Extra-hepatic replication and infection of hepatitis E virus in neuronal-derived cells.
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. Infection usually leads to acute hepatitis that can become fulminant, particularly among pregnant women and in patients with preexisting liver disease, or may evolve to a chronic state, especially in immunosuppressed individuals. HEV has been shown to produce a range of extra-hepatic manifestations including aplastic anaemia, acute thyroiditis, glomerulonephritis as well as neurological disorders such as Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis. The pathogenesis of these neurological injuries remains largely unknown, and it is also uncertain whether or not HEV can directly infect neuronal cells. In this study, we investigated whether HEV is capable of completing the viral life cycle in human neuronal-derived cell lines such as neuroepithelioma (SK-N-MC), desmoplastic cerebellar medulloblastoma (DAOY), glioblastoma multiforme (DBTRG), glioblastoma astrocytoma (U-373 MG) and oligodendrocytic (M03.13) cells. Following transfection of these cells with HEV Gaussia luciferase reporter virus, all tested cell lines supported HEV RNA replication. Furthermore, extra- and intracellular viral capsid was detected by an HEV antigen ELISA as a marker for virus assembly and release. Permissiveness for HEV cell entry could be demonstrated for the oligodendrocytic cell line M03.13. In conclusion, these results indicate that HEV tropism is not restricted to the liver and HEV can potentially complete the full viral life cycle in neuronal-derived tissues explaining neurologic disorders during HEV infection.


The differential effects of reward on space- and object-based attentional allocation.
Estimating reward contingencies and allocating attentional resources to a subset of relevant information are the most important contributors to increasing adaptability of an organism. Although recent evidence suggests that reward- and attention-based guidance recruits overlapping cortical regions and has similar effects on sensory responses, the exact nature of the relationship between the two remains elusive. Here, using event-related fMRI on human participants, we contrasted the effects of reward on space- and object-based selection in the same experimental setting. Reward was either distributed randomly or biased a particular object. Behavioral and neuroimaging results show that space- and object-based attention is influenced by reward differentially. Space-based attentional allocation is mandatory, integrating reward information over time, whereas object-based attentional allocation is a default setting that is completely replaced by the reward signal. Nonadditivity of the effects of reward and object-based attention was observed consistently at multiple levels of analysis in early visual areas as well as in control regions. These results provide strong evidence that space- and object-based allocation are two independent attentional mechanisms, and suggest that reward serves to constrain attentional selection.


Branch retinal artery occlusion: a complication of iron-deficiency anemia in a young adult with a rectal carcinoid.
We report a case of branch retinal artery occlusion (BRAO) in a patient with iron-deficiency anemia. Various ophthalmological and laboratory studies were performed. A 32-year-old man had a sudden decrease of vision in his left eye to counting fingers at 30 cm two days ago. The left fundus showed a cherry-red spot and milky-white edema, except for the upper temporal region of the macula, and an optic disc malformation. Fluorescein angiography revealed leakage from the disc and a slightly delayed filling time in the left eye but an arterial filling defect was not noted. The differential diagnosis in this young patient includes polycythemia, hypercoagulopathy, coagulation abnormalities, trauma, hypertension, and autoimmune diseases such as systemic lupus erythematosus. Laboratory examinations revealed no abnormalities except for iron-deficiency anemia. The patient was treated with stellate ganglion block, hyperbaric oxygen, and ferrous sulfate. His visual acuity never recovered to better than 0.08. He had a coincidental rectal carcinoid and the tumor was excised surgically. No metastasis was observed. BRAO can be a complication of anemic retinopathy and can lead to severe visual loss without early medication.


Contaminated land liability issues: legal perspective.
Until recently, companies that contaminated land faced little prospect of being prosecuted or having claims made against them for any personal injuries or property damage arising from the contamination. Most companies would have considered it to be inconceivable that they could be required to clean up contamination resulting from an historic disposal, particularly if the disposal had been neither negligent nor unlawful. Current environmental law differs significantly, however, from the law which existed even 10 years ago. This paper examines liabilities arising from contaminated land. First, it discusses the new contaminated land regime and a parallel regime to remediate sites that are contaminated with radioactive substances. Second, it discusses remediation liabilities for water pollution. Such liabilities may well involve the remediation of contaminated land when groundwater is polluted. Finally, the paper examines liabilities for property damage and personal injuries arising from contamination by radioactive substances.


Activation of complement by pathogenic and nonpathogenic Entamoeba histolytica.
Previous studies had demonstrated that strains of Entamoeba histolytica isolated from patients with colitis or amebic liver abscess were resistant to complement-mediated killing, whereas strains from asymptomatic patients were readily lysed by non-immune serum. Both serum-sensitive and serum-resistant strains of E. histolytica depleted complement rapidly as assessed by CH50, C3, and C7, and C5-9 hemolytic activities. Activation of the alternative pathway was important in lysis of nonpathogenic strains, as demonstrated by lysis by NHS (60.9 +/- 15.6%) and NHS + 5 mM EGTA (59.3 +/- 4.5%) as well as by C4-deficient guinea pig serum (72.8 +/- 7.1%) and C2-deficient human serum (64.4 +/- 11.1%), but not by NHS + 5 mM EDTA. Classical pathway activation also occurs as both pathogenic and nonpathogenic strains deplete greater than 98% of C4 activity, although it is not necessary for lysis. Pathogenic strains are not lysed by either the classical or the alternative pathway. These results suggest that pathogenic strains of E. histolytica activate complement but are able to evade an important host defense, complement-mediated lysis.


Outcome of combination therapy using BRAF and MEK inhibitors among Asian patients with advanced melanoma: An analysis of 112 cases.
As most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Minh) have been conducted in Western countries, little is known about the effect of B + Minh among East Asian populations. Data from patients with advanced melanoma treated using B + Minh (either dabrafenib + trametinib or encorafenib + binimetinib) were retrospectively collected from 16 institutes in Japan. Response rates, adverse events, patterns of failure and survival were analysed. We analysed 112 of 144 collected patient records and, of these, 14 had acral/mucosal melanoma. The response rate for the entire cohort was 75.0%. There were no statistical differences in response rates between acral/mucosal and cutaneous melanomas (64.3% versus 76.5%), whereas previous treatment using immune checkpoint inhibitors (ICIs) did not affect response (72.7% versus 73.9%) to B + Minh, response to ICI after B + Minh was only 20%. Patients who achieved complete response had the best overall survival rates at 24 months (94.7%). Elevated serum lactate dehydrogenase levels and 3 or more metastatic sites were independently associated with survival. The most common relapse site was the brain (17.9%). More than half of the patients (58.8%) experienced grade III/IV pyrexia. B + Minh was effective among Japanese patients with melanoma, including those with acral/mucosal melanoma. Factors associated with survival were similar to previous Western studies. B + Minh response was not affected by the previous use of ICI; however, vigilance against brain metastasis during B + Minh therapy is required as the brain was our most commonly encountered relapse site.


[Effects of anesthetics on oxidative stress changes in patients with high anesthetic risk in the perioperative period of coronary bypass surgery].
The study included 44 patients who were divided into 3 groups according to the type of anesthesia. In group 1 patients (n = 15), initial anesthesia was accomplished by inhaled sevoflurane and intravenous fentanyl (2.5-3.5 microg/kg); basal anesthesia was performed with sevoflurane. In Group 2, midazolam, 0.1-0.15 mg/kg, fentanyl, 5.2 +/- 0.01 vg/kg, and ketamine, 0.85 +/- 0.13 mg/kg were given for induction. Basic anesthesia was carried out, by administering fentanyl in a dose of 4.71 +/- 0.4 microg/kg/hour, halothane, 0.5-1.5 ob %. In Group 3, midazolam, 1.2 +/- 0.01 mg/kg) and fentanyl, 7.8 +/- 0.6 microg/kg) were used to induce anesthesia. Basic anesthesia was effected with fentanyl, 5.31 +/- 0.5 microg/kg/hour, ketamine, and diprivan. Anesthetic management using halogen-containing inhalational anesthetics at coronary bypass surgery in patients at high anesthetic risk was ascertained to cause a significant reduction in the degree of manifestations of oxidative stress and facilitated a better intraoperative period. Sevorane was found to have the most significant effect on oxidative stress.


Medial Patellofemoral Ligament Repair Versus Reconstruction for Recurrent Patellar Instability: Two-Year Results of an Algorithm-Based Approach.
Patellar instability remains a challenging problem for both the patient and surgeon. Medial patellofemoral ligament (MPFL) repair has historically had poor results, and due to this, there is currently a trend toward reconstruction. This study was undertaken to investigate experience with repair versus reconstruction of the MPFL using a multifactorial treatment algorithm approach. Our hypothesis was that there will be no significant difference in outcome scores between patients in the MPFL repair and reconstruction groups. Cohort study; Level of evidence, 2. A total of 24 patients with recurrent (≥2) lateral patellar dislocations were included. All had failed nonoperative treatment for more than 6 months, and all were observed for a minimum of 2 years. First, magnetic resonance imaging (MRI) was used to find the location of the MPFL tear. A tilt test was used to determine whether a lateral retinacular lengthening was required to allow the patella to have neutral tilt. If the MRI showed a tibial tubercle-trochlear groove (TT-TG) distance greater than 20 mm, a tibial tubercle osteotomy (TTO) was recommended. An MPFL reconstruction was performed if the entire ligament was inadequately visualized on MRI or if it was torn from both insertion sites. Failure was defined as recurrent lateral patellar instability after surgery. As a secondary outcome measure, Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm score, and Tegner score were calculated. All patients were evaluated with a mean follow-up of 51 months (range, 25-79 months). Sixteen patients initially underwent MPFL repair, 8 underwent reconstruction, and 3 also underwent TTO. MPFL reconstructions were performed in all patients who underwent TTO. One MPFL repair was to the anatomic femoral origin and 15 were to the patellar insertion corresponding to the site of tearing on MRI. A lateral retinacular lengthening was performed in 21 patients. There was 1 failure in the repair group (6%) and none in the reconstruction group. However, the patient who failed had a TT-TG distance of 26 mm but refused a TTO. She subsequently underwent revision with a TTO and MPFL reconstruction and did not have any further instability events. There were no significant differences between groups for any of the secondary outcome scores. Using an algorithm-based approach, MPFL repair or reconstruction may lead to clinically acceptable results at 2-year follow-up.


Is lateral bias anomalous in early-onset schizophrenia? Selected comparisons with normal populations.
The aim of this study was to investigate lateral bias in patients with early-onset schizophrenia. Hand, eye, and foot preferences and relative hand skill were examined in early-onset patients (n=44) and matched controls (n=39), and were compared with population estimates. Patients demonstrated a significant excess in mixed handedness (20.5% vs. 8.5%) relative to population estimates and reduced relative hand skill on a pegboard task compared with controls. Left eye preference was significantly less common in schizophrenic patients relative to population estimates. Crossed eye-hand and eye-foot preferences were not significantly increased in the patient group as a whole but were present, respectively, in four of nine and five of nine mixed-handed patients but in none of five mixed-handed controls. These findings are consistent with the view that lateralisation is anomalous in schizophrenia early in the course of illness.


Amino acids as substrates in children with growth hormone deficiency and hypoglycemia.
In order to investigate the role of amino acid (AA) substrates in the hypoglycemia associated with human growth hormone (hGH) deficiency, we measured 12-hour fasting blood glucose and total quantitative AA concentrations in 11 children with hGH deficiency during three study periods: (1) before hGH replacement; (2) after 12 months of hGH treatment; and (3) after discontinuation of hGH for three months. The results were compared to studies in 16 control subjects. Fasting blood glucose concentrations were significantly (P less than .05) lower in the hGH-deficient children prior to hGH treatment as compared to the control subjects (67.0 +/- 5.3 vs 80.7 +/- 5.3 mg/100 ml, mean +/- SE). Fasting total serum AA concentrations were similar in the patients and in the control subjects; however, after 12 months of hGH replacement, there was a significant (P less than .01) elevation of serum AA (2,750 +/- 170 vs 2,283 micromoles/liter). Fasting serum concentrations of alanine, glycine, arginine, and tryptophan were also significantly elevated (P less than .01) with hGH treatment; ornithine, tyrosine, lysine, methionine, and phenylalanine showed lesser elevations (P less than 0.5), whereas threonine decreased significantly (P less than 0.01). The fasting hypoglycemia seen with isolated hGH deficiency is not an AA substrate-limited disorder. The finding of increased concentrations of AA with hGH replacement suggests increased retention of nitrogen and synthesis of AA for gluconeogenesis due to availability of other substrates.


Role of a Water Network around the Mn4CaO5 Cluster in Photosynthetic Water Oxidation: A Fourier Transform Infrared Spectroscopy and Quantum Mechanics/Molecular Mechanics Calculation Study.
Photosynthetic water oxidation takes place at the Mn4CaO5 cluster in photosystem II. Around the Mn4CaO5 cluster, a hydrogen bond network is formed by several water molecules, including four water ligands. To clarify the role of this water network in the mechanism of water oxidation, we investigated the effects of the removal of Ca(2+) and substitution with metal ions on the vibrations of water molecules coupled to the Mn4CaO5 cluster by means of Fourier transform infrared (FTIR) difference spectroscopy and quantum mechanics/molecular mechanics (QM/MM) calculations. The OH stretching vibrations of nine water molecules forming a network between D1-D61 and YZ were calculated using the QM/MM method. On the the calculated normal modes, a broad positive feature at 3200-2500 cm(-1) in an S2-minus-S1 FTIR spectrum was attributed to the vibrations of strongly hydrogen-bonded OH bonds of water involving the vibrations of water ligands to a Mn ion and the in-phase coupled vibration of a water network connected to YZ, while bands in the 3700-3500 cm(-1) region were assigned to the coupled vibrations of weakly hydrogen-bonded OH bonds of water. All the water bands were lost upon Ca(2+) depletion and Ba(2+) substitution, which inhibit the S2 → S3 transition, indicating that a solid water network was broken by these treatments. By contrast, Sr(2+) substitution slightly altered the water bands around 3600 cm(-1), reflecting minor modification in water interactions, consistent with the retention of water oxidation activity with a decreased efficiency. These results suggest that the water network around the Mn4CaO5 cluster plays an essential role in the water oxidation mechanism particularly in a concerted process of proton transfer and water insertion during the S2 → S3 transition.


Predicting Composition of Genetic Circuits with Resource Competition: Demand and Sensitivity.
The design of genetic circuits typically relies on characterization of constituent modules in isolation to predict the behavior of modules' composition. However, it has been shown that the behavior of a genetic module changes when other modules are in the cell due to competition for shared resources. In order to engineer multimodule circuits that behave as intended, it is thus necessary to predict changes in the behavior of a genetic module when other modules load cellular resources. Here, we introduce two characteristics of circuit modules: the demand for cellular resources and the sensitivity to resource loading. When both are known for every genetic module in a circuit library, they can be used to predict any module's behavior upon addition of any other module to the cell. We develop an experimental approach to measure both characteristics for any circuit module using a resource sensor module. Using the measured resource demand and sensitivity for each module in a library, the outputs of the modules can be accurately predicted when they are inserted in the cell in arbitrary combinations. These resource competition characteristics may be used to inform the design of genetic circuits that perform as predicted despite resource competition.


Methods to assess stem cell lineage, fate and function.
Stem cell therapy has the potential to regenerate injured tissue. For stem cells to achieve their full therapeutic potential, stem cells must differentiate into the target cell, reach the site of injury, survive, and engraft. To fully characterize these cells, evaluation of cell morphology, lineage specific markers, cell specific function, and gene expression must be performed. To monitor survival and engraftment, cell fate imaging is vital. Only then can organ specific function be evaluated to determine the effectiveness of therapy. In this review, we will discuss methods for evaluating the function of transplanted cells for restoring the heart, nervous system, and pancreas. We will also highlight the specific challenges facing these potential therapeutic areas.


Analysis of UV-absorbing photoprotectant mycosporine-like amino acid (MAA) in the cyanobacterium Arthrospira sp. CU2556.
Mycosporine-like amino acids (MAAs) are ecologically important biomolecules with great photoprotective potential. The present study aimed to investigate the biosynthesis of MAAs in the cyanobacterium Arthrospira sp. CU2556. High-performance liquid chromatography (HPLC) with photodiode-array detection studies revealed the presence of a UV-absorbing compound with an absorption maximum at 310 nm. Based on its UV absorption spectrum and ion trap liquid chromatography/mass spectrometry (LC/MS) analysis, the compound was identified as a primary MAA mycosporine-glycine (m/z: 246). To the best of our knowledge this is the first report on the occurrence of MAA mycosporine-glycine (M-Gly) in Arthrospira strains studied so far. In contrast to photosynthetic activity under UV-A radiation, the induction of the biosynthesis of M-Gly was significantly more prominent under UV-B radiation. The content of M-Gly was found to increase with the increase in exposure time under UV-B radiation. The MAA M-Gly was highly stable under UV radiation, heat, strongly acidic and alkaline conditions. It also exhibited good antioxidant activity and photoprotective ability by detoxifying the in vivo reactive oxygen species (ROS) generated by UV radiation. Our results indicate that the studied cyanobacterium may protect itself by synthesizing the UV-absorbing/screening compounds as important defense mechanisms, in their natural brightly-lit habitat with high solar UV-B fluxes.


[Preoperative neutrophil-lymphocyte ratio as an independent prognostic predictor for pancreatic cancer].
To evaluate the impact value of preoperative neutrophil-lymphocyte ratio (NLR) for the prognosis of pancreatic cancer patients. The clinical data of 65 patients with resectable pancreatic cancer were analyzed retrospectively. According to preoperative NLR, the patients were divided into high group (NLR ≥ 2.4) and low group (NLR < 2.4). Caner-specific survival was assessed using the Kaplan-Meier method. The 1-year survival rates and the clinic pathological factors in the two groups were analyzed using univariate analysis and COX regression model. The 1-year survival rate of higher NLR group and lower NLR group was 64.5% and 73.5% respectively, with statistic significance. A high NLR was identified as an independent risk factor of poorer prognosis for patients with pancreatic cancer (RR: 1.465; 95% CI: 1.078-1.993; P = 0.015). Preoperative NLR can be a clinically significant factor for the assessment of prognosis of Pancreatic Cancer.


Rogue waves of the Kundu-Eckhaus equation in a chaotic wave field.
In this paper we study the properties of the chaotic wave fields generated in the frame of the Kundu-Eckhaus equation (KEE). Modulation instability results in a chaotic wave field which exhibits small-scale filaments with a free propagation constant, k. The average velocity of the filaments is approximately given by the average group velocity calculated from the dispersion relation for the plane-wave solution; however, direction of propagation is controlled by the β parameter, the constant in front of the Raman-effect term. We have also calculated the probabilities of the rogue wave occurrence for various values of propagation constant k and showed that the probability of rogue wave occurrence depends on k. Additionally, we have showed that the probability of rogue wave occurrence significantly depends on the quintic and the Raman-effect nonlinear terms of the KEE. Statistical comparisons between the KEE and the cubic nonlinear Schrödinger equation have also been presented.


Self-assembled hybrid supraparticles that proteolytically degrade tumor necrosis factor-α.
The strategies of pathogens to evade the human immune system are highly sophisticated and modulate a variety of inflammatory pathways. The similarities in the demands for modulation of inflammatory responses during disease treatment and during pathogenic infection provide opportunities to use pathogenic virulence factors to develop a new class of therapeutic materials that control inflammation. In this work, we harness a strategy from Porphyromonas gingivalis by transforming its major virulence factor, an arginine-specific cysteine protease, into self-assembled protease-inorganic hybrid supraparticles. The cysteine protease degrades the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α). It is an irreversible inhibition of TNF-α, which avoids some of the adverse effects of current TNF-α antagonists. We fabricated self-assembled porous supraparticles that specifically incorporate the pathogen-derived protease and showed improved inactivation of TNF-α over soluble enzyme, creating a potential therapeutic for various autoimmune diseases or other sources of inflammation.


A baculovirus vector can express intron-containing genes.
A simjan virus 40 genomic fragment containing the genes coding for the large T and small t antigens was inserted into the genome of the baculovirus Autographa californica nuclear polyhedrosis virus downstream of the strong polyhedrin promoter. Infection of eucaryotic Spodoptera frugiperda (SF9) cells with this recombinant virus produced significant amounts of small t antigen and little or no large T protein. Analysis by Northern blotting and S1 nuclease digestion revealed correct and preferential utilization of the small t splicing signals.


The influence of exogenous steroids on the growth of Aspergillus niger and Torula ***lis.
The yield of Aspergillus niger mycelium from a synthetic medium can be increased by the addition of microgram quantities of cholesterol, ergosterol, cholestanol, 7-dehydrocholesterol, stigmasterol, sitosterol, pregnenolone, and the vitamins D. The stimulation is not due to degradation to the acetate level. It is obtained only in highly aerated cultures. The rate of growth of Torula utilis was not increased. Both organisms were inhibited by desoxycorticosterone, testosterone, androstenedione, cortisone acetate, progesterone, and diethylstilbestrol. T. utilis was also inhibited by estradiol. A small decrease in progesterone inhibition of T. utilis was obtained by adding ergosterol, cholesterol, or pregnenolone. Of the compounds which have been adequately tested the order of stimulatory activity for A. niger is: ergosterol > cholesterol > stigmasterol > 7-dehydrocholesterol > cholestanol > pregnenolone. Progesterone was inhibitory at low concentrations but stimulatory at higher ones, while 17-hydroxyprogesterone was neither inhibitory nor stimulatory. Desoxycorticosterone and testosterone were inhibitory at all concentrations. Complete inhibition of the growth of the fungus was not obtained with any of the steroids. It is concluded that A. niger has a metabolic requirement for a steroid with a hydroxy group on carbon 3, a double bond in the 5-6 position, and a side chain similar to that in ergosterol or cholesterol and that this material is growth-limiting in the early stages of the cultures described.


Glycoprotein C of herpes simplex virus type 1: characterization of O-linked oligosaccharides.
In contrast to other viral glycoproteins, the herpes simplex virus (HSV) glycoprotein C(gC) binds to the N-acetylgalactosamine-specific Helix pomatia lectin (HPA). In the present paper gC was purified by affinity chromatography with monospecific antibodies and the purified glycoprotein was subjected to protease digestion. HPA-binding protease-resistant glycopeptides were isolated by lectin affinity chromatography. The isolated structures did not bind to concanavalin A and seemed to lack charged groups as determined by ion-exchange chromatography. In gel filtration, the glycopeptides appeared in two peaks with molecular weights higher than 4000. The HPA-binding structures of gC were synthesized in the presence of tunicamycin, indicating that they belong to the O-glycosyl class of oligosaccharides. In addition to HPA-binding oligosaccharides, synthesis of tunicamycin-resistant wheat germ lectin-binding gC oligosaccharides was demonstrable. These were sensitive to sialidase and apparently unrelated to the HPA-binding oligosaccharides.


Health care satisfaction and medical literacy habits among caregivers of individuals with Down syndrome.
Patients with Down syndrome have significant specialized health care needs. Our objective was to understand the needs, satisfaction, and online habits of caregivers as they care for persons with Down syndrome. A mixed-method survey was distributed through REDCap from April 2022 to June 2022 in the United States; a Spanish-translated version was distributed through SurveyMonkey from August 2022 to March 2023 in Mexico. We received 290 completed responses from the United States and 58 from caregivers in Mexico. We found that current health care options are not meeting the needs of many individuals with DS in both the United States (39.7%) and Mexico (46.6%). Caregivers expressed frustrations with the inaccessibility and inapplicability of health care information. In particular, they often found the volume of information overwhelming, given their limited medical background. Additionally, health care recommendations were not customized and lacked practical recommendations. Most caregivers in both the United States (72.1%) and Mexico (82.8%) believe it is not easy to find answers to medical questions about their loved ones with DS. Online platforms with customized, specific health information related to DS could offer innovative solutions to these unmet needs for families and primary care providers.


Perceptions of people with multiple sclerosis on social determinants of health: Mixed methods.
To explore the social determinants of health (SDOH) in people with multiple sclerosis (MS) with SDOH, elucidating the SDOH variables of highest salience in this geographical region. Focus groups and a structured survey of Massachusetts residents with SDOH and a diagnosis of MS were conducted by a neurologist and staff, December 2022-July 2023, via Zoom™. Twenty-one consecutively-recruited, convenience-sampled adults participated in four groups. A thematic inductive approach was taken. Participants (average age 45 years old; average time since MS diagnosis 13.7 years; 14 cisgender female, 1 transgender female, 5 cisgender male, 1 non-binary; 33 % white, 57 % black, 5 % Asian, 5 % other; 18 % Hispanic/Latinx; modal response of 5 SDOH) identified the following key SDOH: (1) race and ethnicity, related to (a) diagnostic delays in MS, (b) limited familiarity with MS and its etiology, and (c) value of ongoing MS care; (2) gender, focused on limited published data in African American men and transgender people; (3) social and community contexts; and (4) financial burdens, related to (a) out-of-pocket costs of MS disease modifying therapies, (b) lost work time, and (c) transportation. Lower frequency SDOH variables were access to public toilets, lost job promotions, environmental exposures, and concern about discrimination. Unmet needs emphasized (1) public understanding of MS; (2) financial support for DMT costs, closer access to infusion centers, and culturally competent care; (3) support for research participation; (4) reliable transportation; and (5) patient awareness of extant services and support programs. This in-depth assessment of people with MS who possess multiple SDOH identified the most salient and commonly experienced SDOH, common themes related to the SDOH in MS, unmet needs, and future opportunities.


Patients' experiences of breathing retraining for asthma: a qualitative process analysis of participants in the intervention arms of the BREATHE trial.
Poor symptom control and impaired quality of life are common in adults with asthma, and breathing retraining exercises may be an effective method of self-management. This study aimed to explore the experiences of participants in the intervention arms of the BREATHE trial, which investigated the effectiveness of breathing retraining as a mode of asthma management. Sixteen people with asthma (11 women, 8 per group) who had taken part in the intervention arms of the BREATHE trial (breathing retraining delivered by digital versatile disc (DVD) or face-to-face sessions with a respiratory physiotherapist) took part in semi-structured telephone interviews about their experiences. Interviews were analysed using thematic analysis. Breathing retraining was perceived positively as a method of asthma management. Motivations for taking part included being asked, to enhance progress in research, to feel better/reduce symptoms, and to reduce medication. Participants were positive about the physiotherapist, liked having the materials tailored, found meetings motivational, and liked the DVD and booklet. The impact of breathing retraining following regular practice included increased awareness of breathing and development of new habits. Benefits of breathing retraining included increased control over breathing, reduced need for medication, feeling more relaxed, and improved health and quality of life. Problems included finding time to practice the exercises, and difficulty mastering techniques. Breathing retraining was acceptable and valued by almost all participants, and many reported improved wellbeing. Face to face physiotherapy was well received. However, some participants in the DVD group mentioned being unable to master techniques. PATIENTS RECEPTIVE TO BREATHING RETRAINING: Patients with asthma taught how to change their unconscious breathing patterns generally like non-pharmacological interventions. Researchers in the UK, led by Mike Thomas from the University of Southampton, interviewed 16 people about their experiences in a trial that tested breathing retraining exercises delivered by DVD or face-to-face sessions with a respiratory physiotherapist. Overwhelmingly, trial participants reported that breathing retraining sessions gave them greater control over their symptoms, helped them relax, improved their quality of life and reduced the need for medications. Some participants who received DVD instruction said they had trouble mastering the techniques, and many in both groups found it hard to find time to practice the exercises. Overall, however, patients were positive about the experience. The authors conclude that breathing exercises are likely to be a well-received method of asthma management.


In Vivo Evaluation of Engineered Self-Assembling Silk Fibroin Hydrogels after Intracerebral Injection in a Rat Stroke Model.
Targeting the brain cavity formed by an ischemic stroke is appealing for many regenerative treatment strategies but requires a robust delivery technology. We hypothesized that self-assembling silk fibroin hydrogels could serve as a reliable support matrix for regeneration in the stroke cavity. We therefore performed in vivo evaluation studies of self-assembling silk fibroin hydrogels after intracerebral injection in a rat stroke model. Adult male Sprague-Dawley rats (n = 24) underwent transient middle cerebral artery occlusion (MCAo) 2 weeks before random assignment to either no stereotaxic injection or a stereotaxic injection of either self-assembling silk fibroin hydrogels (4% w/v) or PBS into the lesion cavity. The impact on morbidity and mortality, space conformity, interaction with glial scar, interference with inflammatory response, and cell proliferation in the lesion cavity were examined for up to 7 weeks by a blinded investigator. Self-assembling hydrogels filled the stroke cavity with excellent space conformity and presented neither an overt microglial/macrophage response nor an adverse morbidity or mortality. The relationship between the number of proliferating cells and lesion volume was significantly changed by injection of self-assembling silk hydrogels. This in vivo stroke model confirmed that self-assembling silk fibroin hydrogels provide a favorable microenvironment as a future support matrix in the stroke cavity.


Blunted feedback suppression of SREBP processing by dietary cholesterol in transgenic mice expressing sterol-resistant SCAP(D443N).
Feedback regulation of cholesterol biosynthesis is mediated by membrane-bound transcription factors designated sterol regulatory element-binding proteins (SREBP)-1 and -2. In sterol-deprived cultured cells, SREBPs are released from membranes by a proteolytic process that is stimulated by SREBP cleavage-activating protein (SCAP), a membrane protein containing a sterol-sensing domain. Sterols suppress SREBP cleavage by blocking the action of SCAP, thereby decreasing cholesterol synthesis. A point mutation in SCAP(D443N) causes resistance to sterol suppression. In this article, we produced transgenic mice that express mutant SCAP(D443N) in liver. In these livers the nuclear content of SREBP-1 and -2 was increased, mRNAs encoding proteins involved in uptake and synthesis of cholesterol and fatty acids were elevated, and the livers were engorged with cholesteryl esters and triglycerides enriched in monounsaturated fatty acids. When the mice were challenged with a high cholesterol diet, cleavage of SREBP-1 and -2 was reduced in wild-type livers and less so in transgenic livers. We conclude that SCAP(D443N) stimulates proteolytic processing of native SREBPs in liver and decreases the normal sterol-mediated feedback regulation of SREBP cleavage, suggesting a central role for SCAP as a sterol sensor in liver.


Differential gene expression in relation to mating system in Peromyscine rodents.
Behaviors that increase an individual's exposure to pathogens are expected to have important effects on immunoactivity. Because sexual reproduction typically requires close contact among conspecifics, mating systems provide an ideal opportunity to study the immunogenetic correlates of behaviors with high versus low risks of pathogen exposure. Despite logical links between polygynandrous mating behavior, increased pathogen exposure, and greater immunoactivity, these relationships have seldom been examined in nonhuman vertebrates. To explore interactions among these variables in a different lineage of mammals, we used RNAseq to study the gene expression profiles of liver tissue-a highly immunoactive organ-from sympatric populations of the monogamous California mouse (Peromyscus californicus) and two polygynandrous congeners (P. maniculatus and P. boylii). Differential expression and co-expression analyses revealed distinct patterns of gene activity among species, with much of this variation associated with differences in mating system. This tendency was particularly pronounced for MHC genes, with multiple MHC Class I genes being upregulated in the two polygynandrous species, as expected if exposure to sexually transmitted pathogens varies with mating system. Our results underscore the role of mating behavior in influencing patterns of gene expression and highlight the use of emerging transcriptomic tools in behavioral studies of free-living animals.


The three-dimensional structure of the EBV genome plays a crucial role in regulating viral gene expression in EBVaGC.
Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different latency-associated transcriptional repertoires, each with distinct three-dimensional structures. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents 1.3-30.9% of all gastric cancers globally. EBV-positive gastric cancers exhibit an intermediate viral transcription profile known as 'Latency II', expressing specific viral genes and noncoding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II and III latencies exhibit different 3D structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV genome at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.


Does Preincisional Infiltration with Bupivacaine Reduce Postoperative Pain in Laparoscopic Bariatric Surgery?
Current evidence suggests that local anesthetic wound infiltration should be employed as part of multimodal postoperative pain management. There is scarce data concerning the benefits of this anesthetic modality in laparoscopic weight loss surgery. Therefore, we analyzed the influence of trocar site infiltration with bupivacaine on the management of postoperative pain in laparoscopic bariatric surgery. This retrospective randomized study included 47 patients undergoing primary obesity surgery between January and September 2014. Laparoscopic gastric bypass was performed in 39 cases and sleeve gastrectomy in 8 cases. Patients were stratified into two groups depending on whether preincisional infiltration with bupivacaine and epinephrine was performed (study group, 27 patients) or not (control group, 20 patients). Visual analogue scale (VAS), International Pain Outcomes questionnaire, and rescue medication records were reviewed to assess postoperative pain. VAS scores in the study group and sleeve gastrectomy group were lower than those in the control and gastric bypass groups in the first 4 h postoperatively without reaching statistical significance (p > 0.05). VAS scores did not differ in any other period of time. No statistically significant differences in pain perception were registered according to the patient's pain outcomes questionnaire or the need for rescue medication. The present study did not conclusively prove the efficacy of bupivacaine infiltration by any of the three evaluation methods analyzed. Nevertheless, preincisional infiltration provides good level of comfort in the immediate postoperative period when analgesia is most urgent.


Haemodialysis Impairs the Human Microcirculation Independent from Macrohemodynamic Parameters.
Hemodynamic changes during haemodialysis are common. Often these changes are associated with symptoms that are thought to be the result of reduced microcirculatory blood flow and oxygen delivery. The microcirculatory effect of hemodialysis is scarcely researched, though of possible influence on patient outcome. New techniques have become available to visualise and analyse microvascular blood flow. We performed an observational study using Sidestream Dark Field imaging, a microscopic technique using polarised light to visualise erythrocytes passing through sublingual capillaries, to analyse the effect of haemodyalisis on central microvascular blood flow. We showed that there is a substantial impairment of microvascular blood flow and a discrepancy between micro- and macro-vascular parameters.


Osmotic stress decreases complexity underlying the electrophysiological dynamic in soybean.
Studies on plant electrophysiology are mostly focused on specific traits of single cells. Inspired by the complexity of the signalling network in plants, and by analogy with neurons in human brains, we sought evidence of high complexity in the electrical dynamics of plant signalling and a likely relationship with environmental cues. An EEG-like standard protocol was adopted for high-resolution measurements of the electrical signal in Glycine max seedlings. The signals were continuously recorded in the same plants before and after osmotic stimuli with a -2 MPa mannitol solution. Non-linear time series analyses methods were used as follows: auto-correlation and cross-correlation function, power spectra density function, and complexity of the time series estimated as Approximate Entropy (ApEn). Using Approximate Entropy analysis we found that the level of temporal complexity of the electrical signals was affected by the environmental conditions, decreasing when the plant was subjected to a low osmotic potential. Electrical spikes observed only after stimuli followed a power law distribution, which is indicative of scale invariance. Our results suggest that changes in complexity of the electrical signals could be associated with water stress conditions in plants. We hypothesised that the power law distribution of the spikes could be explained by a self-organised critical state (SOC) after osmotic stress.


CD8+ tumor-infiltrating T cells are trapped in the tumor-dendritic cell network.
Chemotherapy enhances the antitumor adaptive immune T cell response, but the immunosuppressive tumor environment often dominates, resulting in cancer relapse. Antigen-presenting cells such as tumor-associated macrophages (TAMs) and tumor dendritic cells (TuDCs) are the main protagonists of tumor-infiltrating lymphocyte (TIL) immunosuppression. TAMs have been widely investigated and are associated with poor prognosis, but the immunosuppressive activity of TuDCs is less well understood. We performed two-photon imaging of the tumor tissue to examine the spatiotemporal interactions between TILs and TuDCs after chemotherapy. In a strongly immunosuppressive murine tumor model, cyclophosphamide-mediated chemotherapy transiently enhanced the antitumor activity of adoptively transferred ovalbumin-specific CD8(+) T cell receptor transgenic T cells (OTI) but barely affected TuDC compartment within the tumor. Time lapse imaging of living tumor tissue showed that TuDCs are organized as a mesh with dynamic interconnections. Once infiltrated into the tumor parenchyma, OTI T cells make antigen-specific and long-lasting contacts with TuDCs. Extensive analysis of TIL infiltration on histologic section revealed that after chemotherapy the majority of OTI T cells interact with TuDCs and that infiltration is restricted to TuDC-rich areas. We propose that the TuDC network exerts antigen-dependent unproductive retention that trap T cells and limit their antitumor effectiveness.


Differential expression of multiple transglutaminases in human brain. Increased expression and cross-linking by transglutaminases 1 and 2 in Alzheimer's disease.
The transglutaminase (TGase) family of enzymes, of which seven different members are known in the human genome, participate in many biological processes involving cross-linking proteins into large macromolecular assemblies. The TGase 2 enzyme is known to be present in neuronal tissues and may play a role in neuronal degenerative diseases such as Alzheimer's disease (AD) by aberrantly cross-linking proteins. In this paper, we demonstrate by reverse transcriptase-polymerase chain reaction and immunological methods with specific antibodies that in fact three members, the TGase 1, TGase 2, and TGase 3 enzymes, and are differentially expressed in various regions of normal human brain tissues. Interestingly, the TGase 1 and 3 enzymes and their proteolytically processed forms are involved in terminal differentiation programs of epithelial cell development and barrier function. In addition, we found that the levels of expression and activity of the TGase 1 and 2 enzymes were both increased in the cortex and cerebellum of AD patients. Furthermore, whereas normal brain tissues contain approximately 1 residue of cross-link/10,000 residues, AD patient cortex and cerebellum tissues contain 30-50 residues of cross-link/10,000 residues. Together, these findings suggest that multiple TGase enzymes are involved in normal neuronal structure and function, but their elevated expression and cross-linking activity may also contribute to neuronal degenerative disease.


Pharmacokinetic modeling and simulation with pharmacogenetic insights support the relevance of therapeutic drug monitoring for myeloablative busulfan dosing in adult HSCT.
Therapeutic drug monitoring (TDM) of busulfan (Bu) is well-established in pediatric hematopoietic stem cell transplantation (HSCT), but its use in adults is limited due to a lack of clear recommendations and scarcity of evidence regarding its utility. GSTA1 promoter variants are reported to affect Bu clearance in both adults and pediatric patients. This study aimed to evaluate the value of preemptive genotyping GSTA1 and body composition (obesity) in individualizing Bu dosing in adults, through pharmacokinetic (PK) modeling and simulations. A population pharmacokinetic (PopPK) model was developed and validated with data from 60 adults who underwent HSCT. Simulations assessed different dosing scenarios based on body size metrics and GSTA1 genotypes. Due to the limited number of obese patients in the cohort, the effect of obesity on Bu pharmacokinetics (PK) was evaluated in silico using a physiologically-based pharmacokinetic (PBPK) model and relevant virtual populations from Simcyp software. Patients with at least one GSTA1*B haplotype had 16% lower clearance on average. PopPK simulations indicated that adjusting doses based on genotype increased the probability of achieving the target exposure (3.7-5.5 mg.h/L) from 53 to 60 % in GSTA1*A homozygous patients, and from 50 to 61 % in *B carriers. Still, Approximately 40% of patients would not achieve this therapeutic window without TDM. A two-sample optimal design was validated for routine model-based Bu first dose AUC0-∞ estimation, and the model was implemented in the Tucuxi user-friendly TDM software. PBPK simulations confirmed body surface area-based doses of 29 to 31 mg/m2/6h as the most appropriate, regardless of obesity status. This study emphasizes the importance of individualized Bu dosing strategies in adults to achieve therapeutic targets. Preemptive genotyping alone may not have a significant clinical impact, and routine TDM may be necessary for optimal transplantation outcomes.


[Distribution and potential ecological risk assessment of heavy metals in surface sediments of Hongze Lake].
In order to investigated horizontal distribution patterns of heavy metals in surface sediments of Hongze Lake, heavy metal contents in every samples were measured by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) and Atomic Fluorescence spectrometry (AFS) and the potential ecological risks of each heavy metals were analyzed. The average contents of heavy metals Cu, Zn, Pb, Cd, Cr, Hg, As, Fe, Al and Mn are 34.99 mg/kg, 72.44 mg/kg, 18.82 mg/kg, 3.24 mg/kg, 57.59 mg/kg, 0.07 mg/kg, 23.67 mg/kg, 29.63 mg/g, 37.19 mg/g and 0.69 mg/g, respectively. Horizontal distribution patterns of every heavy metals (Cu, Zn, Pb, Cd, Fe, Al, Cr, Hg, Mn and As) in surface sediments were very similar. By impact of hydodynamical and topographical condition, the contents of heavy metals were significantly lower in the inflow river mouth areas than that of open water area in the eastern part of the lake, and that of bays and outflow river mouth areas. This distribution pattern belongs to Turbidity Flood Model. These heavy metals are highly related with each other positively, indicating that they are from the same pollution source. The geo-accumulation index (I(geo)) and the Hakanson potential ecological risk index were applied for assessing the status of sediment heavy metal enrichment and the extent of potential ecological risk. The pollution extent of heavy metals followed the order: Cd > As > Cu > Cr > Zn > Hg > Pb, while the single potential ecological risk of heavy metals followed the order: Cd > As > Hg > Cu > Pb > Cr > Zn. The pollution extent and potential ecological risk of Cd were the most serious among all heavy metals. The distribution pattern of Cd individual potential ecological risk indices is exactly the same as that of general potential ecological risk indices for all heavy metals, indicating the important contribution of Cd in the general indices. Analysis showed that heavy metal pollution and the potential ecological risk existed in three risk regions: the central open water area and outflow river mouth region (S9, S1 and S8), the northern bay region (S6) and the western bay region (S5).


[Local immunity in pathology of the IgA system (IgA subclasses in the saliva of patients with A-paraproteinemia)].
In 39 patients with A-paraproteinemia, the local immunity status was estimated according to the level of IgA subclasses in the saliva and antibody activity of secretory IgA to E. coli and S. Sonnei. Local production of normal IgA was undisturbed only in 12 patients with A-paraproteinemia, since in the saliva of those patients, there was a normal correlation of IgA subclasses and the level of antimicrobial IgA antibodies was the same as in healthy persons. The overwhelming majority of the patients with A-paraproteinemia and all the patients suffering from heavy alpha-chain disease manifested deficiency of local production of normal IgA, which consisted in the impairment of the normal correlation of IgA subclasses in the saliva and in the reduction of sIgA function. A-paraprotein was detected in many samples of the saliva using agar electrophoresis followed by immunoblotting. Secretion was shown to be mainly penetrated by the polymeric forms of A-paraprotein.


Imaging of the spinal cord and cauda equina.
Magnetic resonance imaging continues to dominate the literature on spinal imaging and further advances have occurred during the last year. It is now the investigation of choice for most problems. Intraoperative sonography also may have a place, but other modalities are being superseded. Plain films retain a value in trauma.


Assessment of nutrition education: urban mother understanding of weight for age graphs.
One third (34.5%) of 319 mothers attending four urban Maternal and Child Health clinics in Lae, Morobe Province, Papua New Guinea succeeded in correctly identifying all four test weight for age graphs. Mothers were more accurate in identifying weight graphs if they were educated, if their child was older than 12 months, and if their last visit to an MCH clinic had been during a scheduled clinic week. In regard to weight for age status of 321 children sampled at the four clinics 18.6% were less than 80% of the Harvard standard weight for their age, with 3.8% less than 70% of the standard. Mothers' ability to identify weight graphs was not directly related to their children's nutritional status. Children had better weight for age if their fathers had employment, and if their family lived in professionally built housing. Weight for age tended to decline after 12 months of age. Analysis of the results suggested that mothers with children older than 12 months who understood weight graphs were more likely to have well nourished children than those who did not.


Circ_0058124 Upregulates MAPK1 Expression to Promote Proliferation, Metastasis and Metabolic Abilities in Thyroid Cancer Through Sponging miR-940.
Thyroid cancer (TC) is an endocrine disease, and its progression is regulated by many factors, including circular RNAs (circRNAs). However, as a new circRNA, the role of circ_0058124 in TC is worth further exploration. The expression levels of circ_0058124, microRNA-940 (miR-940) and mitogen-activated protein kinase 1 (MAPK1) were assessed by quantitative polymerase chain reaction (q-PCR). The circular characteristic of circ_0058124 was identified by oligo (dT)18 primers, Ribonuclease R (RNase R) and Actinomycin D (ActD), and its localization was determined by nuclear-cytoplasmic separation assay. Also, cell proliferation was detected by colony formation assay, and cell migration and invasion were assessed by transwell assay. Further, Seahorse XF Extracellular Flux Analyzer was used to measure the oxygen consumption rate (OCR) of cells. Besides, dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were used to identify the mechanism of circ_0058124. Western blot (WB) analysis was used to test the MAPK1 protein level. In addition, mice xenograft models were constructed to test the effect of circ_0058124 on TC tumor growth in vivo. Circ_0058124 was highly expressed in TC and is a stable cyclic transcript, mainly located in the cytoplasm. Circ_0058124 knockdown suppressed proliferation, migration, invasion and metabolic abilities in TC cells. MiR-940 could be absorbed by circ_0058124, and the inhibition effect of its overexpression on TC progression could be reversed by overexpressed-circ_0058124. MAPK1 was a target of miR-940, and the suppression effect of its silencing on TC progression could be inverted by miR-940 inhibitor. Besides, MAPK1 expression was regulated by circ_0058124 and miR-940. Interference of circ_0058124 also reduced TC tumor growth in vivo. Circ_0058124 might play a carcinogenic role in TC progression by regulating the miR-940/MAPK1 axis, which might provide a new idea for the treatment of TC.


[Clinical profile of cytomegalovirus (CMV) enterocolitis in acquired immunodeficiency syndrome].
To determine the clinical profile of CMV colitis in AIDS patients, comparing clinical, endoscopic parameters and survival time between 2 groups of AIDS patients having chronic diarrhea. Group A being CMV colitis and group B without CMV colitis. 48 patients with diarrhea that lasted more than 30 days, being 27 in Group A and 21 in Group B, were studied. Age, risk factors, interval time between the diagnosis of HIV infection and the beginning of diarrhea, hematochesia, the endoscopic findings and life table in both groups, were analysed. All of them were diagnosed by stool culture and stools for ovum and parasites, along colonoscopy with biopsies. The unpaired t test was used to assess statistical significance of differences observed in the means of continuous and the chi-square with Yates correction for non-parametric variables. The survival curves were assessed by the Kaplan-Meier and the Mantel-Haenszel's tests. A P value of less than 0,05 was considered to indicate statistical significance. The mucosal lesions associated with the CMV infection are typically ulcerative on a background of hemorrhagic erythema 14 (51,8%) p < 0,01. The life table analysis disclosed shorter survival time in the CMV colitis group 0,005> P>0,001. The others studied data did not achieve statistical significance. AIDS patients with CMV colitis have a poorer long-term survival. Among the colonoscopic findings, ulcerations with hemorrhagic background were the most common lesions.


Evaluation of Autothermal Thermophilic Aerobic Digester Performance for the Stabilization of Municipal Wastewater Sludge.
Sludge stabilization process in terms of operational, environmental and economic indexes is the most important stage of treatment and its disposal. This study was aimed to determine the performance of Autothermal Thermophilic Aerobic Digestion (ATAD) system as one of the low-cost and biocompatible methods of sludge treatment. This study has been done using a laboratory scale Autothermal Thermophilic Aerobic Digestion (ATAD). The reactor was consisted of two polyethylene tanks with a final capacity of 100 L for each tank. Both tanks with all fittings were installed on a metal frame. The variables of study were temperature, dissolved oxygen, pH, volatile organic compounds, total solids, COD and the number of Ascaris eggs and fecal coliforms per gram of dry matter of the sludge. The temperature was measured hourly and the pH and dissolved oxygen were measured and controlled twice per day. One-way ANNOVA was applied to analyze reasults. According to the results, the temperature of sludge increased from 11.7-61.2°C by biological reactions. Pathogen organisms were reduced from 80×106 to 503 in number during 72 h. After 6 days pathogen organisms and Ascaris eggs were removed completely. Volatile organic compounds and COD were reduced 42 and 38.3% respectively during the 6 days. It is concluded that the performance of ATAD in removing organic compounds from wastewater sludge were desirable. Resulted sludge from stabilization process were appropriate for use in agriculture as a soil supplement and met the indexes of class A sludge according to EPA's standards (CFR 40 Part 503).


Syphilis test availability and uptake at medical facilities in southern China.
To examine syphilis testing capacity, screening coverage rates and types of syphilis tests used in medical facilities in southern China. Eleven of the 14 municipalities in Guangdong province participated. Data on syphilis testing capacity, screening coverage and types of syphilis tests used were collected from all types of public medical facilities offering prenatal care (n = 109). A total of 494 680 women who delivered during 2004-2008 were studied. In 2008, 54 196 pregnant women (43.1%) were not screened for syphilis. Among such women, 32 863 (60.6%) attended clinics without any syphilis testing capacity and 21 333 (39.4%) attended clinics that performed testing but were not screened. The likelihood of not having syphilis test capacity was much higher for hygiene stations (odds ratio, OR: 10; 95% confidence interval, CI: 4-25), services at the township level (OR: 33; 95% CI: 10-100) and services with ≤ 1000 deliveries per year (OR: 1.002; 95% CI: 1.001-1.003). These same service characteristics correlated with lower screening coverage rates (P < 0.01). Only one antenatal clinic had the capacity to conduct both treponemal and non-treponemal tests for diagnosing syphilis. Syphilis screening is available in very few of the basic medical facilities offering prenatal care where most neonates in southern China are delivered. In light of this and of the increasing incidence of syphilis in the area, expanding point-of-care rapid syphilis testing is a priority.


Regulation of cation-selective channels in liver cells.
In liver cells, cation-selective channels are permeable to Ca2+ and have been postulated to represent a pathway for receptor-mediated Ca2+ influx. This study examines the mechanisms involved in the regulation of these channels in a model liver cell line. Using patch-clamp recording techniques, it is shown that channel open probability is a saturable function of cytosolic [Ca2+], with half-maximal opening at 660 nm. By contrast, channel opening is not affected by membrane voltage or cytosolic pH. In intact cells, reduction of cytosolic [Cl-], a physiological response to Ca2+-mobilizing hormones and cell swelling, is also associated with an increase in channel opening. Finally, channel opening is inhibited by intracellular ATP through a mechanism that does not involve ATP hydrolysis. These findings suggest that opening of cation-selective channels is coupled to the metabolic state of the cell and provides a positive feedback mechanism for regulation of receptor-mediated Na+ and Ca2+ influx.


Arginine is preferred to glucagon for stimulation testing of β-cell function.
A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess β-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m²). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) μU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) μU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of β-cell function.


Test ordering by GP trainees: Effects of an educational intervention on attitudes and intended practice.
To assess the effectiveness of an educational intervention on test-ordering attitudes and intended practice of GP trainees, and any associations between changes in test ordering and trainee characteristics. Preworkshop and postworkshop survey of attitudes to test ordering, intended test-ordering practices for 3 clinical scenarios (fatigue, screening, and shoulder pain), and tolerance for uncertainty. Three Australian regional general practice training providers. General practice trainees (N = 167). A 2-hour workshop session and an online module. Proportion of trainees who agreed with attitudinal statements before and after the workshop; proportion of trainees who would order tests, mean number of tests ordered, and number of appropriate and inappropriate tests ordered for each scenario before and after the workshop. Of 167 trainees, 132 (79.0%) completed both the preworkshop and postworkshop questionnaires. A total of 122 trainees attended the workshop. At baseline, 88.6% thought that tests can harm patients, 84.8% believed overtesting was a problem, 72.0% felt pressured by patients, 52.3% believed that tests would reassure patients, and 50.8% thought that they were less likely to be sued if they ordered tests. There were desirable changes in all attitudes after the workshop. Before the workshop, the mean number of tests that trainees would have ordered was 4.4, 4.8, and 1.5 for the fatigue, screening, and shoulder pain scenarios, respectively. After the workshop there were decreases in the mean number of both appropriate tests (decrease of 0.94) and inappropriate tests (decrease of 0.24) in the fatigue scenario; there was no change in the mean number of appropriate tests and a decrease in inappropriate tests (decrease of 0.76) in the screening scenario; and there was an increase in the proportion of trainees who would appropriately not order tests in the shoulder pain scenario. There were no significant associations between changes in test ordering and trainee demographic characteristics or tolerance for uncertainty subscale scores. General practice trainees have conflicting attitudes to test ordering and demonstrate nonrational test ordering in 3 common scenarios. A workshop on rational test ordering led to desirable changes in attitudes and more rational intended test ordering. Our findings inform the development of appropriate educational interventions that address nonrational testing in family medicine.


A review of intervention studies to promote NCLEX-RN success of baccalaureate students.
Numerous studies have identified factors to predict NCLEX-RN but few have evaluated interventions to promote success. An integrative literature review of intervention studies used in baccalaureate programs to improve NCLEX-RN success demonstrated that although pass rates increased, researchers were limited in their ability to attribute success specifically to the interventions. Further investigation using more rigorous designs with larger, diverse student groups to evaluate both type and timing of various interventions is recommended.


Relaxation by bradykinin in porcine ciliary artery. Role of nitric oxide and K(+)-channels.
To assess the effects of K(+)-channel blockers on bradykinin-induced relaxations in porcine ciliary artery. Vascular isometric forces were measured with a myograph system. Ciliary vascular rings were precontracted with thromboxane A2 analog (U 46619, 10(-7) M) to assess dose-dependent (10(-10)-3 x 10(-6) M) bradykinin-induced relaxation after addition of one of the following: the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or inactive enantiomer (D-NAME, 10(-4) M); the nonspecific K(+)-channel blocker tetra-ethylammonium (TEA, 10(-2) M); or the ATP-sensitive K(+)-channel blocker glibenclamide (10(-5) M). The effect of TEA on relaxations to the NO donor, sodium nitroprusside (SNP, 10(-10)-10(-4) M) was investigated. The membrane potential of vascular smooth muscle cells (VSMC) was recorded after exposure to bradykinin (2.5 x 10(-7) M). Endothelium-dependent relaxations to bradykinin (maximal [max], 99% +/- 3%) were strongly inhibited by L-NAME (max, 39% +/- 4%, P < 0.01) and partially by TEA (max, 62% +/- 3%, P < 0.01) or glibenclamide (max, 77% +/- 4%, P < 0.01). Administration of glibenclamide plus L-NAME further suppressed bradykinin-induced relaxation (max, 23% +/- 6%; P < 0.01), whereas TEA and L-NAME (max, 6% +/- 2%; P < 0.01) abolished the relaxation. SNP relaxations were unaffected by TEA. Bradykinin had no effect on the membrane potential of VSMC. In porcine ciliary artery, the endothelium-dependent relaxations to bradykinin are primarily mediated by NO and involve K(+)-channels. As only relaxations to bradykinin, but not those mediated by SNP, were inhibited by TEA, this implies that K(+)-channel blockers most likely affect the bradykinin-evoked NO production or release by the endothelium.


The role of ferroptosis and its mechanism in ischemic stroke.
Ischemic stroke is an acute cerebrovascular disease with a high morbidity, mortality, and disability rate. Persistent ischemia of brain tissue can cause irreversible damage to neurons, leading to neurological dysfunction and seriously affecting patients' quality of life. However, current clinical therapies are limited and have not achieved satisfactory outcome, due to the incomplete understanding of the mechanism of neuronal damage during ischemic stroke. Recent studies have found that ferroptosis is implicated in the pathophysiology of ischemic stroke. Ferroptosis is an iron-dependent regulated cell death driven by lipid peroxidation. Under normal physiological conditions, GSH/GPX4, FSP1/CoQ10, GCH/BH4 and other anti-ferroptosis pathways can function effectively to suppress the occurrence of ferroptosis. After ischemic stroke, two typical ferroptosis characteristics, lipid peroxidation and iron accumulation, are observed, accompanied by changes in the expression of ferroptosis related genes such as GPX4, ACSL4, and SLC7A11, suggesting that ferroptosis plays a key role in ischemic stroke, which provides a new idea for the clinical treatment of ischemic stroke. This article reviewed the pathological mechanisms of ferroptosis in the occurrence and development of ischemic stroke, as well as the related progress of ferroptosis targeted therapy.


Evaluation of factors associated with work-related injuries to veterinary technicians certified in Minnesota.
To evaluate the magnitude and consequences of work-related injuries and associated factors among veterinary technicians certified in Minnesota. Cross-sectional survey. 1,427 certified veterinary technicians (CVTs). Surveys were used to collect data on demographics, personal characteristics, injury occurrences in the 12 months prior to survey completion, and injury consequences. Annual injury rates were estimated on the basis of demographic and work-related characteristics. Risk of injury associated with various factors was estimated by calculation of incidence rate ratios, controlling for multiple factors. 465 of 873 eligible CVTs reported 1,827 injury events (total and bite injury rates, 237 and 78 injuries/100 persons/y). Primary injury sources were cats and dogs, and most injuries occurred during animal restraint or treatment. Self-reported most severe injuries involved bites; cuts, lacerations, or scratches; bruises or contusions; and abrasions. Injury consequences included treatment and restricted work activity. Risk of work-related injury was lower for CVTs who worked < 40 h/wk than for those who worked ≥ 40 h/wk. The risk was higher for CVTs working in small animal or mixed mostly small animal facilities and lower for those working in mixed large and small animal facilities, commercial or industry operations, and government or regulatory facilities, compared with CVTs in colleges or universities. Handling 4 to > 6 (vs < 4) animal species during the 12 months prior to the survey and belief that injuries are not preventable were also associated with higher risk of injury. Several factors associated with the risk of work-related injury among CVTs were identified. Beyond these risk factors, investigation of additional exposures is integral to relevant intervention strategies.


IL-2 limits IL-12 enhanced lymphocyte proliferation during Leishmania amazonensis infection.
C3H mice infected with Leishmania amazonensis develop persistent, localized lesions with high parasite loads. During infection, memory/effector CD44(hi)CD4(+) T cells proliferate and produce IL-2, but do not polarize to a known effector phenotype. Previous studies have demonstrated IL-12 is insufficient to skew these antigen-responsive T cells to a functional Th1 response. To determine the mechanism of this IL-12 unresponsiveness, we used an in vitro assay of repeated antigen activation. Memory/effector CD44(hi)CD4(+) T cells did not increase proliferation in response to either IL-2 or IL-12, although these cytokines upregulated CD25 expression. Neutralization of IL-2 enhanced CD4(+) T cell proliferation in response to IL-12. This cross-regulation of IL-12 responsiveness by IL-2 was confirmed in vivo by treatment with anti-IL-2 antibodies and IL-12 during antigen challenge of previously infected mice. These results suggest that during chronic infection with L. amazonensis, IL-2 plays a dominant, immunosuppressive role independent of identifiable conventional T(reg) cells.


[About making up for manpower resource of paramedical personnel].
The article deals with the analysis of quality of training of paramedical personnel in the medical colleges of Kursk oblast during last ten years. It is established that during last decade the number of graduates of the Kursk medical college has a tendency to decrease. If in 2001 the college graduated 169 medical nurses, 44 feldshers, and 30 midwives (243 in total) then in 2011 graduated 121 medical nurses, 64 feldshers (185 in totals). The number of college entrants with 11th grade is decreasing against the background of increasing of number of college entrants with 9th grade. Basically, the educational institutions are completed with graduates of rural schools whose resources are limited. The graduates from urban schools have no intent to acquire the profession of medical nurse. Hence, in Kursk oblast under annual decrease of number of paramedical personnel concurrently decreases number of graduates of medical colleges. This situation makes quite problematic the making up of manpower resource both in nowadays and in near-term outlook.


Transvascular delivery of talaporfin sodium to subcutaneous tumors in mice by nanosecond pulsed laser-induced photomechanical waves.
We previously developed a site-specific transvascular drug delivery system (DDS) based on photomechanical waves (PMWs) or laser-induced stress/shock waves (LISWs). In this study, we investigated the validity of this method to deliver a clinical photosensitizer, talaporfin sodium (TS), to subcutaneous tumors in mice and to enhance the efficacy of photodynamic therapy (PDT). TS solution (2.5 mg/kg) was intravenously injected into mice. Immediately thereafter, PMWs were applied to the tumor by irradiating a laser target with a Q-switched ruby laser pulse (0.8 J/cm2). Five hours after TS administration, some tumors were excised to evaluate the depth distribution of the delivered TS under a fluorescence microscope. Other tumors were subjected to PDT by irradiating the tissues with a 665 nm continuous-wave laser diode (75 mW/cm2, 667 s) at this timepoint. The effects of PDT were evaluated on the basis of the two primary therapeutic mechanisms of TS-mediated PDT: i) damage to tumor cells and ii) damage to endothelial cells of tumor vessels, i.e., the vascular shutdown effect on tumors. PMW application significantly increased the accumulation of TS in the tumor parenchyma but not in the tumor vessel walls; the endothelial cell junctions of tumor vessels should be the route of TS delivery enhanced by PMWs. Thus, as a result of PMW application followed by PDT, while the vascular shutdown effect on the tumors was not enhanced, direct damage to the tumor cells was increased, resulting in significant tumor growth retardation without body weight loss for 7 days after treatment.


The research-design interaction: lessons learned from an evidence-based design studio.
As evidence-based design (EBD) emerges as a model of design practice, considerable attention has been given to its research component. However, this overshadows another essential component of EBD-the change agent, namely the designer. EBD introduced a new skill set to the practitioner: the ability to interact with scientific evidence. Industry sources suggest adoption of the EBD approach across a large number of design firms. How comfortable are these designers in integrating research with design decision making? Optimizing the interaction between the primary change agent (the designer) and the evidence is crucial to producing the desired outcomes. Preliminary to examining this question, an architectural design studio was used as a surrogate environment to examine how designers interact with evidence. Twelve students enrolled in a healthcare EBD studio during the spring of 2009. A three-phase didactic structure was adopted: knowing a hospital, knowing the evidence, and designing with knowledge and evidence. Products of the studio and questionnaire responses from the students were used as the data for analysis. The data suggest that optimization of the research-design relationship warrants consideration in four domains: (1) a knowledge structure that is easy to comprehend; (2) phase-complemented representation of evidence; (3) access to context and precedence information; and (4) a designer-friendly vocabulary.


Fin-fold development in paddlefish and catshark and implications for the evolution of the autopod.
The evolutionary origin of the autopod involved a loss of the fin-fold and associated dermal skeleton with a concomitant elaboration of the distal endoskeleton to form a wrist and digits. Developmental studies, primarily from teleosts and amniotes, suggest a model for appendage evolution in which a delay in the AER-to-fin-fold conversion fuelled endoskeletal expansion by prolonging the function of AER-mediated regulatory networks. Here, we characterize aspects of paired fin development in the paddlefish Polyodon spathula (a non-teleost actinopterygian) and catshark Scyliorhinus canicula (chondrichthyan) to explore aspects of this model in a broader phylogenetic context. Our data demonstrate that in basal gnathostomes, the autopod marker HoxA13 co-localizes with the dermoskeleton component And1 to mark the position of the fin-fold, supporting recent work demonstrating a role for HoxA13 in zebrafish fin ray development. Additionally, we show that in paddlefish, the proximal fin and fin-fold mesenchyme share a common mesodermal origin, and that components of the Shh/LIM/Gremlin/Fgf transcriptional network critical to limb bud outgrowth and patterning are expressed in the fin-fold with a profile similar to that of tetrapods. Together these data draw contrast with hypotheses of AER heterochrony and suggest that limb-specific morphologies arose through evolutionary changes in the differentiation outcome of conserved early distal patterning compartments.


Maximum exercise responses of men and women mountaineering trainees on induction to high altitude (4350 m) by trekking.
Maximum aerobic capacity decreases at high altitude. This study was conducted to compare the changes in maximum aerobic capacity in men and women mountaineering trainees on induction to high altitude at 4350 m by trekking. Eight men and 8 women mountaineering trainees in a mountaineering course were selected for the study. The initial study was conducted at 2100 m (586 mm Hg) and then during 6 to 7 days of sojourn at 4350 m (435 mm Hg). Maximum oxygen consumption (VO(2max)), maximum heart rate (HR(max)), pulse arterial oxygen saturation (SaO(2)), and maximum ventilation (VE(max)) were measured. VO(2max), HR(max), duration of work (minutes), and SaO(2) saturation decreased significantly (P < .05) with increasing altitude in both sexes. Conversely, VE(max) and ventilatory equivalent (VE/VO(2)) increased significantly (P < .05). Men showed a relatively higher value of maximum exercise variables (total exercise time, exercise intensity, and VO(2)) than women trainees at both altitude locations. The decrement of VO(2max) was 13% in women and 17% in men (P < .05). The results indicate that the decrement of maximum aerobic capacity at 4350 m was less in women than in men under similar modes of ascent.


Visual Processing Recruits the Auditory Cortices in Prelingually Deaf Children and Influences Cochlear Implant Outcomes.
Although visual processing recruitment of the auditory cortices has been reported previously in prelingually deaf children who have a rapidly developing brain and no auditory processing, the visual processing recruitment of auditory cortices might be different in processing different visual stimuli and may affect cochlear implant (CI) outcomes. Ten prelingually deaf children, 4 to 6 years old, were recruited for the study. Twenty prelingually deaf subjects, 4 to 6 years old with CIs for 1 year, were also recruited; 10 with well-performing CIs, 10 with poorly performing CIs. Ten age and sex-matched normal-hearing children were recruited as controls. Visual ("sound" photo [photograph with imaginative sound] and "nonsound" photo [photograph without imaginative sound]) evoked potentials were measured in all subjects. P1 at Oz and N1 at the bilateral temporal-frontal areas (FC3 and FC4) were compared. N1 amplitudes were strongest in the deaf children, followed by those with poorly performing CIs, controls and those with well-performing CIs. There was no significant difference between controls and those with well-performing CIs. "Sound" photo stimuli evoked a stronger N1 than "nonsound" photo stimuli. Further analysis showed that only at FC4 in deaf subjects and those with poorly performing CIs were the N1 responses to "sound" photo stimuli stronger than those to "nonsound" photo stimuli. No significant difference was found for the FC3 and FC4 areas. No significant difference was found in N1 latencies and P1 amplitudes or latencies. The results indicate enhanced visual recruitment of the auditory cortices in prelingually deaf children. Additionally, the decrement in visual recruitment of auditory cortices was related to good CI outcomes.


The making of an expert.
Popular lore tells us that genius is born, not made. Scientific research, on the other hand, reveals that true expertise is mainly the product of years of intense practice and dedicated coaching. Ordinary practice is not enough: To reach elite levels of performance, you need to constantly push yourself beyond your abilities and comfort level. Such discipline is the key to becoming an expert in all domains, including management and leadership. Those are the conclusions reached by Ericsson, a professor of psychology at Florida State University; Prietula, a professor at the Goizueta Business School; and Cokely, a research fellow at the Max Planck Institute for Human Development, who together studied data on the behavior of experts, gathered by more than 100 scientists. What consistently distinguished elite surgeons, chess players, writers, athletes, pianists, and other experts was the habit of engaging in "deliberate" practice--a sustained focus on tasks that they couldn't do before. Experts continually analyzed what they did wrong, adjusted their techniques, and worked arduously to correct their errors. Even such traits as charisma can be developed using this technique. Working with a drama school, the authors created a set of acting exercises for managers that remarkably enhanced executives' powers of charm and persuasion. Through deliberate practice, leaders can improve their ability to win over their employees, their peers, or their board of directors. The journey to elite performance is not for the impatient or the faint of heart. It takes at least a decade and requires the guidance of an expert teacher to provide tough, often painful feedback. It also demands would-be experts to develop their "inner coach" and eventually drive their own progress.


Triplet fusion upconversion using sterically protected 9,10-diphenylanthracene as the emitter.
Improving the efficiency of triplet fusion upconversion (TF-UC) in the solid-state is still challenging due to the aggregation and phase separation of chromophores. In this work, two 9,10-diphenylanthracene (DPA) derivatives based on the modification of the 9,10-phenyl rings with bulky isopropyl groups (bDPA-1 and bDPA-2) were used as emitters. By using platinum octaethylporphyrin (PtOEP) as the sensitizer, TF-UC performance was comprehensively investigated in 3 media: toluene solution, polyurethane thin film and nano/micro-crystals in a polyvinyl alcohol matrix. Only a small difference in upconversion efficiency between the bulky DPAs and the DPA reference was observed in toluene solution and polyurethane thin film. However, a large improvement of TF-UC quantum yield was achieved in bDPA-2/PtOEP crystals (ΦUC = (0.92 ± 0.05)%) with a low excitation intensity threshold (52 mW cm-2) compared to that of DPA/PtOEP crystals (ΦUC = (0.09 ± 0.03)%). This difference was largely attributed to improved dispersibility of the PtOEP sensitizer in the bDPA-2 emitter crystals. The bulky DPAs also show excellent stability under UV irradiation with exposure to oxygen compared to DPA. These results provide a strategy for developing efficient solid-state TF-UC systems based on nano/micro-particles of emitter-sensitizer mixtures.


Krüppel-like transcription factor 4 contributes to maintenance of telomerase activity in stem cells.
The zinc finger Krüppel-like transcription factor 4 (KLF4) has been implicated in cancer formation and stem cell regulation. However, the function of KLF4 in tumorigenesis and stem cell regulation are poorly understood due to limited knowledge of its targets in these cells. In this study, we have revealed a surprising link between KLF4 and regulation of telomerase that offers important insight into how KLF4 contributes to cancer formation and stem cell regulation. KLF4 sufficiently activated expression of the human telomerase catalytic subunit, human telomerase reverse transcriptase (hTERT), in telomerase-low alternative lengthening of telomeres (ALT), and fibroblast cells, while downregulation of KLF4 reduced its expression in cancerous and stem cells, which normally exhibits high expression. Furthermore, KLF4-dependent induction of hTERT was mediated by a KLF4 binding site in the proximal promoter region of hTERT. In human embryonic stem cells, expression of hTERT replaced KLF4 function to maintain their self-renewal. Therefore, our findings demonstrate that hTERT is one of the major targets of KLF4 in cancer and stem cells to maintain long-term proliferation potential.


Neuropilin-1 identifies a subset of highly activated CD8+ T cells during parasitic and viral infections.
Neuropilin-1 (Nrp-1) expression on CD8+ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it interferes with the development of long-lived memory T cell responses. In parasitic and acute viral infections, the role of Nrp-1 expression on CD8+ T cells remains unclear. Here, we demonstrate a strong induction of Nrp-1 expression on CD8+ T cells in Plasmodium berghei ANKA (PbA)-infected mice that correlated with neurological deficits of experimental cerebral malaria (ECM). Likewise, the frequency of Nrp-1+CD8+ T cells was significantly elevated and correlated with liver damage in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. Transcriptomic and flow cytometric analyses revealed a highly activated phenotype of Nrp-1+CD8+ T cells from infected mice. Correspondingly, in vitro experiments showed rapid induction of Nrp-1 expression on CD8+ T cells after stimulation in conjunction with increased expression of activation-associated molecules. Strikingly, T cell-specific Nrp-1 ablation resulted in reduced numbers of activated T cells in the brain of PbA-infected mice as well as in spleen and liver of LCMV-infected mice and alleviated the severity of ECM and LCMV-induced liver pathology. Mechanistically, we identified reduced blood-brain barrier leakage associated with reduced parasite sequestration in the brain of PbA-infected mice with T cell-specific Nrp-1 deficiency. In conclusion, Nrp-1 expression on CD8+ T cells represents a very early activation marker that exacerbates deleterious CD8+ T cell responses during both, parasitic PbA and acute LCMV infections.


Personal exposure to ultrafine particles from PVC welding and concrete work during tunnel rehabilitation.
To investigate the exposure to number concentration of ultrafine particles and the size distribution in the breathing zone of workers during rehabilitation of a subsea tunnel. Personal exposure was measured using a TSI 3091 Fast Mobility Particle Sizer (FMPS), measuring the number concentration of submicrometre particles (including ultrafine particles) and the particle size distribution in the size range 5.6-560 nm. The measurements were performed in the breathing zone of the operators by the use of a conductive silicone tubing. Working tasks studied were operation of the slipforming machine, operations related to finishing the verge, and welding the PVC membrane. In addition, background levels were measured. Arithmetic mean values of ultrafine particles were in the range 6.26×10(5)-3.34×10(6). Vertical PVC welding gave the highest exposure. Horizontal welding was the work task with the highest maximum peak exposure, 8.1×10(7) particles/cm(3). Background concentrations of 4.0×10(4)-3.1×10(5) were found in the tunnel. The mobility diameter at peak particle concentration varied between 10.8 nm during horizontal PVC welding and during breaks and 60.4 nm while finishing the verge. PVC welding in a vertical position resulted in very high exposure of the worker to ultrafine particles compared to other types of work tasks. In evaluations of worker exposure to ultrafine particles, it seems important to distinguish between personal samples taken in the breathing zone of the worker and more stationary work area measurements. There is a need for a portable particle-sizing instrument for measurements of ultrafine particles in working environments.


Generation of small 32P-labeled peptides as a potential approach to colorectal cancer therapy.
Cancers have been revealed to be extremely heterogenous in terms of the frequency and types of mutations present in cells from different malignant tumors. Thus, it is likely that uniform clinical treatment is not optimal for all patients, and that the development of individualized therapeutic regimens may be beneficial. We describe the generation of multiple, unique small peptides nine to thirty-four amino acids in length which, when labeled with the radioisotope (32)P, bind with vastly differing efficiencies to cell lines derived from different colon adenocarcinomas. In addition, the most effective of these peptides permanently transfers the (32)P radioisotope to colorectal cancer cellular proteins within two hours at a rate that is more than 150 times higher than in cell lines derived from other cancers or from the normal tissues tested. Currently, the only two FDA-approved radioimmunotherapeutic agents in use both employ antibodies directed against the B cell marker CD20 for the treatment of non-Hodgkin's lymphoma. By using the method described herein, large numbers of different (32)P-labeled peptides can be readily produced and assayed against a broad spectrum of cancer types. This report proposes the development and use of (32)P-labeled peptides as potential individualized peptide-binding therapies for the treatment of colon adenocarcinoma patients.


Haploidentical transplantation for hematologic malignancies: where do we stand?
The fundamental obstacle to the successful application of partially HLA-mismatched related donor, or HLA-haploidentical stem cell transplantation, is the strength of the host and donor T-cell response to allogeneic HLA molecules, which results in increased incidences of graft failure, GVHD, and nonrelapse mortality. The holy grail of haplo-SCT is to mitigate host-versus-graft and graft-versus-host responses while preserving immune responses to infection and the patient's malignancy. Two strategies have been taken to achieve this goal. The first strategy is to supplement a T cell-depleted graft with pathogen-specific T cells or populations of T cells in which alloreactivity can be controlled. The second strategy is to eliminate alloreactive T cells selectively from a T cell-replete graft. Substantial progress has been made with both approaches so that the safety of haplo-SCT now approaches that of SCT using grafts of umbilical cord blood or from HLA-matched donors. In light of the rapid and near universal availability of HLA-haploidentical related donors, it should now be possible to identify and mobilize a donor for every patient referred for allogeneic SCT. Prospective comparisons between haploidentical SCT and unrelated donor SCT should be performed to identify the most efficacious approach to alternative donor transplantation.


Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice.
The molecular mechanisms underlying the pathogenesis of diffuse-type gastric cancer (DGC) have not been adequately explored due to a scarcity of appropriate animal models. A recently developed tool well suited for this line of investigation is the Pdx-1-Cre;Cdh1F/+ ;Trp53F/F ;Smad4F/F (pChe PS) mouse model that spontaneously develops metastatic DGC showing nearly complete E-cadherin loss. Here, we performed a proteogenomic analysis to uncover the molecular changes induced by the concurrent targeting of E-cadherin, p53, and Smad4 loss. The gene expression profiles of mouse DGCs and in vivo gastric phenotypes from various combinations of gene knockout demonstrated that these mutations collaborate to activate cancer-associated pathways to generate aggressive DGC. Of note, WNT-mediated epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM)-cytokine receptor interactions were prominently featured. In particular, the WNT target gene osteopontin (OPN) that functions as an ECM cytokine is highly upregulated. In validation experiments, OPN contributed to DGC stemness by promoting cancer stem cell (CSC) survival and chemoresistance. It was further found that Bcl-xL acts as a targetable downstream effector of OPN in DGC CSC survival. In addition, Zeb2 and thymosin-β4 (Tβ4) were identified as prime candidates as suppressors of E-cadherin expression from the remaining Cdh1 allele during DGC development. Specifically, Tβ4 suppressed E-cadherin expression and anoikis while promoting cancer cell growth and migration. Collectively, these proteogenomic analyses broaden and deepen our understanding of the contribution of key driver mutations in the stepwise carcinogenesis of DGC through novel effectors, namely OPN and Tβ4.


Awareness of technology-induced errors and processes for identifying and preventing such errors.
There is a need to determine if organizations working with health information technology are aware of technology-induced errors and how they are addressing and preventing them. The purpose of this study was to: a) determine the degree of technology-induced error awareness in various Canadian healthcare organizations, and b) identify those processes and procedures that are currently in place to help address, manage, and prevent technology-induced errors. We identified a lack of technology-induced error awareness among participants. Participants identified there was a lack of well-defined procedures in place for reporting technology-induced errors, addressing them when they arise, and preventing them.


Enhanced Osteogenic Differentiation Potential of Stem-Cell Spheroids Created From a Coculture of Stem Cells and Endothelial Cells.
This study was performed to fabricate stem-cell spheroids formed with human gingiva-derived stem cells and endothelial cells and to evaluate their viability and osteogenic differentiation potential. Gingiva-derived stem cells were isolated, and stem cells and endothelial cells with a total of 6 × 10 cells were seeded into concave micromolds with different ratios of 6:0 (group 1), 4:2 (group 2), 3:3 (group 3), and 2:4 (group 4). Gingiva-derived stem cells and/or endothelia cells formed spheroids in concave microwells. There was a decreasing trend in the diameter of spheroids with increasing amounts of endothelial cells, but there were no statistically significant differences between the groups. The secretion of vascular endothelial growth factor from the spheroids was noted. The results of the alkaline phosphatase activity assays showed significantly higher values for groups 2, 3, and 4 when compared with the value of group 1. Conclusively, stem-cell spheroids formed with human gingiva-derived stem cells and endothelial cells using concave microwells enhanced osteogenic differentiation potential, and multicell spheroid-based cell delivery could be a simple and effective strategy for improving stem-cell therapy.