Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.
Studies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD. We systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling. 13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2, with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; I2 =60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias. This large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.


Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes.
Deep brain stimulation (DBS) of the globus pallidus internus (GPI) is a promising new procedure for the treatment of dystonia. The authors describe their technical approach for placing electrodes into the GPI in awake patients with dystonia, including methodology for electrophysiological mapping of the GPI in the dystonic state, clinical outcomes and complications, and the location of electrodes associated with optimal benefit. Twenty-three adult and pediatric patients with various forms of dystonia were included in this study. Baseline neurological status and DBS-related improvement in motor function were measured using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The implantation of DBS leads was performed using magnetic resonance (MR) imaging-based stereotaxy, single-cell microelectrode recording, and intraoperative test stimulation to determine thresholds for stimulation-induced adverse effects. Electrode locations were measured on computationally reformatted postoperative MR images according to a prospective protocol. Physiologically guided implantation of DBS electrodes in patients with dystonia was technically feasible in the awake state in most patients, and the morbidity rate was low. Spontaneous discharge rates of GPI neurons in dystonia were similar to those of globus pallidus externus neurons, such that the two nuclei must be distinguished by neuronal discharge patterns rather than rates. Active electrode locations associated with robust improvement (> 70% decrease in BFMDRS score) were located near the intercommissural plane, at a mean distance from the pallidocapsular border of 3.6 mm.


Resting Heart Rate Trajectory Pattern Predicts Arterial Stiffness in a Community-Based Chinese Cohort.
To examine whether the long-term resting heart rate (RHR) pattern can predict the risk of having arterial stiffness in a large ongoing cohort. This community-based cohort included 12 554 participants in the Kailun study, who were free of myocardial infarction, stroke, arrhythmia, and cancer. We used latent mixture modeling to identify RHR trajectories in 2006, 2008, and 2010. We used multivariate linear regression model to examine the association between RHR trajectory patterns and the risk of having arterial stiffness, which was assessed by brachial-ankle pulse wave velocity in 2010 to 2016. We adjusted for possible confounding factors, including socioeconomic status, lifestyle factors, use of medications, comorbidities, and serum concentrations of lipids, glucose, and high-sensitivity C-reactive proteins. We identified 5 distinct RHR trajectory patterns based on their 2006 status and on the pattern of change during 2006 to 2010 (low-stable, moderate-stable, moderate-increasing, elevated-decreasing, and elevated-stable). We found that individuals with elevated-stable RHR trajectory pattern had the highest brachial-ankle pulse wave velocity value and individuals with the low-stable RHR trajectory pattern had the lowest value (adjusted mean difference=157 cm/s; P<0.001). Adjusted odds ratio for risk of having arterial stiffness (brachial-ankle pulse wave velocity ≥1400 cm/s) was 4.14 (95% confidence interval, 2.61-6.57) relative to these 2 extreme categories. Consistently, a higher average RHR, a higher annual RHR increase rate, and a higher RHR variability were all associated with a higher risk of having arterial stiffness. Long-term RHR pattern is a strong predictor of having arterial stiffness.


Left-right asymmetry of fly wings and the evolution of body axes.
The body plan of Drosophila, and presumably that of other insects, develops under the control of anterio-posterior and dorsal ventral axes, but no evidence for a left-right axis has yet been found. We used geometric morphometrics to study the wings in three species of flies: Drosophila melanogaster, Musca domestica and Glossina palpalis gambiensis. In all three species, we found that both size and shape showed subtle, but statistically significant directional asymmetry. For size, these asymmetries were somewhat inconsistent within and between species, but for shape, highly significant directional asymmetry was found in all samples examined. These systematic left-right differences imply the existence of a left-right axis that conveys distinct positional identities to the wing imaginal discs on either body side. Hence, the wing discs of Drosophila may be a new model to study the developmental genetics of left-right asymmetry. The asymmetries of shape were similar among species, suggesting that directional asymmetry has been evolutionarily conserved since the three lineages diverged. We discuss the implications of this evolutionary conservatism in conjunction with results from earlier studies that showed a lack of genetic variation for directional asymmetry in Drosophila.


Vittorio Benussi, hypnosuggestive methods, and emotional functional autonomy.
This article reconstructs Vittorio Benussi's (1878-1927) research on autonomia funzionale emotiva [emotional functional autonomy], carried out in Padua between 1920 and 1927. Its aim is to demonstrate that Benussi believed-against the intellectualist mainstream of the psychology of his time and even against the Brentanian-Meinongian tradition in which he was educated-in the fundamental independence of emotions from the cognitive functions that usually accompany them. To study this autonomy, Benussi used hypnosis as an experimental tool designed to disassemble the phenomena of mental life from their global functional unity. Benussi thus compared the work of psychologists with that of physicists or chemists. This was a unique undertaking for theoretical ambitions and experimental techniques, which was completely abandoned after his premature death. To conclude, the legacy of Benussi's research on emotions is highlighted, and the resumption of his research model within current studies on the relationships between emotion and cognition is encouraged. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Identification and characterization of the murine and human gene encoding the tuberoinfundibular peptide of 39 residues.
By screening public databases, we identified human and mouse genomic DNA clones that encode the tuberoinfundibular peptide of 39 residues (TIP39). The TIP39 precursor is encoded by at least three exons; a noncoding exon U1, exon 1 encoding residues -61 (initiator methionine) to -19 of the leader sequence, and exon 2 encoding residues -18 to -1 and residues +1 to +39. Secreted human TIP39 is identical to the previously isolated bovine TIP39, whereas mouse TIP39 differs by four amino acids. Phylogenetic analyses suggested that TIP39, PTH, and PTHrP may have evolved from a common ancestor. Synthetic human and mouse TIP39 showed indistinguishable potencies [EC(50): 0.54 (human) vs. 0.74 nM (mouse)] at the human PTH2-receptor stably expressed in LLCPK(1) cells; furthermore, TIP-(9-39) was an inhibitor of cAMP accumulation stimulated by either [Tyr(34)]PTH(1-34)amide or human/bovine TIP39. In the mouse, an approximately 4.5-kb mRNA encoding TIP39 was identified by Northern blot analysis in testis and, less abundantly, in liver and kidney, whereas other tissues revealed additional smaller transcripts. In situ hybridizations revealed TIP39 expression in seminiferous tubuli and several brain regions, including nucleus ruber, nucleus centralis pontis, and nucleus subparafascicularis thalami. Because PTH2 receptor expression was previously shown to be highest in brain, pancreas, and testis, our findings are consistent with the notion that TIP39 is a neuropeptide which may also have a role in spermatogenesis.


[Interiliac-abdominal amputation in sarcoma of the bones and soft tissues of the pelvic girdle].
The interilio-abdominal amputation was fulfilled in 62 patients for the period from 1960 to 1979. The postoperative mortality was 6,4%. General five-year survival was 24,3% +/- 5,6. The survival terms were dependent first of all on the tumor type. The advances of anesthesiology, reanimatology and operative oncology have considerably reduced the danger of interilio-abdominal amputation. So, indications for the operation can become wider even in the cases when it has a palliative character.


Drug and Opioid-Involved Overdose Deaths - United States, 2017-2018.
Of the 70,237 drug overdose deaths in the United States in 2017, approximately two thirds (47,600) involved an opioid (1). In recent years, increases in opioid-involved overdose deaths have been driven primarily by deaths involving synthetic opioids other than methadone (hereafter referred to as synthetic opioids) (1). CDC analyzed changes in age-adjusted death rates from 2017 to 2018 involving all opioids and opioid subcategories* by demographic characteristics, county urbanization levels, U.S. Census region, and state. During 2018, a total of 67,367 drug overdose deaths occurred in the United States, a 4.1% decline from 2017; 46,802 (69.5%) involved an opioid (2). From 2017 to 2018, deaths involving all opioids, prescription opioids, and heroin decreased 2%, 13.5%, and 4.1%, respectively. However, deaths involving synthetic opioids increased 10%, likely driven by illicitly manufactured fentanyl (IMF), including fentanyl analogs (1,3). Efforts related to all opioids, particularly deaths involving synthetic opioids, should be strengthened to sustain and accelerate declines in opioid-involved deaths. Comprehensive surveillance and prevention measures are critical to reducing opioid-involved deaths, including continued surveillance of evolving drug use and overdose, polysubstance use, and the changing illicit drug market; naloxone distribution and outreach to groups at risk for IMF exposure; linkage to evidence-based treatment for persons with substance use disorders; and continued partnerships with public safety.


Dental caries and fluorosis in 7-9 and 11-14 year old children who received fluoride supplements from birth.
One hundred and sixty children who had lived from birth in a region with low fluoride levels in the drinking water, and who had been offered sodium fluoride supplementation in the form of drops for daily use, were examined to evaluate dental caries and dental fluorosis. Two age ranges were selected: 7-9 years and 11-14 years. In addition to the dental examinations, questionnaires were mailed to the parents, followed-up by telephone interviews, to gather information on compliance with the fluoride supplementation program. The results showed no statistically significant differences in dental caries activity between the regular and irregular users of fluoride supplementation. Considerable dental fluorosis was found in both regular and irregular user groups of the fluoride supplement (38 to 63 per cent of the children seen), however, with no statistical difference between the user groups. Most of the fluorosis detected was of a mild degree. Fluoride supplementation under the daily control of a parent or child is not recommended because of the difficulty in maintaining regular compliance and the risk of fluorosis.


Babesia sp.: emerging intracellular parasites in Europe.
The emergence of Lyme borreliosis as the most prevalent arthropod disease of humans in the temperate northern hemisphere has resulted in renewed interest in human babesiosis, transmitted by the same tick vectors. The advent of new molecular tools has made possible a reappraisal of the main parasites involved (Babesia divergens in Europe and Babesia microti in the USA). B. divergens is probably restricted to European cattle, though there are several nearly identical species. B. microti occurs as a world-wide species complex rather than as a single species, and although both phenotypic and genotypic features lend support to suggestions that zoonotic B. microti may occur in Europe, convincing medical evidence is lacking. Comparative biology should support genetic data in taxonomic studies of these parasites.


Evidence that activation of 2-deoxy-D-glucose transport in rat thymocyte suspensions results from enhanced coupling between transport and hexokinase activity.
1. Suspensions of rat thymocytes accumulate free 2-deoxy-D-glucose (2-dGlc) within the cytosol to a concentration approx. 25-fold above the external concentration. This active accumulation was enhanced by 40 nM-phorbol 12-myristate 13-acetate (phorbol). 2. The Km for zero-trans uptake in control cells was 2.3 +/- 0.14 mM and Vmax. was 0.41 +/- 0.08 mumol/min per 10(10) cells (n = 6). In cells treated with phorbol (40 nM) the Km for zero-trans uptake was 1.2 +/- 0.13 mM and Vmax. 0.46 +/- 0.03 mumol/min per 10(10) cells (n = 6). The Km was decreased significantly by phorbol (P less than 0.01). 3. Phorbol-dependent activation of thymocytes delayed exit of free 2-dGlc into sugar-free solution and prevented exchange exit. Activation had no effect on 3-O-methyl D-glucoside (3-OMG) exit. 4. Coupling of 2-dGlc transport to hexokinase activity was determined by observing the effects of various concentrations of unlabelled cytosolic 2-dGlc on influx of labelled 2-dGlc into the hexose phosphate pool. In control cells this coupling was 0.81 +/- 0.02 and in phorbol-activated cells it was 0.92 +/- 0.01 (P less than 0.01). 5. The high-affinity inhibitor of hexokinase, mannoheptulose, inhibited uptake of 2-dGlc in both control and phorbol-treated cells. These data are consistent with a model for activation of sugar transport in which hexokinase activity is integrated with the sugar transporter at the endofacial surface. The results suggest that phorbol increases the degree of coupling transport with hexokinase activity, thereby leading to an increase in the rate of uptake of 2-dGlc, a decrease in exit of free 2-dGlc from the cytosol and an increase in free 2-dGlc accumulation.


Modulation of single-chain antibody affinity with temperature-responsive elastin-like polypeptide linkers.
Single-chain antibodies are genetically engineered constructs composed of a VH and VL domain of an antibody linked by a flexible peptide linker, commonly (GGGGS)3. We asked whether replacement of this flexible linker with peptides known to undergo environmentally induced structural transitions could lead to antibodies with controlled binding and release characteristics. To this end, we genetically modified and produced a series of anti-fluorescein single-chain antibodies with the general linker sequence (VPGXG)n, where n is 1.2 to 3 and X is Val or His, to evaluate the effects of linker length and composition. Our results indicate that single-chain antibodies containing elastin-like polypeptide linkers have equilibrium affinity (KD) comparable to wild-type (GGGGS)3 at room temperature but altered binding kinetics and faster ligand release as the temperature is raised. These results are consistent with the increased molecular order and contraction that elastin-like polypeptides are known to undergo with increased temperature. Modulation of antibody affinity using stimulus-responsive linkers may have applications in biosensors, drug delivery, and bioseparations.


Diminished protein kinase C-activated arachidonate metabolism accompanies rat macrophage differentiation in the lung.
Alveolar macrophages (AM) differ from other macrophage (m phi) populations in their profile of eicosanoids synthesized from arachidonic acid (AA)3. Little information is available regarding possible differences in the regulation of AA metabolism among various m phi populations. In our study, we compared the ability of cultured resident rat AM and peritoneal m phi (PM) to release and metabolize AA in response to exogenous activators of protein kinase C (PKC). When stimulated with PMA, prelabeled PM released free [3H]AA in a dose-dependent manner over the concentration range 1 to 100 nM. As assessed by HPLC, PMA-stimulated PM metabolized AA to a variety of predominantly cyclooxygenase products. The dose-dependent synthesis of PGE2 by unlabeled PM stimulated with PMA was confirmed using RIA. The ability of PMA to trigger AA release and metabolism in PM was a function of its capacity to activate PKC, as indicated by the following: 1) an additional activator of PKC, oleoyl acetylglycerol, also triggered PM AA metabolism, whereas phorbol didecanoate, which lacks the ability to activate PKC, did not; 2) two structurally unrelated inhibitors of PKC activation (staurosporine and sphinganine) both abrogated PMA induced AA release in PM; and 3) pretreatment for 18 h with high dose PMA (used to deplete cellular PKC), but not phorbol didecanoate, rendered PM refractory to subsequent PMA stimulation of AA release. In contrast to PM, AM cultured in identical fashion failed to release or metabolize AA in response to either PMA or oleoyl acetylglycerol. PM and AM were also compared for their ability to release extracellular superoxide anion in response to PMA; once again, PM exhibited significantly greater release than did AM. Inasmuch as this unresponsiveness to activation of PKC distinguishes AM from other m phi populations, we conclude that it is a unique consequence of m phi differentiation in the lung. Moreover, because both AA metabolism and the respiratory burst are affected, this refractoriness appears to reflect a defect at some proximal level in PKC-mediated signaling.


Uncoupling of proximal sodium bicarbonate from sodium phosphate transport by bumetanide.
Re-collection micropuncture of late proximal tubular segments and simultaneous clearance studies were performed in chronically thyroparathyroidectomized dogs before and after the intravenous administration of bumetanide. The drug, a new sulfonamide-derivative diuretic, inhibited proximal fractional sodium and fluid transport by 0.12 (from 0.44 +/- 0.04 to 0.32 +/- 0.04, P less than 0.05) and that of bicarbonate by 0.14 (from 0.43 +/- 0.05 to 0.29 +/- 0.07, P less than 0.02). Tubular fluid bicarbonate concentration was unchanged, indicating a reduction in the transport of this ion proportionate to that of tubular fluid. However, unlike sodium and bicarbonate reabsorption, fractional proximal phosphate transport was unaltered (from 0.65 +/- 0.04 to 0.62 +/- 0.04, P greater than 0.40). The drug induced a substantial natriuresis; the percentage of filtered sodium excreted rose from 0.4 +/- 0.1 to 13.1 +/- 2.4% (P less than 0.005). Bicarbonate and phosphate excretion rose more modestly: the percentage excretion of the former ion increased from 0.9 +/- 0.3 to 3.7 +/- 0.08% (P less than 0.005) and that for phosphate doubled (from 3.4 +/- 1.0 to 6.8 +/- 1.3%, P less than 0.025). However, urinary pH did not change. Accordingly, bumetanide uncoupled the transport of sodium bicarbonate from that of sodium phosphate in the proximal convoluted tubule. It is concluded from these data that the action of bumetanide in the proximal convoluted tubule is probably not related either to carbonic anhydrase inhibition or to the impairment of sodium-phosphate-linked transport.


AMA offers technology assessment program.
This issue of Physician Executive inaugurates a new column designed to provide information and insights regarding current issues in medical technology. The introductory offering in the column describes the Diagnostic and Therapeutic Technology Assessment (DATTA) program, the foundation of the American Medical Association's major activities in health care technology.


Dynamic spin ice: Pr2Sn2O7.
In this Letter, we report a new spin ice--Pr2Sn2O7--which appears to have enhanced residual entropy due to the dynamic nature of the spins. Neutron scattering experiments show that at 200 mK, there is a significant amount of magnetic diffuse scattering which can be fit to the dipolar spin-ice model. However, these short-ranged ordered spins have a quasielastic response that is atypical of the canonical spin ices, and suggests that the ground state is dynamic (i.e., composed of locally ordered two-in-two-out spin configurations that can tunnel between energetically equivalent orientations). We report this as an example of a dynamic spin ice down to 200 mK.


First anesthesia exposure effects on short-term neurocognitive function among 1- to 36-month-old children: a case-control pilot study.
Multiple human studies have shown no significant long-term results of anesthesia exposure during early childhood compared to the general population; however, reports on short-term neurodevelopmental assessment before and after anesthesia exposure are limited. This study aimed to evaluate the short-term characteristics of neurocognitive function post-anesthesia in noncardiac surgery compared with baseline. This prospective case-control pilot study recruited healthy participants in the control group and hospitalized children in the anesthesia group. Children aged 1-36 months without previous anesthesia were included. Neurocognitive function was assessed at baseline and seven days after anesthesia administration using a cognitive scale of the Bayley Scales of Infant and Toddler Development, third edition. The control group received only a baseline assessment. The cognitive composite score had a mean of 100 and a standard deviation (SD) of 15, with a difference of score >1/3 SD (5 points) defined as clinically significant. Twenty and 39 participants in the control and anesthesia groups, respectively, were included in the final analysis. The baseline cognitive scale score of the anesthesia group was statistically and clinically lower than that of the control group. The mean (SD) cognitive composite scores in the control and anesthesia group were 111.50 (11.71) and 97.13 (9.88), P<0.001. The mean difference [95% confidence interval (CI)] was -14.37 (-8.28 to -20.47). In the anesthesia group, the post-anesthesia cognitive composite score was statistically higher than that at baseline, but without clinical significance. The mean (SD) of baseline and post-anesthesia cognitive composite scores were 97.05 (9.85) and 101.28 (10.87), P=0.039, respectively. The mean difference (95% CI) was 4.23 (0.23-8.23). However, 7 (17.9%) participants had decreased cognitive composite scores after anesthesia exposure. Children in the anesthesia group had lower baseline cognitive composite scores than those in the control group. The post-anesthesia cognitive score did not decrease compared with the baseline assessment. Anesthetic exposure resulted in a decline in the cognitive composite score in 17.9% of the participants.


Expectation maximization reconstruction of positron emission tomography images using anatomical magnetic resonance information.
Using statistical methods the reconstruction of positron emission tomography (PET) images can be improved by high-resolution anatomical information obtained from magnetic resonance (MR) images. We implemented two approaches that utilize MR data for PET reconstruction. The anatomical MR information is modeled as a priori distribution of the PET image and combined with the distribution of the measured PET data to generate the a posteriori function from which the expectation maximization (EM)-type algorithm with a maximum a posteriori (MAP) estimator is derived. One algorithm (Markov-GEM) uses a Gibbs function to model interactions between neighboring pixels within the anatomical regions. The other (Gauss-EM) applies a Gauss function with the same mean for all pixels in a given anatomical region. A basic assumption of these methods is that the radioactivity is homogeneously distributed inside anatomical regions. Simulated and phantom data are investigated under the following aspects: count density, object size, missing anatomical information, and misregistration of the anatomical information. Compared with the maximum likelihood-expectation maximization (ML-EM) algorithm the results of both algorithms show a large reduction of noise with a better delineation of borders. Of the two algorithms tested, the Gauss-EM method is superior in noise reduction (up to 50%). Regarding incorrect a priori information the Gauss-EM algorithm is very sensitive, whereas the Markov-GEM algorithm proved to be stable with a small change of recovery coefficients between 0.5 and 3%.


MTA1 promotes proliferation and invasion in human gastric cancer cells.
Although metastasis-associated protein 1 (MTA1) has been widely linked to tumor metastasis, the relevant mechanisms remain to be elucidated, especially in gastric cancer. The aim of this study was to examine whether the MTA1 gene is associated with the process of proliferation and invasion by regulating several molecular targets in gastric cancer. MTA1 expression in 61 gastric cancer tissue and adjacent noncancerous tissues was analyzed by immunohistochemistry. The prognostic value of MTA1 for overall survival and disease-free survival was determined by Kaplan-Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. Furthermore, overexpression of MTA1 in SGC7901 and BGC823 cells promoted cell cycle progression, cell adhesion, and cell invasion. Our study found that MTA1 is overexpressed in gastric cancers, which contributes to malignant cell growth by facilitating cell cycle progression through upregulation of cyclin D1 and accelerates the migration and invasion of human gastric cancer cells by regulating expression of fibronectin and MMP2/MMP9. Taken together, MTA1 was involved in the pathogenesis of gastric cancer and might be a candidate therapeutic target in gastric cancer.


Theoretical and experimental study of laser radiation propagating in a medium with thermally induced birefringence and cubic nonlinearity.
We consider a problem of laser radiation propagating in a medium with birefringence of two types: linear birefringence independent of intensity and polarization, and intensity and polarization dependent circular birefringence caused by cubic nonlinearity. It is shown theoretically and experimentally that the efficiency of the broadly employed method of linear depolarization compensation by means of a 90° polarization rotator decreases with increasing В-integral (nonlinear phase incursion induced by cubic nonlinearity). The accuracy of polarization transformation by means of a half-wave and a quarter-wave plate also decreases if В > 1. By the example of a λ/4 plate it is shown that this parasitic effect may be suppressed considerably by choosing an optimal angle of inclination of the optical axis of the plate.


Health expenditures in Texas, 1988.
Expenditures for health care in Texas during 1988 totaled $32.4 billion. Health spending by category of service and sources of payment was estimated and compared with estimates for prior years and with national trends. Texas differed from the nation as a whole in average annual increases in total spending, the percentage of spending for prepayment and administration, and the percentage of spending paid by consumers, the federal government, and private insurance. Proposed expansions in insurance coverage for the large proportion of uninsured Texans will probably require strong efforts to contain costs.


Arsenic in the environment: Biology and Chemistry.
Arsenic (As) distribution and toxicology in the environment is a serious issue, with millions of individuals worldwide being affected by As toxicosis. Sources of As contamination are both natural and anthropogenic and the scale of contamination ranges from local to regional. There are many areas of research that are being actively pursued to address the As contamination problem. These include new methods of screening for As in the field, determining the epidemiology of As in humans, and identifying the risk of As uptake in agriculture. Remediation of As-affected water supplies is important and research includes assessing natural remediation potential as well as phytoremediation. Another area of active research is on the microbially mediated biogeochemical interactions of As in the environment. In 2005, a conference was convened to bring together scientists involved in many of the different areas of As research. In this paper, we present a synthesis of the As issues in the light of long-standing research and with regards to the new findings presented at this conference. This contribution provides a backdrop to the issues raised at the conference together with an overview of contemporary and historical issues of As contamination and health impacts.


Estimating the Time Since Deposition of Saliva Stains With a Targeted Bacterial DNA Approach: A Proof-of-Principle Study.
Information on the time when a stain was deposited at a crime scene can be valuable in forensic investigations. It can link a DNA-identified stain donor with a crime or provide a post-mortem interval estimation in cases with cadavers. The available methods for estimating stain deposition time have limitations of different types and magnitudes. In this proof-of-principle study we investigated for the first time the use of microbial DNA for this purpose in human saliva stains. First, we identified the most abundant and frequent bacterial species in saliva using publicly available 16S rRNA gene next generation sequencing (NGS) data from 1,848 samples. Next, we assessed time-dependent changes in 15 identified species using de-novo 16S rRNA gene NGS in the saliva stains of two individuals exposed to indoor conditions for up to 1 year. We selected four bacterial species, i.e., Fusobacterium periodonticum, Haemophilus parainfluenzae, Veillonella dispar, and Veillonella parvula showing significant time-dependent changes and developed a 4-plex qPCR assay for their targeted analysis. Then, we analyzed the saliva stains of 15 individuals exposed to indoor conditions for up to 1 month. Bacterial counts generally increased with time and explained 54.9% of the variation (p = <2.2E-16). Time since deposition explained ≥86.5% and ≥88.9% of the variation in each individual and species, respectively (p = <2.2E-16). Finally, based on sample duplicates we built and tested multiple linear regression models for predicting the stain deposition time at an individual level, resulting in an average mean absolute error (MAE) of 5 days (ranging 3.3-7.8 days). Overall, the deposition time of 181 (81.5%) stains was correctly predicted within 1 week. Prediction models were also assessed in stains exposed to similar conditions up to 1 month 7 months later, resulting in an average MAE of 8.8 days (ranging 3.9-16.9 days). Our proof-of-principle study suggests the potential of the DNA profiling of human commensal bacteria as a method of estimating saliva stains time since deposition in the forensic scenario, which may be expanded to other forensically relevant tissues. The study considers practical applications of this novel approach, but various forensic developmental validation and implementation criteria will need to be met in more dedicated studies in the future.


Geographies of education, volunteering and the lifecourse: the Woodcraft Folk in Britain (1925-75).
This article extends the current scholarly focus within the geographies of education and the geographies of children, youth and families through an original examination of the Woodcraft Folk - a British youth organization founded in 1925 that aimed to create a world built on equality, friendship and peace. This article illustrates how voluntary uniformed youth organizations had a much wider spatial remit and more complex institutional geographies than have been hitherto acknowledged, with their active involvement in the training of adults (namely parents and volunteers) as well as the education of children and young people. Drawing on archival research and a range of sources, the article explores the Woodcraft Folk's philosophies and political activities across its first 50 years, and in doing so, makes two central academic contributions to the discipline. First, the article provides a timely focus on training and its analytical purchase for geographers as part of a growing body of work on the geographies of education. Second, the article shows how geographers can account for both children and adults' geographies in institutional spaces, in this case through mapping out the enlivened historical geographies of voluntarism across the lifecourse. This article demonstrates the complex and often fluid relationship between formal and informal education, as well as the important connections between parenting and volunteering. Overall, the article reflects on the subsequent challenges and opportunities for researchers concerned with debates on education, youth and volunteering within geography and beyond.


Blood Biomarkers as Outcome Measures in Inflammatory Neurologic Diseases.
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system. Only a few biomarkers are available in MS clinical practice, such as cerebrospinal fluid oligoclonal bands and immunoglobulin index, serum anti-aquaporin 4 antibodies, and serum anti-John Cunningham virus antibodies. Thus, there is a significant unmet need for biomarkers to assess prognosis, response to therapy, or potential treatment complications. Here we describe emerging biomarkers that are in development, focusing on those from peripheral blood. There are several limitations in the process of discovery and validation of a good biomarker, such as the pathophysiological complexity of MS and the technical difficulties in globally standardizing methods for sampling, processing, and conserving biological specimens. In spite of these limitations, ongoing international collaborations allow the exploration of many interesting molecules and markers to validate diagnostic, prognostic, and therapeutic-response biomarkers.


Analysis of Sulfated Glycosaminoglycans in ECM Scaffolds for Tissue Engineering Applications: Modified Alcian Blue Method Development and Validation.
Accurate determination of the amount of glycosaminoglycans (GAGs) in a complex mixture of extracellular matrix (ECM) is important for tissue morphogenesis and homeostasis. The aim of the present study was to investigate an accurate, simple and sensitive alcian blue (AB) method for quantifying heparin in biological samples. A method for analyzing heparin was developed and parameters such as volume, precipitation time, solvent component, and solubility time were evaluated. The AB dye and heparin samples were allowed to react at 4 ℃ for 24 h. The heparin-AB complex was dissolved in 25 N NaOH and 2-Aminoethanol (1:24 v/v). The optical density of the solution was analyzed by UV-Vis spectrometry at 620 nm. The modified AB method was validated in accordance with U.S. Food and Drug Administration guidelines. The limit of detection was found to be 2.95 µg/mL. Intraday and interday precision ranged between 2.14-4.83% and 3.16-7.02% (n = 9), respectively. Overall recovery for three concentration levels varied between 97 ± 3.5%, confirming good accuracy. In addition, this study has discovered the interdisciplinary nature of protein detection using the AB method. The basis for this investigation was that the fibrous protein inhibits heparin-AB complex whereas globular protein does not. Further, we measured the content of sulfated GAGs (sGAGs; expressed as heparin equivalent) in the ECM of decellularized porcine liver. In conclusion, the AB method may be used for the quantitative analysis of heparin in ECM scaffolds for tissue engineering applications.


Operating a pilot-scale nitrification/distillation plant for complete nutrient recovery from urine.
Source-separated urine contains most of the excreted nutrients, which can be recovered by using nitrification to stabilize the urine before concentrating the nutrient solution with distillation. The aim of this study was to test this process combination at pilot scale. The nitrification process was efficient in a moving bed biofilm reactor with maximal rates of 930 mg N L(-1) d(-1). Rates decreased to 120 mg N L(-1) d(-1) after switching to more concentrated urine. At high nitrification rates (640 mg N L(-1) d(-1)) and low total ammonia concentrations (1,790 mg NH4-N L(-1) in influent) distillation caused the main primary energy demand of 71 W cap(-1) (nitrification: 13 W cap(-1)) assuming a nitrogen production of 8.8 g N cap(-1) d(-1). Possible process failures include the accumulation of the nitrification intermediate nitrite and the selection of acid-tolerant ammonia-oxidizing bacteria. Especially during reactor start-up, the process must therefore be carefully supervised. The concentrate produced by the nitrification/distillation process is low in heavy metals, but high in nutrients, suggesting a good suitability as an integral fertilizer.


A double-blind comparison of lidocaine and mepivacaine during epidural anaesthesia.
The effects of epidural anaesthesia with plain 2% lidocaine or mepivacaine were compared in 200 patients undergoing extracorporeal shock wave lithotripsy in a double-blind manner. The onset, spread, duration and quality of analgesia were similar in both groups. The numbers of patients who needed vasoconstrictor or atropine were almost equal in both the lidocaine and the mepivacaine groups. Mild but significant hypotension continued for a longer period in the mepivacaine group than in the lidocaine group. A transient decrease in arterial oxygen saturation was seen in two patients receiving lidocaine and in three patients receiving mepivacaine. Mild systemic toxicity was observed in eight patients in both groups, although serious complications such as convulsions did not occur. It is concluded that both drugs can be used equally safely for epidural anaesthesia, although the maximum recommended doses differ.


Variation in heart rate regulation and the effects of particle exposure in inbred mice.
Altered autonomic control of heart rate (HR) rhythm during exposure to particulate matter (PM) has been suggested in human and animal studies. Our lab has shown strain variation in HR regulation between quiescent C3H/HeJ (C3) and C57BL/6J (B6) mice: that is, C3 mice show a consistently higher HR by approximately 80 bpm compared with B6 mice during a normal 24-h circadian cycle. In the current study, we hypothesize that the balance between sympathetic and parasympathetic control of HR during PM exposure varies between C3 and B6 mice. Radiotelemeters were implanted in C3 and B6 mice to measure HR responses and HR variability (HRV) parameters during successive 3-h exposures to filtered air (FA) or carbon black (CB, < 300 mug/m3). Exposures were repeated following administration of saline or parasympathetic (PS; atropine, 0.5 mg/kg i.p.) and sympathetic (S; propranolol, 1 mg/kg i.p.) blockade to study the autonomic regulation of HR during CB exposure. During FA exposure with saline, a significantly (p < .05) greater 3-h average HR response (bpm +/- SEM) occurred in C3 compared with B6 mice (496 +/- 22 vs. 427 +/- 3). With PS blockade, the strain difference between C3 and B6 mice was not evident (485 +/- 23 vs. 503 +/- 61). With S blockade, the 3-h average HR responses for C3 mice were significantly (p < .05) reduced compared with saline (413 +/- 18 vs. 392 +/- 15 for B6). During CB exposure with saline, HR responses were again significantly (p < 0.05) elevated in C3 compared with B6 mice, but these HR responses were not different relative to FA exposure. With S blockade, HR was significantly (p < .05) elevated in B6 mice during CB relative to FA, but was unchanged in C3 mice. Collectively, these results suggest that strain variation in HR regulation is due to a robust PS tone evident in B6 mice and a predominant S tone in C3 mice. Furthermore, CB exposure alters HR regulation in B6 mice by modulating a withdrawal of PS tone. Finally, strain variation in HR between B6 and C3 mice in responding to acute PM exposure implies that robust genetic determinants modulate altered autonomic regulation in susceptible individuals.


Allogeneic HLA-A*02-restricted WT1-specific T cells from mismatched donors are highly reactive but show off-target promiscuity.
T cells recognizing tumor-associated Ags such as Wilms tumor protein (WT1) are thought to exert potent antitumor reactivity. However, no consistent high-avidity T cell responses have been demonstrated in vaccination studies with WT1 as target in cancer immunotherapy. The aim of this study was to investigate the possible role of negative thymic selection on the avidity and specificity of T cells directed against self-antigens. T cell clones directed against the HLA-A*0201-binding WT1(126-134) peptide were generated from both HLA-A*02-positive (self-HLA-restricted) and HLA-A*02-negative [nonself (allogeneic) HLA [allo-HLA]-restricted] individuals by direct ex vivo isolation using tetramers or after in vitro priming and selection. The functional avidity and specificity of these T cell clones was analyzed in-depth. Self-HLA-restricted WT1-specific clones only recognized WT1(126-134) with low avidities. In contrast, allo-HLA-restricted WT1 clones exhibited profound functional reactivity against a multitude of HLA-A*02-positive targets, even in the absence of exogenously loaded WT1 peptide, indicative of Ag-binding promiscuity. To characterize this potential promiscuity, reactivity of the T cell clones against 400 randomly selected HLA-A*0201-binding peptides was investigated. The self-HLA-restricted WT1-specific T cell clones only recognized the WT1 peptide. In contrast, the allo-HLA-restricted WT1-reactive clones recognized besides WT1 various other HLA-A*0201-binding peptides. In conclusion, allogeneic HLA-A*02-restricted WT1-specific T cells isolated from mismatched donors may be more tumor-reactive than their autologous counterparts but can show specific off-target promiscuity of potential clinical importance. As a result of this, administration of WT1-specific T cells generated from HLA-mismatched donors should be performed with appropriate precautions against potential off-target effects.


How safe is blood, really?
Blood is safer than it has ever been, however the progression of transfusion from dangerous intervention to reliable supportive care been non-linear. Disparities resulting from geography, economy, and social class persist. Some risks are known, others are unknown but predictable, and still others may be totally unpredictable. Among the known risks are infectious and immunologic events that can be calculated per unit of blood transfused. These risks vary by component. Among the unknown risks are the potential for emerging pathogens transmitted by blood and for processing or storage lesions to result in short or long-term toxicity. National registries provide some reassurance that transfusion may not affect mortality significantly beyond the first few weeks after administration. Nevertheless, transmission of novel pathogens, repeated allogeneic stimulation, and infusion of cytokines or chemokines may have unrecognized consequences. Blood safety can be effected dramatically with small investment in developing countries. In the developed world, technologies such as pathogen inactivation, antigen camouflage, component substitutes, or cell expansion promise relatively small advances in safety at substantial cost. No strategy guarantees zero-risk.


A scheme for electrical detection of single-electron spin resonance.
We study a scheme for electrical detection of the spin resonance of a single-electron trapped near a field effect transistor (FET) conduction channel. In this scheme, the resonant Rabi oscillations of the trapped electron spin cause a modification of the average charge of a shallow trap, which can be detected through the change in the FET channel resistivity. We show that the dependence of the channel resistivity on the frequency of the rf field can have either peak or dip at the Larmor frequency of the electron spin in the trap.


Formation of i-motifs from acyclic (l)-threoninol nucleic acids.
Acyclic (l)-threoninol nucleic acids ((l)-aTNA) containing poly-cytosines are prepared and investigated at various pH values, revealing the formation of a highly stable structure at lower pH that have the characteristics of an i-motif. Depending on the sequence, the aTNA forms inter-, bi- and intra-molecular i-motif structures. Pyrene was conjugated to aTNA sequences and both monomeric and excimer fluorescence were efficiently quenched by the i-motif structures and thus demonstrated that the aTNA i-motif can serve as a pH switch.


EXPERIMENTAL INFECTION WITH INFLUENZA A VIRUS IN MICE : THE INCREASE IN INTRAPULMONARY VIRUS AFTER INOCULATION AND THE INFLUENCE OF VARIOUS FACTORS THEREON.
Following intranasal inoculation of influenza A virus (strain PR8) there is a rapid increase of the virus in the lungs which with large doses reaches a maximum within 24 hours. With smaller doses, although the proportional increase is greater, the maximum concentration is not reached until 48 hours following inoculation. If a lethal dose is administered, the ultimate concentration of the virus in the lungs is the same, irrespective of the size of the dose. If a sublethal dose is given, the titer of the virus in the lungs does not achieve the titer reached in mice receiving a lethal dose. Within 48 hours following inoculation of a sublethal dose the lungs of a mouse may contain at least 76,000 M.L.D., yet the mouse survives. The intranasal instillation of sterile fluid (distilled water, varying concentrations of NaCl, broth, or 10 per cent normal serum) into a mouse sublethally infected produces a sharp rise in the virus content of the lung usually followed by death within 3 to 8 days. If, however, the instillate consists of 10 per cent immune serum, there is no rise in the virus titer, and no apparent harm results from the instillation. The implications of these phenomena are discussed and an hypothesis presented to explain their occurrence.


Murine mucopolysaccharidosis type VII: long term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation.
We demonstrated previously that short term administration of recombinant beta-glucuronidase to newborn mice with mucopolysaccharidosis type VII reduced lysosomal storage in many tissues. Lysosomal storage accumulated gradually after cessation of enzyme replacement therapy. Mice alive at 1 yr of age had decreased bone deformities and less lysosomal storage in cortical neurons. Here we compare the effects of long term enzyme replacement initiated either at birth or at 6 wk of age, and of enzyme administration initiated at birth followed by syngeneic bone marrow transplantation (BMT) at 5 wk of age. Several mice from each treatment group lived to at least 1 yr of age. Liver and spleen samples had beta-glucuronidase levels ranging from 2.4 to 19.8% of normal and showed a parallel decrease in lysosomal storage. The combination of enzyme replacement therapy followed by BMT reduced lysosomal distension in meninges, corneal fibroblasts, and bone when compared with treatment with enzyme alone. Mice treated at birth had less lysosomal storage in some neurons of the brain and the skeletal dysplasia was less severe when compared to mice whose treatment was delayed until 6 wk of age. We conclude that both enzyme replacement alone and early enzyme replacement followed by BMT have long term positive effects on murine mucopolysaccharidosis type VII. In addition, treatment started at birth is far more effective than treatment initiated in young adults.


A new local anesthesia technique for cataract extraction by one quadrant sub-Tenon's infiltration.
A new technique of local anesthetic administration has been used for 50 patients undergoing cataract extraction. The simple technique involves direct transconjunctival infiltration of local anaesthetic directly to the sub-Tenon's space, in the inferior-nasal quadrant, using a blunt 19-gauge Southampton cannula. This method seeks to avoid the risks of retrobulbar haemorrhage, perforation of the globe, damage to the optic nerve, and injection into the subarachnoid space, whilst providing prolonged and reliable anaesthesia. Akinesia is achieved by the inferior-nasal placement of solution and if not sufficient, a top-up can easily be given. Patients graded any discomfort or pain using a 10 cm visual analogue graphical pain score chart with numerical and descriptive rating scale. The delivery of 50:50 mixture of lignocaine 2% and bupivacaine 0.5% anaesthetic was evaluated by patients with a median response of 'slight discomfort'. The operative procedure was graded with a median of 'no pain or discomfort', both for extracapsular cataract extraction and phakoemulsification. This is a new, modified, sub-Tenon technique which is simple, reliable, and which offers excellent anaesthesia and akinesia and avoids a sharp instrument being passed into the orbit.


Testosterone Deficiency, Long-Term Testosterone Therapy, and Inflammation.
We aimed to evaluate the association of testosterone deficiency with inflammation and how long-term testosterone therapy affects inflammation biomarkers over time. We conducted a 2-component study. First, we conducted a cross-sectional study using the recently released 2015-2016 National Health and Nutrition Examination Survey (NHANES) data to examine the association between testosterone deficiency and inflammation biomarkers including high sensitivity C-reactive protein (hsCRP), liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the US general population. Then we conducted a longitudinal study to investigate the longitudinal effect of testosterone therapy on inflammation biomarkers and the risk of cardiovascular events, using data from 776 hypogonadal men based on a registry study in Germany with up to 11 years' follow-up. The adjusted odds ratios (ORs) describing the associations between testosterone deficiency and hsCRP ≥ 3mg/L, ALT > 40U/L, and AST > 40U/L were 1.81 (P-value < 0.001), 1.46 (P-value = 0.009), and 0.99 (P-value = 0.971), respectively. In the control group, CRP, ALT, and AST levels increased by 0.003 (95%CI: -0.001, 0.007) mg/L, 0.157 U/L (95%CI: 0.145, 0.170), and 0.147 (95%CI: 0.136, 0.159) U/L per month, while in the treatment group, CRP, ALT, and AST levels decreased by 0.05 (95%CI: -0.055, -0.046) mg/L, 0.142 U/L (95%CI: -0.154, -0.130), and 0.148 (95%CI: -0.158, -0.137) U/L per month. Testosterone deficiency was associated with an increased level of inflammation; long-term testosterone therapy alleviated inflammation among hypogonadal men, which may contribute to the reduced cardiovascular risk. Future large trials are warranted to confirm our observational study findings.


Influence of pilin glycosylation on Pseudomonas aeruginosa 1244 pilus function.
The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of nosocomial pneumonia. Among its virulence factors, the type IV pili of P. aeruginosa strain 1244 contain a covalently linked, three-sugar glycan of previously unknown significance. The work described in this paper was carried out to determine the influence of the P. aeruginosa 1244 pilin glycan on pilus function, as well as a possible role in pathogenesis. To accomplish this, a deletion was introduced into the pilO gene of this organism. The isogenic knockout strain produced, 1244G7, was unable to glycosylate pilin but could produce pili normal in appearance and quantity. In addition, this strain had somewhat reduced twitching motility, was sensitive to pilus-specific bacteriophages, and could form a normal biofilm. Analysis of whole cells and isolated pili from wild-type P. aeruginosa strain 1244 by transmission electron microscopy with a glycan-specific immunogold label showed that this saccharide was distributed evenly over the fiber surface. The presence of the pilin glycan reduced the hydrophobicity of purified pili as well as whole cells. With regard to pathogenicity, P. aeruginosa strains producing glycosylated pili were commonly found among clinical isolates and particularly among those strains isolated from sputum. Competition index analysis using a mouse respiratory model comparing strains 1244 and 1244G7 indicated that the presence of the pilin glycan allowed for significantly greater survival in the lung environment. These results collectively suggest that the pilin glycan is a significant virulence factor and may aid in the establishment of infection.


In vivo retinal optical coherence tomography at 1040 nm - enhanced penetration into the choroid.
For the first time in vivo retinal imaging has been performed with a new compact, low noise Yb-based ASE source operating in the 1 microm range (NP Photonics, lambdac = 1040 nm, Deltalambda = 50 nm, Pout = 30 mW) at the dispersion minimum of water with ~7 microm axial resolution. OCT tomograms acquired at 800 nm are compared to those achieved at 1040 nm showing about 200 microm deeper penetration into the choroid below the retinal pigment epithelium. Retinal OCT at longer wavelengths significantly improves the visualization of the retinal pigment epithelium/choriocapillaris/choroids interface and superficial choroidal layers as well as reduces the scattering through turbid media and therefore might provide a better diagnosis tool for early stages of retinal pathologies such as age related macular degeneration which is accompanied by choroidal neovascularization, i.e., extensive growth of new blood vessels in the choroid and retina.


LncRNA AERRIE Is Required for Sulfatase 1 Expression, but Not for Endothelial-to-Mesenchymal Transition.
Endothelial cells can acquire a mesenchymal phenotype through a process called Endothelial-to-Mesenchymal transition (EndMT). This event is found in embryonic development, but also in pathological conditions. Blood vessels lose their ability to maintain vascular homeostasis and ultimately develop atherosclerosis, pulmonary hypertension, or fibrosis. An increase in inflammatory signals causes an upregulation of EndMT transcription factors, mesenchymal markers, and a decrease in endothelial markers. In our study, we show that the induction of EndMT results in an increase in long non-coding RNA AERRIE expression. JMJD2B, a known EndMT regulator, induces AERRIE and subsequently SULF1. Silencing of AERRIE shows a partial regulation of SULF1 but showed no effect on the endothelial and mesenchymal markers. Additionally, the overexpression of AERRIE results in no significant changes in EndMT markers, suggesting that AERRIE is marginally regulating mesenchymal markers and transcription factors. This study identifies AERRIE as a novel factor in EndMT, but its mechanism of action still needs to be elucidated.


Boosting Highly Efficient Hydrocarbon Solvent-Processed All-Polymer-Based Organic Solar Cells by Modulating Thin-Film Morphology.
Many highly efficient all-polymer-based organic solar cells (OSCs) have been achieved owing to material design and device engineering. However, most of them were achieved by using halogenated solvents to process the active layers, being not beneficial to its nature of green energy technology. In this work, we compared chloroform- and toluene-processed PM6:PY-IT-based all-polymer devices with the same blend solution recipe, same film formation speed, and same postcast treatment. The film cast from toluene exhibited weaker crystallinity. For device performance, toluene enabled a better power conversion efficiency (PCE) of 15.51%, outperforming that of chloroform (15.00%), and it is the highest value for non-halogenated solvent-cast all-polymer-based OSCs to date. Toluene's morphology tuning effect was characterized to increase and balance the charge transport and then suppress the exciton recombination and improve the charge extraction, considered to be the reason for efficiency enhancement. Besides, the toluene-cast active layer-based devices showed slightly better photostability than the chloroform-driven ones. This work provided a new direction for building low-toxicity solvent-treated all-polymer OSCs with cutting-edge performance.


Online clinical skills education using a wearable action camera for medical students.
The purpose of this study is to analyze medical students' satisfaction and educational effectiveness after real-time online clinical skills education using a wearable action camera. One hundred eighteen third-year medical students participated in this study. The education program consisted of clinical skills (wound management and vascular access procedures) and a medical interview with a simulated patient. The author wore the head-mounted action camera throughout the class. A systematic questionnaire survey was issued to the students after the education program to analyze the educational satisfaction and effectiveness. This education program showed their high educational satisfaction. The online environment was also mostly positive except for some negative comments about video quality. In the educational satisfaction, though the comparative satisfaction with the face-to-face skill class was slightly lower, the rest of the questionnaire items also showed high relative satisfaction. Online video education using a wearable camera could be a good modality that can replace a face-to-face class when it is impossible to open the class.


Impact of nations meeting the MPOWER targets between 2014 and 2016: an update.
Since the WHO released the Monitoring tobacco use and tobacco control policies; Protecting from the dangers of tobacco smoke; Offering help to quit tobacco; Warning the public about the dangers; Enforcing bans on advertising, promotion and sponsorship; and Raising tobacco taxes (MPOWER) policy package to assist nations with implementing the Framework Convention on Tobacco Control (FCTC), 88 countries have adopted at least one MPOWER policy at the highest level as of 2014. Building on previous evaluations, we estimated the reduction in smoking-attributable deaths (SADs) from all policies newly adopted at the highest level between 2014 and 2016. For each nation that implemented highest level policies, the difference in policy effect sizes from previously validated SimSmoke models for the policies in effect in 2014 and 2016 were multiplied by the number of smokers in that nation to derive the reduction in the number of smokers. Based on research that half of all smokers die from smoking, we derived SADs averted. In total, 43 nations adopted at least one highest-level MPOWER policy between 2014 and 2016, resulting in 14.6 million fewer SADs. The largest number of SADs averted were due to stronger health warnings (13.3 million), followed by raising taxes (0.6 million), increased marketing bans (0.4 million), smoke-free air laws (0.3 million) and cessation interventions (2500). These findings demonstrate the continuing public health impact of tobacco control policies adopted globally since the FCTC, and highlight the importance of more countries adopting MPOWER policies at the highest level to reduce the global burden of tobacco use.


The medical director--the untapped potential of the position.
The increasing complexities of hospitals and their relationships with their medical staffs require a complete examination of the environment to reveal ways to enhance hospital outcomes. A properly trained and empowered medical director can be the missing link that ensures the continuity and coordination necessary for the best possible outcomes in patient care, economic survival and growth, or simply a more collegial work atmosphere. The medical director can assume vital responsibilities with physicians, policymakers, and departments and other hospital areas to enable an institution and its medical staff to carry out their mission in an increasingly difficult and hostile environment.


Biomechanical investigation of titanium elastic nail prebending for treating diaphyseal long bone fractures.
This study numerically investigated the deformation of titanium elastic nails prebent at various degrees during implantation into the intramedullary canal of fractured bones and the mechanism by which this prebending influenced the stability of the fractured bone. Three degrees of prebending the implanted portions of the nails were used: equal to, two times, and three times the diameter of the intramedullary canal. Furthermore, a simulated diaphyseal fracture with a 5-mm gap was created in the middle shaft portion of the bone fixed with two elastic nails in a double C-type configuration. End caps were simulated using a constraint equation. To confirm that the simulation process is able to present the mechanical response of the nail inside the intramedullary, an experiment was conducted by using sawbone for validation. The results indicated that increasing the degrees of nail prebending facilitated straightening the nails against the inner aspect of canal after implantation, with increase in stability under torsion. Furthermore, reducing nail prebending caused a larger portion of the nails to move closer to the loading site and center of bone after implantation; the use of end caps prevented the nail tips from collapsing and increased axial stability. End cap use was critical for preventing the nail tips from collapsing and for increasing the stability of the nails prebent at a degree equal to the diameter of the canal with insufficient frictional force between the nail and canal. Therefore, titanium elastic nail prebending in a double C-type configuration with a degree three times the diameter of the canal represents a superior solution for treating transverse fractures without a gap, whereas that with a degree equal to the diameter of the intramedullary canal and combined with end cap use represents an advanced solution for treating comminuted fractures in a diaphyseal long bone fracture.


Skeletal Muscle Disuse Atrophy and the Rehabilitative Role of Protein in Recovery from Musculoskeletal Injury.
Muscle atrophy and weakness occur as a consequence of disuse after musculoskeletal injury (MSI). The slow recovery and persistence of these deficits even after physical rehabilitation efforts indicate that interventions designed to attenuate muscle atrophy and protect muscle function are necessary to accelerate and optimize recovery from MSI. Evidence suggests that manipulating protein intake via dietary protein or free amino acid-based supplementation diminishes muscle atrophy and/or preserves muscle function in experimental models of disuse (i.e., immobilization and bed rest in healthy populations). However, this concept has rarely been considered in the context of disuse following MSI, which often occurs with some muscle activation during postinjury physical rehabilitation. Given that exercise sensitizes skeletal muscle to the anabolic effect of protein ingestion, early rehabilitation may act synergistically with dietary protein to protect muscle mass and function during postinjury disuse conditions. This narrative review explores mechanisms of skeletal muscle disuse atrophy and recent advances delineating the role of protein intake as a potential countermeasure. The possible synergistic effect of protein-based interventions and postinjury rehabilitation in attenuating muscle atrophy and weakness following MSI is also considered.


Equisetum arvense L. Extract Induces Antibacterial Activity and Modulates Oxidative Stress, Inflammation, and Apoptosis in Endothelial Vascular Cells Exposed to Hyperosmotic Stress.
The antimicrobial activity of the Equisetum arvense L. extract and the mechanisms involved in the in vitro effects on endothelial vascular cells exposed to hyperosmotic stress were evaluated. Antimicrobial activity was evaluated by disk diffusion method and minimum inhibitory concentration (MIC) determination, and oxidative stress, inflammation, and apoptosis, in pretreatment with Equisetum arvense L., caffeic acid, and cathechin, were quantified. The results have shown that Equisetum arvense L. exhibited antibacterial effects only on pathogenic gram-positive cocci. The modulatory activity of Equisetum arvense L. on endothelial cells exposed to hypertonic medium was different and depended on the concentration used. Low concentrations of tested compounds exerted antioxidant effect and diminished the activity of caspase-8 and also increased IκB expression while in high doses, Equisetum arvense L. was prooxidant, induced apoptosis, and decreased IL-6 secretion. These experimental findings suggest that Equisetum arvense L. has antibacterial effects on gram-positive cocci and, administered in low dose, may be a new therapeutic approach for diseases associated with hypertonic conditions or oxidative stress and apoptosis.


Regulation of interleukin-1beta by interferon-gamma is species specific, limited by suppressor of cytokine signalling 1 and influences interleukin-17 production.
Reports describing the effect of interferon-gamma (IFNgamma) on interleukin-1beta (IL-1beta) production are conflicting. We resolve this controversy by showing that IFNgamma potentiates IL-1beta release from human cells, but transiently inhibits the production of IL-1beta from mouse cells. Release from this inhibition is dependent on suppressor of cytokine signalling 1. IL-1beta and Th17 cells are pathogenic in mouse models for autoimmune disease, which use Mycobacterium tuberculosis (MTB), in which IFNgamma and IFNbeta are anti-inflammatory. We observed that these cytokines suppress IL-1beta production in response to MTB, resulting in a reduced number of IL-17-producing cells. In human cells, IFNgamma increased IL-1beta production, and this might explain why IFNgamma is detrimental for multiple sclerosis. In mice, IFNgamma decreased IL-1beta and subsequently IL-17, indicating that the adaptive immune response can provide a systemic, but transient, signal to limit inflammation.


Casein kinase I delta controls centrosome positioning during T cell activation.
Although termed central body, the centrosome is located off-center in many polarized cells. T cell receptor (TCR) engagement by antigens induces a polarity switch in T cells. This leads to the recruitment of the centrosome to the immunological synapse (IS), a specialized cell-cell junction. Despite much recent progress, how TCR signaling triggers centrosome repositioning remains poorly understood. In this paper, we uncover a critical requirement for the centrosomal casein kinase I delta (CKIδ) in centrosome translocation to the IS. CKIδ binds and phosphorylates the microtubule plus-end-binding protein EB1. Moreover, a putative EB1-binding motif at the C terminus of CKIδ is required for centrosome translocation to the IS. We find that depletion of CKIδ in T lymphocytes and inhibition of CKI in epithelial cells reduce microtubule growth. Therefore, we propose that CKIδ-EB1 complexes contribute to the increase in microtubule growth speeds observed in polarized T cells, a mechanism that might serve to generate long-stable microtubules necessary for centrosome translocation.


Canal Transportation and Centering Ability of ProTaper and SafeSider in Preparation of Curved Root Canals: A CBCT Evaluation.
Maintaining the original central canal path is an important parameter in efficient root canal preparation. Instruments causing minimal changes in original canal path are preferred for this purpose. This study sought to compare canal transportation and centering ability of ProTaper and SafeSider instruments in curved mesiobuccal root canals of mandibular first molars using cone beam computed tomography (CBCT). In this experimental study, 30 mesiobuccal root canals of extracted human mandibular first molars with 20° to 40° curvature were randomly divided into two groups (n=15). After mounting in putty, preoperative CBCT scans were obtained of teeth. Root canals in group A were shaped using S1, S2, F1 and F2 of ProTaper system. Root canals in group B were instrumented to size 25 using SafeSider system according to the manufacturers' instructions. Postoperative CBCT scans were then obtained. The distance between the external root surface and internal canal wall was measured at the mesial and distal at 1, 3 and 7 mm from the apex. The values measured on primary and secondary CBCT scans were compared to assess possible changes in original central canal path and canal transportation. Data were compared using the t-test and repeated measure ANOVA. ProTaper and SafeSider were significantly different in terms of canal transportation and centering ability, and ProTaper was significantly superior to SafeSider in this respect (P<0.001). ProTaper (in contrast to SafeSider) is well capable of maintaining the original central canal path with the least amount of transportation.


Linked anatomical and functional brain alterations in children with attention-deficit/hyperactivity disorder.
Neuroimaging studies have independently demonstrated brain anatomical and functional impairments in participants with ADHD. The aim of the current study was to explore the relationship between structural and functional brain alterations in ADHD through an integrated analysis of multimodal neuroimaging data. We performed a multimodal analysis to integrate resting-state functional magnetic resonance imaging (MRI), structural MRI, and diffusion-weighted imaging data in a large, single-site sample of children with and without diagnosis for ADHD. The inferred subject contributions were fed into regression models to investigate the relationships between diagnosis, symptom severity, gender, and age. Compared with controls, children with ADHD diagnosis showed altered white matter microstructure in widespread white matter fiber tracts as well as greater gray matter volume (GMV) in bilateral frontal regions, smaller GMV in posterior regions, and altered functional connectivity (FC) in default mode and fronto-parietal networks. Age-related growth of GMV of bilateral occipital lobe, FC in frontal regions as well as age-related decline of GMV in medial regions seen in controls appeared reversed in children with ADHD. In the whole group, higher symptom severity was related to smaller GMV in widespread regions in bilateral frontal, parietal, and temporal lobes, as well as greater GMV in intracalcarine and temporal cortices. Through a multimodal analysis approach we show that structural and functional alterations in brain regions known to be altered in subjects with ADHD from unimodal studies are linked across modalities. The brain alterations were related to clinical features of ADHD, including disorder status, age, and symptom severity.


Bayesian neural network approach for determining the risk of re-intervention after endovascular aortic aneurysm repair.
This article proposes a Bayesian neural network approach to determine the risk of re-intervention after endovascular aortic aneurysm repair surgery. The target of proposed technique is to determine which patients have high chance to re-intervention (high-risk patients) and which are not (low-risk patients) after 5 years of the surgery. Two censored datasets relating to the clinical conditions of aortic aneurysms have been collected from two different vascular centers in the United Kingdom. A Bayesian network was first employed to solve the censoring issue in the datasets. Then, a back propagation neural network model was built using the uncensored data of the first center to predict re-intervention on the second center and classify the patients into high-risk and low-risk groups. Kaplan-Meier curves were plotted for each group of patients separately to show whether there is a significant difference between the two risk groups. Finally, the logrank test was applied to determine whether the neural network model was capable of predicting and distinguishing between the two risk groups. The results show that the Bayesian network used for uncensoring the data has improved the performance of the neural networks that were built for the two centers separately. More importantly, the neural network that was trained with uncensored data of the first center was able to predict and discriminate between groups of low risk and high risk of re-intervention after 5 years of endovascular aortic aneurysm surgery at center 2 (p = 0.0037 in the logrank test).


Acute respiratory failure revealing a multilocular thymic cyst in an infant: a case report.
Multilocular thymic cysts are rare benign lesions of the neck and mediastinum that can occur at any age. In children, multilocular thymic cysts are usually symptomatic after the age of 2 years and produce few symptoms. We present an unusual case of a multilocular thymic cyst diagnosed in a 3-month-old girl and causing severe respiratory failure. A 3 month-old-girl, with a medical history of dyspnea and wheezing since the age of 20 days, presented in our pediatric intensive care unit for acute respiratory failure requiring mechanical ventilation. The chest radiograph showed thoracic distension without any other abnormalities. The diagnosis of severe asthma was initially suspected and the patient was treated by intravenous corticosteroids and continuous perfusion of salbutamol without any improvement. A chest tomography scan was performed and demonstrated an anterior mediastinal multiseptated cystic mass extending from the inferior face of the thyroid gland to the left cardiophrenic angle. Sternotomy and excision biopsy were planned urgently. The cystic mass was excised completely. The histopathological examination confirmed the diagnosis of a multilocular thymic cyst. The particularities of our observation are the occurrence of a multilocular thymic cyst in a young infant and its presentation by a severe acute respiratory failure mimicking asthma.


Augmentation of pulmonary host defense against Pseudomonas by FcgammaRIIA cDNA transfer to the respiratory epithelium.
Fcgamma receptors on the surface of phagocytic cells bind the Fc region of IgG and mediate binding, phagocytosis, and destruction of particulate antigens opsonized by the antigen-specific IgG molecule. The present study evaluates the feasibility of converting lung epithelial cells into phagocytic cells using adenovirus (Ad) vector-mediated gene transfer of FcgammaRIIA cDNA to induce expression of the human FcgammaRIIA receptor. Binding and phagocytosis of opsonized sheep red blood cells (SRBCs) by the A549 human lung epithelial cell line after Ad-mediated FcgammaRIIA gene transfer was demonstrated using light and fluorescence microscopy and phagocytic assays with (51)Cr-labeled SRBCs. When A549 cells were infected with an Ad vector expressing a FcgammaRIIA mutant in which 2 of 3 cytoplasmic tyrosines have been replaced with phenylalanine, only binding, but not phagocytosis, of opsonized SRBCs was observed. In vivo expression of FcgammaRIIA in the lung after intratracheal administration of the AdFcgammaRIIA enhanced clearance of opsonized Pseudomonas aeruginosa from the lung in normal rats and in mice deficient in Fcgamma receptor expression. Similar results were observed with a chimeric FcgammaRIIA construct containing the extracellular domain of FcgammaRIIIA. Together, these data demonstrate that Ad-mediated FcgammaRIIA receptor cDNA expression can mediate the binding and phagocytosis of opsonized particulate antigens by normally nonphagocytic cells, suggesting that gene-transfer strategies might be used to utilize nonphagocytic cells to clear bacteria or other opsonized particulate antigens from the respiratory tract.


[Use of infliximab in patients of a rheumatologic center].
The objective of this study was to obtain post-marketing information about the use of infliximab in an ambulatory setting. We studied--retrospectively and prospectively--the case records of patients with rheumatoid arthritis (n=37), psoriatic arthritis (n=5), mixed connective tissue disease (n=1), and ankylosing spondylitis (n=2) who received infliximab (3 mg/kg) from August 2000 to January 2003. Descriptive values were given as percentage, mean or median, and standard deviation or interquartile range. Wilcoxon test was used for paired analysis of pre/post doses of corticosteroids, non-steroidal anti-inflammatory drugs, and methotrexate therapy. A p value < or = 0.05 was considered significant. Forty-five patients were included. A total of 207 infusions were administered. In 4 patients the treatment was permanently discontinued due to severe back pain during the infusion (2 cases) and serious anaphylactic reactions (2 cases). Other adverse reactions occurring during infusions were mild and successfully managed with standard treatment. A case of staphylococcal septic arthritis resolved with standard antibiotic treatment. No patient had evidence of active tuberculosis. One patient with rheumatoid arthritis and chronic renal insufficiency, received treatment with infliximab 1.9 mg/kg, every 30 days, with no changes in renal function. Due to improvement of symptoms, 14/39 (35.9%) patients could decrease the doses of corticosteroids, 15/43 (34.8%) decreased the doses of antiinflammatory drugs and 12/34 (35.3%) decreased methotrexate dosage. Although some questions remain to be elucidated, this case series shows the drug safety profile, the possibility to reduce concomitant drug doses, as well as individual approaches for situations where there are not yet guidelines available, so that rheumatologists have to make decisions based on clinical needs.


The expanded footprint of the Deepwater Horizon oil spill in the Gulf of Mexico deep-sea benthos.
The 2010 Deepwater Horizon blowout off the coast of Louisiana caused the largest marine oil spill on record. Samples were collected 2-3 months after the Macondo well was capped to assess damage to macrofauna and meiofauna communities. An earlier analysis of 58 stations demonstrated severe and moderate damage to an area of 148 km2. An additional 58 archived stations have been analyzed to enhance the resolution of that assessment and determine if impacts occurred further afield. Impacts included high levels of total petroleum hydrocarbons (TPH) and polycyclic aromatic hydrocarbons (PAH) in the sediment, low diversity, low evenness, and low taxonomic richness of the infauna communities. High nematode to copepod ratios corroborated the severe disturbance of meiofauna communities. Additionally, barium levels near the wellhead were very high because of drilling activities prior to the accident. A principal component analysis (PCA) was used to summarize oil spill impacts at stations near the Macondo well, and the benthic footprint of the DWH oil spill was estimated using Empirical Bayesian Kriging (EBK) interpolation. An area of approximately 263 km2 around the wellhead was affected, which is 78% higher than the original estimate. Particularly severe damages to benthic communities were found in an area of 58 km2, which is 142% higher than the original estimate. The addition of the new stations extended the area of the benthic footprint map to about twice as large as originally thought and improved the resolution of the spatial interpolation. In the future, increasing the spatial extent of sampling should be a top priority for designing assessment studies.


Additive subdistribution hazards regression for competing risks data in case-cohort studies.
In survival data analysis, a competing risk is an event whose occurrence precludes or alters the chance of the occurrence of the primary event of interest. In large cohort studies with long-term follow-up, there are often competing risks. Further, if the event of interest is rare in such large studies, the case-cohort study design is widely used to reduce the cost and achieve the same efficiency as a cohort study. The conventional additive hazards modeling for competing risks data in case-cohort studies involves the cause-specific hazard function, under which direct assessment of covariate effects on the cumulative incidence function, or the subdistribution, is not possible. In this paper, we consider an additive hazard model for the subdistribution of a competing risk in case-cohort studies. We propose estimating equations based on inverse probability weighting methods for the estimation of the model parameters. Consistency and asymptotic normality of the proposed estimators are established. The performance of the proposed methods in finite samples is examined through simulation studies and the proposed approach is applied to a case-cohort dataset from the Sister Study.


Experimental and modeling study of collagen scaffolds with the effects of crosslinking and fiber alignment.
Collagen type I scaffolds are commonly used due to its abundance, biocompatibility, and ubiquity. Most applications require the scaffolds to operate under mechanical stresses. Therefore understanding and being able to control the structural-functional integrity of collagen scaffolds becomes crucial. Using a combined experimental and modeling approach, we studied the structure and function of Type I collagen gel with the effects of spatial fiber alignment and crosslinking. Aligned collagen scaffolds were created through the flow of magnetic particles enmeshed in collagen fibrils to mimic the anisotropy seen in native tissue. Inter- and intra- molecular crosslinking was modified chemically with Genipin to further improve the stiffness of collagen scaffolds. The anisotropic mechanical properties of collagen scaffolds were characterized using a planar biaxial tensile tester and parallel plate rheometer. The tangent stiffness from biaxial tensile test is two to three orders of magnitude higher than the storage moduli from rheological measurements. The biphasic nature of collagen gel was discussed and used to explain the mechanical behavior of collagen scaffolds under different types of mechanical tests. An anisotropic hyperelastic constitutive model was used to capture the characteristics of the stress-strain behavior exhibited by collagen scaffolds.


Patient Safety Indicators: using administrative data to identify potential patient safety concerns.
To develop Patient Safety Indicators (PSI) to identify potential in-hospital patient safety problems for the purpose of quality improvement. The data source was 2,400,000 discharge records in the 1997 New York State Inpatient Database. PSI algorithms were developed using systematic literature reviews of indicators and hand searches of the ICD-9-CM code book. The prevalence of PSI events and associations between PSI events and patient-level and hospital-level characteristics, length of stay, in-hospital mortality, and hospital charges were examined. PSIs were developed for 12 distinct clinical situations and an overall summary measure. The 1997 event rates per 10,000 discharges varied from 1.1 for foreign bodies left during procedure to 84.7 for birth traumas. Discharge records with PSI events had twofold to threefold longer hospital stays, twofold to 20-fold higher rates of in-hospital mortality, and twofold to eightfold higher total charges than records without PSI events. Multivariate logistic regression revealed that PSI events were primarily associated with increasing age (p < .001), hospitals performing more inpatient surgery (p < .001), and hospitals with higher percentage of beds in intensive care units (p < .001). The PSIs provide an efficient and user-friendly tool to identify potential inhospital patient safety problems for targeted institution-level quality improvement efforts. Until better error-reporting systems are developed the PSIs can serve to shed light on the problem of medical errors not limited solely to mortality because of errors.


Patient-evaluated dentistry: development and validation of a patient satisfaction questionnaire for fixed prosthodontic treatment.
The aim of this study was to develop and verify the reliability and validity of a questionnaire to assess patient satisfaction with fixed dental prostheses (FDPs). A questionnaire was developed, pilot-tested, and modified. It assessed esthetics, masticatory function, phonetics, cleansibility, and cost satisfaction using a visual analog scale and whether patients would elect to undergo the same treatment again (yes/no). It was sent to patients with a known evidence-based outcome (survival) who received FDPs from 1984 to 2005 (n = 986) in one private prosthodontic practice. Reliability and validity were analyzed using the Student t, Mann-Whitney U, Kruskal Wallis, Cronbach alpha, Spearman-Brown, Correlation matrix, Bartlett sphericity, Kaiser-Meyer-Olkin (KMO), and factor analysis tests. Significance was set at P = .05. Five hundred patients responded (50.7%). A Cronbach alpha value of 0.8 and split-sample Spearman-Brown value of 0.7 indicated good reliability. Step-wise removal of items did not improve internal consistency. Discriminant construct validity assessment showed no item redundancy. Satisfaction of patients who had experienced prosthesis failure (n = 52) was significantly less than their counterparts (73% ± 3% vs 83% ± 0.6%, P = .004), ascertaining convergent construct validity. Factor analysis (Bartlett sphericity, P < .001; KMO = 0.84) identified two components (Eigenvalues ⋝ 1.0) that explained 93.18% (varimax rotation) of variations. Component 1 included satisfaction with function (esthetics, mastication, phonetics, and cleansibility); component 2 included satisfaction with costs and whether patients would undergo the same treatment again. The Patient Satisfaction Questionnaire developed proved reliable and valid for assessing patient-evaluated outcomes of FDPs. Use of this questionnaire in further research is justified. Int J Prosthodont 2011;24:332-341.


Influence of aspirin on outcome following aneurysmal subarachnoid hemorrhage.
Previous studies have indicated an increased incidence of death in patients with subarachnoid hemorrhage (SAH) who are currently receiving anticoagulation therapy. The significance of previous aspirin use in patients with SAH is unknown. The authors analyzed the effects of prior aspirin use on clinical course and outcomes following aneurysmal SAH. The medical records of 305 patients with angiogram-confirmed aneurysmal SAH who consecutively presented to our institution between 1990 and 1997 within 7 days of ictus were analyzed. Twenty-nine (9.5%) of these patients had a history of regular aspirin use before onset of the SAH. The Glasgow Outcome Scale (GOS) was used to measure patient outcome at the longest available follow up. Aspirin users were older on average than nonusers (59 years of age compared with 53 years; p = 0.018). The mean admission Hunt and Hess grades of patients with and without aspirin use were similar (2 compared with 2.3; p = 0.51). Two trends, which did not reach statistical significance, were observed. 1) The rebleeding rate in aspirin users was 14.3%, compared with a 4.7% rebleeding rate in nonusers (p = 0.06). 2) Permanent disability from vasospasm was less common among aspirin users (23% compared with 50%; p = 0.069). Outcomes did not differ between aspirin users and nonusers (mean GOS Score 3.83 compared with GOS Score 3.86, respectively; p = 0.82). Despite trends indicating increased rebleeding rates and a lower incidence of permanent disability due to delayed ischemic neurological deficits, there was no significant effect of previous aspirin use on overall outcome following aneurysmal SAH. Based on these preliminary data, the presence of an intracranial aneurysm is not a strict contraindication to aspirin use.


In vivo determination of mu opioid receptor turnover in rhesus monkeys after irreversible blockade with clocinnamox.
In a warm-water tail withdrawal antinociception assay performed at 45, 50 and 55 degrees C in the rhesus monkey, the irreversible opioid antagonist clocinnamox at a dose of 0.1 mg/kg s.c. produced an acute rightward shift of the dose-response curves of the selective mu opioid agonists alfentanil and morphine at all tested temperatures. In addition, clocinnamox depressed the maxima of the dose-response curves for both agonists at 50 and 55 degrees C. Analysis of these data according to Furchgott as modified by Black and Leff showed that clocinnamox acutely decreased mu opioid receptors available for alfentanil by 88%; receptor numbers returned to control levels with a half-life of 6.3 days. Assessment of receptor population changes after clocinnamox administration with either alfentanil or morphine gave essentially identical results: 2 to 4 weeks after clocinnamox, the receptor population not only returned to preclocinnamox levels, but actually showed an overshoot. In contrast, apparent values of alfentanil affinity; its efficacy, e; the theoretically obtainable maximum effect of the mu opioid antinociceptive system, Em; and the stimulus-response transducing factor, n; did not change significantly over time. Alfentanil showed a 29-fold higher affinity than morphine, the respective KA values being 0.84 mg/kg for alfentanil and 24 mg/kg for morphine. The efficacy of alfentanil was always 2- to 3-fold higher than that of morphine for any temperature tested, the efficacies of both mu opioid agonists being higher at lower temperatures.(ABSTRACT TRUNCATED AT 250 WORDS)


Disability and health outcomes - from a cohort of people on long-term anti-retroviral therapy.
Human-immunodeficiency virus (HIV)/Acquired immunodeficiency Syndrome (AIDS) remains a major health problem in South Africa - even after two decades since the introduction of antiretroviral therapy (ART). Long-term survival with HIV is associated with new health-related issues and a risk of functional limitation/disability. The aim of this study was to assess functional limitation associated with HIV/AIDS among people living with HIV (PLHIV) in South Africa. This study is a cross-sectional survey using a cohort in an urban area in Gauteng province, South Africa. Data were collected using questionnaires through an interview process. The information collected included aspects such as demographics, livelihood, the state of mental and physical health, adherence and disability. A total of 1044 participants with an average age of 42 ± 12 years were included in the study, with 51.9% of the participants reporting functional limitations (WHODAS ≥ 2). These were reported mainly in the domains of participation (40.2%) and mobility (38.7%). In addition, adherence to ART, symptoms of poor physical health and depression were strongly associated with their functional limitations/disability. HIV as a chronic disease is associated with functional limitations that are not adequately addressed and pose a risk of long-term disability and negative adherence outcomes. Therefore, wellness for PLHIV/AIDS needs to include interventions that can prevent and manage disability.


Mechanical Buckling Analysis of Saturated Porous Functionally Graded Elliptical Plates Subjected to In-Plane Force Resting on Two Parameters Elastic Foundation Based on HSDT.
In this paper, mechanical buckling analysis of a functionally graded (FG) elliptical plate, which is made up of saturated porous materials and is resting on two parameters elastic foundation, is investigated. The plate is subjected to in-plane force and mechanical properties of the plate assumed to be varied through the thickness of it according to three different functions, which are called porosity distributions. Since it is assumed that the plate to be thick, the higher order shear deformation theory (HSDT) is employed to analyze the plate. Using the total potential energy function and using the Ritz method, the critical buckling load of the plate is obtained and the results are verified with the simpler states in the literature. The effect of different parameters, such as different models of porosity distribution, porosity variations, pores compressibility variations, boundary conditions, and aspect ratio of the plate, is considered and has been discussed in details. It is seen that increasing the porosity coefficient decreases the stiffness of the plate and consequently the critical buckling load will be reduced. Also, by increasing the pores' compressibility, the critical buckling load will be increased. Adding the elastic foundation to the structure will increase the critical buckling load. The results of this study can be used to design more efficient structures in the future.


Organizational Structure Reduces Processing Load in the Prefrontal Cortex During Discourse Processing of Written Text: Implications for High-Level Reading Issues After TBI.
Adults with traumatic brain injury (TBI) can demonstrate marked difficulty producing discourse during story retell and story generation tasks. Changes in discourse production have been detailed in terms of fewer content units and infrequent use of story grammar elements essential for organization. One implication is that poor use of story grammar elements during discourse production may signal reduced ability to utilize these elements in other communication realms (e.g., reading comprehension). The neural architecture that supports discourse organization, primarily the medial prefrontal cortex, is particularly susceptible to damage secondary to acquired brain injury. In this event related functional magnetic resonance imaging (fMRI) study, we describe cortical activation patterns of unimpaired readers as they are presented with discourse that is varied in terms of structural organization. The results suggest reading discourse with less structure is associated with increased cortical activity (e.g., higher processing demands) as compared to reading discourse with more traditional structural cues (e.g., story grammar). We discuss cortical areas implicated and potential implications for supporting discourse communication in persons following TBI.


Suppressing glucose transporter gene expression in schistosomes impairs parasite feeding and decreases survival in the mammalian host.
Adult schistosomes live in the host's bloodstream where they import nutrients such as glucose across their body surface (the tegument). The parasite tegument is an unusual structure since it is enclosed not by the typical one but by two closely apposed lipid bilayers. Within the tegument two glucose importing proteins have been identified; these are schistosome glucose transporter (SGTP) 1 and 4. SGTP4 is present in the host interactive, apical tegumental membranes, while SGTP1 is found in the tegumental basal membrane (as well as in internal tissues). The SGTPs act by facilitated diffusion. To examine the importance of these proteins for the parasites, RNAi was employed to knock down expression of both SGTP genes in the schistosomula and adult worm life stages. Both qRT-PCR and western blotting analysis confirmed successful gene suppression. It was found that SGTP1 or SGTP4-suppressed parasites exhibit an impaired ability to import glucose compared to control worms. In addition, parasites with both SGTP1 and SGTP4 simultaneously suppressed showed a further reduction in capacity to import glucose compared to parasites with a single suppressed SGTP gene. Despite this debility, all suppressed parasites exhibited no phenotypic distinction compared to controls when cultured in rich medium. Following prolonged incubation in glucose-depleted medium however, significantly fewer SGTP-suppressed parasites survived. Finally, SGTP-suppressed parasites showed decreased viability in vivo following infection of experimental animals. These findings provide direct evidence for the importance of SGTP1 and SGTP4 for schistosomes in importing exogenous glucose and show that these proteins are important for normal parasite development in the mammalian host.


Cannabidiol promotes apoptosis of osteosarcoma cells in vitro and in vivo by activating the SP1-CBX2 axis.
Osteosarcoma is the most common primary malignant bone tumor that often occurs in children, adolescents, and young adults. Cannabidiol plays an essential role in cancer treatment. However, its effects on osteosarcoma have not yet been addressed. In the present study, we investigated the pharmacological effects of cannabidiol on osteosarcoma. We found that cannabidiol effectively suppressed the proliferation and colony formation of osteosarcoma cells. Further studies showed that cannabidiol significantly promoted cell apoptosis and changes in cell apoptosis-related gene proteins in vitro. In addition, cannabidiol administration inhibited tumor growth and promoted the apoptosis of osteosarcoma cells in a mouse xenograft model. The in vitro study also demonstrated that SP1 contributes to chromobox protein homolog 2 (CBX2) reduction in cannabidiol-treated MG63 and HOS cells, and that cannabidiol may recruit SP1 into the CBX2 promoter regions to downregulate CBX2 expression at the transcriptional level and promote osteosarcoma cell apoptosis. Further, the result showed that cannabidiol suppressed osteosarcoma cell migration. In summary, cannabidiol effectively promoted the apoptosis of osteosarcoma cells in vitro and in vivo and suppressed tumor growth in a mouse xenograft model by regulating the SP1-CBX2 axis. This finding provides novel therapeutic strategies for osteosarcoma in the clinic.