Relational and instrumental perspectives on compliance with the law among people experiencing homelessness.
We conducted an exploratory study testing procedural justice theory with a novel population. We assessed the extent to which police procedural justice, effectiveness, legitimacy, and perceived risk of sanction predict compliance with the law among people experiencing homelessness. We did not develop formal a priori hypotheses but examined five general research questions. First, are there positive associations between police procedural justice, police legitimacy, and compliance? Second, do procedural justice and legitimacy differentially predict compliance, depending on the particular type of offending? Third, are there positive associations between police effectiveness, perceived risk of sanction, and compliance? Fourth, does the perceived risk of sanction differentially predict compliance, depending on the particular type of offending? And fifth, are there positive associations between moral judgments about different offending behaviors and compliance? Two hundred people (87% male, 49% aged 45-64, 37% White British) experiencing homelessness on the streets of an inner London borough completed a survey that included measures of procedural justice, police legitimacy, perceived risk of sanction, morality, and compliance with the law. Procedural justice and police legitimacy were only weakly (and not significantly) associated with any of the three types of compliance (compliance with laws prohibiting low-level crimes, behaviors specific to the street population, and high-level crimes). Police effectiveness positively predicted compliance via perceived risk of sanction, but only for street-population-specific offenses that can be important for survival on the streets, such as begging and sleeping in certain localities. Morality was positively associated with all three types of compliance behaviors. Supplementary analyses suggested a small amount of instability in the results, however, possibly because of the relatively small sample size. The lack of relevant relational connections to legal authority may explain why procedural fairness and perceptions of police legitimacy were not particularly important predictors of compliance in this context. More research is needed into the types of marginalized communities for whom structural factors of alienation and lack of access to resources may serve to reduce normative group connections. Future work should test whether the need to survive on the streets leads people to discount some social and relational constraints to behavior, making people (almost by definition) more instrumental in relation to law and law enforcement. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Cancer cell progression and chemoimmunotherapy--dual effects in the induction of resistance to therapy.
To determine whether resistance to chemoimmunotherapy is acquired during therapy, we investigated the effects of chemotherapeutic agents and anti-tumour polysaccharide, lentinan, on the progression of Rous sarcoma virus-induced S908.D2 fibrosarcomas. The chemoimmunotherapy was effective against the parental S908.D2-bearing mice. Nearly all the mice that were treated with cyclophosphamide (CY) and lentinan achieved complete tumour regression. Only a few of the mice that achieved complete regression of the primary tumours showed a recurrence of the tumour in regional lymph nodes. S908.D2-vp.1 was established from metastatic tumours that developed in the regional lymph nodes of parental S908.D2-bearing mice during therapy. S908.D2-vp.2-or vp.3 cells were sequentially derived in a similar way from S908.D2-vp.1-or-vp.2-bearing mice respectively, in which complete tumour regression at each primary site was achieved during therapy. These lines acquired resistance to CY and lentinan and also to 5-fluorouracil (5-FU)/5'-deoxy-5-fluorouracil and lentinan. No significant difference in either the sensitivity to 5-FU or 4-deoxycyclophosphamide in vitro or in the susceptibility to immune effector cells was observed between the parental and progressed lines (S908.D2-vp1 -vp3). There was an increase in the level of prostaglandin E2 (PGE2) in the progressed lines during repeated therapy (parental, 1171 pg ml(-1); vp.1, 2199 pg ml(-1); vp.2, 5500pg ml(-1); vp3, 16187 pg ml(-1)). There was no significant increase in the production of transforming growth factor beta (TGF-beta). The amount of interleukin-2 (IL-2) produced by spleen cells isolated from the S908.D2-vp.2-bearing mice was decreased compared with the amount produced by the parental S908.D2- bearing mice. Furthermore, combination therapy with lentinan and IL-2 achieved complete tumour regression in all the mice transplanted with S908.D2 progressed tumour lines, although IL-2 alone did not show any anti-tumour effects in either the S908.D2 parental or progressed lines. The findings suggest that the reduced production of IL-2 induced an increase in the production of the PGE2 by progressed tumour lines is involved in the acquisition of resistance.


Differential effects of vascular endothelial growth factor on glycocalyx of endothelial and tumor cells and potential targets for tumor metastasis.
On the surface of every mammalian cell, there is a matrix-like glycocalyx (GCX) consisting of proteoglycans and glycosaminoglycans (GAGs). Disruption of endothelial cell (EC) GCX by a vascular endothelial growth factor (VEGF, VEGF-A165), a tumor secretion, was found to be an early event in tumor cell (TC) metastasis across vascular barriers. However, how the TC secretion VEGF affects its own GCX is unknown. To investigate the VEGF effect on TC GCX and to elucidate the ultrastructural organization of EC and TC GCX and their alteration by VEGF, we employed super-resolution stochastic optical reconstruction microscopy to observe the spatio-chemical organizations of the heparan sulfate (HS) and hyaluronic acid (HA), two representative GAGs of GCX, on human cerebral microvascular endothelial cells (hCMEC) and malignant breast cancer cells MDA-MB-231 (MB231). We found that HS and HA have distinct organizations on hCMEC and MB231. Only HS of hCMEC is perpendicular to the cell surface, while HA of hCMEC as well as HS and HA of MB231 all lie in the same plane as the cell surface where they appear to weave into a 2D network covering the cell. We also found that VEGF significantly reduces the length and coverage of HS on hCMEC but does not change the thickness and coverage of HA on hCMEC. On the contrary, VEGF significantly enhances the coverage of HS and HA on MB231 although it does not alter the thickness. The differential effects of VEGF on the GCX of TC and that of EC may favor TC adhesion and transmigration across EC barriers for their metastasis.


Cytological Criteria for Predicting the Luminal Phenotype of Breast Carcinoma.
Specific cytological criteria for the luminal phenotype of breast carcinoma, despite it being the most common and having a better prognosis as well as targeted therapies under study, remain to be established. Using fine-needle aspiration cytology (FNAC), we aimed to identify the luminal phenotype through the evaluation of cytological criteria recognized in routine practice. We correlated 169 FNACs of breast carcinomas with their tissue specimens, classified into phenotypes by immunohistochemistry (applying tissue microarray technology) as luminal A, luminal B, HER2 overexpression, and triple negative. All FNAC samples were blindly reviewed according to cellularity, cell cohesion, necrosis, nucleoli, and nuclear atypia. Fisher's exact test was used to test associations between the cytological criteria and phenotypes. The following phenotypes were obtained - luminal A: 107 (63.3%), luminal B: 39 (23.1%), HER2 overexpression: 8 (4.7%), and triple negative: 15 (8.9%). The luminal phenotype showed mild/moderate cellularity (40.4%) (OR = 7.12, 95% CI: 1.61-31.52), inconspicuous, present nucleoli (55.5%) (OR = 8.31, 95% CI: 2.36-29.19), and mild/moderate nuclear atypia (44.5%) (OR = 8.42, 95% CI: 1.90-37.25). The criteria that might indicate the luminal phenotype of breast carcinoma in FNAC were mild/moderate cellularity, inconspicuous, present, and nonprominent nucleoli, and mild/moderate nuclear atypia.


Increasing the Collision Rate of Particle Impact Electroanalysis with Magnetically Guided Pt-Decorated Iron Oxide Nanoparticles.
An integrated microfluidic/magnetophoretic methodology was developed for improving signal response time and detection limits for the chronoamperometric observation of discrete nanoparticle/electrode interactions by electrocatalytic amplification. The strategy relied on Pt-decorated iron oxide nanoparticles which exhibit both superparamagnetism and electrocatalytic activity for the oxidation of hydrazine. A wet chemical synthetic approach succeeded in the controlled growth of Pt on the surface of FeO/Fe3O4 core/shell nanocubes, resulting in highly uniform Pt-decorated iron oxide hybrid nanoparticles with good dispersibility in water. The unique mechanism of hybrid nanoparticle formation was investigated by electron microscopy and spectroscopic analysis of isolated nanoparticle intermediates and final products. Discrete hybrid nanoparticle collision events were detected in the presence of hydrazine, an electrochemical indicator probe, using a gold microband electrode integrated into a microfluidic channel. In contrast with related systems, the experimental nanoparticle/electrode collision rate correlates more closely with simple theoretical approximations, primarily due to the accuracy of the nanoparticle tracking analysis method used to quantify nanoparticle concentrations and diffusion coefficients. Further modification of the microfluidic device was made by applying a tightly focused magnetic field to the detection volume to attract the magnetic nanoprobes to the microband working electrode, thereby resulting in a 6-fold increase to the relative frequency of chronoamperometric signals corresponding to discrete nanoparticle impact events.


Functional divergence caused by ancient positive selection of a Drosophila hybrid incompatibility locus.
Interspecific hybrid lethality and sterility are a consequence of divergent evolution between species and serve to maintain the discrete identities of species. The evolution of hybrid incompatibilities has been described in widely accepted models by Dobzhansky and Muller where lineage-specific functional divergence is the essential characteristic of hybrid incompatibility genes. Experimentally tractable models are required to identify and test candidate hybrid incompatibility genes. Several Drosophila melanogaster genes involved in hybrid incompatibility have been identified but none has yet been shown to have functionally diverged in accordance with the Dobzhansky-Muller model. By introducing transgenic copies of the X-linked Hybrid male rescue (Hmr) gene into D. melanogaster from its sibling species D. simulans and D. mauritiana, we demonstrate that Hmr has functionally diverged to cause F1 hybrid incompatibility between these species. Consistent with the Dobzhansky-Muller model, we find that Hmr has diverged extensively in the D. melanogaster lineage, but we also find extensive divergence in the sibling-species lineage. Together, these findings implicate over 13% of the amino acids encoded by Hmr as candidates for causing hybrid incompatibility. The exceptional level of divergence at Hmr cannot be explained by neutral processes because we use phylogenetic methods and population genetic analyses to show that the elevated amino-acid divergence in both lineages is due to positive selection in the distant past-at least one million generations ago. Our findings suggest that multiple substitutions driven by natural selection may be a general phenomenon required to generate hybrid incompatibility alleles.


An exploratory study of substance use and misuse among college students with and without ADHD and other disabilities.
The present study investigated potential differences between college students with and without disabilities (including ADHD, Asperger's syndrome, executive functioning disorder, and learning, mental health, vision, hearing, and physical/chronic disabilities) regarding self-reported substance use and misuse, perceived stress, and sensation seeking. Students responded to a Stimulant Survey Questionnaire (SSQ), Perceived Stress Scale (PSS), Sensation-Seeking Scale (SSS), and items from the National College Health Assessment (NCHA). The hypotheses were part supported as MANOVA results revealed that students with disabilities provided significantly lower ratings on the SSS and also reported lower alcohol and marijuana use. Students with ADHD were more likely to use or misuse prescription stimulant medication but were less likely to use alcohol than did students without ADHD. Students with disabilities compared to those without disabilities differed on levels of sensation seeking and alcohol and marijuana use.


Effect of one single auditory cue on movement kinematics in patients with Parkinson's disease.
The purpose of this study was to determine whether one single auditory cue affected movement kinematics of more than one step in a sequential upper limb task in patients with Parkinson's disease. A counter-balanced repeated-measures design was employed. A total of 16 male patients with Parkinson's disease and 16 age-matched male and female controls performed the task under two conditions. In the signal-present condition, the participants were instructed to start the movement when they heard a bell ring. In the signal-absent condition, there was no bell ringing, and they were told to start the movement when they were ready. Kinematic performances for the first two movement segments (i.e., reaching for the pen and bringing the pen to the paper) were compared between conditions. The results indicated that the presence of the single auditory cue affected movement kinematics of the patients with Parkinson's disease but not that of the controls. When given external cueing, the patients elicited faster, more forceful, more efficient, more stable, but less smooth movement. The results suggest that therapists should provide external cues according to their treatment goals. In addition, researchers should be aware of the influence of start signals when designing subsequent experiments.


Benefits of long-term beta-blockade in experimental chronic aortic regurgitation.
The objective of this study was to assess the long-term effects of beta-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a beta-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg.kg(-1).day(-1)) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals (P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). beta-Adrenergic receptor ratio (beta(1)/beta(2)) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the beta-adrenergic receptor ratio.


Progress and problems in understanding and managing primary Epstein-Barr virus infections.
Epstein-Barr virus (EBV) is a gammaherpesvirus that infects a large fraction of the human population. Primary infection is often asymptomatic but results in lifelong infection, which is kept in check by the host immune system. In some cases, primary infection can result in infectious mononucleosis. Furthermore, when host-virus balance is not achieved, the virus can drive potentially lethal lymphoproliferation and lymphomagenesis. In this review, we describe the biology of EBV and the host immune response. We review the diagnosis of EBV infection and discuss the characteristics and pathogenesis of infectious mononucleosis. These topics are approached in the context of developing therapeutic and preventative strategies.


Spindle microtubule differentiation and deployment during micronuclear mitosis in Paramecium.
Spindles underwent a 12-fold elongation before anaphase B was completed during the closed mitoses of micronuclei in Paramecium tetraurelia. Two main classes of spindle microtubules have been identified. A peripheral sheath of microtubules with diameters of 27-32 nm was found to be associated with the nuclear envelope and confined to the midportion of each spindle. Most of the other microtubules had diameters of approximately 24 nm and were present along the entire lengths of spindles. Nearly all of the 24-nm microtubules were eliminated from spindle midportions (largely because of microtubule disassembly) at a relatively early stage of spindle elongation. Disassembly of some of these microtubules also occurred at the ends of spindles. About 60% of the total microtubule content of spindles was lost at this stage. Most, perhaps all, peripheral sheath microtubules remained intact. Many of them detached from the nuclear envelope and regrouped to form a compact microtubule bundle in the spindle midportion. There was little, if any, further polymerization of 24-nm microtubules after the disassembly phase. Polymerization of microtubules with diameters of 27-32 nm continued as spindle elongation progressed. Most microtubules in the midportions of well-elongated spindles were constructed from 14-16 protofilaments. A few 24-nm microtubules with 13 protofilaments were also present. The implications of these findings for spatial control of microtubule assembly, disassembly, positioning, and membrane association, that apparently discriminate between microtubules with different protofilament numbers have been explored. The possibility that microtubule sliding occurs during spindle elongation has also been considered.


Cuticle and subsurface ornamentation of intact plant leaf epidermis under confocal and superresolution microscopy.
Plant cuticle micromorphology is an invaluable tool in modern ecology and paleoecology. It has expanded our knowledge of systematic relationships among diverse plant groups and can be used to identify fossil plants. Furthermore, fossil plant leaf micromorphology is used for reconstructing past environments, most notably for estimating atmospheric CO2 concentration. Here we outline a new protocol for imaging plant cuticle for archival and paleoecological applications. Traditionally, both modern reference and fossil samples undergo maceration with subsequent imaging via environmental SEM, widefield fluorescence, or light microscopy. In this paper, we demonstrate the capabilities of alternative preparation and imaging methods using confocal and superresolution microscopy with intact leaf samples. This method produces detailed three-dimensional images of surficial and subsurface structures of the intact leaf. Multiple layers are captured simultaneously, which previously required independent maceration and microtome steps. We compared clearing agents (chloral hydrate, KOH, and Visikol); mounting media (Eukitt and Hoyer's); fluorescent stains (periodic acid Schiff, propidium iodide); and confocal vs. superresolution microscopes. We conclude that Eukitt is the best medium for long-term preservation and imaging. Because of nontoxicity and ease of procurement, Visikol made for the best clearing agent. Staining improves contrast and under most circumstances PAS provided the clearest images. Supperresolution produced higher clarity images than traditional confocal, but the information gained was minimal. This new protocol provides the botanical and paleobotanical community an alternative to traditional techniques. Our proposed workflow has the net benefit of being more efficient than traditional methods, which only capture the surface of the plant epidermis. Microsc. Res. Tech. 81:129-140, 2018. © 2016 Wiley Periodicals, Inc.


Dynamic evolution in coarse-grained molecular dynamics simulations of polyethylene melts.
We test a coarse-grained model assigned based on united atom simulations of C50 polyethylene to seven chain lengths ranging from C76 to C300. The prior model accurately reproduced static and dynamic properties. For the dynamics, the coarse-grained time evolution was scaled by a constant value [t=alphatCG] predictable based on the difference in intermolecular interactions. In this contribution, we show that both static and dynamic observables have continued accuracy when using the C50 coarse-grained force field for chains representing up to 300 united atoms. Pair distribution functions for the longer chain systems are unaltered, and the chain dimensions present the expected N0.5 scaling. To assess dynamic properties, we compare diffusion coefficients to experimental values and united atom simulations, assign the entanglement length using various methods, examine the applicability of the Rouse model as a function of N, and compare tube diameters extracted using a primitive path analysis to experimental values. These results show that the coarse-grained model accurately reproduces dynamic properties over a range of chain lengths, including systems that are entangled.


[Development of the neural apparatus of the human pancreas in prenatal ontogeny].
In human embryos, prefetuses and fetuses from 6 to 40 weeks of development 82 preparations of the pancreas have been studied; 39 series of slices of the human embryos have been impregnated after Bielschowsky-Boeke. For the first time the nerves grow into the pancreas anlage in embryos of 16 mm long (6 weeks). The main sources supplying the pancreas with the nerves in the period studied are nervus vagus, celiac, hepatic, splenic, right adrenal, superior mesenteric and intermesenteric plexuses. Three stages in formation of the innervational apparatus of the pancreas are distinguished during the intrauterine development. The first stage is characterized by beginning of the nerve growing into the pancreas anlage. For the second stage an increased development of the intraorganic innervational apparatus and appearance of the all main sources of the organ's innervation are specific. The third stage is characterized with an increased differentiation of receptor zones in various parts of the pancreas. The development of the pancreatic innervational apparatus by the time of birth is not completed.


Three-dimensional echocardiographic evaluation of a patient with double-orifice mitral valve, bicuspid aortic valve, and coarctation of aorta.
A 16-year-old male patient was diagnosed with bicuspid aortic valve and coarctation of aorta, and had a history of a subclavian patch plasty operation at 1 year of age. In addition, we detected double-orifice mitral valve (DOMV) at a routine evaluation and demonstrated by both two-dimensional and three-dimensional (3D) echocardiographic examinations. DOMV should be kept in mind in cases with left ventricular obstructive lesions and 3D echocardiography may provide a more detailed assessment of mitral valve and subvalvular apparatus.


Cerebral sinus thrombosis associated with severe active ulcerative colitis.
A 19-year-old man with severe active ulcerative colitis was admitted to our hospital where he was prescribed 80 mg prednisolone and underwent leukocytapheresis (LCAP). Two weeks after initiating therapy, his symptoms had not recovered. We administered cyclosporin via continuous intravenous infusion for 12 days. Although his clinical symptoms improved, he complained of severe headache. Immediate plain computed tomography (CT) and magnetic resonance imaging angiography (MRA) revealed extensive thrombosis in the superior sagittal sinus and right transverse sinus. We treated this condition with the anticoagulant agent, heparin, which prevents and can treat venous thrombosis. We report an occurrence of cerebral sinus thrombosis accompanying ulcerative colitis, where active anticoagulant therapy was useful.


Impingement and stability of total hip arthroplasty versus femoral head resurfacing using a cadaveric robotics model.
We identified and compared the impingent-free range of motion (ROM) and subluxation potential for native hip, femoral head resurfacing (FHR), and total hip arthroplasty (THA). These constructs were also compared both with and without soft tissue to elucidate the role of the soft tissue. Five fresh-frozen bilateral hip specimens were mounted to a six-degree of freedom robotic manipulator. Under load-control parameters, in vivo mechanics were recreated to evaluate impingement free ROM, and the subluxation potential in two "at risk" positions for native hip, FHR, and THA. Impingement-free ROM of the skeletonized THA was greater than FHR for the anterior subluxation position. For skeletonized posterior subluxations, stability for THA and FHR constructs were similar, while a different pattern was observed for specimens with soft tissues intact. FHR constructs were more stable than THA constructs for both anterior and posterior subluxations. When the femoral neck is intact the joint has an earlier impingement profile placing the hip at risk for subluxation. However, FHR design was shown to be more stable than THA only when soft tissues were intact.


Pulmonary vascular and alveolar development in preterm lambs chronically colonized with Ureaplasma parvum.
Ureaplasma species, the most commonly isolated microorganisms in women with chorioamnionitis, are associated with preterm delivery. Chorioamnionitis increases the risk and severity of bronchopulmonary dysplasia and persistent pulmonary hypertension in newborns. It is not known whether the timing of exposure to inflammation in utero is an important contributor to the pathogenesis of bronchopulmonary dysplasia. We hypothesized that chronic inflammation would alter the pulmonary air space and vascular development after 70 days of exposure to infection. Pregnant ewes were given intra-amniotic injection of Ureaplasma parvum serovars 3 or 6 at low (2 x 10(4) cfu) or high doses (2 x 10(7) cfu) or media (controls) at 55 days gestational age. Fetuses were delivered at 125 days (term = 150 days). U. parvum was grown from the lungs of all exposed fetuses, and neutrophils and monocytes were increased in the air spaces. Lung mRNA expression of IL-1beta and IL-8, but not IL-6, was modestly increased in U. parvum-exposed fetuses. U. parvum exposure increased surfactant and improved lung gas volumes. The changes in lung inflammation and maturation were independent of serovar or dose. Exposure to U. parvum did not change multiple indices of air space or vascular development. Parenchymal elastin and collagen content were similar between groups. Expression of several endothelial proteins and pulmonary resistance arteriolar media thickness were also not different between groups. We conclude that chronic exposure to U. parvum does not cause sustained effects on air space or vascular development in premature lambs.


The baby cooling project of Japan to implement evidence-based neonatal cooling.
Therapeutic hypothermia was first recommended as a standard of care by international guidelines in 2010. However, at that time, the number of centers capable of providing standard cooling was limited even in Japan. The aim of this project was to implement a nationwide network of evidence-based cooling within 3 years. A taskforce was formed in June 2010 to undergo the primary nationwide practice survey, design of action plans, and the appraisal of interventions by involving all registered level-II/III neonatal intensive care units in Japan. Based on findings from the primary survey, aggressive action plans were introduced that focused on the formulation of clinical recommendations, facilitation of educational events, and opening of an online case registry. Findings from the follow-up survey (January 2013) were compared with the results from the primary survey (June 2010). Four workshops and three consensus meetings were held to formulate clinical recommendations, which were followed by the publication of practical textbooks, large-scale education seminars, and implementation of a case registry. A follow-up survey covering 253 units (response rate: 89.1%) showed that cooling centers increased from 89 to 135. Twelve prefectures had no cooling centers in 2010, whereas all 47 prefectures had at least one in 2013. In cooling centers, adherence to the standard cooling protocols and the use of servo-controlled cooling devices improved from 20.7% to 94.7% and from 79.8% to 98.5%, respectively. A rapid improvement in the national provision of evidence-based cooling was achieved. International consensus guidelines coupled with domestic interventions might be effective in changing empirical approaches to evidence-based practice.


Rheogenic transport in the renal proximal tubule.
The electrophysiology of the renal Na-K ATPase was studied in isolated perfused amphibian proximal tubules during alterations in bath (serosal) potassium. Intracellular and extracellular ionic activity measurements permitted continuous evaluation of the Nernst potentials for Na+, K+, and Cl- across the basolateral membrane. The cell membrane and transepithelial potential differences and resistances were also determined. Return of K to the basal (serosal) solution after a 20-min incubation in K-free solution hyperpolarized the basolateral membrane to an electrical potential that was more negative than the Nernst potential for either Na, Cl, or K. This constitutes strong evidence that at least under stimulated conditions the Na-K ATPase located at the basolateral membrane of the renal proximal tubule mediates a rheogenic process which directly transfers net charge across the cell membrane. Interpretation of these data in terms of an electrical equivalent circuit permitted calculation of both the rheogenic current and the Na/K coupling ratio of the basolateral pump. During the period between 1 and 3 min after pump reactivation by return of bath K, the basolateral rheogenic current was directly proportional to the intracellular Na activity, and the pump stoichiometry transiently exceeded the coupling ratio of 3Na to 2K reported in other preparations.


The fetal cheek-to-cheek diameter and abdominal circumference: are they correlated?
The cheek-to-cheek diameter (CCD) has been shown to be an indicator of subcutaneous tissue mass in the fetus. However, the correlation between CCD and the abdominal circumference (AC) has not been investigated yet. The objective of the present study was to demonstrate whether a correlation exists between fetal CCD, AC, estimated fetal weight (EFW), and the 1 h, 50 g, glucose challenge test (GCT) levels in patients with and without gestational diabetes mellitus. A prospective, institutional review board approved study was performed. The CCD was obtained as part of the ultrasound for obstetric interval growth scans and biophysical profiles. Exams were performed during the third trimester. The CCD was obtained on a coronal view of the fetal face, at the level of the nostrils and lips. Patients were enrolled between November 2005 and May 2006. Pearson correlation coefficient and linear regression modeling were used as appropriate. Eighty-three patients were enrolled, 29 (33%) of them were diabetic. The mean gestational age is 34.8 +/- 3 weeks and the mean maternal age is 29.9 +/- 5.1. A significant linear association was found between CCD and EFW (Pearson coefficient of correlation being 0.51, P = 0.01). The Pearson correlation coefficient of the relationship between the CCD and AC was 0.47 (P = 0.01). Using a linear regression model, controlling for gestational age at performance of the ultrasound, the association between CCD and EFW remained significant (P = 0.021). There were no significant differences between diabetic and non-diabetic patients regarding the CCD (6.2 +/- 0.9 vs. 6.3 +/- 0.9 respectively, P = 0.669) or the EFW (2,527.9 +/- 705 vs. 2,645 +/- 760 g). While AC was significantly correlated with the GCT levels (Pearson coefficient of correlation = 0.46, P = 0.024), no such correlation was demonstrated for CCD (Pearson correlation coefficient = 0.23, P = 0.160). The cheek-to-cheek diameter is significantly correlated to the abdominal circumference and the estimated fetal weight. However, the abdominal circumference has a tighter correlation with the glucose challenge test.


The Risk Factors of Chronic Kidney Disease among Nursing Home Residents.
The prevalence of end-stage renal disease in Taiwan is the highest in the world; haemodialysis accounts for about 7% of the expenditure of the National Health Insurance. Nursing home residents with chronic kidney disease (CKD) have not been identified yet in Taiwan, along with associated risk factors. The objective of this study is to investigate the risk factors of CKD in long-term care facilities in Taiwan and those significantly associated with the presence of CKD. The nursing home residents who received health examination between January and June 2012, age ≥ 55 years, were enrolled in this study. They were categorized into two subgroups according to estimated glomerular filtration rate (eGFR): < 60 and ≥ 60 mL/min. Risk factors were evaluated per recommendations from the National Kidney Foundation: body mass index (BMI), waist circumference, blood pressure, fasting glucose and lipid profile. Metabolic syndrome among the residents was also identified. Fifty-three nursing home residents were enrolled in the final study; 16 (30%) had eGFR below 60 mL/min, and nine (56%) of them had BMI higher than 25 kg/m2. The residents with advanced CKD had significantly higher BMI, triglyceride and lower high-density lipoprotein (HDL). Twelve (75%) had metabolic syndrome. Central obesity was observed in 10 (63%) with advanced CKD. Most of the nursing home elderly with advanced CKD have poor control of associated risk factors, including obesity, hypertension, dyslipidaemia and hyperglycaemia. For them, metabolic syndrome may be a major contributant to the aetiology. Monitoring their BMI and waist circumference is a simple but effective way to suspect the presence of CKD.


Neuropsychological sequelae of arteriovenous malformations.
A total of 24 patients harboring arteriovenous malformations (AVMs) in either the dominant hemisphere (n = 12) or the nondominant hemisphere (n = 12) were examined neuropsychologically. When compared with 24 matched normal control subjects, the AVM patients demonstrated differential degrees of impairment in verbal or visuospatial processing, depending on whether the lesion involved the dominant or nondominant hemisphere. As predicted, most compelling were the findings of cognitive deficit associated with the hemisphere contralateral to the AVM relative to matched normal control subjects. Evidence of higher cortical dysfunction contralateral to the residing AVM is discussed in the context of cerebrovascular steal.


An efficient method for introducing defined lipids into the plasma membrane of mammalian cells.
An efficient method has been devised to introduce lipid molecules into the plasma membrane of mammalian cells. This method has been applied to fuse lipid vesicles with the apical plasma membrane of Madin-Darby canine kidney cells. The cells were infected with fowl plague or influenza N virus. 4 h after infection, the hemagglutinin (HA) spike glycoprotein of the virus was present in the apical plasma membrane of the cells. Lipid vesicles containing egg phosphatidylcholine, cholesterol, and an HA receptor (ganglioside) were then bound to the cells at 0 degrees C. More than 85% of the vesicles were released by external neuraminidase at 0 degrees C or by simply warming the cells to 37 degrees C for 10 s, probably because of the action of the viral neuraminidase at the cell surface. However, when the cells were warmed to 37 degrees C in a pH 5.3 medium for 30 s, 50% of the bound vesicles could no longer be released by external neuraminidase. This only occurred when the HA protein had been cleaved into its HA1 and HA2 subunits. When we used influenza N virus, whose HA is not cleaved in Madin-Darby canine kidney cells, cleavage with external trypsin was required. The fact that the HA protein has fusogenic properties at low pH only in its cleaved form suggests that fusion of the vesicles with the plasma membrane had taken place. Further confirmation for fusion was obtained using an assay based on the decrease of energy transfer between two fluorescent phospholipids in a vesicle upon fusion of the vesicle with the plasma membrane (Struck, D. K., D. Hoekstra, and R. E. Pagano. 1981. Biochemistry, 20:4093-4099).


[Effect of microwave oven over the growth and survival of Escherichia coli O157:H7 inoculated in bovine minced meat samples].
The use of microwave ovens in food industry is a growing trend. It is used for thawing, drying and cooking food, but the microorganism's inactivation that this treatment may exert or not is still a subject of worldwide discussion. At the same time. Escherichia coli O157:H7 now presents itself as an emerging pathogen, distributed worldwide and associated with food. Its resistance to adverse environments has been widely discussed. The purpose of this work was to determine the effect of different times of exposure and cooking intensities of microwave oven on the survival of this bacterium inoculated into minced meat samples. These were inoculated with a high (10(7)-10(9) CFU/mL) or low (10(7)-10(7) CFU/mL) population of E. coli O157:H7, frozen for 3 days at-4 degrees C and thawed in a Whirlpool microwave oven according to their weight. They were radiated at levels of 70%, 80%, 90% and 100% for periods of 30, 60, 90 and 120 seconds. In each sample the rate of survival of the bacteria was determined according to the methodology described by Vanderzant & Splittstoesser. The results obtained showed that the rate of destruction of the bacteria analyzed was significant (p < 0.005). The number of bacteria present in the meat samples diminished dramatically as the exposure time and temperature increased, even though, for the complete elimination of this microorganism, a prolonged exposure was necessary, even though it did cause undesirable organoleptic characteristics in the food samples.


Advanced glycation end product receptor-mediated cellular dysfunction.
Advanced glycation end products (AGEs), S100/calgranulins, and HMGB1 proteins supposedly play a pivotal role in diabetes mellitus and other chronic inflammatory diseases by promoting cellular dysfunction via binding to cellular surface receptors. Particularly, engagement of the receptor for AGEs (RAGE) has gained major attention because it converts short-lasting cellular activation in sustained cellular dysfunction. Consistently, blockade of ligand-RAGE interaction with soluble RAGE (sRAGE) suppresses chronic cellular activation and dysfunction in animal models of chronic diseases. RAGE-/- mice, however, demonstrate that the protection conferred by RAGE deficiency is lower than that mediated by sRAGE. Furthermore, RAGE-/- mice can be protected by sRAGE in certain settings of the adaptive immune response. This finding implies that abounding RAGE ligands overworking the RAGE pathway might also activate other receptors.


Synthesis and selective in vitro anti-melanoma effect of enantiomeric alpha-methyl- and alpha-ethyl-4-S-cysteaminylphenol.
Melanogenesis provides a unique target for the development of antitumour agents specific for malignant melanoma. Among the anti-melanoma compounds we have examined, 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine, was found to have the most promising anti-melanoma effects. To further improve its efficacy as an anti-melanoma agent, we synthesized the R- and S-enantiomers (99% enantiomer excess) of alpha-methyl- 4-S-cysteaminylphenol (alpha-Me-4-S-CAP) and alpha-ethyl- 4-S-cysteaminylphenol (alpha-Et-4-S-CAP) by coupling 4-hydroxythiophenol with the oxazolines obtained from the (R)- and (S)-enantiomers of 2-amino-1-propanol and 2-amino-1-butanol, respectively. The enantiomers of alpha-Me-4-S-CAP and alpha-Et-4-S-CAP were found to be better substrates for tyrosinase than the natural substrate, L-tyrosine. In vitro experiments showed that all four enantiomers were highly cytotoxic to pigmented B16-F1 melanoma cells, the effect being 70-fold and 160-fold greater than that on non-pigmented B16-G4F melanoma cells and 3T3 fibroblasts, respectively. The cytotoxic effect against B16-F1 cells was completely inhibited by phenylthiourea, a tyrosinase inhibitor, or by N-acetyl-L-cysteine, which increases the intracellular reduced glutathione (GSH) level. 4-S-CAP and the enantiomers were taken up into B16-F1 cells at comparable rates, but showed varying rates of GSH depletion that were inversely correlated to the cytotoxicity. These results suggest that the use of enantiomers would increase the efficacy of tyrosinase-dependent cytotoxic phenols.


Outcome of a Resident Spine Surgical Skills Training Program.
Cadaver training lab. To determine if a technical cadaver skills training lab for spinal surgery increases resident confidence, satisfaction in training, and perception of operating room safety. Resident training is an important topic in the setting of work hour reform. The use of supplemental materials such as videos, sawbones, and simulators may become important to adequately train orthopedic residents. At present, there are no established curricula for training orthopedic surgery residents on anatomy and common procedures encountered during a spinal surgery rotation. Residents were assembled into teams of a PGY-5 and PGY-2 and/or PGY-1 to perform dissection and procedures on 5 fresh-frozen spine cadavers. With attending and spine fellow supervision, residents performed anterior cervical, posterior cervical, and posterior thoracolumbar surgical exposure, decompression, and fusion procedures in the operating room using surgical tools and instrumentation. Residents were then queried about their confidence levels, satisfaction in training, and perception of safety using a Likert scale (0-10). Strong agreement (scores ≥8) and strong disagreement (scores ≤3) and correlations were evaluated. Seventeen residents completed the training program (7 PGY-1s, 2 PGY-2s, and 8 PGY-5s). After the training, the majority of residents strongly agreed that they had an increased confidence of their own abilities (59%). A significant majority (65%) of residents strongly agreed that they were satisfied with the benefits provided by the training program. Compared with other methods of education, residents strongly agreed that the training was more helpful than textbook chapters (94%), sawbones (94%), web-based training (94%), or a virtual-based (completely electronic) training (94%). After the training, residents strongly agreed that the training improved feelings of preparation (47%), safety (41%), and ability to prevent intraoperative errors (41%). The vast majority of residents strongly agreed "Before performing surgery on me, I would want a resident to perform this cadaveric training" (88%). These results demonstrate that team-based, cadaveric training with adequate attending supervision, before onset of a spine surgical rotation, may lead to high resident confidence, satisfaction in training, and perception of patient safety.


Genetics of long QT syndrome.
Long QT syndrome (LQTS) is a potentially life-threatening cardiac arrhythmia characterized by delayed myocardial repolarization that produces QT prolongation and increased risk for torsades des pointes (TdP)-triggered syncope, seizures, and sudden cardiac death (SCD) in an otherwise healthy young individual with a structurally normal heart. Currently, there are three major LQTS genes (KCNQ1, KCNH2, and SCN5A) that account for approximately 75% of the disorder. For the major LQTS genotypes, genotype-phenotype correlations have yielded gene-specific arrhythmogenic triggers, electrocardiogram (ECG) patterns, response to therapies, and intragenic and increasingly mutation-specific risk stratification. The 10 minor LQTS-susceptibility genes collectively account for less than 5% of LQTS cases. In addition, three atypical LQTS or multisystem syndromic disorders that have been associated with QT prolongation have been described, including ankyrin-B syndrome, Anderson-Tawil syndrome (ATS), and Timothy syndrome (TS). Genetic testing for LQTS is recommended in patients with either a strong clinical index of suspicion or persistent QT prolongation despite their asymptomatic state. However, genetic test results must be interpreted carefully.


Is it time to revise the nomenclature of Leishmania?
Leishmania is notable for a large number of described species. Molecular phylogenies of Leishmania have increasingly suggested that the number of species could be too large. A recent phylogenetic analysis of the heat-shock protein 70 gene (hsp70) by Fraga and colleagues supports the existence of only eight medically relevant species compared to 17 species as defined by multilocus enzyme electrophoresis. Whether a revised classification system should be introduced for Leishmania is discussed.


β-Lactam Dosing in Critical Patients: A Narrative Review of Optimal Efficacy and the Prevention of Resistance and Toxicity.
Antimicrobial prescription in critically ill patients represents a complex challenge due to the difficult balance between infection treatment and toxicity prevention. Underexposure to antibiotics and therapeutic failure or, conversely, drug overexposure and toxicity may both contribute to a worse prognosis. Moreover, changes in organ perfusion and dysfunction often lead to unpredictable pharmacokinetics. In critically ill patients, interindividual and intraindividual real-time β-lactam antibiotic dose adjustments according to the patient's condition are critical. The continuous infusion of β-lactams and the therapeutic monitoring of their concentration have both been proposed to improve their efficacy, but strong data to support their use are still lacking. The knowledge of the pharmacokinetic/pharmacodynamic targets is poor and is mostly based on observational data. In patients with renal or hepatic failure, selecting the right dose is even more tricky due to changes in drug clearance, distribution, and the use of extracorporeal circuits. Intermittent usage may further increase the dosing conundrum. Recent data have emerged linking overexposure to β-lactams to central nervous system toxicity, mitochondrial recovery delay, and microbiome changes. In addition, it is well recognized that β-lactam exposure facilitates resistance selection and that correct dosing can help to overcome it. In this review, we discuss recent data regarding real-time β-lactam antibiotic dose adjustment, options in special populations, and the impacts on mitochondria and the microbiome.


Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS-Hemo project.
The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation. Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78 years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated. Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02 IU/mL, respectively. The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles.


Multiple origins of Ashkenazi Levites: Y chromosome evidence for both Near Eastern and European ancestries.
Previous Y chromosome studies have shown that the Cohanim, a paternally inherited Jewish priestly caste, predominantly share a recent common ancestry irrespective of the geographically defined post-Diaspora community to which they belong, a finding consistent with common Jewish origins in the Near East. In contrast, the Levites, another paternally inherited Jewish caste, display evidence for multiple recent origins, with Ashkenazi Levites having a high frequency of a distinctive, non-Near Eastern haplogroup. Here, we show that the Ashkenazi Levite microsatellite haplotypes within this haplogroup are extremely tightly clustered, with an inferred common ancestor within the past 2,000 years. Comparisons with other Jewish and non-Jewish groups suggest that a founding event, probably involving one or very few European men occurring at a time close to the initial formation and settlement of the Ashkenazi community, is the most likely explanation for the presence of this distinctive haplogroup found today in >50% of Ashkenazi Levites.


Corneal Segmentation Analysis Increases Glaucoma Diagnostic Ability of Optic Nerve Head Examination, Heidelberg Retina Tomograph's Moorfield's Regression Analysis, and Glaucoma Probability Score.
Purpose. To study whether a corneal thickness segmentation model, consisting in a central circular zone of 1 mm radius centered at the corneal apex (zone I) and five concentric rings of 1 mm width (moving outwards: zones II to VI), could boost the diagnostic accuracy of Heidelberg Retina Tomograph's (HRT's) MRA and GPS. Material and Methods. Cross-sectional study. 121 healthy volunteers and 125 patients with primary open-angle glaucoma. Six binary multivariate logistic regression models were constructed (MOD-A1, MOD-A2, MOD-B1, MOD-B2, MOD-C1, and MOD-C2). The dependent variable was the presence of glaucoma. In MOD-A1, the predictor was the result (presence of glaucoma) of the analysis of the stereophotography of the optic nerve head (ONH). In MOD-B1 and MOD-C1, the predictor was the result of the MRA and GPS, respectively. In MOD-B2 and MOD-C2, the predictors were the same along with corneal variables: central, overall, and zones I to VI thicknesses. This scheme was reproduced for model MOD-A2 (stereophotography along with corneal variables). Models were compared using the area under the receiver operator characteristic curve (AUC). Results. MOD-A1-AUC: 0.771; MOD-A2-AUC: 0.88; MOD-B1-AUC: 0.736; MOD-B2-AUC: 0.845; MOD-C1-AUC: 0.712; MOD-C2-AUC: 0.838. Conclusion. Corneal thickness variables enhance ONH assessment and HRT's MRA and GPS diagnostic capacity.


Evolutionary history of the GABA transporter (GAT) group revealed by marine invertebrate GAT-1.
The GABA transporter (GAT) group is one of the major subgroups in the solute career 6 (SLC6) family of transmembrane proteins. The GAT group, which has been well studied in mammals, has 6 known members, i.e., a taurine transporter (TAUT), four GABA transporters (GAT-1, -2, -3, - 4), and a creatine transporter (CT1), which have important roles in maintaining physiological homeostasis. However, the GAT group has not been extensively investigated in invertebrates; only TAUT has been reported in marine invertebrates such as bivalves and krills, and GAT-1 has been reported in several insect species and nematodes. Thus, it is unknown how transporters in the GAT group arose during the course of animal evolution. In this study, we cloned GAT-1 cDNAs from the deep-sea mussel, Bathymodiolus septemdierum, and the Antarctic krill, Euphausia superba, whose TAUT cDNA has already been cloned. To understand the evolutionary history of the GAT group, we conducted phylogenetic and synteny analyses on the GAT group transporters of vertebrates and invertebrates. Our findings suggest that transporters of the GAT group evolved through the following processes. First, GAT-1 and CT1 arose by tandem duplication of an ancestral transporter gene before the divergence of Deuterostomia and Protostomia; next, the TAUT gene arose and GAT-3 was formed by the tandem duplication of the TAUT gene; and finally, GAT-2 and GAT-4 evolved from a GAT-3 gene by chromosomal duplication in the ancestral vertebrates. Based on synteny and phylogenetic evidence, the present naming of the GAT group members does not accurately reflect the evolutionary relationships.


The COP9 signalosome.
The COP9 signalosome (CSN) is composed of eight distinct subunits and is highly homologous to the lid sub-complex of the 26S proteasome. CSN was initially defined as a repressor of photomorphogenesis in Arabidopsis, and it has now been found to participate in diverse cellular and developmental processes in various eukaryotic organisms. Recently, CSN was revealed to have a metalloprotease activity centered in the CSN5/Jab1 subunit, which removes the post-translational modification of a ubiquitin-like protein, Nedd8/Rub1, from the cullin component of SCF ubiquitin E3 ligase (i.e., de-neddylation). In addition, CSN is associated with de-ubiquitination activity and protein kinase activities capable of phosphorylating important signaling regulators. The involvement of CSN in a number of cellular and developmental processes has been attributed to its control over ubiquitin-proteasome-mediated protein degradation.


Sustained antiretroviral treatment adherence in survivors of the pre-HAART era: attitudes and beliefs.
The objective of this study was to assess adherence of HIV-1-infected patients who started treatment in the pre-HAART era and to determine variables associated with better adherence, including relevant attitudes and beliefs. This is a cross-sectional study enrolling patients who had received antiretroviral therapy for >or=10 years. Adherence was evaluated through self-reporting and plasma drug concentrations. Treatment variables, attitudes and beliefs were collected during structured interviews. The results show that for 87 patients the median (interquartile range) time on therapy was 13 (10-19) years; 80 were on therapy at the time of analysis. Adherence was >or=95% in 54 patients (67.5%), 90-94% in 22 (27.5%) and <90% in 4 (5%). Drug concentrations were below the lower limit of detection in five patients. Younger age (p=0.014), female gender (p=0.005), current substance abuse (p=0.004) and hepatitis C virus co-infection (p<0.001) were related to lower adherence. Adherence did not differ in relation to different drug families or once- or twice-daily regimens. Patients with adherence <95% were more likely to have interrupted treatment without doctor's recommendation (p=0.009). Adherent patients exhibited a higher perception of risk of developing the illness and of benefits of therapy, higher self-efficacy and intention to adhere and were more influenced by events that motivate medication intake. To conclude, adherence was >90% in most patients on antiretroviral therapy for >or=10 years. Adherence was more related to beliefs about health and illness than to the characteristics of medication or level of knowledge about treatment. Care adherence interventions should include assessment of health beliefs.


Programmatic aspects of dropouts in child vaccination in Bangladesh: findings from a prospective study.
The present study investigated prospectively programmatic factors relating to dropouts in child vaccination in 6 subdistricts of Bangladesh. A cross-sectional survey (n = 2700) was conducted estimating overall coverage of immunization using cluster sampling. The eligible subsample of children (n = 1064) was followed up prospectively to understand reasons for dropouts. In-depth interviews (n = 73) with mothers/caregivers and service providers were done and EPI (Expanded Programme on Immunization) sessions were observed (n = 131). Irregular EPI sessions were the prime cause of dropouts particularly in low-performing subdistricts. The other programmatic factors linked with dropouts were (a) no reminder about subsequent session/doses, (b) unfriendly behavior or absence of vaccinator, ( c) refusal due to lost card or vaccine exhausted, and (d) short duration of sessions. Providers highlighted constraints such as financial problems for transportation, particularly in the hard-to-reach areas and vacancies of the posts of health assistants. The barriers to completing full schedules of vaccination can be removed to a large extent through programmatic adjustments.


Advantages of high cell concentration prior to cryopreservation of initial leukapheresis in CAR-T cell therapy.
Chimeric antigen receptor (CAR) T-cell therapy is increasingly used in patients affected by B-cell lymphoma and acute lymphoblastic leukemia. For logistical reasons, initial apheresis products may be cryopreserved for shipment to manufacturing centers. Due to the characteristics of these patients, cells are often collected in large volumes, meaning more bags must be cryopreserved. This requires increased storage, time and monetary costs. In this context, we aimed to evaluate a high cell concentration cryopreservation protocol by centrifugation to standardize the initial CAR-T manufacturing procedure. Sixty-eight processes of leukapheresis of 57 patients affected by refractory/relapsed B cell lymphoma and 9 patients affected by acute lymphoblastic leukemia who were eligible for anti-CD19 CAR-T cell treatment performed between June 2019 and October 2022 were analyzed. Whole blood count, percentage and number of T cells were assessed on the apheresis final product. The apheresis product, which was alternatively stored overnight at 4°C, was centrifuged, adjusting the volume to approximately 40 mL. The product was immediately cryopreserved to achieve a final cell concentration of 50-200×106 cells/ml for cryopreservation. Leukapheresis volume was reduced by almost fivefold (median: 185 to 40 mL), resulting in a higher product concentration in one bag. In addition, the number of non-target cells (monocytes, platelets and erythrocytes) was also reduced during the development of CAR T cell therapy, thereby maintaining T lymphocyte levels and providing a purer starting material. The advantages of the protocol include reducing economic costs, saving storage space, simplifying the manufacturing process, and facilitating shipping logistics. In conclusion, we present a validated, simple, and cost-effective cell enrichment processing protocol that provides high-quality cryopreserved products as starting material for the CAR-T cell manufacturing process.


Syntrophothermus lipocalidus gen. nov., sp. nov., a novel thermophilic, syntrophic, fatty-acid-oxidizing anaerobe which utilizes isobutyrate.
A new anaerobic, thermophilic, syntrophic, fatty-acid-oxidizing bacterium designated strain TGB-C1T was isolated from granular sludge in a thermophilic upflow anaerobic sludge blanket (UASB) reactor. The cells were slightly curved rods and were weakly motile. Spore formation was not observed. The optimal temperature for growth was around 55 degrees C and growth occurred in the range 45 to 60 degrees C. The pH range for growth was 5.8-7.5, and the optimum pH was 6.5-7.0. Crotonate was the only substrate that allowed the strain to grow in pure culture. However, in co-culture with the thermophilic, hydrogenotrophic Methanobacterium thermoautotrophicum strain delta H, the isolate could syntrophically oxidize saturated fatty acids with 4-10 carbon atoms, including isobutyrate. During the degradation of isobutyrate by the co-culture, isobutyrate was isomerized to butyrate, which was then oxidized. The strain was not able to utilize sulfate, sulfite, thiosulfate, nitrate, fumarate or Fe(III) as electron acceptor. The DNA base composition was 51.0 mol%. 16S rDNA sequence analysis revealed that the strain belongs to the family Syntrophomonadaceae, but it was only distantly related to other known species of beta-oxidizing syntrophs. Hence, the name Syntrophothermus lipocalidus is proposed for TGB-C1T as a new species of a new genus.


Overcoming barriers to diabetes care in the hospital: The power of qualitative observations to promote positive change.
Despite advocacy by diabetes societies and evidence about how to prevent the deleterious consequences of dysglycemia among hospitalized patients, deficits in clinical practice continue to present barriers to care. The purpose of this study was to examine inpatient rounding practices using a qualitative research lens to assess challenges on the care of hospitalized patients with diabetes and to develop ideas for positive changes in hospital management of diabetes and hyperglycemia. We conducted an interpretive analysis of qualitative observations during medical and surgical inpatient rounds at an academic institution. We coded, analysed, and reported data as thematic findings. Emerging themes include omissions in discussions during rounds; unpreparedness to address diabetes or dysglycemia during rounds; identifying practice improvement opportunities to address diabetes issues: and recognizing accountability within the routine of practice. This work guides clinicians and informs systems of practice about improvement strategies that can emerge from within hospital teams. These recommendations emphasize the interconnectedness of practice elements including thoughtful review of glucose status during rounds among patients with and without diabetes; fostering doctors and nurses to work in unison; promoting awareness and integration within and across disciplines; and advocating for better use of existing resources.


Activation of the extracellular signal-regulated kinases signaling pathway in squamous cell carcinoma of the skin.
Activation of the extracellular signal-regulated kinase (ERK) pathway is involved in many human tumors. Little is known about the role of activated ERK1/2 in squamous cell carcinoma (SCC) of the skin. In this study, the expression and distribution of phosphorylated ERK (p-ERK) in normal human skin and SCC with different degrees of differentiation was examined by immunohistochemical analysis using formalin-fixed paraffin embedded sections. PD98059, a specific ERK pathway inhibitor, was used to evaluate the effect a blockade of ERK activation has on the proliferation of a cutaneous SCC cell line (DJM-1) in culture. In this study, p-ERK 1/2 positive staining was observed in all cases of SCC examined but rarely in the control specimens of normal skin. Moreover, the expression of p-ERK1/2 was significantly higher in poorly differentiated SCC in comparison to well-differentiated ones. Expression levels were positively associated with the degree of malignancy and proliferative activity of SCC. In contrast, inhibition of ERK pathway signaling markedly suppressed tumor cell proliferation. These results suggest that ERK1/2 signal pathways play an important role in the proliferation of SCC and that the inhibition of this signal pathway may be effective in the treatment of cutaneous SCC.


Management issues in chronic viral hepatitis: hepatitis C.
The natural history of chronic hepatitis C virus (HCV) infection and intervention with antiviral therapy are closely linked issues that cause the greatest controversy and concern for the person infected with HCV, as well as for the clinician involved in the assessment and treatment of people with chronic HCV infection. The outstanding challenge of natural history is to identify the person who is likely to develop serious liver disease, and to make that determination early in the course of chronic HCV infection when treatment is likely to be of the greatest benefit. Significant advances in the therapy of chronic HCV infection have occurred over the past decade. A sustained virological response (SVR), defined as undetectable HCV-RNA in blood 6 months after completing antiviral treatment, is the best indicator of a beneficial treatment effect. Relapse, breakthrough or non-response should all be regarded as unsuccessful outcomes of therapy. Interferons are still the mainstay of antiviral therapy for chronic HCV infection. The combination of interferon and ribavirin has improved SVR by decreasing the relapse rate. Treatment responses vary according to host factors such as age and gender, fibrotic severity and to viral factors like genotype and viral load. Patients with genotype 1 HCV and a high viral load require 12 months of treatment to achieve a SVR in approximately 30%, compared to those with genotypes 2 or 3 who achieve a SVR in approximately 65% after 6 months. Patients who relapse after an end-of-treatment response to interferon monotherapy have a good chance of responding to combination interferon and ribavirin given for 6 months, but a longer treatment course should be considered in less optimal cases. At present, the treatment of those with non-response is less clear, but there is interest in more intense forms of interferon therapy, such as induction dosing or pegylated interferon in combination with ribavirin. Clinicians need to be aware of the common side-effects of interferon and ribavirin so that appropriate counseling and testing can be instituted before and during therapy. The combination of pegylated interferon and ribavirin will be the new standard of therapy for hepatitis C and pegylated interferon monotherapy provides quite acceptable efficacy for those patients intolerant of ribavirin. Current data strongly support the concept that SVR in HCV infection (or treatment-induced latency) provides a cure in terms of its beneficial effects on quality of life and sustained amelioration of liver injury.


A 115,000-year-old expedient bone technology at Lingjing, Henan, China.
Activities attested since at least 2.6 Myr, such as stone knapping, marrow extraction, and woodworking may have allowed early hominins to recognize the technological potential of discarded skeletal remains and equipped them with a transferable skillset fit for the marginal modification and utilization of bone flakes. Identifying precisely when and where expedient bone tools were used in prehistory nonetheless remains a challenging task owing to the multiple natural and anthropogenic processes that can mimic deliberately knapped bones. Here, we compare a large sample of the faunal remains from Lingjing, a 115 ka-old site from China which has yielded important hominin remains and rich faunal and lithic assemblages, with bone fragments produced by experimentally fracturing Equus caballus long bones. Our results provide a set of qualitative and quantitative criteria that can help zooarchaeologists and bone technologists distinguish faunal remains with intentional flake removal scars from those resulting from carcass processing activities. Experimental data shows marrow extraction seldom generates diaphyseal fragments bearing more than six flake scars arranged contiguously or in interspersed series. Long bone fragments presenting such characteristics can, therefore, be interpreted as being purposefully knapped to be used as expediency tools. The identification, based on the above experimental criteria, of 56 bone tools in the Lingjing faunal assemblage is consistent with the smaller size of the lithics found in the same layer. The continuity gradient observed in the size of lithics and knapped bones suggests the latter were used for tasks in which the former were less or not effective.


Variations in mortality of the coloured, white and Asian population groups in the RSA, 1978-1982. Part V. Hypertensive diseases.
An analysis was undertaken of mortality from hypertensive disease in the RSA between 1978 and 1982 among whites, coloureds and Asians. The age-specific mortality rates for each group are presented and comparisons are also made between these groups based on age-standardised mortality rates. As with a similar study undertaken for the period 1969-1971, marked variations are seen between the various population groups. The rates for Asians exceeded those for coloureds substantially, and both these groups had far higher rates than whites. These results demonstrate an interesting variation when compared with mortality from ischaemic heart disease and recent prevalence studies of hypertension. The possibility that this variation is due to better control of hypertension in whites or is a result of a different ratio of risk factors in each group studied is considered.


Experiments in text recognition with the modified viterbi algorithm.
In this paper a modification of the Viterbi algorithm is formally described, and a measure of its complexity is derived. The modified algorithm uses aheuristic to limit the search through a directed graph or trellis. The effectiveness of the algorithm is investigated via exhaustive experimentation on an input of machine-printed text. The algorithm assumes language to be a Markov chain and uses transition probabilities between characters. The results empirically answer the long-standing question of what is the benefit, if any, of using transition probabilities that depend on the length of a word and their position in it.


Comparison of five tests for the detection of antibodies against chlamydial (enzootic) abortion of ewes.
Five tests for antibodies against chlamydial (enzootic) abortion of ewes were compared using 255 sera from experimentally (group 1) or naturally (group 2) infected animals, flocks free of the disease (group 3) and individual animals testing positively by the complement fixation test but from flocks with no evidence of chlamydial abortion (group 4). Sera from five specific pathogen-free lambs vaccinated with two different subtypes of Chlamydia pecorum were also included (group 5). All tests used some form of processed culture of C psitiaci as antigen. Specificities, established with group 3 and 4 sera, ranged between 96 per cent (ELISA using lipopolysaccharide antigen) and 59 per cent (Immunocomb). Reactions with group 5 sera suggested that the cause of false positive results in the field might be cross-reactive antibodies against the arthritogenic subtype of C pecorum. Sensitivities, established with groups 1 and 2 sera, ranged between 81 per cent (Immunocomb) and 51 per cent (ELISA using solubilised protein antigen). The minimum sample sizes required to be 95 per cent certain of detecting at least five seropositives in two infected flocks (combined data) were 15 to 48, dependent on the test applied. The Western blot test, applied to a proportion of samples, yielded no false positives with group 3 sera but 31.7 per cent with group 4 sera. Thus, none of the tests in this comparison emerged as sufficiently satisfactory in all respects, suggesting that further improvements in chlamydial serology must come through the use of non-native antigens or in the form of a competitive ELISA.


Neural activity of inferences during story comprehension.
In this event-related functional magnetic resonance imaging (fMRI) study, participants listened to and comprehended short stories implying or explicitly stating inference events. The aim of this study was to examine the neural mechanisms that underlie inference generation, a process essential to successful comprehension. We observed distinct patterns of increased fMRI signal for implied over explicit events at two critical points during the stories: (1) within the right superior temporal gyrus when a verb in the text implied the inference; and (2) within the left superior temporal gyrus at the coherence break or when participants need to generate an inference to understand the story. To find the most compelling evidence of neural activity during inference generation, we examined fMRI signal at these two critical points separately for people with high working memory capacity (i.e., those individuals who are most likely to draw inferences during text comprehension). Interestingly, high working memory individuals showed greater fMRI signal for implied than explicit events in the left inferior frontal gyrus at the coherence break compared to low working memory individuals. This present study provides evidence that areas within the superior temporal gyrus and inferior frontal gyrus are heavily recruited when individuals generate inferences, even during ongoing comprehension that demands many cognitive processes. In addition, the data suggest that the right hemisphere superior temporal gyrus is particularly involved during early inferential processing, whereas the left hemisphere superior temporal gyrus is particularly involved during later inferential processing in story comprehension.


The effect of chronic CRF1 receptor blockade on the central CCK systems of Fawn-Hooded rats.
Corticotropin-releasing factor (CRF) is a neuropeptide associated with the integration of physiological and behavioural responses to stress. More recently, the CRF system has been implicated in the modulation of affective state and in the actions of abused drugs, including ethanol. As such, we have previously demonstrated that the selective, centrally acting CRF(1) receptor antagonist antalarmin displays an acute anxiolytic action and reduces established volitional ethanol consumption in isolation-reared Fawn-Hooded rats [Neuroscience 117 (2003) 243]. Similar to CRF, CCK is a neuropeptide found in high abundance throughout the neuraxis and is involved in the control of appetite, anxiety, reward and hormone regulation. Given the similar functions regulated by the neuropeptides CRF and CCK, it is of importance to determine whether interactions exist between these neuropeptides. Therefore, the aim of the present study was to examine the effects of chronic CRF(1) receptor blockade on the central CCK systems of Fawn-Hooded (FH) rats. Thus, bi-daily antalarmin treatment (20 mg/kg ip) induced a significant increase in CCK-B receptor-binding density throughout the neuraxis, indicative of either a global increase in receptor number or an increase in receptor affinity. In contrast, chronic antalarmin treatment resulted in bidirectional, region-specific changes in preproCCK messenger ribonucleic acid (mRNA) expression. Interestingly, this effect on CCK mRNA expression was restricted to the thalamocortico-limbic system, which is intimately involved in the integration of emotive behaviour and central reward processing. Therefore, these data provide clear evidence of the ability of chronic CRF(1) receptor blockade to significantly influence the central CCK systems of the rat.


The role of uveal and retinal antigens in experimental autoimmune ocular pathology.
Guinea pigs immunized with retina antigen, located by immunofluorescence in the photoreceptor cell layers, develop retina-specific immune responses and autoimmune uveoretinitis. Ocular pathology is characterized by cellular infiltration and destruction of the photoreceptor cells subsequent to inflammation of the iris, ciliary body and choroid. Guinea pigs immunized with homologous choroid antigen, localized by immunofluorenscence in the area of Bruch's membrane or pigment epithelium, developed choroiditis, subretinal exudation and loss of photoreceptor outer segments. The pathology is associated with immune responses directed primarily against antigens recovered with choroid, but which demonstrated partial cross reactions with outer segment antigens. Possible relationship of uveal and retinal antigens is discussed.


Two-dimensional shear-wave elastography: a new method comparable to acoustic radiation force impulse imaging?
Two-dimensional shear-wave elastography (2D-SWE) is an ultrasound-based technique for the noninvasive assessment of tissue stiffness. In contrast to the well-established point-shear-wave elastography (pSWE) method acoustic radiation force impulse imaging, there is little evidence on the performance and usefulness of 2D-SWE in the assessment of liver stiffness. Thus, the aim of our study was to compare 2D-SWE versus pSWE. 2D-SWE and pSWE were performed in 20 cirrhotic patients, 20 healthy individuals and an elasticity phantom. Stiffness values, examination time and number of measurements were compared. For 2D-SWE, the influence of size of the region of interest (ROI) was assessed. Elastography values in healthy individuals were slightly higher for 2D-SWE versus pSWE (1.4 m/s, range: 1.21-1.68 vs. 1.23 m/s, range: 1.07-1.39). In cirrhotic patients, there were no significant differences (3.06 m/s, range: 1.83-5.35 vs. 3 m/s, range: 1.67-4.37 m/s). Examination times were significantly longer for 2D-SWE in both patient groups (mean values for healthy/cirrhotic patients: 129.6/157.1 vs. 75/71.6 s). For 2D-SWE, variation of ROI size (5, 10, 20 mm) produced comparable results. After eight measurements, 90% of cirrhotic patients showed less than 5% of deviation from the results after the gold standard of 10 measurements; for healthy individuals, this was observed after six measurements. 2D-SWE seems to be comparable to pSWE (acoustic radiation force impulse-imaging) in cirrhotic patients, with slightly higher values in healthy individuals. 2D-SWE measurements require considerably more time. For 2D-SWE, ROI size seems to be of minor importance; multiple measurements should be obtained as single measurements differ. These preliminary results should be confirmed in larger patient collectives with histology as the reference standard.


[Tubular bone structure in residents of the Krasnoiarsk region].
Using osteoscopic, osteometric, radiographic and chemical methods, a study of long tubular bones (tibia) was performed to compare their parameters in Krasnoyarsk men that lived in XVII-XVIII centuries (50 observations) and at present time (30 observations). Main regularities of their variability were established taking into account the factor of time. Bones of modern men were found to have more expressed relief, greater values of osteometric parameters, among which the increase of longitudinal parameters was prevalent over the increase of width parameters and perimeters. The incidence of diaphyseal cross-sectional forms flattened in medial plane was increased, while the degree of bone mineralization was reduced with the appearance of a tendency towards decline of strength index. The data obtained demonstrate the gracilization of the skeleton of the modern city population and permit to distinguish the regional peculiarities of its variability.


Social support and health promotion outcomes of adults with psoriasis.
Illness and health behavior, social support, and health promotion outcomes (time of recovery from an acute illness episode and psychosocial adjustment to illness) were investigated in 44 adults with psoriasis. Illness behavior was significantly associated with shortened recovery time.


Perioperative antibiotic prophylaxis for prevention of postoperative neurosurgical infections. A randomized clinical trial.
The authors report the results of a randomized, prospective study to assess the effectiveness of perioperative antibiotic prophylaxis in preventing postoperative infections following clean neurosurgical operations. The study group comprised 846 patients treated between October, 1979, and June, 1984. Antibiotics, including cefazolin and gentamicin, were administered only in the immediate preoperative and intraoperative periods. Sixteen patients, none of whom developed infections, were excluded from final statistical analysis because they had inadvertently been entered into the study while failing to meet entry criteria. Fifteen wound infections (3.64%) developed in the group of 412 patients who did not receive antibiotics, whereas only four infections (0.96%) were identified among the 418 patients who received antibiotics. The difference is statistically significant (p = 0.008) and represents a 74% reduction in infection rate with antibiotics. An analysis of subgroups of surgical procedures revealed a dramatic decrease in craniotomy infections from 6.77% to 0% (p = 0.003). Of the four infections that occurred among the antibiotic-treated patients, three were in cases where foreign bodies had been implanted. No complications of antibiotic usage were identified. The rates of infection in areas of the body other than the surgical wound were no different in the antibiotic-treated and nontreated groups. All wound infections in both antibiotic-treated and nontreated patients involved similar types of Gram-positive organisms, suggesting that antibiotic prophylaxis did not produce infections with resistant or unusual organisms. This study, combined with other recently published analyses, suggests that routine perioperative antibiotic prophylaxis can significantly reduce the incidence of postoperative neurosurgical infections.


Cognitive biases, dark patterns, and the 'privacy paradox'.
Scholars and commentators often argue that individuals do not care about their privacy, and that users routinely trade privacy for convenience. This ignores the cognitive biases and design tactics platforms use to manipulate users into disclosing information. This essay highlights some of those cognitive biases - from hyperbolic discounting to the problem of overchoice - and discusses the ways in which platform design can manipulate disclosure. It then explains how current law allows this manipulative and anti-consumer behavior to continue and proposes a new approach to reign in the phenomenon.


Antibiotic resistances and plasmids in Staphylococcus aureus from Italian hospitals.
A total of 473 Staphylococcus aureus isolates from six Italian hospitals was examined for susceptibility to several antimicrobial agents and for plasmid content. Methicillin-resistant S. aureus (MRSA) were characterised by a plasmid of mol. wt (10(6)) 18-22 or 25 that carried the determinants for penicillinase production, resistance to cadmium ions and resistance to tetracycline. MRSA isolates usually harboured other smaller plasmids of mol. wt (10(6)) 2.8, 2.6 and 1.65 that encoded resistance to tetracycline, chloramphenicol and erythromycin, respectively, and cryptic plasmids of mol. wt (10(6)) c. 2 and 1 were found frequently. Methicillin-sensitive S. aureus (MSSA) that produced penicillinase often carried plasmids of mol. wt (10(6)) 11 or 13. No particular difference was found in plasmid patterns of strains from the various sources. Analysis of plasmids by EcoRI digestion showed that plasmids of similar mol. wt and phenotypic characteristics may have different restriction patterns, but often share one or more fragments in common.


Depletion of polyamines and increase of transforming growth factor-beta1, c-myc, collagen-type I, matrix metalloproteinase-1, and metalloproteinase-2 mRNA in primary human gingival fibroblasts.
The polyamines spermidine, spermine, and putrescine are known to be deeply linked with growth processes, gene expression, and extracellular matrix synthesis. Their cellular content depends primarily on the activity of the enzyme ornithine decarboxylase. High levels of ornithine decarboxylase and polyamines have been found in proliferative, inflammatory, and neoplastic pathologies of the oral cavity and in gingival fluid. Difluoromethylornithine (DFMO) selectively inhibits ornithine decarboxylase, thus depleting polyamine content and preventing cell proliferation and synthesis activity. The aim of this study was to investigate whether DFMO treatment could modify the genes involved in cell proliferation and extracellular matrix turnover. Fibroblasts derived from non-inflamed gingiva were maintained in Dulbecco's modified Eagle's medium (DMEM) plus alpha-difluoromethylornithine for 4 days. At 0, 24, 48, 72, and 96 hours cell number was assessed, polyamine levels were quantified with high performance liquid chromatography (HPLC) method, and transforming growth factor-beta1 (TGF-beta1), c-myc, matrix metalloproteinases (MMP)-1 and 2, collagen type I (COL-I) and tissue inhibitor of matrix metalloproteinases (TIMP)-1 were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Fibroblasts treated with DFMO significantly decreased cell proliferation, ornithine decarboxylase activity, and putrescine levels at all treatment times, spermidine after 72 and 96 hours, and spermine after 96 hours of culture. Total polyamines decreased (P < or =0.01) at 96 hours after DFMO treatment, while c-myc, TGF-beta1, MMP-1 and 2, COL-I mRNA significantly increased. Conversely, TIMP-1 did not show any significant change. The polyamines trend was not correlated to c-myc, TGF-beta1, MMP-1 and -2, and TIMP-1 mRNA levels. Transforming growth factor-beta1 and c-myc mRNA expression were related and correlated to MMP-1 and 2, COL-I and TIMP-1 mRNA trend after DFMO treatment. Our data show that as the polyamine content decreases, TGF-beta1, c-myc, MMP-1 and -2, and COL-I mRNA levels increase, therefore a negative regulatory role of the polyamines on the mRNA expression could be suggested.


Ultrascalable Multifunctional Nanoengineered Copper and Aluminum for Antiadhesion and Bactericidal Applications.
Biofouling disrupts the surface functionality and integrity of engineered substrates. A variety of natural materials such as plant leaves and insect wings have evolved sophisticated physical mechanisms capable of preventing biofouling. Over the past decade, several reports have pinpointed nanoscale surface topography as an important regulator of surface adhesion and growth of bacteria. Although artificial nanoengineered features have been used to create bactericidal materials that kill adhered bacteria, functional surfaces capable of synergistically providing antiadhesion and bactericidal properties remain to be developed. Furthermore, fundamental questions pertaining to the need for intrinsic hydrophobicity to achieve bactericidal performance and the role of structure length scale (nano vs micro) are still being explored. Here, we demonstrate highly scalable, cost-effective, and efficient nanoengineered multifunctional surfaces that possess both antiadhesion and bactericidal properties on industrially relevant copper (Cu) and aluminum (Al) substrates. We characterize antiadhesion and bactericidal performance using a combination of scanning electron microscopy (SEM), atomic force microscopy (AFM), live/dead bacterial staining and imaging, as well as solution-phase and Petrifilm measurements of bacterial viability. Our results showed that nanostructures created on both Cu and Al were capable of physical deformation of adhered Escherichia coli bacteria. Bacterial viability measurements on both Cu and Al indicated a complex interaction between the antiadhesion and bactericidal nature of these materials and their surface topography, chemistry, and structure. Increased superhydrophobicity greatly decreased bacterial adhesion while not significantly influencing surface bactericidal performance. Furthermore, we observed that more densely packed nanoscale structures improved antiadhesion properties when compared to larger features, even over extended time scales of up to 24 h. Our data suggests that the superhydrophobic Al substrate possesses superior antiadhesion and bactericidal effects, even over long time courses. The techniques and insights presented here will inform future work on antiadhesion and bactericidal multifunctional surfaces and enable their rational design.


Diagnosis and management of potentially malignant oral disorders.
The optimum management strategy for potentially malignant disorders remains a constant challenge as our present knowledge is still short of being conclusive. In spite of its shortcomings as an accurate predictive marker, the assessment of the severity of epithelial dysplasia continues to be useful in risk assessment. It is important to use a combination of epidemiological, clinical and histopathological input when deciding on the most appropriate management for an individual patient. Advanced research exploring molecular markers for diagnosis and risk predictions appear to be promising. However, these tests have not evolved to a stage that they could be used for routine diagnostics at the clinical setting.


User-Centered Design of a Controller-Free Game for Hand Rehabilitation.
The purpose of this study was to develop and test a hand therapy game using the Microsoft (Redmond, WA) Kinect(®) sensor with a customized videogame. Using the Microsoft Kinect sensor as an input device, a customized game for hand rehabilitation was developed that required players to perform various gestures to accomplish a virtual cooking task. Over the course of two iterative sessions, 11 participants with different levels of wrist, hand, and finger injuries interacted with the game in a single session, and user perspectives and feedback were obtained via a questionnaire and semistructured interviews. Participants reported high levels of enjoyment, specifically related to the challenging nature of the game and the visuals. Participant feedback from the first iterative round of testing was incorporated to produce a second prototype for the second round of testing. Additionally, participants expressed the desire to have the game adapt and be customized to their unique hand therapy needs. The game tested in this study has the potential to be a unique and cutting edge method for the delivery of hand rehabilitation for a diverse population.


Impact of computed tomography (CT)-derived fractional flow reserve on reader confidence for interpretation of coronary CT angiography.
To assess the impact of computed tomography-derived fractional flow reserve (FFRCT) on reader confidence and reader time for interpretation of coronary computed tomography angiography (CCTA). This IRB-approved, HIPAA-compliant, consent waivered, quality-improvement study included 50 patients (23 women, age 67 ± 12years, body mass index 28.7 ± 5.3 kg/m2). CCTA was acquired on 2nd and 3rd generation dual-source MDCT with use of beta-blockers and nitroglycerin, and FFRCT was calculated (HeartFlow,Redwood City,CA). Two readers with experience level COCATS2 (Core- Cardiology-Training-Symposium) and two with COCATS3 assessed severity of epicardial coronary artery disease (CAD) using CCTA alone and CCTA with FFRCT. Reader confidence for CAD and hemodynamically significant stenosis (HS) was rated on a 4-point Likert-scale (1=high, 2=good, 3=limited, 4=none) for the four major epicardial coronary artery (CA) vessels. Time to interpret was recorded. The severity of CAD in the cohort population was CAD-RADS1 (Coronary-Artery-Disease Reporting-and-Data-System) n = 15, CAD-RADS2 n = 8, CAD-RADS3 n = 11, and CAD-RADS4A n = 16. Sixty-three CA in 30 patients had minimal FFRCT values ≤0.8. Reader confidence when using FFRCT increased for CAD and HS (p = 0.0001) with a reduction of "non-confident" patient reads (rank 3&4) by 27% and 75%, respectively. The change in confidence was not associated with CAD-RADS (p = 0.1) but correlated with reader experience (p < 0.001). The median time-to-read a CCTA study decreased by 5 min when FFRCT was available (p < 0.001). Interpretation of CCTA in conjunction with FFRCT improved reader for assessment of severity of CAD and HS with reduction of "non-confident" reads and decreased the median time-to-interpretation of a CCTA.


Cellular factors modulating the mechanism of tau protein aggregation.
Pathological accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles, is a major hallmark of Alzheimer's disease, the most prevalent neurodegenerative condition worldwide. In addition to Alzheimer's disease, a number of neurodegenerative diseases, called tauopathies, are characterized by the accumulation of aggregated tau in a variety of brain regions. While tau normally plays an important role in stabilizing the microtubule network of the cytoskeleton, its dissociation from microtubules and eventual aggregation into pathological deposits is an area of intense focus for therapeutic development. Here we discuss the known cellular factors that affect tau aggregation, from post-translational modifications to molecular chaperones.


Hypoxia-inducible lipid droplet-associated (HILPDA) is a novel peroxisome proliferator-activated receptor (PPAR) target involved in hepatic triglyceride secretion.
Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and fatty acid oxidation. Here we identify hypoxia-inducible lipid droplet-associated (Hilpda/Hig2) as a novel PPAR target gene and demonstrate its involvement in hepatic lipid metabolism. Microarray analysis revealed that Hilpda is one of the most highly induced genes by the PPARα agonist Wy14643 in mouse precision cut liver slices. Induction of Hilpda mRNA by Wy14643 was confirmed in mouse and human hepatocytes. Oral dosing with Wy14643 similarly induced Hilpda mRNA levels in livers of wild-type mice but not Ppara(-/-) mice. Transactivation studies and chromatin immunoprecipitation showed that Hilpda is a direct PPARα target gene via a conserved PPAR response element located 1200 base pairs upstream of the transcription start site. Hepatic overexpression of HILPDA in mice via adeno-associated virus led to a 4-fold increase in liver triglyceride storage, without any changes in key genes involved in de novo lipogenesis, β-oxidation, or lipolysis. Moreover, intracellular lipase activity was not affected by HILPDA overexpression. Strikingly, HILPDA overexpression significantly impaired hepatic triglyceride secretion. Taken together, our data uncover HILPDA as a novel PPAR target that raises hepatic triglyceride storage via regulation of triglyceride secretion.


Recombinant DNA technology as it relates to human papillomavirus research.
Recombinant DNA technology has enabled investigators to understand papillomavirus biology. HPV DNA has been found in a variety of benign and malignant tumors. Once discovered, this HPV DNA can be extracted, produced in large quantities, and submitted to nucleotide sequence analysis. Ultimately, this research should reveal the mechanism(s) involved in the malignant transformation of HPV-induced papillomas. It may also help us produce a genetically engineered, safe vaccine against the HPV.


Synergistic action of A23187 and phorbol ester on human B cell activation.
We have investigated the existence of a synergy occurring between the calcium ionophore A23187 and phorbol myristic acetate (PMA) with respect to human B cell proliferation and differentiation. The combination of A23187 (250 to 500 nM) with nonmitogenic concentrations of PMA (1 to 3 ng/ml) resulted in a strong proliferative response in human tonsillar, spleen, and peripheral blood B cells. This proliferation could not be blocked by anti-Tac antibody at concentrations that effectively inhibited T cell proliferation under similar culture conditions, suggesting that IL 2 and its receptor are not involved in B cell proliferation in this system. During a 3-day culture period, A23187 (500 nM) did not activate B cells in terms of changes in cell size or in the expression of transferrin receptor, HLA-DR, and Tac antigen. PMA at a nonmitogenic concentration (3 ng/ml) enhanced the expression of the first two markers. Combination of the ionophore with PMA induced the occurrence of Tac and further increased the expression of transferrin receptor and HLA-DR. A23187 similarly enhanced the PMA-mediated increase in cell size. PMA and A23187 did not induce differentiation to lg production. However, when cells were prestimulated with a combination of the two agents and were recultured in the presence of a preparation containing B cell differentiation factor, a strong increase in IgM, IgG, and IgA production was found. We conclude that PMA and A23187 synergistically trigger intracellular events in human B cells, leading to proliferation and to responsiveness to differentiation factors.