ensue from the sum of modern anthropogenic risk factors, including high calorie nutrition, malnutrition, sedentary lifestyle, social stress, environmental toxins, politics and economic factors. Many of these factors are beyond the span of control of individuals, suggesting that CNCD are inevitable. However, various studies, ours included, show that the use of intermittent challenges with hormetic effects improve subjective and objective wellbeing of individuals with CNCD, while having favourable effects on immunological, metabolic and behavioural indices. Intermittent cold, heat, fasting and hypoxia, together with phytochemicals in multiple food products, have widespread influence on many pathways related with overall health. Until recently, most of the employed challenges with hormetic effects belonged to the usual transient live experiences of our ancestors. Our hypothesis; we conclude that, whereas the total inflammatory load of multi-metabolic and psychological risk factors causes low grade inflammation and aging, the use of intermittent challenges, united in a 7-10 days lasting hormetic intervention, might serve as a vaccine against the deleterious effects of chronic low grade inflammation and it's metabolic and (premature) aging consequences.


In vitro assembly of mosaic hepatitis B virus capsid-like particles (CLPs): rescue into CLPs of assembly-deficient core protein fusions and FRET-suited CLPs.
Hepatitis B virus core protein self-assembles into icosahedral, highly immunogenic capsid-like particles (CLPs) that can serve as molecular platforms for heterologous proteins. Insertion into the centrally located c/e1 epitope leads to surface display, fusion to the C terminus to internal disposition of the foreign domains. However, symmetry-defined space restrictions on the surface and particularly inside the CLPs limit the size of usable heterologous fusion partners. Further, CLPs carrying differing foreign domains are desirable for applications such as multivalent vaccines, and for structure probing by distance sensitive interactions like fluorescence resonance energy transfer (FRET). Here, we report an in vitro co-assembly system for such mosaic-CLPs allowing successful CLP formation with a per se assembly-deficient fusion protein, and of CLPs from two different fluoroprotein-carrying fusions that exert FRET in an assembly-status dependent way.


Effects of prenatal gamma-irradiation on postnatal astrogliogenesis in the hippocampal formation of rat.
Female Wistar rats were exposed to a single 1.0 Gy dose of gamma radiation on gestational days 13, 15, 17 or 19 (E13, E15, E17 and E19, respectively). Their 8- and 16-day old male offsprings were injected with 3H-thymidine and sacrificed 4 h after the injection. Brain sections were immunostained for S100beta protein and subjected to autoradiography. Thereafter, the dorsal part of the hippocampal formation was examined microscopically and numbers and locations of proliferating astrocytes were recorded. Following prenatal irradiation, the intensity of astrocyte proliferation was considerably reduced, especially in the region of dentate gyrus. The reduction showed regular trend of changes being much stronger in brains irradiated on E19 than in those irradiated on E13. The changes, therefore, were related to the stage of brain development at which the irradiation was performed. A possible role of neuronal regulatory influence on the postnatal development of glial cells was discussed.


The lived experiences of resilience in Iranian adolescents living in residential care facilities: A hermeneutic phenomenological study.
Resilience is one of the main factors affecting human health, and perceiving its meaning for high-risk adolescents is of particular importance in initiating preventive measures and providing resilience care. This qualitative study was conducted to explain the meaning of resilience in the lived experiences of Iranian adolescents living in governmental residential care facilities. This study was conducted using the hermeneutic phenomenological method. Semi-structured interviews were conducted with eight adolescents aged 13-17 living in governmental residential care facilities of Tehran province affiliated to the Welfare Organization of Iran who articulated their experiences of resilience. Sampling lasted from May 2014 to July 2015 and continued until new themes were no longer emerging. The researchers analyzed the verbatim transcripts using Van Manen's six-step method of phenomenology. The themes obtained in this study included "going through life's hardships," "aspiring for achievement," "self-protection," "self-reliance," and "spirituality." Our study indicates that the meaning of resilience coexists with self-reliance in adolescents' lived experiences. Adolescents look forward to a better future. They always trust God in the face of difficulties and experience resilience by keeping themselves physically and mentally away from difficulties. Adverse and bitter experiences of the past positively affected their positive view on life and its difficulties and also their resilience. The five themes that emerged from the findings describe the results in detail. The findings of this study enable nurses, health administrators, and healthcare providers working with adolescents to help this vulnerable group cope better with their stressful life conditions and improve their health through increasing their capacity for resilience.


Fabrication of microcavity-array superhydrophobic surfaces using an improved template method.
We fabricated the first superhydrophobic (SH) surface with microcavities, using a simple process. The process included an improved template method (ITM) for constructing the SH surface with cavities, using taro leaves as a pattern mask, and a dip-coating method for modifying the SH surface. The results obtained using the ITM are significantly better than those achieved using traditional template methods. In addition, the water-repellence of the microcavities surface was significantly enhanced by decorating with a layer of polymerized n-octadecylsiloxane nanosheets.


Students nurses' knowledge and prevalence of Needle Stick Injury in Jordan.
Student nurses are at high risk of blood-borne pathogens transmitted via Needle Stick Injury (NSI). Understanding various aspects of NSI is essential if they are to avoid the risks associated with it. The study was conducted to measure student nurses' level of knowledge about NSI and to examine its prevalence and post-exposure measures in Jordan. A cross-sectional and descriptive design was used. A sample of 279 student nurses studying at one private and four government universities distributed throughout Jordan. The study used an online survey composed of 22 questions developed from NSI literature. The questionnaire was divided into three parts: background, to measure students' demographics; knowledge, to measure nurses' understanding of NSI; and prevalence, to measure exposure to NSI and the follow-up measures. Student nurses were recruited through Facebook. The survey was available online for one full semester in 2016/2017. The total number of completed surveys was 279 (response rate=61%). Most of the students were female (n=198; 71%), in their fourth year (n=114; 40.9%). Their mean age was 21years (SD=2.5). The mean score for the knowledge part was 7 out of 10 (SD=1.7). Almost a third of the students had at least one incident of exposure to NSI (n=73; 26.2%). Most of the students who had suffered NSI did not inform their clinical instructors (67.1%) or write an incident report (86.3%). The results showed that there was no significant difference in the knowledge total scores between males and females or between students across different universities. However, a significant difference was found between students in different years of study (F (276, 2)=6.77, p=0.001). Student nurses in Jordan have a moderate understanding of issues regarding NSI. This knowledge improved with seniority. However, exposure to NSI and its under-reporting is a prevalent problem. This study recommends focusing on NSI in the nursing curriculum, and providing more protection and post-exposure intervention for students during their clinical practice.


The development of daytime rearing behavior in methylazoxymethanol-treated rats: methodological considerations.
The development of daytime rearing behavior was studied in the offspring of pregnant rats which received injections of methylaxymethanol acetate (MAM) or saline during the 15th day of gestation. MAM and control rats were tested at 10, 15, 20, 25, and 30 days of age. The results indicated that the onset of rearing for both groups appeared at approximately 15 days of age, with no significant differences found between sexes. No rearing deficits were seen in MAM rats through 25 days of age despite the fact that these animals sustained greater than a 50% reduction in telencephalic mass. However, at 30 days of age MAM rats reared for significantly longer periods of time during each episode than did their control counterparts, although the actual number of rears did not differ between groups. The results are discussed in terms of neuroplastic events which follow MAM-induced damage and the need for multivariate research when analyzing rearing behavior.


Synthesis of a water-soluble fullerene [C60] under ultrasonication.
A water-soluble fullerene [C60] is prepared with fullerene [C60] and a mixture of strong inorganic acids at the ratio (v/v) of 3:1 under ultrasonic condition at 25-43 degrees C. The MALDI-TOF MS and 13C-NMR spectra confirmed that the product of a water-soluble fullerene compound was C60.


Comparative in silico characterization of Klebsiella pneumoniae hypervirulent plasmids and their antimicrobial resistance genes.
The hypervirulent pathotype of Klebsiella pneumoniae (hvKp) is mainly mediated by large virulent plasmids. It seems that these hypervirulent plasmids (HVPs) are accumulating antimicrobial resistance genes (ARGs) and are turning quickly into drug-resistant hypervirulent hybrids. Therefore, molecular mechanisms involved in this convergence needs to be investigated to control their global spread. In this study, the complete sequence of 79 non-redundant hypervirulent plasmids were retrieved from GenBank and their genetic features, hypervirulence and antimicrobial resistance patterns (AMR) as well as their putative transmission capability were compared using bioinformatics tools. The majority of HVPs belonged to clonal complex (CC)23, and sequence type (ST)11. IncFIB and IncHI1B were the most prevalent plasmid replicon types. Out of 79 plasmids, 78 were positive for iutA and iucA. The iucC, iucB and iucD genes were found in 77 plasmids. Almost 26% of the HVPs were potentially conjugative of which 71% carried AGRs. ARGs against beta-lactams, carbapenems, quinolones, aminoglycosides, chloramphenicols, tetracyclines and macrolides were detected in 30% of HVPs. Class 1 integron and prophage structures harboring multiple ARGs were found in eight plasmids. Insertion sequences (IS)6, IS110 and IS1380 appeared to be important genetic elements in transmission of ARGs. The high prevalence of iucA and iutA suggests their strong capability for rapid and accurate genetic markers for discrimination of hvKp in the laboratory. This study indicated the important role of mobile genetic elements (MGEs) in the emergence of drug-resistance in hypervirulent strains. The high prevalence of putative conjugative hybrids implies higher incidence of multidrug-resistant (MDR)-hvKp strains in near future.


High-throughput functional characterization of combinations of transcriptional activators and repressors.
Despite growing knowledge of the functions of individual human transcriptional effector domains, much less is understood about how multiple effector domains within the same protein combine to regulate gene expression. Here, we measure transcriptional activity for 8,400 effector domain combinations by recruiting them to reporter genes in human cells. In our assay, weak and moderate activation domains synergize to drive strong gene expression, whereas combining strong activators often results in weaker activation. In contrast, repressors combine linearly and produce full gene silencing, and repressor domains often overpower activation domains. We use this information to build a synthetic transcription factor whose function can be tuned between repression and activation independent of recruitment to target genes by using a small-molecule drug. Altogether, we outline the basic principles of how effector domains combine to regulate gene expression and demonstrate their value in building precise and flexible synthetic biology tools. A record of this paper's transparent peer review process is included in the supplemental information.


Paternal care paradoxically increases offspring seizure susceptibility in the El mouse model of epilepsy.
The El mouse is a model of idiopathic epilepsy in which seizures emerge on Postnatal Days (PNDs) 80-90, although time to first seizure can be modified by experiential factors including handling during development and history of past seizures. This study tested the hypothesis that a significant increase in the amount of parental investment would impact seizure susceptibility in adult El offspring. The study used a single dam control, in which the litter was reared by a female biological parent, and a biparental experimental group, in which both biological parents reared the litter. Components of parental care and pup body weights were quantified on PNDs 2-21, and adult offspring were examined using a handling-induced seizure susceptibility (HISS) test on PNDs 80-90 to assess the long-term impact of alterations in the perinatal environment. As expected, presence of both parents did increase parental/pup contact time by 350% relative to single-mother parenting and also reduced body weight, an index of perinatal stressor exposure, in already underweight El offspring. Accordingly, HISS testing of adult El offspring revealed a deleterious effect of biparental rearing, which increased seizure incidence to 30% relative to 0% for the single dam condition. These results suggest that the presence of a second care provider in addition to the dam constitutes a form of stressor exposure in El pups and, as a consequence, reduces the time to first seizure in genetically susceptible offspring.


Endothelial colony forming cells (ECFCs) as a model for studying effects of low-dose ionizing radiation: growth inhibition by a single dose.
Identification of measurable nontransient responses to low-dose radiation in human primary cell cultures remains a problem. To this end, circulating endothelial colony-forming (progenitor) cells (ECFCs) were examined as an experimental model. ECFCs were isolated from three cord blood donors. Cells were positive for endothelial cell markers and remained highly proliferative after long-term cryopreservation. A single dose of X-ray radiation (0.06-0.38 Gy) inhibited ECFC culture growth. This effect was evident at 48 hours and persisted up to 72 hr postirradiation. Such protracted cytostatic response of ECFCs to low-dose radiation suggests that ECFC primary cultures can be used to study low-dose radiation effects.


Can artificial intelligence identify effective COVID-19 therapies?
In this issue of EMBO Molecular Medicine, Stebbing et al (2020b) validate an artificial intelligence-assisted prediction that a drug used to treat rheumatoid arthritis could be a potent weapon against COVID-19. Using liver organoids infected with SARS-CoV-2, they confirm dual antiviral and anti-inflammatory activities and show that its administration in four COVID-19 patients is correlated with disease improvement, paving the way for more rigorous placebo-controlled trials.


Equity of uptake of a diabetic retinopathy screening programme in a geographically and socio-economically diverse population.
At the time of undertaking the audit, the uptake of diabetic retinopathy screening in Derbyshire was 73%, below the national standard of 80%. To assess equity of access to diabetic retinopathy screening in a geographically and ethnically diverse population and determine predictors for poor uptake that will inform service improvements. Mixed methods health equity audit. Postal questionnaires were issued to 1000 people invited for diabetic retinopathy screening in May 2010 and telephone interviews were conducted with subsample of 32 people who had not made a screening appointment. Routine data from the screening programme was used to identify characteristics of people who did not respond to screening invitation. The adjusted odds ratios (OR) and 95% confidence intervals (95% CI) using multivariate methods were calculated in this study. The response rate to the postal questionnaire was 43%. Of these, 28% of respondents did not recall discussing the importance of diabetic retinopathy screening with their primary care team and 11% of people did not understand the term 'diabetic retinopathy'. Non-uptake of screening was associated with deprivation (OR 1.19, 95% CI 1.10-1.29 for those living in the most deprived areas compared to the least deprived) and young people were over three times more likely not to participate than older people (OR 3.13, 95% CI 2.70-3.64 for men under 40 compared to men over 80 and OR 3.03, 95% CI 1.54-5.98 for people with type 1 diabetes under 40 compared to those over 80). Ensuring that primary care and other health care and third sector organisations convey the importance of diabetic retinopathy screening with patients and improving patients' understanding of the screening programme may improve uptake. Interventions to increase uptake should be targeted to younger people, especially those with type 1 diabetes and people living in more deprived areas.


High HMGA2 expression without gene rearrangement in meningiomas.
High mobility group AT-hook 2 (HMGA2) is a non-histone transcriptional regulator protein. Aberrant expression of the HMGA2 gene (HMGA2) and structural rearrangement at the chromosomal region 12q14 with HMGA2 involvement have been reported in several mesenchymal tumors. We analyzed truncated and full-length HMGA2 expression in 55 cases of meningioma, the most common brain tumor of mesenchymal origin. Fluorescence in situ hybridization and 3'-rapid amplification of cDNA ends were used to investigate the possibility of gene rearrangements. Moreover, the relationship between HMGA2 expression and clinicopathological features was assessed. Compared with normal brain tissues, 95% of the meningioma tissues exhibited increased HMGA2 expression. In 14 cases, the expression of truncated HMGA2 was more than two-fold higher than that of paired full-length HMGA2. Chromosomal translocation involving the chromosomal region 12q14 was undetectable. No significant correlation was found between the Ki-67 labeling index and HMGA2 expression and between the HMGA2 expression and the clinicopathological features. The majority of the meningioma cases displayed increased HMGA2 expression, which was not attributed to the chromosomal rearrangement at the corresponding region. Similar to that in the other mesenchymal tumors, increased HMGA2 expression was not associated with tumor cell proliferation in meningiomas.


Percutaneous cholecystostomy in patients with acute cholecystitis: experience of 45 patients at a US referral center.
Standard treatment for acute cholecystitis is cholecystectomy, but some patients are at high risk for immediate surgery. Percutaneous cholecystostomy might be the procedure of choice in this group. We reviewed the experience of percutaneous cholecystostomy in a large tertiary center population. We performed a retrospective analysis of patients who underwent percutaneous cholecystostomy, and recorded indications for cholecystostomy, duration of tube placement, clinical outcome, death within 30 days of procedure, complications, bacteriology of aspirated bile, gallbladder contents, and performance of interval cholecystectomy. Forty-five patients (mean age 63 years) had cholecystostomy tubes placed from July 1999 to March 2002. All had confirmed or presumed acute cholecystitis. Mean duration of tube insertion was 54.3 days. Thirty-six patients improved clinically within 5 days. Nine patients died within 30 days; only one death was directly related to gallbladder sepsis. Nine patients subsequently had laparoscopic cholecystectomy, eight had open cholecystectomy, and two had cholecystoenterostomy. Cholecystectomy was planned in another five patients. Cholecystostomy tubes leaked in two patients, blocked in four, and dislodged in one. One patient developed a hemoperitoneum. Bile aspirated at cholecystostomy was culture positive in 12 patients, negative in 16, and not sent or recorded in 17. Twenty-two patients had gallstones, 10 had sludge, 9 had both, and 4 had neither. In experienced hands, percutaneous cholecystostomy is easy to perform, with low complication and high success rates. It is the procedure of choice in patients with acute cholecystitis unfit for emergency surgery. Patients often improve clinically, so that cholecystectomy can be done electively.


An automatically contamination-avoiding technique for intracorporeal esophagojejunostomy using a transorally inserted anvil during laparoscopic total gastrectomy for gastric cancer.
Intracorporeal Roux-en-Y esophagojejunostomy during laparoscopic total gastrectomy for gastric cancer remains a challenging manipulation due to the uncontrolled direction of the jejunal side or unintended embedded tissues, although several methods have been introduced. In this study, we simplified the procedure based on a surgical string fixing technique using a transorally inserted anvil (OrVil™; Covidien Ltd., Mansfield, MA, USA). From March 2012 to September 2013, 14 consecutive patients underwent simplified intracorporeal Roux-en-Y esophagojejunostomy using OrVil™ during laparoscopic total gastrectomy for gastric cancer at our hospital. Clinicopathologic characteristics and surgical outcomes of these patients were retrospectively analyzed. All of the procedures were successful completed with no complication or conversion to open surgery. The mean overall operative time was 193.8 ± 41.8 min, whereas the mean reconstruction time was 32.6 ± 4.6 min. The mean estimated blood loss was 105.7 ± 65.4 ml. The mean diameter of anastomosis measured by upper gastrointestinal contrast X-ray test at 1 month after operation was 2.3 cm. During a median follow-up period of 12 months, neither local recurrence nor anastomosis-related morbidity was observed. Our preliminary results suggested that this automatically contamination-avoiding technique based on a surgical-string-fixing strategy using OrVil™ during laparoscopic total gastrectomy for gastric cancer might be feasible and safe and provide a simple solution for intracorporeal Roux-en-Y esophagojejunostomy.


Experimental acute pancreatitis: action of atropine and beta-haloethylamine furoate on muscarine-induced exocrine pancreatic secretion.
Intraarterially administered muscarine induced predictable and reproducible experimental acute pancreatitis with a simultaneous increase in amylase levels in blood. Muscarine also caused a transient rise followed by a lowering of blood glucose levels. The stimulated amylase secretion was dose-response related. The guinea pigs survived 2--2 1/2 h after muscarine administration. Atropine (3 and 5 mg/kg), an antimuscarinic agent, injected intraperitoneally 2 h prior to muscarine administration, (a) inhibited muscarine-induced amylase secretion, and (b) marginally increased the survival time of guinea pigs, but could not sustain the animals for further experimentation. The high death rate of experimental animals prevented the use of this method as a model for investigation of experimental acute pancreatitis.


Application of band-target entropy minimization (BTEM) and residual spectral analysis to in situ reflection-absorption infrared spectroscopy (RAIRS) data from surface chemistry studies.
The band-target entropy minimization (BTEM) curve resolution technique has been used to analyze in situ reflection-absorption infrared spectroscopy (RAIRS) data of CO chemisorption on Ni(111) single crystal surfaces. The bilinearity assumption for pRAIRS data, that is, negative logarithm to the base 10 of raw reflectance RAIRS data, was found to be sufficiently valid for the test data. A total of 11 real pure component pRAIRS spectra were elucidated via BTEM in tandem with an iterative residual spectral data analysis. Furthermore, 2 abstract pure component right singular vectors were found to account for all the pRAIRS non-linearities, baseline drifts and other spectral noise. In total, 100.2% of the pRAIRS signals were accounted for by these 13 spectral components. The 11 real pure component pRAIRS spectra and their corresponding relative concentration kinetic sequences correlate with 6 well-known adsorbed CO domain structures. Moreover, amongst the BTEM resolved spectra were five new bands that were not previously observed using conventional visual identification methods adopted by surface chemists. These new bands engendered new understanding to the mechanism of CO chemisorption on Ni(111). The combination of BTEM with residual spectral analysis was thus demonstrated to be efficacious for curve resolution of in situ RAIRS data obtained from surface chemistry studies.