Maternal dietary pattern in early pregnancy is associated with gestational weight gain and hyperglycemia: A cohort study in South West of Iran.
Maternal dietary pattern could influence on fetal health outcome. Thus, this study was conducted to evaluate the relationship between maternal dietary pattern and Gestational Weight Gain (GWG) in each trimester and hyperglycemia amongst Arab pregnant women in south-west of Iran. This longitudinally study was performed in urban healthcare centers of south-west of Iran. Among 610 candidates, 488 pregnant women were included in the final analysis. Consequently, two diet patterns were determined by principal component analysis and the association between GWG and blood glucose level was determined using quartile regression. Using generalized linear model, a model was adjusted for pre-pregnancy BMI, maternal age, income, and education levels. Two dietary patterns were identified as follows: "high fat -fast food" and "vegetable-fruits & protein" pattern. High adherence to "high fat -fast food" pattern was associated with higher GWG and hyperglycemia in 3rd trimester (adjusted β: 0.029 95%CI 0.012; 0.049 P = 0.001) (adjusted β: 0.029 95%CI 0.012; 0.049 P = 0.001) respectively. High tendency to "vegetable-fruits & protein" pattern was inversely associated with development of hyperglycemia in 3rd trimester. Higher SES level was associated with low adherence to "high fat-fast food" pattern. Findings of the study revealed that, higher adherence to high -fat diet is related to excessive GWG and hyperglycemia in late pregnancy.


Systolic aortic pressure-time area is a useful index describing arterial wave properties in rats with diabetes.
The accurate measurement of arterial wave properties in terms of arterial wave transit time (τw) and wave reflection factor (Rf) requires simultaneous records of aortic pressure and flow signals. However, in clinical practice, it will be helpful to describe the pulsatile ventricular afterload using less-invasive parameters if possible. We investigated the possibility of systolic aortic pressure-time area (PTAs), calculated from the measured aortic pressure alone, acting as systolic workload imposed on the rat diabetic heart. Arterial wave reflections were derived using the impulse response function of the filtered aortic input impedance spectra. The cardiovascular condition in the rats with either type 1 or type 2 diabetes was characterized by (1) an elevation in PTAs; and (2) an increase in Rf and decrease in τw. We found that an inverse linear correlation between PTAs and arterial τw reached significance (τw = 38.5462 - 0.0022 × PTAs; r = 0.7708, P < 0.0001). By contrast, as the PTAs increased, the reflection intensity increased: Rf = -0.5439 + 0.0002 × PTAs; r = 0.8701; P <0 .0001. All these findings suggested that as diabetes stiffened aortas, the augmented aortic PTAs might act as a useful index describing the diabetes-related deterioration in systolic ventricular workload.


Emergency Medical Services Personnel Awareness and Training about Personal Protective Equipment during the COVID-19 Pandemic.
Background: With the emergence of the 2019 novel coronavirus disease (COVID-19), appropriate training for emergency medical services (EMS) personnel on personal protective equipment (PPE) is essential. We aimed: 1) to examine the change in proportions of EMS personnel reporting awareness of and training in PPE during the COVID-19 pandemic; and 2) to determine factors associated with reporting these outcomes.We conducted a cross-sectional analysis of data collected from October 1, 2019 to June 30, 2020 from currently working, nationally certified EMS personnel (n = 15,339), assessing N95 respirator fit testing; training in air purified respirators (APR) or powered APR (PAPR) use; and training on PPE use for chemical, biological, and nuclear (CBN) threats. We used an interrupted time series analysis to determine changes in proportions of EMS personnel reporting training per week, using the date of Centers for Disease Control and Prevention's (CDC) initial EMS guidance (February 6, 2020) as the interruption. We fit multivariable logistic regression models to understand factors associated with each outcome.Results: We found high awareness of N95 respirators (99%) and APR/PAPR (91%), but only 61% reported N95 fit testing and 64% reported training on PPE for CBN threats in the prior 12 months. There was a significant, positive slope change after CDC guidance for N95 respirator fit testing, and significant post-interruption mean increases for fit testing (0.9%, 95% CI 0.6-1.1%), APR/PAPR training (0.3%, 95% CI 0.2-0.5%), and PPE for CBN threats training (0.6%, 95% CI 0.3-0.9%). Factors consistently associated with lower odds of awareness/training included part-time employment, providing 9-1-1 response service, working at a non-fire-based EMS agency, and working in a rural setting.Conclusions: CDC guidance on COVID-19 for EMS may have increased N95 fit testing and training, but there remain substantial gaps in training on PPE use among EMS personnel. As the pandemic continues in our communities, EMS agencies should be supported in efforts to adequately prepare their staff.


The possible prognostic significance of immunophenotype in feline alimentary lymphoma: a pilot study.
Twenty-three retrospective biopsy specimens from feline intra-abdominal lymphomas including tumours affecting the gastrointestinal tract, mesenteric lymph nodes, liver and spleen were immunohistochemically labelled with monoclonal antibodies to CD79a (B-cell phenotype) and CD3 (T-cell phenotype). Positive labelling occurred in 15 (65%) and 6 (26%) of the tumours, respectively. No statistically significant relationship was found between tumour cell immunophenotype and age, breed, or gender. There was no significant difference in survival time between the two immunophenotypes, based on the 16 cats for which this information was available.


Single blind, multicentre, randomized, controlled trial testing the effects of a novel nutraceutical compound on plasma lipid and cardiovascular risk factors: Results of the interim analysis.
The clustering of high levels of LDL cholesterol (LDL-C) and other risk factors represents a predisposing condition for atherosclerotic disease development. Cardiovascular prevention is based on effective control of these conditions. In adult subjects with mild hypercholesterolemia we compared in the real life the effects of a new combination of nutraceuticals on lipid and glucose metabolism and blood pressure with those of an established nutraceutical combination. This multicenter, controlled, randomized, single-blind trial was designed to compare the effect of Armolipid Plus® versus that of LopiGLIK® on lipid and glucose levels and blood pressure (BP) in subjects with mild hypercholesterolemia not on statin therapy. Primary outcome was the proportion of subjects achieving therapeutic targets of LDL-C (<130 mg/dl); secondary outcomes were the effects on HDL-C, glycated haemoglobin and insulin levels. Data from an overall sample of 359 adult individuals (age 55.2 ± 11.1 years, women 57.7%, LDL-C 157.3 ± 22.6 mg/dl, HDL-C 50.7 ± 13.0 mg/dl) are reported. 72% of subjects treated with LopiGLIK® and 43% treated with Armolipid Plus® achieved the primary endpoint (p < 0.0001). Both treatments reduced plasma levels of total and LDL-C and triglycerides (p < 0.001 for all comparisons). The treatments also reduced systolic and diastolic blood pressure, plasma levels of glycated haemoglobin, insulin and HOMA index. The changes induced by LopiGLIK® in all these metabolic parameters were greater than those obtained with Armolipid Plus®. The present analysis shows that LopiGLIK® may represent a more effective tool for clinical management of CV risk factors in subjects with mild hypercholesterolemia.


A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer.
Trastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/- 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24low/CD44high subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.


A rapid luminescently monitored enzyme immunoassay for IgE.
A novel halophenol-enhanced luminol-peroxide luminescent detection method for horseradish peroxidase has been tested in an enzyme immunoassay for IgE. The luminescent enzyme immunoassay was reproducible (within-batch CV, 3.9-13.2%) and values obtained on serum samples showed good agreement with those obtained by colorimetric enzyme immunoassay. The major advantages of the luminescent detection method are that it is rapid, 30 s compared with 30 min for the colorimetric assay using o-phenylenediamine, and the luminescent signal is intense and stable for several minutes.


Cephalometric changes associated with treatment using the activator, the Fränkel appliance, and the fixed appliance.
Treatment with the activator, the Fränkel appliance, and the edgewise appliance was compared in three separate groups; each group consisted of twenty-five nonextraction cases of Class II, Division 1 malocclusion. Hard- and soft-tissue profile changes caused by growth and treatment were assessed by means of pretreatment and posttreatment lateral cephalograms. Anterior movement of A point was 1.6 mm more in the activator group than in the fixed-appliance group. The most anterior point on the maxillary incisor moved 1.5 mm more distally in the fixed-appliance sample than in the functional groups. Among the three groups, the activator sample showed the most anterior movement of the mandible (2.3 mm); the fixed group showed the least (0.6 mm). The fixed-appliance group showed more posterior rotation of the mandible than the activator group. However, relative to cranial base, the movement of the mandibular symphysis was not statistically different in the three groups. There were little differences among the treatment groups with regard to changes in the soft-tissue profile. In clinical terms, there was a remarkable similarity in the changes that occurred in the three treatment groups.


Concomitant boost radiotherapy compared with conventional radiotherapy in squamous cell carcinoma of the head and neck--a phase III trial from a single institution in India.
To test the efficacy of an accelerated fractionation schedule (concomitant boost) against standard conventional fractionation in squamous cell carcinomas of the head and neck region in our patient population. Patients were randomised to receive either conventional radiotherapy with 2 Gy/fraction/day, to a dose of 66 Gy in 33 fractions over 6.5 weeks or accelerated radiotherapy in the form of concomitant boost to a dose of 67.5 Gy/40 fractions over 5 weeks (phase 1: 45 Gy/25 fractions/5 weeks and phase 2: 22.5 Gy/15 fractions/3 weeks as a second daily fraction after a 6h gap). The primary and secondary end points were disease-free survival and locoregional control respectively. The compliance was 97.2% and 96.5% in the concomitant boost and conventional arms, respectively. Patients treated with concomitant boost had a better 2-year disease-free survival (71.7% vs 52.17%, P=0.0007) and locoregional control rates (73.6% vs 54.5%, P=0.0006) than with conventional fractionation. On exploratory subgroup analysis, the oropharynx (P<0.001), T4 lesions (P=0.017), N+ disease (P<0.001) and stage IV disease (P<0.001) were statistically significant prognostic variables in favour of the concomitant boost arm. Grade 3 mucositis was seen in 35% of patients in the concomitant boost arm, whereas in the conventional arm only 19% of patients had grade 3 mucositis (P=0.01). The median radiotherapy duration in the concomitant boost arm was 36 days (range 36-53 days), whereas in the conventional arm it was 46 days (range 46-64 days). The mean gap in radiation treatment in the concomitant boost arm was 1.68 days (range 0-14 days), whereas the mean gap in the conventional arm was 1.58 days (range 0-14 days). Concomitant boost is a therapeutically superior and logistically feasible accelerated radiotherapy regimen in advanced head and neck cancers, especially in the setting of a developing country.


World Health Organization myth busters and indigenous perceptions of COVID-19: Quechua and Shipibo communities.
When the COVID (SARS-V2) pandemic swept across the world, it impacted Indigenous communities more than others. This is due to a variety of reasons: socioeconomic injustice and racialization, lack of access to equitable healthcare, and linguistic discrimination. As a result, several communities and community types demonstrated this effect when perceptions of inferences or other COVID-related information were measured. This paper reports on a participatory collaborative study with two Indigenous communities in rural Peru-ten Quechua-speaking communities in Southern Cuzco and three Shipibo-speaking communities in Ucayali regions. We investigate the communities' level of preparedness for the crisis by eliciting answers based on the World Health Organization COVID 'MythBusters' in a form of a semi-structured interview. Interviews were transcribed, translated, and analyzed in search of the effect of three variables: gender (male/female), language group (Shipibo/Quechua), and proficiency in the Indigenous language (from 0 to 4). Data reveal that all three variables have some effect on the target comprehension of COVID-related messages. Additionally, we explore other possible explanations.


A two year follow-up of somatic complaints among Israeli combat stress reaction casualties.
The relationships of somatic complaints and health related habits to combat stress reaction and post-traumatic stress disorder were assessed one and two years after the 1982 Lebanon War. The sample consisted of 285 combat stress reaction Israeli casualties and 198 comparable controls. Results showed that higher rates of somatic complaints were reported by both combat stress reaction and post-traumatic stress disorder casualties at the two points in time. Theoretical and methodological implications were discussed.


An approach to practical problems in the diagnosis of lymphoproliferative disorders using cytochemistry and immunocytochemistry.
The use of enzyme histochemical and immunohistochemical markers has improved our understanding of the biology of lymphoproliferative disorders. These same techniques can now provide practical information when applied to the diagnosis of lymphoproliferative disorders.


Evaluation of narrow band imaging in the assessment of laryngeal granuloma.
Laryngeal granulomas belong to common complications following trans-oral laser microsurgery (TLM). The aim of this study was to evaluate NBI in the differentiation between granuloma-like lesions and local tumor recurrence. 154 consecutive patients after TLM due to early laryngeal cancer were enrolled. In the group, a monthly follow-up including NBI endoscopy was performed. Moderate and severe dysplasia, carcinoma in situ and invasive cancer were defined as positive histology, laryngeal granuloma and other benign laryngeal lesions as negative histology and premalignant lesions as suspicious histology. In 47/154 (31%) cases, granuloma-like lesion (GLL) was found. Patients with GLL were divided into two groups based on the NBI classification. In all patients, the microvascular pattern in NBI was compared with the final histology. In group A, with suspicious, perpendicular vessels, 13/13 (100%) samples were positive. In group B, with normal vascular pattern 3/34 (9%) samples were positive and 31/34 (91%) samples were negative. There was a significant correlation between the positive NBI vascular pattern and the final histology (p = 0.00001). Sensitivity, specificity, accuracy of NBI were as follows: 81%, 100%, 94%, respectively.Based on our results, NBI can reliably differentiate between postoperative laryngeal granuloma and local tumor recurrence. In such a manner, this method is very helpful in the follow-up of tumor patients.


Anatomically realistic three-dimensional meshes of the pelvic floor & anal canal for finite element analysis.
Three anatomically realistic meshes, suitable for finite element analysis, of the pelvic floor and anal canal regions have been developed to provide a framework with which to examine the mechanics, via finite element analysis of normal function within the pelvic floor. Two cadaver-based meshes were produced using the Visible Human Project (male and female) cryosection data sets, and a third mesh was produced based on MR image data from a live subject. The Visible Man (VM) mesh included 10 different pelvic structures while the Visible Woman and MRI meshes contained 14 and 13 structures, respectively. Each image set was digitized and then finite element meshes were created using an iterative fitting procedure with smoothing constraints calculated from 'L'-curves. These weights produced accurate geometric meshes of each pelvic structure with average Root Mean Square (RMS) fitting errors of less than 1.15 mm. The Visible Human cadaveric data provided high resolution images, however, the cadaveric meshes lacked the normal dynamic form of living tissue and suffered from artifacts related to postmortem changes. The lower resolution MRI mesh was able to accurately portray structure of the living subject and paves the way for dynamic, functional modeling.


Semisynthetic analogs of cytochrome c reconstructed from natural and synthetic peptides.
A biologically active semisynthetic hybrid of horse heart cytochrome c has been prepared by combining the heme peptide 1 through 65 (HP 1-65), prepared by CNBr cleavage of natural cytochrome c, with a semisynthetic peptide corresponding to positions 66 through 104. A fully protected synthetic peptide 66--79 was prepared by a modified solid phase peptide synthesis procedure and was converted to its N-hydroxysuccinimide ester. A peptide corresponding to residues 81--104 of cytochrome c was also isolated from the CNBr cleavage mixture and its epsilon-amino groups and tyrosyl hydroxyl group were protected selectively with the t-butyloxycarbonyl group. This partially protected peptide was reacted with t-butyloxycarbonyl methionine N-hydroxysuccinimide ester to give a derivative having methionine at position 80. This product was deprotected, purified and then t-butyloxycarbonyl groups were again introduced specifically on the epsilon-amino groups to give the peptide, Boc(Lys,Tyr)80--104. A semisynthetic peptide corresponding to residues 66 through 104 of cytochrome c was prepared by condensing the synthetic peptide 66--79 N-hydroxysuccinimide ester with t-butyloxycarbonyl (Lys,Tyr)80--104. The semisynthetic product was deprotected, purified and combined under anaerobic conditions with a heme peptide, HP 1-65, that was isolated from the products of CNBr cleavage of native cytochrome c. The reconstituted semisynthetic cytochrome c was purified by ion exchange chromatography and was shown to have the same oxygen uptake as native cytochrome c when assayed in the succinate oxidase system.


[General practitioners' evaluation of the out-of-hours service in Copenhagen County].
This investigation was part of a large project concerning quality development in the primary care out-of-hours service in Copenhagen County, Denmark. In August 2003 a questionnaire was sent out to all the general practitioners in Copenhagen County (n = 365, return rate: 82%). 56% of the GPs were not working in the out-of-hours service. In total, 95% of those surveyed felt that the out-of-hours service is doing a good job; 95% expressed satisfaction with the professional level; and only 3% found that they did not have good cooperation with the service. 63% did not agree with the statement that the out-of-hours service is used only in acute cases of disease or acute deterioration of disease. Overall, the GPs expressed a high level of satisfaction with the out-of-hours service. They also felt that their patients were satisfied. However, the study pointed out the difference in perception between patients and doctors regarding the aim of the service.


Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1–G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1–G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7–G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9–G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.


Analysis of alcohol polyethoxylates and polyethylene glycols in marine sediments.
Alcohol polyethoxylates (AEOs) are the most commercially important type of nonionic surfactants, used in a wide variety of products such as household cleaning detergents, industrial cleaners, textiles, adjuvants in pesticides, wetting and dispersing agents, and emulsifiers. Our main objective in this work was to develop a methodology for the extraction, isolation and analysis of these compounds and their main degradation products and precursors (polyethylene glycols, PEGs) in solid environmental matrices. First, analytes were extracted by pressurized liquid extraction (PLE) using methanol at 120°C as solvent and 3 cycles (5 min per cycle). Clean-up and concentration of the extracts were carried out by solid-phase extraction (SPE), using Oasis HLB cartridges and a mixture dicloromethane/methanol 1:1 as eluting solvent. Recovery percentages were usually between 54% and 106% for most compounds. Identification and quantification of analytes were performed using a liquid chromatography-mass spectrometry (LC-MS) system equipped with an electrospray interface (ESI) operating in positive ionization mode. Water content, cone voltage and adduct formation were optimized to this end. Limits of detection were usually below 50 ng g(-1), being higher for some shorter ethoxymers (>100 ng g(-1)) because of poor ionization. Finally, the protocol proposed here was applied to the determination of the concentration of AEOs and PEGs in selected surface sediment samples collected in Mar Menor Lagoon (Murcia, Spain). In this sense, this paper presents some of the first data relative to the occurrence of these analytes in coastal sediments, showing relatively high concentrations of PEGs (up to 9000 ng g(-1)) compared to those measured for AEOs (<100 ng g(-1)).


Estimation of local cerebral glucose utilization by positron emission tomography of [18F]2-fluoro-2-deoxy-D-glucose: a critical appraisal of optimization procedures.
Various approaches estimating local cerebral glucose utilization by positron emission tomography of labeled deoxyglucose are compared. Autoradiographic methods that predict the glucose utilization rate from a single scan are unreliable in pathologic tissue because of abnormal values of the model rate constants. A normalization procedure using the ratio of measured tissue activity to activity calculated with standard rate constants is proposed to readjust the values of the rate constants. Reliable estimates of metabolic rates can be obtained from dynamic recordings of tracer uptake. In the graphic approach, metabolic rate can be derived from the slope of a segment of a transformed uptake curve, which becomes linear at 15-20 min after intravenous tracer injection, with an accuracy comparable with that in complete dynamic studies. However, by recording and analyzing full-length uptake curves, in addition to metabolic rate, the model rate constants can be determined regionally. The physiological significance of those parameters is demonstrated in crossed cerebellar deactivation in 30 patients with supratentorial infarcts. Mild hypometabolism both within the ischemic lesion and in the morphologically intact cerebellum is accompanied by a reduction of the phosphorylation rate only. Severe metabolic depression, by contrast, affects both cerebellar transport and phosphorylation processes, whereas in the cerebrum, only the rate constant k1 is significantly correlated with the degree of metabolic disturbance.


Multidimensional gas chromatographic‒Mass spectrometric method for separation and identification of triacylglycerols in olive oil.
A 'heart-cut' multidimensional gas chromatography‒mass spectrometry (H/C MDGC‒MS) method for separation and identification of triacylglycerols (TAGs) in extra virgin olive oil was developed. A GC configuration, comprising a non-polar first dimension (1D) column (15 m length) and a mid-polarity second dimension (2D) column (9 m length), was employed. Standard TAGs were used to test and demonstrate the H/C MDGC method, for identification of TAG components and to validate the method. Various chromatographic conditions such as column flow and temperature program were evaluated. The 1D separation resulted in overlap of some standard TAG peaks. These overlapped 1D regions of the standard TAGs were H/C to 2D for further separation and resulted in clearly distinguished individual TAG component peaks. The 1D separation of olive oil TAGs displayed three major peaks and four minor peaks. The application of the H/C MDGC method to olive oil TAGs resulted in the separation of each sampled 1D region into two or more TAG peaks. TAG components in olive oil resolved on the 2D column were identified based on characteristic mass fragment ions such as [M-RCO2]+, [RCO+128]+, [RCO+74]+ and RCO+ and comparison of their mass spectra with that of the standard TAGs. Sixteen olive oil TAGs were identified by MS after 2D separation. The repeatability of the H/C method was evaluated in terms of retention time shift and area response in the 2D and found to be <0.02% and <8% RSD respectively.


Toxicity assessment of reference and natural freshwater sediments with the LuminoTox assay.
We examined the possibility of adapting the LuminoTox, a recently-commercialized bioanalytical testing procedure initially developed for aqueous samples, to assess the toxic potential of sediments. This portable fluorescent biosensor uses photosynthetic enzyme complexes (PECs) to rapidly measure photosynthetic efficiency. LuminoTox testing of 14 CRM (Certified Reference Material) sediments was first undertaken with (1) a "solid phase assay" (Lum-SPA) in which PECs are in intimate contact with sediment slurries for a 15 min exposure period and (2) an elutriate assay (Lum-ELU) in which PECs are exposed for 15 min to sediment water elutriates. CRM sediment toxicity data were then compared with those generated with the Microtox Solid Phase Assay (Mic-SPA). A significant correlation (P < 0.05) was shown to exist between Lum-SPA and Mic-SPA, indicating that both tests display a similar toxicity response pattern for CRM sediments having differing contaminant profiles. The sediment elutriate Lum-ELU assay displayed toxicity responses (i.e. measurable IC20s) for eight of the 14 CRM sediments, suggesting that it is capable of determining the presence of sediment contaminants that are readily soluble in an aqueous elutriate. Lum-SPA and Mic-SPA bioassays were further conducted on 12 natural freshwater sediments and their toxicity responses were more weakly, yet significantly, correlated. Finally, Lum-SPA testing undertaken with increasing mixtures of kaolin clay confirmed that its toxicity responses, in a manner similar to those reported for the Mic-SPA assay, are also subject to the influence of grain size. While further studies will be required to more fully understand the relationship between Lum-SPA assay responses and the physicochemical makeup of sediments (e.g., grain size, combined presence of natural and anthropogenic contaminants), these preliminary results suggest that LuminoTox testing could be a useful screen to assess the toxic potential of solid media.


Vascular abnormalities in pediatric craniopharyngioma patients treated with radiation therapy.
Craniopharyngioma is a benign brain tumor that can be treated with some combination of surgery, intracystic chemotherapy and radiation therapy. Treatment for craniopharyngioma, especially radiation therapy, is associated with a variety of long-term toxicities including vascular abnormalities. We report on the incidence of vascular abnormalities seen in the children with craniopharyngioma who received radiation therapy at our institution. We reviewed our experience with craniopharyngioma patients who received radiation therapy from 1995 to 2008. We reviewed clinical data including surgery, chemotherapy, radiation therapy and imaging for vasculopathy. Twenty of the 22 children with craniopharyngioma who received radiation therapy had imaging available. Six of the 20 were found to have some type of vasculopathy. One had bilateral temporal cavernomas, one had moyamoya syndrome, one had an aneurysm of the internal carotid artery and three children had decreases in the caliber of the carotid or cerebral arteries, but were asymptomatic. Two of the six children with abnormalities also received intracystic bleomycin prior to radiation therapy. We report a high incidence of vascular abnormalities in children with craniopharyngioma. The data suggest that intracystic bleomycin may contribute to radiation-related vasculopathy. We now include magnetic resonance angiography as part of our routine follow up in these children.


Teratogenic effects of nitroimidazopyridazine on the CNS in fetal Wistar (WU) rats.
Teratogenic effects caused by a new nitroimidazopyridazine were examined in Wistar (WU) rats after repeated oral administration of 0, 2.5, 10, and 40 mg/kg, given on days 6-17 post coitum (p.c.) (Day of mating = Day 0) in a regular study on embryo-fetal development according to ICH S5A. At day 20 p.c., fetuses were removed and carefully examined under a dissecting microscope for external, visceral and skeletal malformations. The exposure to the high dose of the test compound during the organogenesis and early histogenesis periods of prenatal development induced prominent CNS malformations (exencephaly, neural tube defects (NTD)) associated with external malformations (hyperflexion of the forelimbs). To support the data from this study additional histological evaluation of the brains was performed with the following results: disorganization of the cerebral cortex associated with ectopic subcommissural organs. Additionally, an in vitro test (whole embryo culture, WEC) showed alterations of the developing neural tube after the incubation of rat embryos with the test compound on gestation days 9.5-11.5. Our data demonstrated that nitroimidazopyridazine caused NTDs and limb malformations during organogenesis. Based on these data the further development of the test compound was stopped.


Surface complexation modeling of Sr(II) and Eu(III) adsorption onto oxidized multiwall carbon nanotubes.
Acid-base titrations of oxidized multiwall carbon nanotubes (MWCNTs), Sr(II) and Eu(III) adsorptions onto oxidized MWCNTs were conducted to investigate the surface charge characteristics of oxidized MWCNTs and the surface complexation interactions between Sr(II)/Eu(III) and oxidized MWCNTs. The results suggested that Sr(II) and Eu(III) adsorptions onto oxidized MWCNTs increased with increasing pH, and decreased with increasing ionic strength, and the affinity of oxidized MWCNTs for Eu(III) was much higher than that for Sr(II). The diffuse layer model (DLM) fitted the experimental data of Sr(II) and Eu(III) adsorptions well with the aid of FITEQL 3.2.


Primary anetoderma associated with antiphospholipid antibodies and micromorphologic vascular lesions: case report and literature review.
A 40-year-old male patient with primary anetoderma is presented in whom antiphospholipid antibodies were detected while not fulfilling diagnostic criteria for antiphospholipid syndrome. The possible pathogenic role of antiphospholipid antibodies in the disease development is postulated.


Isobenzofuran-1(3H)-one derivatives: Amoebicidal activity and program cell death in Acanthamoeba castellanii Neff.
The genus Acanthamoeba is characterized by being a group of ubiquitous and free-living amoebae that inhabit a variety of environments. Generally, human infections by this parasite are associated with Acanthamoeba keratitis, especially in contact lens wearers, and with chronic but fatal granulomatous amoebic meningoencephalitis. Current treatments used for eradication of amoeba from infection sites represent a challenge for pharmacotherapy, due to the lack of effective treatment and the amoebae highly resistant to anti-amoebic drugs. In this study, we describe the results of the assessment of the IC50 of 10 isobenzofuran-1(3H)-one derivatives (QOET) against four Acanthamoeba strains. The compounds QOET-3 and QOET-9 were the selected derivatives with the lowest IC50 in A. castellanii Neff trophozoites (73.71 ± 0.25 and 69.99 ± 15.32 µM, respectively). Interestingly, analysis of the compound effects on the cell apoptosis-like features showed that both active molecules triggered programmed cell death (PCD) in A. castellanii Neff. The results obtained in this study highlights that isobenzofuranone derivatives could represent an interesting source for developing novel antiamoebic drugs.


The effect of serum calcium level on the success of diltiazem treatment: A retrospective cohort study.
Diltiazem is an antiarrhythmic drug widely used in the treatment of atrial fibrillation (AFib) with rapid ventricular response (RVR). It reveals its effect by blocking L-type calcium channels. Thus, it inhibits the extracellular calcium influx into the cytosol. The relationship between serum calcium level and the efficacy of intravenous (IV) diltiazem used in the treatment of AFib with RVR has not been investigated in vivo. The aim of this study is to investigate the mentioned relationship. This study was planned as a single-center retrospective study. The data of 349 patients who presented to the emergency department with AFib with RVR and treated with diltiazem were retrospectively analyzed. A patient was considered to have responded to diltiazem treatment if the existing heart rhythm returned to sinus rhythm, or the heart rate decreased below 100 beats/min, or the heart rate decreased >20% provided that it was below 120 beats/min. The ionized calcium levels were recorded. The relationship between serum calcium level and the success of diltiazem treatment was examined. Fifty five percent of the patients were female. The median age was 75 years. The rate of response to diltiazem treatment was 67.3%. The median of ionized calcium levels in the group which responded to diltiazem treatment (n = 235) was 1.14 mmol/L (IQR: 0.12), and the group which did not respond to diltiazem treatment (n = 114) was 1.11 mmol/L (IQR: 0.12) (p = 0.322). The patients were divided into three groups as low, normal, and high calcium levels according to the calcium reference levels determined by the hospital laboratory. The rate of response to diltiazem treatment was 61.4% in patients with low ionized calcium levels, 76.1% in patients with normal ionized calcium levels, and 40.0% in patients with high ionized calcium levels. The rate of response to diltiazem treatment was higher in patients with normal ionized calcium levels compared to patients with low or high ionized calcium levels (p = 0.004, p = 0.003). The success rate of diltiazem used in the treatment of AFib with RVR was highest in physiological calcium levels. The current study may provide the clinician with awareness about the consideration of serum ionized calcium levels when choosing drugs in patients with AFib with RVR.


Successful control of scleritis caused by Nocardia farcinica: A case report.
Nocardia farcinica is an opportunistic pathogen that rarely causes ocular infections. This study reviewed a case of N. farcinica-mediated scleritis involving the corneal limbus. A 56-year-old man was admitted to the Department of Keratology of Jinan Second People's Hospital due to "a red and swollen right eye accompanied with severe pain for >1 month." He denied any history of hypertension, diabetes, systemic immune diseases and eye surgery. Corneal defect and scleral necrosis were observed by slit lamp. Combination of anterior segment optical coherence tomography and ophthalmic ultrasound biomicroscopy was used for diagnosis and evaluation of corneal and scleral conditions. Culture and metagenomic sequencing verified that the pathogen of scleritis was N. farcinica. The patient was treated by sulfacetamide sodium eye drops, oral administration of sulfamethoxazole tablets, amikacin anterior chamber flushing, scleral debridement, and allogeneic scleral transplantation. The disease was successfully controlled. Infectious scleritis caused by N. farcinica is extremely rare. Culture of pathogenic microorganisms remains to be the gold standard for the diagnosis of infectious eye diseases. Metagenomic sequencing shows potential promise in the diagnosis of infectious eye diseases. N. farcinica is sensitive to sulfonamides and amikacin.


Detection of an occult transclival cerebrospinal fluid fistula by CT and MRI.
We describe an unusual occult transclival cerebrospinal fluid (CSF) fistula to the sphenoid sinus demonstrated by MRI. CT was performed because of a posterior cerebral infarct caused by cardiac arrhythmia. Axial sections showed fluid in the sphenoid sinus. High-resolution scans revealed a bony defect 3 mm in diameter of the posterior wall of the sphenoid sinus, and MRI showed a transclival CSF fistula. This occult lesion was confirmed by surgery and duraplasty was successfully performed via an endonasal approach.


The first organically templated open-framework metal-sulfites with layered and three-dimensional diamondoid structures.
The crystallographic signatures and characterization data of two novel organically templated open-framework zinc-sulfites (NH3CH2CH2NH3)[Zn3(SO3)4], 1, and (CN3H6)2[Zn(SO3)2], 2, are reported for the first time, synthesized under hydrothermal conditions using different amines, namely, ethylenediamine and guanidine, to generate 2D (for 1) and 3D (for 2) assemblies with 4-, 6-, 8- and 12-membered rings.


Prevalence, correlates, and network analysis of Internet addiction symptoms among Chinese pregnant and postpartum women.
Excessive Internet use is a common health problem globally. This study aimed to assess the prevalence, correlates, and network structure of Internet addiction symptoms (Internet addiction hereafter) among Chinese pregnant and postpartum women. This was a multicenter cross-sectional study using Internet Addiction Test (IAT) and the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) to evaluate Internet addiction and quality of life (QOL), respectively. Univariate analyses, multivariate logistic regression analyses, and network analyses were performed. Of a total of 1,060 women who completed the study, 320 (30.19%, 95% CI=27.42%-32.96%) women reported Internet addiction during or after pregnancy. Women with previous adverse pregnancy experiences (OR=1.831, P=0.001) and physical comorbidities (OR=1.724, P=0.004) had a higher likelihood of developing Internet addiction. Internet addiction was significantly associated with poor QOL in all domains. Network analyses revealed that IAT item 16 (request an extension for longer time spent online) was the most central symptom in the analyses, and also one of the strongest bridging symptoms linking the Internet addiction and QOL communities. This was a cross-sectional study, all study findings were based on self-reported data, and possible recall bias and selection bias may exist. Internet addiction is common among Chinese pregnant and postpartum women, and is significantly associated with lower QOL. Effective strategies, especially focusing on central symptoms, are needed to reduce the impact of Internet addiction and improve QOL in pregnant and postpartum women.


General surgeon shortage in the United States: fact or fiction, causes and consequences.
There is evidence that supports a current undersupply of general surgeons with a potential for worsening workforce shortages in the future. This article examines this potential shortage along with its causes and possible consequences.


Effects of general anesthesia on the human blink reflex.
The blink reflex was studied in 10 patients undergoing elective procedures under general anesthesia. Anesthetic agents were isoflurane, halothane, nitrous oxide, methohexital, and thiopental in various combinations. At induction, blink reflexes were diminished by low-dose thiopental (1-1.5 mg/kg) and abolished by high-dose thiopental (4-8 mg/kg) and methohexital (1.5 mg/kg). Blink reflexes were absent during halogenated volitile inhalational anesthesia and did not return until patients were in the recovery room, well after end-tidal anesthetic levels were zero by mass spectroscopy. Recovery of consciousness and the ability to blink on command often preceded return of any blink reflex activity, indicating that the blink reflex is not useful as a postoperative test of facial nerve function in the operating room after anesthesia. In six patients, blink reflexes were still diminished 2-3 hours after cessation of anesthesia, at a time when patients were fully oriented and corneal and eyelid reflexes were clinically normal. This finding suggests that the blink reflex might be a sensitive test of subtle CNS dysfunction after inhalational anesthesia and potentially could serve as a useful objective indicator of recovery from anesthesia for outpatient surgery.


Childhood and adult ALL: differences in epigenetic lesions associated with cell cycle genes.
The impact of silencing tumor suppressor genes involved in cell proliferation in adult and pediatric ALL is still unknown. We analyzed methylation of the master regulators (p73, p53, Rb), CDKIs (p27, p57), and the INK4 locus (p15) in childhood ALLs and describe a relatively low frequency. Comparisons with adult ALL showed that p57 clearly differed in children (7% methylation) and adults (50% methylation). While >20% of adult ALL Ph1 chromosome-negative undergo methylation of p73, p57, and p15, only 3% of childhood ALL carried such anomalies, which is very significant when a higher fraction of pediatric patients has non-Ph1 ALL than do the adult patients. We have studied a large p57 CpG island and expression by real-time RT-PCR. We observed that 53% of childhood leukemias lacked p57 transcripts, and the overall level was 8-fold lower than in normal lymphocytes (P < 0.0001). However, no correlation with methylation was found. Thus, loss of p57 expression in the absence of methylation may be frequent in childhood ALL, suggesting that methylation is not the sole mechanism of p57 downregulation. Methylation differences in ALL may be age-related or, alternatively, reflect different pathogenesis.


Evolutionary rate of human tissue-specific genes are related with transposable element insertions.
The influence of transposable elements (TEs) on genome evolution has been widely studied. However, it remains unclear whether TE insertions also impact on evolutionary rate of human genes. In this study, we have compared the differences in TEs and evolutionary rates between human tissue-specific genes. Our results showed that various functional categories of human tissue-specific genes contained different TE numbers and divergent values of Ka/Ks, with human nucleic acid binding transcription factor activity genes having the fewest TE density and Ka/Ks value. Interestingly, we also found that human tissue-specific genes with TEs have also undergone faster evolution than those without TEs. Therefore, TEs have significant impact on the evolutionary rates of human tissue-specific genes. Furthermore, local genomic properties such as gene length, GC content and recombination rate may reflect a true transpositional bias for the particular TEs. Our results may provide important insights for further elucidating the evolution of human tissue-specific genes.


The study of the variability of anticipatory postural adjustments in patients with recurrent non-specific low back pain.
Intrinsic variability is present in all actions, including repetitive tasks. The aim of this study was to evaluate the variability of anticipatory postural adjustments (APAs) of trunk muscles in participants with low back pain (LBP). The study included 21 participants with recurrent non-specific LBP (15 men, 6 women) and 21 healthy volunteers. Standard deviation of electromyographic activity of the external oblique (EO), transverse abdominis/internal oblique (TrA/IO), and erector spinae (ES) muscles onset relative to deltoid muscle onset was recorded in 75 rapid arm flexions, and the correlation with the participants' avoidance belief (the FABQ score) and disability (the Roland-Morris Questionnaire score) was statistically analyzed. participants with LBP exhibited less variability in timing of APAs of the TrA/IO muscle compared with the control group (P=0.047). The timing of APAs of the TrA/IO muscle was significantly correlated with the FABQ score (P=0.006). There was no significant correlation between this variable and disability (P=0.09). Decrease in variability of the timing of APA of the EO (P=0.45) and ES (P=0.6) muscles was not significant. The variability of the postural responses of participants with LBP decreased. Restoring variability in postural control responses might be a goal in rehabilitating these patients.


Caffeoylquinic Acid Derivatives Protect SH-SY5Y Neuroblastoma Cells from Hydrogen Peroxide-Induced Injury Through Modulating Oxidative Status.
Oxidative stress has been confirmed as a contribution to the pathogenesis and pathophysiology of many neurological disorders such as Alzheimer's disease and Parkinson's disease. Caffeoylquinic acids (CQAs) are considered to have anti-oxidative stress ability in a previous study, but the structure-activity relationships (SARs) of CQAs in neuroprotective effects are still unclear. In the present study, we primarily expound the SARs of CQAs in counteracting H2O2-induced injury in SH-SY5Y cells. We found that CQAs (1-10) represented the protection of SH-SY5Y cells against H2O2-induced injury in varying degrees and malonyl groups could obviously increase the anti-oxidative stress ability of CQAs. Intensive studies of 4,5-O-dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid (MDCQA) indicated that the mechanisms could potentially involve activation of endogenous antioxidant enzymes and the regulation of the phosphorylation of MAPKs and AKT. In conclusion, MDCQA could serve as a neuroprotective agent with a potential to attenuate oxidative stress.


Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer.
Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field.


The SOCS box-adapting proteins for ubiquitination and proteasomal degradation.
The suppressor of cytokine signalling (SOCS) box was first identified in the SH2-containing SOCS box family (cytokine-inducible SH2-containing protein, SOCS1-7) and is a 40-amino acid motif, which functions to recruit an E3 ubiquitin ligase complex consisting of the adapter proteins elongins B and C, Rbx2 and the scaffold protein Cullin5. The SOCS box is found in a diverse array of intracellular signalling molecules, many of which contain different protein interaction domains such as SPRY and WD40 domains, leucine and ankyrin repeats or other functional domains such as GTPases. In general, the SOCS box-containing proteins are thought to act as substrate-recognition modules to mediate the polyubiquitination and subsequent degradation of substrate proteins by the 26S proteasome.


Serum Uric Acid Levels and Renal Impairment among ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Intervention.
Elevated serum uric acid (UA) levels are associated with adverse outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). However, the relation between UA and acute kidney injury (AKI) in this population is unclear. We evaluated the effect of elevated UA levels on the risk to develop AKI among consecutive STEMI patients treated with primary PCI. We performed a retrospective analysis of 1,372 consecutive patients admitted with the diagnosis of STEMI between January 2008 and February 2015. Patients were stratified into quartiles according to UA levels as follows: quartile 1, <4.7 mg/dl; quartile 2, 4.8 to <5.6 mg/dl; quartile 3, 5.7 to <6.6 mg/dl, and quartile 4, >6.7 mg/dl. STEMI patients with elevated UA levels had a higher frequency of AKI (4 vs. 6% vs. 10 vs. 24%; p < 0.001). In a subgroup analysis of patients with reduced baseline estimated glomerular filtration rate (≤60 ml/min/1.73 m(2)), an elevated UA level was associated with a significant risk to develop AKI, with 46% of patients developing AKI in the highest UA quartile. In a multivariate logistic regression model, for every 1-mg/dl increase in the UA concentration, the adjusted risk for AKI increased by 46% (OR = 1.46, 95% CI 1.18-1.66; p < 0.001). Among STEMI patients undergoing primary PCI, elevated UA levels are an independent predictor of AKI.


Splicing Enhancers at Intron-Exon Borders Participate in Acceptor Splice Sites Recognition.
Acceptor splice site recognition (3' splice site: 3'ss) is a fundamental step in precursor messenger RNA (pre-mRNA) splicing. Generally, the U2 small nuclear ribonucleoprotein (snRNP) auxiliary factor (U2AF) heterodimer recognizes the 3'ss, of which U2AF35 has a dual function: (i) It binds to the intron-exon border of some 3'ss and (ii) mediates enhancer-binding splicing activators' interactions with the spliceosome. Alternative mechanisms for 3'ss recognition have been suggested, yet they are still not thoroughly understood. Here, we analyzed 3'ss recognition where the intron-exon border is bound by a ubiquitous splicing regulator SRSF1. Using the minigene analysis of two model exons and their mutants, BRCA2 exon 12 and VARS2 exon 17, we showed that the exon inclusion correlated much better with the predicted SRSF1 affinity than 3'ss quality, which were assessed using the Catalog of Inferred Sequence Binding Preferences of RNA binding proteins (CISBP-RNA) database and maximum entropy algorithm (MaxEnt) predictor and the U2AF35 consensus matrix, respectively. RNA affinity purification proved SRSF1 binding to the model 3'ss. On the other hand, knockdown experiments revealed that U2AF35 also plays a role in these exons' inclusion. Most probably, both factors stochastically bind the 3'ss, supporting exon recognition, more apparently in VARS2 exon 17. Identifying splicing activators as 3'ss recognition factors is crucial for both a basic understanding of splicing regulation and human genetic diagnostics when assessing variants' effects on splicing.


Control of Boophilus microplus populations in grazing cattle vaccinated with a recombinant Bm86 antigen preparation.
Current methods for the control of cattle tick Boophilus microplus infestations are not effective and the parasite remains a serious problem for the cattle industry in tropical and subtropical areas. Recently, we developed a vaccine against B. microplus employing a recombinant Bm86 (rBm86) antigen preparation (Gavac, Heber Biotec) and it was shown to induce a protective response in vaccinated animals under controlled conditions. Here we show that, under field conditions in grazing cattle, the vaccine is able to control B. microplus populations. Two parasite-free farms were employed for the study. In the first farm, animals were vaccinated with the recombinant vaccine, while, in the second, animals received a saline injection in adjuvant. After immunization, animals were artificially infected and the infestation rate was recorded. Over the 33 weeks of the experiment, the infestation rate was lower in the vaccinated group compared with the control group. At the end of the experiment it was necessary to use chemicals in the control farm after serious losses in production and animals.


High grade breast ductal carcinomas have high density of tumor-associated macrophages.
The role of tumor-associated macrophages (TAMs) is double-natured and still controversial. Depending on different settings, macrophages may suppress or promote tumor growth. TAM density may be one of the predictive factors of treatment outcome in cancer patients. To evaluate the density of tumor-associated macrophages in breast cancer and its relationship with various histopathologic findings. 55 patients with invasive ductal carcinoma of breast who underwent mastectomy were enrolled. Sections of tumor samples were stained and the density of CD68+ cells was evaluated. There was an association between estrogen receptor (ER) expression and CD68 density (p = 0.010) as the higher densities of CD68 were seen in ER negative tumors. Moreover, there was a significant relationship between histological grade and CD68 density (p = 0.006). The higher TAM density is associated with higher tumor grade and negative ER expression in breast cancer tissues. These findings revealed that inflammation could have an important role in malignancies.


c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Although the pathogenesis of ALS remains unclear, several cellular processes are known to be involved, including apoptosis. A previous study revealed the apoptosis-related gene c-Abl to be upregulated in sporadic ALS motor neurons. We investigated the possibility that c-Abl activation is involved in the progression of ALS and that c-Abl inhibition is potentially a therapeutic strategy for ALS. Using a mouse motor neuron cell line, we found that mutation of Cu/Zn-superoxide dismutase-1 (SOD1), which is one of the causative genes of familial ALS, induced the upregulation of c-Abl and decreased cell viability, and that the c-Abl inhibitor dasatinib inhibited cytotoxicity. Activation of c-Abl with a concomitant increase in activated caspase-3 was observed in the lumbar spine of G93A-SOD1 transgenic mice (G93A mice), a widely used model of ALS. The survival of G93A mice was improved by oral administration of dasatinib, which also decreased c-Abl phosphorylation, inactivated caspase-3, and improved the innervation status of neuromuscular junctions. In addition, c-Abl expression in postmortem spinal cord tissues from sporadic ALS patients was increased by 3-fold compared with non-ALS patients. The present results suggest that c-Abl is a potential therapeutic target for ALS and that the c-Abl inhibitor dasatinib has neuroprotective properties in vitro and in vivo.


The Optimal Type and Management of Biliary Drainage in Patients With Obstructive Jaundice Who Undergo Pancreaticoduodenectomy.
The aims of this study were to clarify optimal type and management of preoperative biliary drainage (PBD) in patients with obstructive jaundice who underwent pancreatoduodenectomy (PD). A total of 156 patients with obstructive jaundice who underwent PD were enrolled. We compared clinical variables and postoperative complications between patients who underwent endoscopic retrograde biliary drainage (ERBD) and those who underwent endoscopic nasobiliary drainage (ENBD). All patients underwent PBD, with ERBD in 117 and ENBD in 39. The incidence of infectious complications and clinically relevant pancreatic fistula (CR-PF) were significantly higher in the ERBD group (39% vs. 13%, p=0.012 and 39% vs. 10%, p<0.00001, respectively). However, there was no significant difference in the postoperative complications between two groups when the duration of drainage exceeded 30 days. ERBD should not be performed in patients with obstructive jaundice prior to PD because of the increased rates of infectious complications and CR-PF following PD, and ENBD should be chosen instead. Furthermore, PD should be performed within 30 days of drainage period in patients with ENBD.


Nanoadjuvants Actively targeting lymph node conduits and blocking tumor invasion in lymphatic vessels.
Great efforts have been made to manipulate nanoparticles (NPs) with a diameter of 10-100 nm to passively target lymph nodes (LNs) to magnitude anti-tumor activity of T cells. However, no attention has been paid to increasing the retention of NPs with active affinity in order to induce a prolonged release of antigens or molecular adjuvants in the LNs mattering the immune response. Here, we formulated two NPs encapsulated with imiquimod (IMQ), a TLR7/8 agonist, and paclitaxel (PTX) and further modified them with tannic acid (TA), respectively, to generate IMQ NP and PTX NP with a final diameter of approximately 40 nm. Attributing a strong affinity of TA molecules to the elastin of LN conduits, the TA modified IMQ NPs can bypass the gaps in the layer of lymphatic endothelial cells and enter the paracortex through the lymph node capsule-associated (LNC) conduits. Similarly, the TA modified PTX NPs increased delivery of PTX to the metastatic tumor site in LNs, where the tumor-associated antigens were released and presented by conduits-lining dendritic cells to activate T cells. Thus, the NPs with deposition to LN conduits showed excellent performance in preventing lymphovascular invasion of triple-negative breast cancer cells and lung metastasis thereafter. On the contrary, the NPs without TA flowed through the subcutaneous sinus existing LNs directly by efferent lymphatic vessels showing relatively poor therapeutic outcomes. This study reveals that TA may mediate the long retention of antigens and molecular adjuvants to be delivered to deep LNs for developing potent vaccination technology.


Influence of biochar remediation on Eisenia fetida in Pb-contaminated soils.
In this study, the remediation influence of maize straw biochar on earthworms (Eisenia fetida) in contaminated soils (with Pb at 0, 300, 700, and 1000 mg kg-1) amended with different amounts of biochar (0%, 1%, 3%, and 5%) was investigated. The results showed that applying biochar to metal-polluted soils effectively reduced the mobility of Pb, promoting the transformation of Pb from exchangeable (EXC) and bound-to-carbonate (Carb) fractions to Fe/Mn oxide (FeMnOx), organic bound (ORG) and residual (RES) fractions. Consequently, a reduction in the mortality and weight loss of earthworms was also achieved by biochar. The accumulation amount of Pb in earthworms steadily increased with exposure time, and with the increasing dosage of biochar, the accumulated Pb decreased by 50.8-78.0% (300 mg kg-1), 30.9-67.3% (700 mg kg-1), and 17.4-55.1% (1000 mg kg-1), which was significantly positively correlated with the mortality of earthworms. Simultaneously, the application of biochar increased the soil pH (0.05-0.23 units), cation exchange capacity (CEC) (0.26-4.54 cmol kg-1), and content of organic matter (0.54-11.66%). There were higher soil enzyme activities (including sucrase activity, urease activity, and alkaline phosphatase activity) in the treatments with a biochar addition of 3%. Through remediation, Proteobacteria (50.82%), Actinobacteriota (32.37%), Firmicutes (4.83%) and Bacteroidota (1.88%) were the most important phyla in the microbiota communities. Furthermore, soil pH value and leaching toxicity concentration showed the most striking effects on earthworms. Therefore, the influence of earthworms must be taken into account in the remediation of Pb-contaminated soil with biochar.


Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay. II: 18 coded chemicals.
Eighteen chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay by the use of procedures based upon those described by Clive and Spector [Mutat Res 44:269-278, 1975] and Clive et al [Mutat Res 59:61-108, 1979]. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with benzofuran, benzyl chloride, bromodichloromethane, butylated hydroxytoluene, chlorendic acid, o-chlorobenzalmalonitrile, 1,2,3,4-diepoxybutane, dimethyl formamide, dimethyl hydrogen phosphite, furfural, glutaraldehyde, hydroquinone, 8-hydroxyquinoline, and resorcinol. Apart from bromodichloromethane, butylated hydroxytoluene and dimethyl hydrogen phosphite, rat liver S9 mix was not a requirement for the activity of any of these compounds. Chemicals not identified as mutagens were water, tert-butyl alcohol, pyridine, and witch hazel.


The role of performativity in informal dementia carers' capability to be mobile.
Informal carers are and will remain a vital part of dementia care. Given the nature of their caring tasks, which focus on enabling the care recipient to engage in meaningful activities, informal dementia carers are affected in their everyday mobility. Expectations manifested by society, loved ones and the carers themselves play a critical role in how carers perform their caring role and how they perceive their opportunity, or capability, to be mobile. This article uses Butler's concept of performativity to understand informal dementia carers' capability to be mobile. In the spring and summer of 2021, we combined remote graphic elicitation with telephone interviews to gather the views of 17 informal dementia carers (aged 50+) living in England. Three key themes emerged from our analysis of the data. Firstly, participants perceived that becoming a carer changed their capability to be mobile. Secondly, the caring role in relation to the capability to be mobile resulted in an emotional toll and perceived loss of autonomy. Thirdly, the performativity of the caring role created feelings of guilt, selfishness and resentment due to the impact caring had on participants' capability to be mobile. Our study enriches the literature on informal dementia carers' mobility, as we suggest that performativity is a key factor in how this population experiences their everyday mobility. The findings suggest that existing ageing-in-place policies should take a more holistic approach by better including those ageing adults who provide the most support: informal dementia carers.


Rotating hinge prosthesis in revision total knee arthroplasty: indications and results.
Reconstruction of the knee joint with an appropriate prosthetic component that accomplishes the alleviation of pain and the restoration of joint function represents the goal of primary and revision TKA. Revision TKA procedures present a variety of complicating factors not found in primary TKA cases.


Investigation of the Proarrhythmic Effects of Antidepressants according to QT Interval, QT Dispersion and T Wave Peak-to-End Interval in the Clinical Setting.
Some antidepressants have been implicated as risk factors for QT prolongation, which is a predictor of sudden cardiac death. However, the QT interval is considered an imperfect biomarker for proarrhythmic risk. Therefore, we reevaluated the risk of sudden cardiac death due to antidepressants using improved. , namely, QT dispersion (QTD), T wave peak-to-end interval (Tp-e), and Tp-e/QT ratio. We compared the effects of antidepressants on QTc (QT/RR1/3), QTD, Tp-e, and Tp-e/QT ratio in 378 patients with mood disorder. We also compared each index between 165 healthy controls and 215 randomly selected age-matched patients. Age (p<0.01), sex (p<0.05), tricyclic antidepressant (TCA) use (p<0.05), and clomipramine (p<0.01) and mianserin (p<0.05) use in particular, significantly associated with a prolonged QTc. We also found that age (p<0.01), TCA use (p<0.05), and clomipramine (p<0.01) and mianserin (p<0.05) use in particular, significantly prolonged QTD. However, there was no correlation between each variable and Tp-e or Tp-e/QT ratio. Significant differences in QTc and QTD were found between the patients and healthy controls. From our results, prediction of risk of sudden cardiac death by QTD, Tp-e, or Tp-e/QT ratio was inconsistent. Increased QTD may be more suitable for predicting sudden cardiac death due to antidepressants.


High loading of hydrophilic/hydrophobic doxorubicin into polyphosphazene polymersome for breast cancer therapy.
Breast cancer remains one of the most common cancers for females. Drug delivery based on cancer nanotechnology could improve the performance of some chemotherapeutic medicines already used in clinic. The emergence of polymersomes provided the potential to encapsulate hydrophobic/hydrophilic drugs. By modifying the weight ratio of methoxy-poly (ethylene glycol) (mPEG) chain to ethyl-p-aminobenzoate (EAB) side group, a series of amphiphilic graft polyphosphazenes (PEPs) was prepared. PEP can be tuned from micelles to polymersomes with the decrease of mPEG content via dialysis. Either hydrophilic doxorubicin hydrochloride (DOX·HCl) or hydrophobic doxorubicin base (DOX) could be encapsulated into PEP polymersomes with high payload and high encapsulation efficiency due to the strong intermolecular interaction with PEP. Compared with free DOX·HCl administration, in vivo investigation in growth inhibition of MCF-7 xenograft tumors in nude mice demonstrated that PEP polymersomes could enhance life safety without compromise of therapeutic efficacy, especially DOX·HCl loaded delivery system. In this preclinical study, polymerosomes based on PEPs were investigated as doxorubicin delivery systems, demonstrating similar efficacy but less toxicity compared to standard delivery methods.


Alterations in tumour suppressor gene p53 correlate with inhibition of thrombospondin-1 gene expression in colon cancer cells.
If activation of the p53 gene is involved in the progression or metastasis of colon cancer, it may affect the angiogenic phenotype in vivo. To verify this hypothesis, we studied the correlation between p53 accumulation and expression of thrombospondin-1 (TSP1) in colon cancer specimens. Levels of TSP1 gene expression were estimated by Northern blotting in 65 colon cancers. Accumulation of p53 and the distribution of TSP1 protein were evaluated immunohistochemically. Various levels of TSP1 gene expression were seen in colon cancers, while p53 accumulation was confirmed in 42 of the 65 colon cancers. The level of TSP1 gene expression demonstrated a significant inverse correlation with p53 accumulation in colon cancer. Colon cancer cells expressed TSP1 protein and p53 accumulation reciprocally in the same nests. These results suggest that alterations in the tumour suppressor gene p53 may inhibit TSP1 expression in colon cancer.


Plasma levels of testosterone and male sexual behaviour in strains of the house mouse (Mus musculus).
This paper investigates whether differences in measures of sexual behaviour between strains of the house mouse (Mus musculus) are related to differences in the levels of plasma testosterone. There was found to be a significant negative correlation between measures of sexual behaviour and plasma testosterone. This correlation was not behaviourally mediated, and could be demonstrated for some of the behavioural measures in an F2 generation.


Elevated visfatin levels in obese children are related to proinflammatory factors.
Obesity and related metabolic diseases are associated with a state of chronic low-grade inflammation,which is characterized by abnormal cytokine production and increased synthesis of proinflammatory proteins.Recent studies have indicated that visfatin is both an adipokine and an inflammatory cytokine. In this study, we assessed the association between serum visfatin concentrations and markers of systemic inflammation [high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and tumor necrosis factor a (TNF-a)] and insulin resistance in Chinese obese children. A total of 44 obese Chinese children (23 boys and 21 girls) and 50 age- and gender-matched normal weight children (23 boys and 27 girls) were enrolled in the study. Anthropometric measurements and blood pressure were taken. Fasting levels of visfatin, hs-CRP, IL-6, TNF-a,glucose, insulin, and lipid profile were assayed, and the homeostasis model assessment for insulin resistance was calculated as a marker of insulin resistance. Serum visfatin levels [obese group (OB):7.48±0.39 vs. C: 5.31±0.28, p<O.OS], hs-CRP (OB: 2.25±0.51vs. C: 0.87±0.18, p<O.OS), and IL-6 levels (OB: 2.22±0.28vs. C: 1.31±0.19, p<O.OS) in obese children were significantly higher than those in the control group, whereas serum TNF-a levels were not significantly different (OB:2.43±0.37 vs. C: 1.89±0.19, p>O.OS); there were no significant differences in visfatin, hs-CRP, IL-6, and TNF-a concentrations between girls and boys. The correlations between visfatin and anthropometric, metabolic parameters,and inflammatory [body mass index (BMI), waist circumference, triglyceride, hs-CRP, IL-6, TNF-a] revealed differences between genders; visfatin correlated with BMI(r=0.247, p=0.029) and IL-6 (r=0.427, p=0.013) in boys only. The association of circulating visfatin with anthropometric parameters, metabolic parameters, and inflammatory factors is dependent on gender, although no such correlation was observed between serum visfatin concentration and insulin resistance. Visfatin could bean important inflammatory cytokine representing a low grade inflammatory state in obesity.


Site-directed isotope labelling and FTIR spectroscopy of bacteriorhodopsin.
Insight into integral membrane proteins function is presently limited by the difficulty of producing three-dimensional crystals. In addition, X-ray structures of proteins normally do not provide information about the protonation state and structural changes of individual residues. We report here the first use of site-directed isotope labelling and Fourier transform infrared (FTIR) difference spectroscopy to detect structural changes at the level of single residues in an integral membrane protein. Two site-directed isotope labeled (SDIL) tyrosine analogues of bacteriorhodopsin were produced which exhibit normal activity. FTIR spectroscopy shows that out of 11 tyrosines, only Tyr 185 is structurally active during the early photocycle and may be part of a proton wire.


Stigma and its correlates among patients with Crohn's disease: A cross-sectional study in China.
Crohn's disease is an incurable disease characterized by unpredictable intestinal symptoms, which unavoidably affect patients' lives and contribute to feelings of stigma. This study aimed to explore the status and its correlates of stigma among patients with Crohn's disease. Using a convenience sampling, 146 hospitalized patients with Crohn's disease were recruited in a tertiary hospital in Southern China from October 2020 to March 2021. The participants were assessed by demographic and disease-related questionnaires, the Social Impact Scale (SIS), Inflammatory Bowel Disease-Self-Efficacy Scale (IBD-SES), and Social Support Rating Scale (SSRS). Multivariate linear regression analysis was conducted to explore the influencing factors of stigma among patients with Crohn's disease. The mean SIS score was 58.14 ± 10.74, representing a moderate effect of stigma, and 85.6% (125/146) of the patients experienced moderate to high levels of stigma. The multiple linear regression analysis showed that perceived public awareness of the disease, family income, age, and self-efficacy were the main influencing factors of stigma, which could explain 52% of the total variation of stigma among patients with Crohn's disease. Stigma among patients with Crohn's disease is influenced by perceived public awareness of the disease, family income, age, and self-efficacy. Interventions aimed at improving self-efficacy and public awareness should be considered to alleviate the level of stigma, especially for those aged 40 years or older or low-income patients.


Categorising: Inside the crow's brain.
Crows can learn to categorise line lengths into experimenter-defined categories. The crow's brain codes and recodes line lengths in individual neurons in the nidopallium caudolaterale, part of the telencephalon.


Zooming into finer brain structures in vitro.
Regionalized organoids have recently been developed to resemble a particular brain region. However, generating organoids with even finer sub-regional resolution has proven challenging. In this issue of Cell Stem Cell, Kiral et al.1 report a new organoid model resembling the human ventral thalamus and thalamic reticular nucleus.


Resumption of Endodontic Practices in COVID-19 Hardest-Hit Area of China: A Web-based Survey.
The purpose of this study was to investigate the resumption of endodontic practices in Hubei Province, China 1 month after the end of the lockdown. A Web-based survey was sent to 1069 active endodontic specialists and general dentists who provided endodontic care in Hubei Province from May 7 to May 9, 2020. The survey consisted of 18 questions on demographics, the current situation of endodontic practice for the participants, and concerns regarding contracting or spreading the virus in newly opened endodontic practices. A total of 322 participants completed the survey. Most respondents (62%) were from Wuhan. Almost 83% of the respondents have resumed their endodontic practice partially or fully. Most respondents in practice (99%) would take measures to screen patients before treatment including paid screening measures. More than 93% of the respondents reported having taken special measures for routine endodontic treatment at this stage, with the most common measure taken being wearing an N95 mask. The rubber dam was recognized as efficient in preventing infection by most respondents. Many respondents were concerned about contracting coronavirus disease 2019 (COVID-19) as a result of routine endodontic practice at this stage, and respondents with more than 11 years of endodontic experience were significantly less concerned about infection compared with those with fewer than 5 years of experience (P < .05). There is a fear of contracting/spreading COVID-19 among endodontic clinicians, the fear is negatively associated with years of practice, and most clinicians believe that rubber dam isolation can protect them and their patients from COVID-19.


Practice on improving fattening local cattle production in Vietnam by increasing crude protein level in concentrate and concentrate level.
Two experiments were conducted to determine the effects of crude protein (CP) level in concentrate (experiment 1) and concentrate level (experiment 2) on feed intake, nutrient digestibility, nitrogen (N) retention, ruminal pH and NH3-N concentration and average daily gain (ADG) of Vietnamese local fattening cattle. Animals (24 cattle, initial live weight (LW) 150.3 ± 11.8 kg in experiment 1 and 145.1 ± 9.8 kg in experiment 2) were allotted based on LW to one of four treatments in a randomised complete block design. In experiment 1, concentrate with four levels of CP (10, 13, 16 and 19 %) was fed at 1.5 % of LW. In experiment 2, concentrate was fed at 1.0, 1.4, 1.8 and 2.2 % of LW. In both experiments, roughage was 5 kg/day native grass and ad libitum rice straw (fresh basis). Results showed that the CP level in concentrate significantly affected dry matter (DM) intake (P < 0.05), N retention, ADG and ruminal NH3-N concentration (P < 0.01), but it had no significant effect on DM, organic matter (OM) and neutral detergent fibre (NDF) digestibility (P > 0.05), whereas CP digestibility increased (P < 0.001) along with the CP level. DM intake, N retention and ADG increased (P < 0.001) linearly with concentrate intake. DM and CP digestibility were not significantly affected by concentrate intake (P > 0.05). OM digestibility and NH3-N concentration increased linearly (P < 0.05), whereas NDF digestibility and ruminal pH declined linearly with increased concentrate consumption (P < 0.01). These results indicate that 16 % CP in concentrate and feeding concentrate at the rate of 2.2 % of LW are recommendable for fattening local cattle in Vietnam.


Regulation of urokinase plasminogen activator localization in keratinocytes by calcium ion and E-cadherin.
In keratinocyte culture, the cellular distribution of many adhesion markers and the organization of intercellular junctions are controlled by the calcium ion concentration of the medium. We show in the present study that urokinase plasminogen activator (uPA) localization in the human keratinocyte is similarly dependent upon calcium concentration. At 30 microM calcium, uPA is present throughout the cell, often with a perinuclear concentration. Upon calcium elevation to 1.0 mM, uPA is concentrated along the cell-cell borders, where it colocalizes (at the light microscope level) with E-cadherin. Blocking antibody to E-cadherin delays the calcium-induced redistribution of uPA, in a manner very similar to the previously observed delay in redistribution of several adhesion-related markers, including vinculin, desmoplakin, and beta 1 integrin. These data suggest a link between the redistribution of uPA to the cell-cell borders and the calcium-induced organization of intercellular junctions in the human keratinocyte. The presence of uPA along the intercellular borders suggests that this enzyme may be involved in regulation of epidermal adhesion through proteolysis.


Obstructive sleep apnea in children and adolescents with cystic fibrosis and preserved lung function or mild impairment: a systematic review and meta-analysis of prevalence.
Sleep disorders in cystic fibrosis may be present before daytime clinical manifestations, regardless of lung function impairment, affecting quality of life and disease progression. This study investigated the prevalence of obstructive sleep apnea in children and adolescents with cystic fibrosis and preserved lung function or mild impairment, and evaluated its association with clinical variables. A systematic review with meta-analysis of prevalence was conducted, including observational studies with polysomnographies in patients with cystic fibrosis who presented mean lung function values > 60% predicted. The methodological quality of the studies was analyzed, and a meta-analysis was performed to assess the prevalence of obstructive sleep apnea. Of the 2318 studies identified, 7 were included in the systematic review and 6 in the meta-analysis of prevalence. The confounding factors and strategies identified were the items with greatest weakness in the methodological quality assessment. Most studies were cross-sectional, and sample size ranged from 9 to 67 individuals. The most frequent criterion for defining obstructive sleep apnea was apnea-hypopnea index (AHI) > 1 per hour. The prevalence found ranged from 32.3 to 100% and the pooled prevalence was 65% (I2 = 53.4%), considering AHI>1, and 52% (I2 = 89.4%) for AHI>2 per hour. It was not possible to verify the association between obstructive sleep apnea and clinical variables. A high prevalence of obstructive sleep apnea in children and adolescents with cystic fibrosis was found, regardless of age and lung function impairment, reinforcing the importance of investigating sleep-disordered breathing during clinical visits even when lung function is not yet compromised.


Polysaccharides from Tetrastigma Hemsleyanum Diels et Gilg ameliorated inflammatory bowel disease by rebuilding the intestinal mucosal barrier and inhibiting inflammation through the SCFA-GPR41/43 signaling pathway.
In this study, the therapeutic effects of Tetrastigma hemsleyanum polysaccharide (THP) on inflammatory bowel disease (IBD) and its possible mechanisms were investigated based on the IBD mouse model induced by dextran sodium sulfate (DSS) and the lipopolysaccharide (LPS)-stimulated Caco-2 cell model. THP significantly alleviated the signs and symptoms of DSS-induced IBD mice, including the reduced weight, shortened colonic length, and increased colitis disease activity index. In vivo, THP significantly reduced inflammatory cell infiltration and oxidative damage, promoted intestinal mucus secretion, and restored the integrity of the intestinal epithelial barrier and mucus barrier. Furthermore, THP reversed the changes in the intestinal flora of colonized mice and restored the levels of short-chain fatty acids (SCFAs) by increasing the abundance of potentially beneficial bacteria and increasing the abundance of butyrate-producing bacteria. In addition, THP upregulated the expression of G-protein-coupled receptors (GPR41 and GPR43) both in vivo and in vitro. In summary, the current investigation showed that THP effectively protected against intestinal inflammation and impairment in the intestinal barrier in the setting of DSS-induced IBD, possibly by regulating gut microbiota structure and corresponding SCFA metabolites, and the pathway of SCFAs action may be related to SCFA-GPR41/43 signaling pathway.


Angiographical follow-up after radioactive "Cold Ends" stent implantation: a multicenter trial.
Radioactive stents with an activity of 0.75 to 12 microCi have shown >40% edge restenosis due to neointimal hyperplasia and negative remodeling. This trial evaluated whether radioactive Cold Ends stents might resolve edge restenosis by preventing remodeling at the injured extremities. The 25-mm long (15-mm radioactive center and 5-mm nonradioactive ends) Cold Ends stents had an activity of 3 to 12 microCi at implantation. Forty-three stents were implanted in 43 patients with de novo native coronary artery disease. Two procedural, 1 subacute, and 1 late stent thrombosis occurred. A restenosis rate of 22% was observed with a shift of the restenosis, usually occurring at the stent edges of radioactive stents, into the Cold Ends stents. The most severe restenosis occurred at the transition zone from radioactive to nonradioactive segments, a region located in dose fall-off. Cold Ends stents did not resolve edge restenosis.


Role of dynesys as pedicle-based nonfusion stabilization for degenerative disc disorders.
Posterior nonfusion pedicle-screw-based stabilization remains a controversial area of spine surgery. To date, the Dynesys system remains the most widely implanted posterior nonfusion pedicle screw system. We review the history of Dynesys and discuss clinical outcome studies and biomechanical evaluations regarding the Dynesys system. Indications for surgery and controversies are discussed. Recommendations are made regarding technical implantation.


Implementing High-Reliability Organization Principles Into Practice: A Rapid Evidence Review.
To promote a safety culture and reduce harm, health care systems are adopting high-reliability organization (HRO) principles. This rapid review synthesizes HRO frameworks, metrics, and implementation effects to help inform health systems' efforts toward becoming HROs. Bibliographic databases were searched from 2010 to 2019. One reviewer used prespecified criteria to assess articles for inclusion, evaluate study quality, extract data, and grade strength of evidence with second reviewer checking. Twenty-three articles were identified: 8 described frameworks, 9 examined metrics, and 9 evaluated implementation outcomes. Five common strategies for HRO implementation emerged (developing leadership, supporting a culture of safety, providing training and learning, building data systems, and implementing quality improvement interventions). The Joint Commission's and Institute for Healthcare Improvement's frameworks emerged as the most comprehensive and widely applicable. The Joint Commission's Oro 2.0 metric for evaluating HRO progress similarly stood out as it was developed through broad stakeholder input and was validated by external researchers. Multicomponent HRO interventions delivered for at least 2 years were associated with improved process and patient safety outcomes. Because each HRO intervention was only supported by a single poor or fair-quality study-none of which contained a concurrent control group-a causal relationship between any HRO initiative and outcomes could not be established. Health care system adoption of HRO principles is associated with improved safety outcomes, yet the level of evidence is low. Priorities for future HRO studies include use of concurrent control groups and examination of specific outcomes measurements.


Patterns of left atrial activation and evaluation of atrial dyssynchrony in patients with atrial fibrillation and normal controls: Factors beyond the left atrial dimensions.
Left atrial (LA) remodeling causing slower and asynchronous conduction is crucial for the maintenance of atrial fibrillation (AF). We propose a simple and quick method to evaluate the LA asynchrony. One hundred thirty patients with AF (AF group) and 70 patients without a history of AF (controls) were examined prospectively using pulsed-wave tissue Doppler imaging. The time intervals from the onset of the P wave to the onset of the A' wave (P-A' intervals) were measured at 4 sites at the mitral annulus: septal, lateral, anterior, and posterior. To assess the LA asynchrony, the differences between the longest and the shortest P-A' interval as well as the standard deviation of all 4 P-A' intervals were calculated. Both groups were matched for the baseline characteristics. The AF group had longer differences between the longest and the shortest P-A' than did controls (37 ± 16 ms vs 28 ± 13 ms; P = .0001). The standard deviation of all 4 P-A' intervals was also higher in the AF group (17 ± 7 ms vs 13 ± 5 ms; P = .0001). Furthermore, distinct patterns of LA activation were observed with most patients with AF showing upward LA activation (86.5%) whereas normal controls were showing downward LA activation (65.5%). Receiver operating characteristic analysis revealed that P-A' anterior successfully discriminated patients with AF from controls (area under the curve 0.85; P < .0001). Furthermore, P-A' anterior > 55 ms discriminated between patients with AF and controls with a sensitivity of 85% a specificity of 81%, a positive predictive value of 0.898, and a negative predictive value of 0.707. Patients with AF showed greater LA asynchrony in pulsed-wave tissue Doppler imaging, upward LA activation, and a prolonged activation time at the anterior mitral annulus. Prolongation of P-A' anterior discriminated between patients with AF and controls with high sensitivity and specificity.


Preclinical development of a long-acting trivalent bispecific nanobody targeting IL-5 for the treatment of eosinophilic asthma.
Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma.


VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots.
Comparative genome- and proteome-wide screens yield large amounts of data. To efficiently present such datasets and to simplify the identification of hits, the results are often presented in a type of scatterplot known as a volcano plot, which shows a measure of effect size versus a measure of significance. The data points with the largest effect size and a statistical significance beyond a user-defined threshold are considered as hits. Such hits are usually annotated in the plot by a label with their name. Volcano plots can represent ten thousands of data points, of which typically only a handful is annotated. The information of data that is not annotated is hardly or not accessible. To simplify access to the data and enable its re-use, we have developed an open source and online web tool with R/Shiny. The web app is named VolcaNoseR and it can be used to create, explore, label and share volcano plots ( https://huygens.science.uva.nl/VolcaNoseR ). When the data is stored in an online data repository, the web app can retrieve that data together with user-defined settings to generate a customized, interactive volcano plot. Users can interact with the data, adjust the plot and share their modified plot together with the underlying data. Therefore, VolcaNoseR increases the transparency and re-use of large comparative genome- and proteome-wide datasets.


Intravenous cocaine-induced place preference: attenuation by haloperidol.
Cocaine reward was demonstrated by establishing a conditioned place preference (CPP) to a distinctive location paired with cocaine administered either intravenously (i.v., 0.5 mg/kg) or intraperitoneally (i.p., 10 mg/kg). Significant i.p. or i.v. cocaine CPP was observed following the second conditioning trial. Haloperidol (0.2 mg/kg) pretreatment disrupted CPP induced by i.v., but not i.p., cocaine. The haloperidol effect built up over successive trials. The involvement of dopaminergic transmission in i.v. cocaine-induced CPP is discussed.


Adsorption of methyl orange (MO) by Zr (IV)-immobilized cross-linked chitosan/bentonite composite.
A Zr (IV)-immobilized cross-linked chitosan/bentonite composite was synthesized and characterized by Fourier transform infrared, field-emission scanning electron microscopy, and X-ray diffraction techniques. This composite was utilized for the removal of methyl orange (MO) from aqueous solutions. Effects of the loading amount of Zr (IV), initial pH value of MO solutions, adsorbent dosage, and contact time on MO adsorption were considered. The adsorption isotherm data were well described by the Langmuir model, and the maximum adsorption capacity was 438.6mg/g at 303K and natural pH. The kinetic data were well described by the pseudo-second-order model. The thermodynamic data showed that the adsorption process of MO was feasible, spontaneous, and exothermic in nature.


Risk factors of massive bleeding related to pancreatic leak after pancreaticoduodenectomy.
Most pancreatic leaks after pancreaticoduodenectomy were initially treated conservatively, and for the most part, they were self-limiting and closed spontaneously. But in a few patients, hemorrhage occurred 1 to 3weeks postoperatively and remained a fatal complication after pancreaticoduodenectomy. To identify possible risk factors for massive bleeding, the medical records of 402 patients who had pancreaticoduodenectomies were reviewed for leak complications and analyzed for associations between the occurrence of massive bleeding and preoperative, intraoperative, postoperative, and pathologic parameters. In univariate logistic regression analysis, infectious clinical signs (p=0.021, odds ratio [OR]=7.06, 95% CI=1.34, 37.12) and bile in the drainage fluid (p=0.036, OR=5.89, 95% CI=1.13, 30.86) were associated with the risk of developing massive hemorrhage. This combination provided the highest estimate of massive bleeding after pancreatic leak (p=0.005, OR=8.57, 95% CI=1.92, 38.35). Both infectious clinical signs and bile content in the drainage fluid considerably increase the risk of massive bleeding after pancreatic leak. Close observation of patients with these ominous signs is warranted.


Fetal dopamine neuron transplants prevent behavioral supersensitivity induced by repeated administration of L-dopa in the rat.
We have studied in adult rats bearing a unilateral nigral lesion the effect of nigral grafts into the striatum on behavioral supersensitivity induced by chronic treatment of L-DOPA (100 mg/kg i.p.) plus benserazide (50 mg/kg i.p.). Repeated administration of L-DOPA increases contraversive circling. In rats without graft the contraversive circling was significantly increased after 8 and 14 daily injections of L-DOPA. On the other hand, the animals with transplants showed no such increase. Behavioral supersensitivity induced by repeated treatment of L-DOPA is often correlated with dyskinesia observed in the Parkinsonian patients. This suggests that the graft might be able to prevent this secondary effect.


Peripheral blood flow cytometry based diagnosis in primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: implications for more extensive use.
Primary cutaneous epidermotropic CD8-positive T-cell lymphoma represents an aggressive form of T-cell cutaneous lymphomas. Diagnosis is based on biopsies obtained from skin lesions. Here, we would like to report a case diagnosed by using flow cytometry performed on peripheral blood mononuclear cells. Moreover, an important finding was the difference in the results on targeting the CD8 antigen by using two different commercially available monoclonal antibodies. Perhaps, more than one antibody should be used in primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphomas, in order to be more accurate in the diagnosis and so in the classification of such diseases.


Influence of artificial tears on corneal epithelium in dry-eye syndrome.
The corneal epithelium of patients with dry-eye syndrome is stressed by both tear film insufficiency and the frequent use of eye drops (artificial tears). In order to quantify corneal epithelial damage, the permeability of corneal epithelium to sodium fluorescein was determined in 40 consecutive patients with dry eyes (BST less than 10 mm), who did not exhibit visible corneal lesions upon slit-lamp examination. The corneal epithelial permeability of dry-eye patients was shown to be 2.8 times greater than that of individuals without ocular disease. Corneal epithelial permeability of patients using artificial tears containing benzalkonium chloride was increased 3.1 times and that of patients using drops preserved with chlorobutanol only 1.7 times.


The difference in the cellular uptake of tocopherol and tocotrienol is influenced by their affinities to albumin.
Vitamin E is classified into tocopherol (Toc) and tocotrienol (T3) based on its side chains. T3 generally has higher cellular uptake than Toc, though the responsible mechanism remains unclear. To elucidate this mechanism, we hypothesized and investigated whether serum albumin is a factor that induces such a difference in the cellular uptake of Toc and T3. Adding bovine serum albumin (BSA) to serum-depleted media increased the cellular uptake of T3 and decreased that of Toc, with varying degrees among α-, β-, γ-, and δ-analogs. Such enhanced uptake of α-T3 was not observed when cells were incubated under low temperature (the uptake of α-Toc was also reduced), suggesting that Toc and T3 bind to albumin to form a complex that results in differential cellular uptake of vitamin E. Fluorescence quenching study confirmed that vitamin E certainly bound to BSA, and that T3 showed a higher affinity than Toc. Molecular docking further indicated that the differential binding energy of Toc or T3 to BSA is due to the Van der Waals interactions via their side chain. Overall, these results suggested that the affinity of Toc and T3 to albumin differs due to their side chains, causing the difference in their albumin-mediated cellular uptake. Our results give a better mechanistic insight into the physiological action of vitamin E.