Lifetime antiretroviral exposure and neurocognitive impairment in HIV.
Despite the availability of modern antiretroviral therapy (ART), neurocognitive impairment persists among some persons with HIV (PWH). We investigated the role of exposure to four major classes of ARTs in neurocognitive impairment in PWH. A single-site cohort of 343 PWH was recruited. Lifetime ART medication history was obtained from medical health records. We evaluated the role of ART exposure as a predictor of neurocognitive impairment using univariate analyses and machine learning, while accounting for potential effects of demographic, clinical, and comorbidity-related risk factors. Out of a total of 26 tested variables, two random forest analyses identified the most important characteristics of a neurocognitively impaired group (N = 59): Compared with a neurocognitively high-performing group (N = 132; F1-score = 0.79), we uncovered 13 important risk factors; compared with an intermediate-performing group (N = 152; F1-score = 0.75), 16 risk factors emerged. Longer lifetime ART exposure, especially to integrase inhibitors, was one of the most important predictors of neurocognitive impairment in both analyses (rank 2 of 13 and rank 4 of 16, respectively), superseding effects of age (rank 11/13, rank 15/16) and HIV duration (rank 13/13, rank 16/16). Concerning specific integrase inhibitors, the impaired group had significantly longer dolutegravir exposure (p = 0.011) compared with the high-performing group (p = 0.012; trend compared with the intermediate group p = 0.063). A longer duration to integrase inhibitor intake was negatively related to cognition in this cohort. Our findings suggest that possible cognitive complications of long-term exposure to integrase inhibitors, in particular dolutegravir, should be closely monitored in PWH.


Modulation of the kinetics of induced neutrophil superoxide generation by fluoride.
Fluoride (F-) is unique in that, depending upon concentration, it can either stimulate or inhibit the synthesis of the neutrophil's major intracellular microbicidal product, superoxide anion (O2-). While a number of studies have delved into F- induction of O2- generation, little has been reported on the effect of F- on the synthesis of O2- induced by other agents. In this report, we show that F- inhibits the activation and activity of neutrophils induced either by formyl-methionyl-leucylphenylalanine (FMLP) or by phorbol myristate acetate (PMA). The extent of increase in lag period and decrease in velocity of O2- synthesis was found to be directly related to the concentrations of F- and of hydrogen ion in the medium and to the length of contact time between the neutrophil and F-. Decreasing the pH of the medium, while maintaining a constant concentration of F-, disproportionately increased the inhibitory effect of the anion over the effect of pH alone. Fluoride inhibited the responsiveness of neutrophils to FMLP more than it did their responsiveness to PMA. A gradual but partial reversal of F-'s inhibition of O2- synthesis could be achieved by transferring inhibited cells to F(-)-free medium. Our study shows that the suppression of both FMLP- and PMA-induced synthesis of O2- by neutrophils is most dramatic at a reduced pH and is probably related to the intracellular accumulation of F-.(ABSTRACT TRUNCATED AT 250 WORDS)


An e-mental health intervention to support burdened people in times of the COVID-19 pandemic: CoPE It.
The outbreak of the novel SARS CoV-2-virus (COVID-19) is pushing national and international healthcare systems to their limits. The aspect of mental health issues, which has been neglected (so far) in times of social isolation and governmental restrictions, now demands innovative and situation-based approaches to support psychological burdened people. The developed e-mental health intervention 'CoPE It' offers manualized, evidence-based psychotherapeutic/psychological support to overcome psychological distress in times of COVID-19. E-mental health approaches offer great possibilities to support burdened people during the SARS-CoV-2 pandemic effectively.


Management of urinary calculous disease in patients with ureterocele.
Of 37 adult patients with ureteroceles, 13 also had calculous disease (35 per cent). Of these 13 cases 7 had single ureters and 6 had duplicated ones. None had a metabolic or urinary abnormality such as hypercalcemia, gout, hypercalciuria or hyperuricuria. Two of the patients were a mother and daugher--the first reported familial incidence of ureterocele with calculous disease. A surgical technique is described for removal of the calculus, excision of the ureterocele and reimplantation of the ureter. The procedure was used in 4 of the 7 patients with single ureters, while the stone passed spontaneously in 2 patients and was treated by ureterolithotomy in 1. A modification of the technique was used in 2 of the 6 patients with duplicated ureters but other surgical procedures were used in the remaining 4. Of 10 stones that were analyzed 2 were struvite and none contained cystine or uric acid. Long-term followup is a requisite to assure control of this clinical entity.


ACCURACY OF REMOVABLE PARTIAL DENTURE METAL FRAMEWORKS FABRICATED BY COMPUTER-AIDED DESIGN/ COMPUTER-AIDED MANUFACTURING METHOD: A SYSTEMATIC REVIEW AND META-ANALYSIS.
This systematic review and meta-analysis aimed to investigate the accuracy of removable partial denture (RPD) frameworks fabricated by computer-aided design/ computer-aided manufacturing (CAD/CAM) systems compared to frameworks produced by conventional casting methods. A systematic literature search was conducted in electronic databases following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, using formulated Boolean operator for searching articles evaluating the fit accuracy of CAD/CAM-fabricated RPD metal frameworks. The agreement of data collection among the reviewers was confirmed using the Cohen kappa coefficient. The modified methodological index for non-randomized studies (MINORS) scale was used to assess the quality of the included studies. Heterogeneity among studies was evaluated, and meta-analyses with global and subgroup analyses were performed. A total of 208 articles were identified with 18 articles available for the narrative review and 7 studies available for meta-analysis on the 3D-printed frameworks for RPD (the overall Cohen kappa coefficient = 0.944). There was no article on the accuracy of RPD frameworks made by milling method. The meta-analysis revealed that the misfit of frameworks obtained with the CAD/CAM method was significantly higher than that of the conventional lost wax and casting method (SMD = 1.23 μm, 95% CI = 0.3610-2.0981 μm, z = 2.77, P = .0055). Regarding the CAD/CAM techniques used for fabricating RPD metal frameworks, the within subgroup analysis showed that the CAD/CAM-based indirect fabrication method produced frameworks with fit accuracy more similar to the conventional lost-wax and casting method (SMD = 1.15 μm, 95% CI = - 0.06136-2.9192 μm, z = 1.28, P < .01) than the CAD/CAM-based direct fabrication method (SMD = 1.35 μm, 95% CI = -0.2722-2.4381 μm, z = 2.45, P < .01), even though there was no statistical difference between the techniques (P = .8482). The fit accuracy of RPD metal frameworks fabricated by the CAD/CAM method was lower than that of frameworks fabricated by the conventional casting method, but it was within the clinically acceptable range in dimensional misfit. The indirect metal 3D printing technique based on pattern printing and subsequent casting produced frameworks with fit accuracy more similar to the conventional method than the direct fabrication technique.


Thermogenesis and related metabolic targets in anti-diabetic therapy.
Exercise, together with a low-energy diet, is the first-line treatment for type 2 diabetes type 2 diabetes . Exercise improves insulin sensitivity insulin sensitivity by increasing the number or function of muscle mitochondria mitochondria and the capacity for aerobic metabolism, all of which are low in many insulin-resistant subjects. Cannabinoid 1-receptor antagonists and β-adrenoceptor agonists improve insulin sensitivity in humans and promote fat oxidation in rodents independently of reduced food intake. Current drugs for the treatment of diabetes are not, however, noted for their ability to increase fat oxidation, although the thiazolidinediones increase the capacity for fat oxidation in skeletal muscle, whilst paradoxically increasing weight gain.There are a number of targets for anti-diabetic drugs that may improve insulin sensitivity insulin sensitivity by increasing the capacity for fat oxidation. Their mechanisms of action are linked, notably through AMP-activated protein kinase, adiponectin, and the sympathetic nervous system. If ligands for these targets have obvious acute thermogenic activity, it is often because they increase sympathetic activity. This promotes fuel mobilisation, as well as fuel oxidation. When thermogenesis thermogenesis is not obvious, researchers often argue that it has occurred by using the inappropriate device of treating animals for days or weeks until there is weight (mainly fat) loss and then expressing energy expenditure energy expenditure relative to body weight. In reality, thermogenesis may have occurred, but it is too small to detect, and this device distracts us from really appreciating why insulin sensitivity has improved. This is that by increasing fatty acid oxidation fatty acid oxidation more than fatty acid supply, drugs lower the concentrations of fatty acid metabolites that cause insulin resistance. Insulin sensitivity improves long before any anti-obesity effect can be detected.


Seasonal expression of extracellular signal regulated kinases in the colon of wild ground squirrels (Spermophilus dauricus).
The purpose of the experiment was to explore the localization and seasonal expression of extracellular signal regulated kinase (ERK) in the colonic tissue of wild ground squirrels (Spermophilus dauricus). Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative PCR and Western blotting were used in this experiment. The histological results showed that the diameter of the colon lumen enlarged and the number of glandular cells increased in the non-breeding season. It was found in the immunochemical results that both ERK1/2 and pERK1/2 were expressed in the cytoplasm of goblet cells and intestinal epithelial cells, while pERK1/2 was also expressed in the nucleus of them. The immune localization of both was more obvious in the non-breeding season, especially in intestinal epithelial cells. Real-time quantitative PCR and Western blotting showed that ERK1/2 and pERK1/2 were seasonally highly expressed in the non-breeding season. The expression of ERK1/2 and pERK1/2 was seasonal changes and had significant increases in the non-breeding season. This study revealed that ERK1/2 had potential roles in the colon to the adaptation of seasonal changes in wild ground squirrels.


VEGF protects rat cortical neurons from mechanical trauma injury induced apoptosis via the MEK/ERK pathway.
Traumatic brain injury (TBI) is a serious insult that frequently leads to neurological dysfunction or death. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and vascular permeability. Recently, VEGF has been identified as a neurotrophic factor and has been implicated in the pathogenic mechanisms of TBI. However, the possible mechanisms of VEGF in primary or secondary injuries after TBI are largely unknown. The present study attempted to determine whether VEGF has a protective effect on primary cortical neurons against mechanical trauma injury, which is an in vitro insult mimicking traumatic brain injury. We found that pretreatment of primary cortical neurons in culture with VEGF decreased neuronal death in a concentration-dependent manner, and VEGF counteracted the mechanical trauma mediated apoptotic death of cultured cortical neurons. VEGF up-regulates the activity of ERK (extracellular signal-regulated kinase) in cultured cortical neurons and U0126 (a mitogen activated protein kinase kinase (MEK) inhibitor) suppressed VEGF induced activity of ERK. Furthermore, incubation of cells with U0126 attenuated the ability of VEGF to protect neurons against mechanical trauma-induced apoptosis. Therefore, the present study supports the notion that MEK/ERK pathway is involved in VEGF mediated neuroprotection against mechanical trauma injury.


Matrix metalloproteinase 2 and matrix metalloproteinase 9 expression in human oral squamous cell carcinoma and the effect of protein kinase C inhibitors: preliminary observations.
The purpose of this study was to investigate gelatinase (matrixmetalloproteinase [MMP]-2 and MMP-9) expression in oral squamous cell carcinoma (OSCC) and to explore the mechanisms that may inhibit gelatinase activity. Thirty biopsy specimens of OSCCs were examined by means of immunohistochemistry. Supernatants from primary cultures of human oral mucosal keratinocyte and oral cancer-derived cells (KB and OC2) were analyzed by means of gelatin zymography. Furthermore, protein kinase C (PKC) inhibitors (H7 and staurosporine) were added to test how they modulate gelatinase production in human oral cancer cells. MMP-2 and MMP-9 expression was significantly higher in oral SCCs and was located in discrete clusters of tumor cells. Oral mucosal keratinocyte cultures, KB, and OC2 were found to secrete and produce MMP-2 and MMP-9. However, the amounts of MMP-2 and MMP-9 were highly elevated in the 2 oral cancer cell lines in comparison with oral mucosal keratinocyte cultures (P <.05). In addition, PKC inhibitors were found to decrease MMP-2 and MMP-9 activities in oral cancer cells (P <.05). Taken together, human oral SCCs produce MMP-2 and MMP-9 in vivo and in vitro, and gelatinase activity is down-regulated by PKC inhibitors in vitro. PKC inhibitors suppressing MMP production and/or activity may represent valuable therapeutic agents through their influence on the pathogenesis of OSCC. These agents may prove clinically useful in combination with standard therapeutic modalities for the treatment of patients with oral cancer.


Consensus statement for the management of generalized tonic-clonic seizures in Spain.
To develop recommendations for the management of patients with primary or secondary generalized tonic-clonic seizures (GTCS) based on best evidence and experience. The Delphi methodology was followed. A multidisciplinary panel of 10 experts was established, who defined the scope, users and preliminary recommendations. Systematic and narrative reviews of the current literature were performed to assess data on the risk of sudden unexpected death in epilepsy and the efficacy and safety of add-on therapy in patients with GTCS. Twenty-five definitive recommendations were generated which were then graded on a scale of 1 (totally disagree) to 10 (totally agree) by the experts and 45 neurologists. Consensus was reached if at least 70% of the participants applied a score of ≥7. Each recommendation was then assigned a level of evidence, a grade of agreement and a grade of recommendation. The entire process was supervised by an expert methodologist. Overall, 24 out of 25 recommendations achieved consensus. These included specific recommendations on diagnosis, evaluation and treatment. The recommendations also emphasized the importance of proper psychological evaluation and effective communication between patients and health professionals, and the importance of patient and family education and support. The recommendations generated by this consensus can be used as a guide for the diagnosis and management of patients with GTCS.


Exciting times to study the identity and evolution of cell types.
The EMBO/EMBL Symposium on 'The Identity and Evolution of Cell Types' took place in Heidelberg, Germany, on 15-19 May 2019. The symposium, which brought together a diverse group of speakers addressing a wide range of questions in multiple model systems, provided a platform to discuss how the concept of a cell type should be considered in the era of single cell omics techniques and how cell type evolution can be studied.


Please take a seat in the virtual waiting room: Telepharmacy education in the pharmacy curriculum.
Student pharmacists who are tasked with providing patient care via telepharmacy may experience difficulty in integrating the clinical skills used for in-person counseling with the virtual environment. Navigation of the telepharmacy environment requires a unique set of skills that are currently lacking in pharmacy education. This commentary highlights opportunities to incorporate telepharmacy training into the current pharmacy curricula. Recent advances in telehealth infrastructure and patient satisfaction with telehealth services will likely result in greater use of telehealth services in all sectors of health care, including pharmacy practice. While certain aspects of pharmacy practice, such as collecting a medication history, may transition smoothly to the virtual environment, other aspects, such as counseling on proper drug administration and device use, require a unique set of skills for successful communication. Teaching skills unique to telepharmacy will ultimately prepare student pharmacists to provide higher quality, patient-centered care. Pharmacy education has the opportunity to expand to accommodate this growing aspect of the field. Schools of pharmacy as well as the Accreditation Council for Pharmacy Education can adopt standards that address teaching telepharmacy. Didactic and experiential pharmacy education can begin to incorporate telepharmacy skills training to best prepare student pharmacists for the future.


Subordinate social status modulates the vulnerability to the immunological effects of social stress.
Social stress has long been known to affect physical and psychological health in humans and a variety of animal species. In mice, disruption of the social hierarchy (social disruption, SDR) resulted in significant changes in the phenotype and function of immune cells taken from the spleen. Interestingly, there were considerable individual differences in the development of this splenic response to SDR. Studies have suggested that these individual differences were mediated by behavioral factors such as social hierarchy. To test this hypothesis, social status within cages of male mice was identified before and after SDR. Results showed that in the majority of the cages social order was stable over time. In addition, examination of the association between social status and splenic function showed that the splenic response to SDR in subordinate mice was significantly augmented compared to dominants. This relationship between subordinate social status and the splenic response to social stress was more notable in cages with stable social hierarchies. To sum up, the current study showed a role for socio-behavioral factors in determining the response to stress. This study further demonstrated the complexity of factors playing a role in mediating the physiological response to social stress resulting in considerable individual differences in the response to stress.


N95 Mask with Exhalation Valve: Reporting of One Safety Issue.
To the editor: COVID-19 is an infectious disease caused by a novel coronavirus that transmits via human to human by aerosol droplets, physical contact, and airborne route.


Protective effects of minocycline on the reduction of dopamine transporters in the striatum after administration of methamphetamine: a positron emission tomography study in conscious monkeys.
Positron emission tomography (PET) studies of methamphetamine (METH) abusers suggest that psychotic symptoms of METH abusers may be attributable to the reduction of dopamine transporters (DAT) in the human brain. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with METH abuse. Using a PET study in conscious monkeys, we investigated whether the second generation antibiotic minocycline could protect against the reduction of DAT in monkeys treated with METH (2 mg/kg x 3, 3-hour intervals). Pretreatment and subsequent administration of minocycline significantly attenuated the reduction of DAT in the striatum of monkeys treated with METH. Furthermore, posttreatment and subsequent administration of minocycline also significantly attenuated the reduction of DAT. In contrast, repeated administration of minocycline alone did not alter the density of DAT in the striatum of monkeys treated with METH. Our findings suggest that minocycline protects against METH-induced neurotoxicity in the monkey brain. Therefore, minocycline is likely to be a promising therapeutic agent for the treatment of several symptoms associated with METH use in humans.


Spinach chloroplast thioredoxins in evolutionary drift.
The amino acid sequences surrounding the active sites of spinach chloroplast thioredoxins m and f have been determined. Both types of thioredoxins share common ancestor genes with the E. coli one, demonstrated by invariant active site sequences. The m-type thioredoxins have closer homology with the E. coli one in the sequence analyzed as well as in enzymatic specificity, whereas the f-type is less homologous both in sequence and specificity. It suggests that the m-type gene represents a prototype conserved throughout evolutionary processes whereas the f-type has undergone mutations resulting in a modified specificity.


A doubly cross-linked human hemoglobin. Effects of cross-links between different subunits.
Human deoxyhemoglobin cross-linked with trimesyl tris(3,5-dibromosalicylate) produces the previously reported cross-linked hemoglobin in which the epsilon amino groups of the two beta chain 82 lysyl residues are joined by a trimesyl bridge. Further specific modification of this protein directed to the alpha subunits with bis(3,5-dibromosalicyl)fumarate gives a doubly cross-linked material in which the epsilon-amino groups of the two alpha chain 99 lysyl residues are now joined by a fumaryl bridge. The singly cross-linked beta chain species binds oxygen cooperatively with a high oxygen affinity (P50 = 4.8 torr at pH 7.4). The addition of the second cross-linking reduces the oxygen affinity to 15.9 torr, which compares with 13.0 torr for the singly cross-linked alpha chain species. The doubly cross-linked hemoglobin retains significant cooperativity with a Hill coefficient of 2.3 compared with 3.0 for unmodified hemoglobin. Because some of the groups responsible for the Bohr effect are acylated, this doubly cross-linked hemoglobin exhibits 25% of the normal Bohr effect and less than 20% of the normal chloride effect. The use of two distinct cross-links within the same tetramer provides a material for physical and structural analysis as well as for further modifications for specific applications. The results indicate that the cross-link introducing the lowest oxygen affinity in the two singly cross-linked species appears to control the overall affinity in this doubly cross-linked species.


Diacylglycerol metabolism in phospholipase C-treated mammalian cells.
Treatment of cultured cells with phospholipase C causes increased rates of hydrolysis of cellular phosphatidylcholine and increased rates of incorporation of choline into phosphatidylcholine. The fate of the diacylglycerol produced by the phospholipase C hydrolysis was examined in two cell lines, Chinese hamster ovary and HeLa. In the former cells, turnover of the glycerol moiety of phosphatidylcholine was not enhanced by phospholipase C treatment, indicating that the phospholipase C-generated diacylglycerol was recycled into new phosphatidylcholine. In HeLa cells, turnover of the glycerol backbone of phosphatidylcholine was enhanced by phospholipase C treatment, and the increased rate of turnover of the glycerol moiety was similar to that of the phosphate moiety. Thus, the fate of diacylglycerol generated at the plasma membrane was demonstrated to differ in these two cell lines. Incorporation of precursors of diacylglycerol into phosphatidylcholine was not enhanced by phospholipase C treatment in either cell line.


A bimodal type of AgPd Plasmonic Blackbody Nanozyme with boosted catalytic efficacy and synergized photothermal therapy for efficacious tumor treatment in the second biological window.
Nanozymes are promising for precise cancer treatment, but are typically limited in terms of the low catalytic efficiency and the complexity in tumor microenvironment (TME). Herein, we describe a bimodal type of AgPd plasmonic blackbody (AgPd PB) nanozyme of compact sizes (< 30 nm), which presents not only boosted enzyme efficacy but also efficient photothermal therapy (PTT) for synergized therapy through tissue-penetrating light in the second biological window (1000-1700 nm). The synthesized hyperbranched AgPd PB nanozymes possess intense and broadband localized surface plasmonic resonance absorption of 400-1300 nm, entailing prominent photothermal efficiency (η = 45.1% at 1064 nm) for PTT. Importantly, PTT was found to significantly boost the nanozyme efficacy of both catalase (CAT) and peroxidase (POD) processes, which correspondingly decompose H2O2 to into O2 to relieve tumor hypoxia, and activate H2O2 to generate oxidative •OH radical. While the generated •OH was found to be able to minimize heat shock proteins (HSPs), which plays a vital role to counterbalance PTT effect both in vitro and in vivo. As compared to control ground without treatment, the synergized nanozyme and PTT activities resulted in about 7-fold reduction of tumor volume, thus elevating the survival rate from 0 to 80% at 30 days posttreatment. Besides the synergistic therapy, the AgPd PB nanozyme were shown to own fluorescence, computed tomography (CT), and photoacoustic (PA) imaging abilities, thus having implications for uses in imaging-guided precise cancer therapy. This study provides a paradigm of TME responsive theranostics under NIR-II light irradiation.


Preventive zinc supplementation for children, and the effect of additional iron: a systematic review and meta-analysis.
Zinc deficiency is widespread, and preventive supplementation may have benefits in young children. Effects for children over 5 years of age, and effects when coadministered with other micronutrients are uncertain. These are obstacles to scale-up. This review seeks to determine if preventive supplementation reduces mortality and morbidity for children aged 6 months to 12 years. Systematic review conducted with the Cochrane Developmental, Psychosocial and Learning Problems Group. Two reviewers independently assessed studies. Meta-analyses were performed for mortality, illness and side effects. We searched multiple databases, including CENTRAL and MEDLINE in January 2013. Authors were contacted for missing information. Randomised trials of preventive zinc supplementation. Hospitalised children and children with chronic diseases were excluded. 80 randomised trials with 205 401 participants were included. There was a small but non-significant effect on all-cause mortality (risk ratio (RR) 0.95 (95% CI 0.86 to 1.05)). Supplementation may reduce incidence of all-cause diarrhoea (RR 0.87 (0.85 to 0.89)), but there was evidence of reporting bias. There was no evidence of an effect of incidence or prevalence of respiratory infections or malaria. There was moderate quality evidence of a very small effect on linear growth (standardised mean difference 0.09 (0.06 to 0.13)) and an increase in vomiting (RR 1.29 (1.14 to 1.46)). There was no evidence of an effect on iron status. Comparing zinc with and without iron cosupplementation and direct comparisons of zinc plus iron versus zinc administered alone favoured cointervention for some outcomes and zinc alone for other outcomes. Effects may be larger for children over 1 year of age, but most differences were not significant. Benefits of preventive zinc supplementation may outweigh any potentially adverse effects in areas where risk of zinc deficiency is high. Further research should determine optimal intervention characteristics and delivery strategies.


Glucose inhibition of human fibroblast proliferation and response to growth factors is prevented by inhibitors of aldose reductase.
Diabetes mellitus is associated with premature senescence of cultured dermal fibroblasts. The present study investigated the effect of elevated glucose concentrations on cultured human fibroblasts from normal donors. Mean population doubling times, population doublings until senescence, saturation density at confluence (cells/cm2), tritiated thymidine incorporation, and response to platelet-derived growth factor (PDGF) were inhibited with the increasing glucose concentrations (11.0, 22, 44, or 55 mM glucose) (P less than 0.05). Replicative life span was markedly diminished by multiple passages in high glucose medium (5.5 mM glucose: 62.4 +/- 7.9 population doublings; 22 mM glucose: 22.8 +/- 3.4 population doublings: P less than 0.05). Aldose reductase activity was present in the cultured fibroblasts (3.9 +/- 0.5 nmol/min per mg protein), and inhibitors of aldose reductase, including sorbinil (10(-4) M--10(-6) M) and tolrestat (10(-6) M--10(-8) M), completely prevented glucose-mediated inhibition of fibroblast proliferation, restored the response to PDGF, and allowed a normal replicative life span. Myo-inositol (11 microM--5.5 mM) also reversed the adverse effects of glucose. These in vitro data demonstrate that elevated concentrations of glucose inhibit cell growth and promote premature senescence, effects which can be prevented with inhibitors of aldose reductase or supplemental myo-inositol. These aldose reductase-related effects may explain the impaired growth and premature senescence of cultured connective tissue from diabetic patients.


Right-ventricular mechanics assessed by cardiovascular magnetic resonance feature tracking in children with hypertrophic cardiomyopathy.
Although hypertrophic cardiomyopathy (HCM) is considered a disease of the left ventricle (LV), right ventricular (RV) abnormalities have also been reported on. Cardiovascular magnetic resonance feature tracking (CMR-FT) accurately and reproducibly quantifies RV myocardial deformation. To investigate RV deformation disorders in childhood HCM using CMR-FT. Consecutive subjects aged <18 years with echocardiographic evidence of HCM were enrolled. Cardiovascular magnetic resonance (CMR) was performed including RV volumetric and functional assessment, and late gadolinium enhancement (LGE) imaging. We included 54 children (37 males, 68.5%) with HCM, of which 28 patients (51.8%; mean extent of 2.18 ± 2.34% of LV mass) had late gadolinium enhancement. LV outflow tract obstruction (LVOTO) was detected in 19 subjects (35.2%). In patients with LVOTO, RV global longitudinal strain (RVGLS) (-16.1±5.0 vs. -20.7±5.3, p<0.01), RVGLS rate (-1.05±0.30 vs. -1.26±0.40, p = 0.03), RV radial strain (RVR) (15.8±7.7 vs. 22.1±7.0, p<0.01) and RVR rate (0.95±0.35 vs. 1.6±0.44, p<0.01) were lower than in patients without LVOTO. The RVR rate (p<0.01) was lower in patients with LGE in comparison to patients without LGE. Children with HCM, especially with LVOTO, have significantly reduced indices of RV mechanics despite normal RV systolic function. It seems that the degree of LVOT obstruction is responsible for compromising the RV dynamics, rather than either mass or the amount of LV fibrosis.


The integument of the paddlefish, Polyodon spathula.
The integument of the paddlefish (Polyodon spathula) is unusual as a relatively small amount of mucus is produced by epithelial cells that are not modified into regular mucous gland cells. A thick compact epidermis and dermis compensate for the slight amount of mucus secreted. Paddlefish have a variety of scales formed of concentric bony lamellae containing osteocytes. There are five kinds of scales: dorsal and ventral fulcra on the caudal fin, rhomboidal scales on the caudal lobe, horny denticles over the pectoral girdle, calcareous denticles on the trunk, and anchor-shaped plates on the rostrum. Except for the fulcra, the scales are undoubtedly vestigial. The numerous surface pits on the rostrum, head, operculum, and throat are epithelial invaginations which are not connected to lateral line canals. No nerves lead to the pits. The spherical to cuboidal and often ciliated cells at the base of the pits are considered to be aplasic cells of unformed neuromasts.


Biantennary glycans as well as genetic variants of alpha1-acid glycoprotein control the enantioselectivity and binding affinity of oxybutynin.
The purpose of this study was to investigate the role of biantennary branching glycans of alpha1-acid glycoprotein (AGP) and its genetic variants in the enantioselective binding of oxybutynin (OXY). Human native AGP was separated using imminodiacetate-copper (II) affinity chromatography into two fractions, the A variant and a mixture of the F1 and S variants (F1-S). These fractionated AGPs were further separated by concanavalin A affinity chromatography into two fractions, with and without biantenarry glycans. An on-line high-performance liquid chromatography (HPLC) system consisting of a high-performance frontal analysis column, an extraction column, and an analytical HPLC column was developed to determine the binding affinities of OXY enantiomers for respective AGP species. The total binding affinity as well as the enantiomeric selectivity of OXY in the F1-S mixed variant was significantly higher than that for the A variant, indicating that the chiral recognition ability of native AGP for the OXY enantiomers highly depends on the F1-S mixed variant. Furthermore, not only the genetic variants but also bianntenary glycans of AGP affect the binding affinity of OXY and are also responsible for the enantioselectivity. Both genetic variants and glycan structures significantly contribute to the enantioselectivity and the binding affinity of OXY.


Wastewater treatment in 2050: Challenges ahead and future vision in a European context.
•Wastewater treatment plants are slowly evolving.•In the next decade, successful implementation of technologies is focused intensification.•New technologies will be focused on gases and bio-based materials.•Academics need more freedom to develop novel concepts.•Collaborative platforms that enable demonstration of high-risk technologies is key.


Impact of norepinephrine on the relationship between pleth variability index and pulse pressure variations in ICU adult patients.
Pleth Variability Index (PVI) is an automated and continuous calculation of respiratory variations in the perfusion index. PVI correlates well with respiratory variations in pulse pressure (ΔPP) and is able to predict fluid responsiveness in the operating room. ICU patients may receive vasopressive drugs, which modify vascular tone and could affect PVI assessment. We hypothesized that the correlation between PVI and ΔPP and the ability of PVI to identify patients with ΔPP > 13% is dependent on norepinephrine (NE) use. 67 consecutive mechanically ventilated patients in the ICU were prospectively included. Three were excluded. The administration and dosage of NE, heart rate, mean arterial pressure, PVI and ΔPP were measured simultaneously. In all patients, the correlation between PVI and ΔPP was weak (r2 = 0.21; p = 0.001). 23 patients exhibited a ΔPP > 13%. A PVI > 11% was able to identify patients with a ΔPP > 13% with a sensitivity of 70% (95% confidence interval: 47%-87%) and a specificity of 71% (95% confidence interval: 54%-84%). The area under the curve was 0.80 ± 0.06. 35 patients (53%) received norepinephrine (NE(+)). In NE(+) patients, PVI and ΔPP were not correlated (r2 = 0.04, p > 0.05) and a PVI > 10% was able to identify patients with a ΔPP > 13% with a sensitivity of 58% (95% confidence interval: 28%-85%) and a specificity of 61% (95% confidence interval:39%-80%). The area under the ROC (receiver operating characteristics) curve was 0.69 ± 0.01. In contrast, NE(-) patients exhibited a correlation between PVI and ΔPP (r2 = 0.52; p < 0.001) and a PVI > 10% was able to identify patients with a ΔPP > 13% with a sensitivity of 100% (95% confidence interval: 71%-100%) and a specificity of 72% (95% confidence interval: 49%-90%). The area under the ROC curve was 0.93 ± 0.06 for NE(-) patients and was significantly higher than the area under the ROC curve for NE(+) patients (p = 0.02). Our results suggest that in mechanically ventilated adult patients, NE alters the correlation between PVI and ΔPP and the ability of PVI to predict ΔPP > 13% in ICU patients.


Performance of candidates on the geriatric medicine items of the American Board of Internal Medicine Certifying Examination.
The performance of candidates on the geriatric medicine items on the American Board of Internal Medicine's 1980, 1981, and 1982 Certifying Examinations was analyzed. For the 1981 and 1982 examinations, candidates who trained in residency programs having a special emphasis on geriatric medicine performed significantly better on the geriatric item than did candidates who attended other residency programs, regardless of overall medical knowledge. This finding suggests the efficacy of training in geriatric medicine as measured by a written examination.


Factors associated with failed and completed railway suicides.
The present analysis aimed to assess the proportion of survivors of railway suicides and to compare survivors and completers in terms of personal characteristics and temporal patterns surrounding the event, to identify potential differences between those who completed suicide and those who survived a serious suicide attempt. A total of 5731 suicide victims (including 4003 cases with complete documentation on sex) of the German central railway registry of person accidents covering a six-year observation period of 1997 to 2002 and satisfying the operational definition of an act of suicidal behaviour according to the ICD-10 were included into the data set. To assess the impact of sex, age, local and temporal factors on case fatality, a multivariate logistic regression analysis was performed. A minority of 540 (9.4%) subjects survived the suicidal event leading to a fatal to non-fatal ratio of 9.6:1 (chi(2)-test for equal proportions, p<0.001). Multivariate logistic regression analysis identified the following variables as risk factors for fatal outcome: men (vs. women: Odds ratio (OR)=2.05; 95% CI: 1.65-2.56), night (vs. day: OR=1.80; 95% CI: 1.43-2.27), open track (vs. station area: OR=2.95; 95% CI: 2.36-2.67) and main railway line (vs. local railway line: OR=2.29; 95% CI: 1.43-3.68). Interactions between two factors on fatal outcome were multivariate tested but showed no significance. Close to 10% of all railway suicide attempts are nonfatal. Fatality of suicidal behaviour on railway tracks is significantly associated with male sex pointing to a certain degree of ambivalence. Higher odds to die on open track area, fast track lines and during night-time suggest a reduced opportunity to survive due to circumstances.


Relationship between bone turnover and bone density at the proximal femur in stroke patients.
To investigate the relationship between the rate of bone turnover and bone loss at the proximal femur in stroke patients. This study was performed between January 1, 2005 and August 31, 2006 at the Stroke Rehabilitation Unit, Istanbul Physical Medicine and Rehabilitation Training Hospital, Istanbul, Turkey. One hundred six patients who had a stroke for the first time were included in the study. The control group consisted of 33 age- and gender-matched healthy subjects. Bone mineral density (BMD) was measured at the proximal hip region by dual energy X-ray absorptiometry (DXA). Serum osteocalcin (OC) and C telopeptide of type 1 collagen (CTX) levels were measured. Barthel Index (BI) was used for the evaluation of daily activities. Ambulation status of the patients was recorded. Mean age was 65.1 +/- 9.8 years in the patient group and 51% were male. Mean disease duration was 16.9 +/- 9.1 months. Mean BI score was 60.5 +/- 25.8 on admission. Femoral neck BMD values were 0.873 +/- 0.95 g/cm(2) and 0.816 +/- 0.180 g/cm(2) for control subjects and hemiplegic sides of the patient group, respectively. Femur total BMD values were 0.948 +/- 0.119 g/cm(2) and 0.872 +/- 0.187 g/cm(2) for control group and hemiplegic sides of the patients, respectively. Femoral neck and femur total BMD values in the hemiplegic side were lower than those of controls' (P < .05). There was no statistically significant difference between the proximal femur BMD values of the intact and hemiplegic sides. Negative correlation was found between the proximal femur BMD values of both the intact and hemiplegic sides, and serum OC and CTX levels. Bone resorption rate was higher among the patients with stroke; however, bone formation rate was normal in this group. Serum CTX levels showed correlation with ambulation status. Femoral neck BMD values on the intact side were lower in the patient group with disease duration of more than 1 year compared to those with shorter disease duration. As a result of this study bone turnover was inversely correlated with bone density at the hip of both hemiplegic and intact sides in stroke patients. Evaluation of bone turnover might be helpful to predict bone loss and to find out the stroke patients with bone loss who can not be decided to begin antiresorptive treatment with bone density measurement.


Usefulness of mobile apps for communication of genetic test results to at-risk family members in a U.S. integrated health system: a qualitative approach from user-testing.
To assess the usefulness a mobile based application to send genetic test results to at-risk family members in a U.S. integrated health system. We conducted semi-structured in-person interviews with members of Kaiser Permanente Washington who had enrolled in a prospective study and received genetic test results. Participants were given the task to use the app and comment on the experience. The moderator asked participants to share perspectives on the usefulness of a mobile based app and their lived experiences of sharing their test results with family members. Fourteen study participants who had undergone genetic testing were interviewed. Four primary themes emerged as relevant to the use of mobile-based apps as a tool for communicating genetic test results to at-risk family members: (i) Participants felt a sense of obligation to share positive test results with relatives; (ii) Participants felt that the advantages of using email were similar to those of the app; (iii) Participants felt that younger individuals would be more comfortable with an app; and, (iv) Participants felt they could use the app independently and in their own time. A mobile based app could be used as a tool to improve cascade screening for pathogenic/likely pathogenic test results. The benefits of such a tool are likely greatest among relatives still at the stage of family planning, as well as among family members with strained relationships. There would be minimal burden on the system to offer a mobile based app as a tool.


Crohn's disease: clinical manifestations of orthodontic interest.
Crohn's disease is a chronic inflammation of the small intestine; it can involve other organs, such as the skin, eyes, lungs, and joints. Oral manifestations are common, especially ulcers and stomatitis, which macroscopically and histologically resemble those found in the gastrointestinal tract. However, orthodontic alterations are not yet known. This article reviews aspects related to the diagnosis of Crohn's disease and clinical considerations for an orthodontic patient.


Tissue deformation controlling fracture healing.
To achieve optimal flexibility in biological internal fracture fixation two questions require clarification: which biomechanical parameter controls healing and what are the boundary conditions thereof? Fracture movement interacts with callus and local stress and strain are influencing the reaction of the tissue cells. A linear gradient of strain was created inside a sheep tibia osteotomy using an active external fixator. The effect of different amounts of strain applied at 10 stimulation cycles/day on the occurrence of callus and on enabling osseous connection of the fragments was evaluated using micro-radiology to determine the amount of calcified new bone formation and its quality of gap bridging. A strong relation between level of strain and amount of callus was observed. Depending on the strain level different pattern of connections were seen. At the lowest investigated gap strain level of about 7% direct connection of the fragments within the gap occurred. Beyond 13% the callus only connected indirectly outside the gap. At over 36% callus did not connect the fragments anymore comparable to a situation in hypertrophic non-unions. The observed strong relation between interfragmentary strain and reduced osseous bridging may support the hypothesis that the elongation at rupture of connecting tissue plays an important role defining the upper limit for solid bridging. In planning fracture treatment, the amount of fracture mobility resulting in interfragmentary strain may play a crucial role to achieve solid healing.


Actin-dependent astrocytic infiltration is a key step for axon defasciculation during remodeling.
Astrocytes are essential for synapse formation, maturation, and plasticity; however, their function during developmental neuronal remodeling is largely unknown. To identify astrocytic molecules required for axon pruning of mushroom body (MB) γ neurons in Drosophila, we profiled astrocytes before (larva) and after (adult) remodeling. Focusing on genes enriched in larval astrocytes, we identified 12 astrocytic genes that are required for axon pruning, including the F-actin regulators Actin-related protein 2/3 complex, subunit 1 (Arpc1) and formin3 (form3). Interestingly, perturbing astrocytic actin dynamics does not affect their gross morphology, migration, or transforming growth factor β (TGF-β) secretion. In contrast, actin dynamics is required for astrocyte infiltration into the axon bundle at the onset of pruning. Remarkably, decreasing axonal adhesion facilitates infiltration by Arpc1 knockdown (KD) astrocytes and promotes axon pruning. Conversely, increased axonal adhesion reduces lobe infiltration by wild-type (WT) astrocytes. Together, our findings suggest that actin-dependent astrocytic infiltration is a key step in axon pruning, thus promoting our understanding of neuron-glia interactions during remodeling.


LOCATE: a prospective evaluation of the value of Leveraging Ongoing Citation Acquisition Techniques for living Evidence syntheses.
Living systematic reviews (LSRs) can expedite evidence synthesis by incorporating new evidence in real time. However, the methods needed to identify new studies in a timely manner are not well established. To explore the value of complementary search approaches in terms of search performance, impact on results and conclusions, screening workload, and feasibility compared to the reference standard. We developed three complementary search approaches for a systematic review on treatments for bronchiolitis: Automated Full Search, PubMed Similar Articles, and Scopus Citing References. These were automated to retrieve results monthly; pairs of reviewers screened the records and commented on feasibility. After 1 year, we conducted a full update search (reference standard). For each complementary approach, we compared search performance (proportion missed, number needed to read [NNR]) and reviewer workload (number of records screened, time required) to the reference standard. We investigated the impact of the new trials on the effect estimate and certainty of evidence for the primary outcomes. We summarized comments about feasibility. Via the reference standard, reviewers screened 505 titles/abstracts, 24 full texts, and identified four new trials (NNR 127; 12.4 h). Of the complementary approaches, only the Automated Full Search located all four trials; these were located 6 to 12 months sooner than via the reference standard but did not alter the results nor certainty in the evidence. The Automated Full Search was the most resource-intensive approach (816 records screened; NNR 204; 17.1 h). The PubMed Similar Articles and Scopus Citing References approaches located far fewer records (452 and 244, respectively), thereby requiring less screening time (9.4 and 5.2 h); however, each approach located only one of the four new trials. Reviewers found it feasible and convenient to conduct monthly screening for searches of this yield (median 15-65 records/month). The Automated Full Search was the most resource-intensive approach, but also the only to locate all of the newly published trials. Although the monthly screening time for the PubMed Similar Articles and Scopus Citing Articles was far less, most relevant records were missed. These approaches were feasible to integrate into reviewer work processes. Open Science Framework. https://doi.org/10.17605/OSF.IO/6M28H .


Pharmacokinetics of tenvermectin in swine, a novel antiparasitic drug candidate-comparison with ivermectin.
Tenvermectin (TVM) is a novel 16-membered macrolide compound isolated and purified from the fermentation broth of genetically engineered Streptomyces avermitilis strain MHJ1011. TVM and ivermectin were administered at the dose of 0.3 mg/kg body weight through a single subcutaneous injection route followed by plasma collectiom and analysis at different time intervals. Plasma concentrations of TVM and IVM were determined by high-performance liquid chromatography with fluorescence detector. Pharmacokinetic analysis was completed using the non-compartmental method with WinNonlin™ 6.4 software. TVM is rapidly absorbed after administration with peak plasma concentrations (Cmax , 9.78 ± 2.34 ng/ml) obtained within 6-22 h. AUC0-last was 586.86 h·ng/ml ± 121.24 h·ng/ml. The mean elimination half-life of TVM (T1/2λz ) was 97.99 h ± 46.41 h. The T1/2λz of IVM was 146.59 h ± 22.26 h in the study. The present study showed that subcutaneous administration of TVM at 0.3 mg/kg body weight (BW) in swine is absorbed more rapidly than IVM in swine. Compared to the pharmacokinetic characteristics of IVM, there was little difference in the half-life of TVM among different individuals. The data will contribute to refining the formulation and dosage regime for TVM administration.


The thyroxine inactivating gene, type III deiodinase, suppresses multiple signaling centers in Dictyostelium discoideum.
Thyroxine deiodinases, the enzymes that regulate thyroxine metabolism, are essential for vertebrate growth and development. In the genome of Dictyostelium discoideum, a single intronless gene (dio3) encoding type III thyroxine 5' deiodinase is present. The amino acid sequence of D. discoideum Dio3 shares 37% identity with human T4 deiodinase and is a member of the thioredoxin reductase superfamily. dio3 is expressed throughout growth and development and by generating a knockout of dio3, we have examined the role of thyroxine 5' deiodinase in D. discoideum. dio3(-) had multiple defects that affected growth, timing of development, aggregate size, cell streaming, and cell-type differentiation. A prominent phenotype of dio3(-) was the breaking of late aggregates into small signaling centers, each forming a fruiting body of its own. cAMP levels, its relay, photo- and chemo-taxis were also defective in dio3(-). Quantitative RT-PCR analyses suggested that expression levels of genes encoding adenylyl cyclase A (acaA), cAMP-receptor A (carA) and cAMP-phosphodiesterases were reduced. There was a significant reduction in the expression of CadA and CsaA, which are involved in cell-cell adhesion. The dio3(-) slugs had prestalk identity, with pronounced prestalk marker ecmA expression. Thus, Dio3 seems to have roles in mediating cAMP synthesis/relay, cell-cell adhesion and slug patterning. The phenotype of dio3(-) suggests that Dio3 may prevent the formation of multiple signaling centers during D. discoideum development. This is the first report of a gene involved in thyroxine metabolism that is also involved in growth and development in a lower eukaryote.


Intrinsic fluorometric determination of the stable state of aggregation in hemoglobins.
Front-face fluorometry can detect steady-state intrinsic fluorescence of hemoglobins (R. E. Hirsch, R. S. Zukin, and R. L. Nagel, 1980, Biochem. Biophys. Res. Commun. 93, 432-439), a property that can be used to study the dimerization of human hemoglobins (R. E. Hirsch, N. A. Squires, C. Discepola, and R. L. Nagel, 1983, Biochem. Biophys. Res. Commun. 116, 712-718). We report that the stable dimeric hemoglobin components of the arcid clams Noetia ponderosa and Anadara ovalis exhibit fluorescence emission maxima shifted to longer wavelengths compared to tetrameric human hemoglobin. Conversely, the tetrameric major hemoglobin (Hb) component of A. ovalis exhibits an emission maximum similar to that of tetrameric Hb A. Hence, stable dimeric hemoglobins can be detected by emission maxima at longer wavelengths relative to Hb A. Fluorescence studies of ligand binding to these clam hemoglobins indicate structural and functional differences among these components and compared to Hb A. We conclude that different stable aggregation states of hemoglobins may be determined by intrinsic fluorescence when studied with front-face optics.


A Novel Framework Using Remote Telesimulation With Standardized Parents to Improve Research Staff Preparedness for Informed Consent in Pediatric Critical Care Research.
The Heart And Lung Failure-Pediatric INsulin Titration study was experiencing poor subject enrollment due to low rates of informed consent. Heart And Lung Failure-Pediatric INsulin Titration investigators collaborated with the Perelman School of Medicine Standardized Patient Program to explore the novel use of telesimulation with standardized parents to train research staff to approach parents of critically ill children for informed consent. We describe the feasibility, learner acceptance, and financial costs of this novel intervention and performed a post hoc analysis to determine if this intervention improved study consent rates. Observational, comparative effectiveness study. Heart And Lung Failure-Pediatric INsulin Titration study enrolling sites. Research staff (at the remote site). Individual 90-minute Skype telesimulation sessions with standardized parent and simulation facilitator (at the training site). Forty telesimulation sessions with 79 Heart And Lung Failure-Pediatric INsulin Titration research staff (participants) at 24 remote sites were conducted. Despite some technical delays, 40 out of 40 simulations (100%) were completed. Based on feedback surveys, 100% of respondents agreed (81% strongly agreed) that telesimulation sessions achieved intended learning objectives to prepare research staff to approach parents of eligible critically ill children to obtain informed consent. Additionally, 100% of respondents agreed (74% strongly agreed) that they would use lessons from the telesimulation when approaching parents to obtain informed consent for research. Telesimulation with standardized parents achieved lower financial costs (approximately $85 per session) compared with traditional in-person site visits for training research staff. There was no significant improvement in study consent rates with the intervention (pre: 46% vs post: 48%; p = 0.78). Remote telesimulation with standardized parents is feasible, acceptable, and associated with lower financial costs to prepare research staff to obtain informed consent from parents of critically ill children eligible for clinical research trials. Despite this novel approach, Heart And Lung Failure-Pediatric INsulin Titration study consent rates did not improve, suggesting that other factors influence parental consent and decision making in complex multicenter clinical research trials.


Preoperative electroretinograms and visual evoked cortical potentials for predicting outcome of vitrectomy in diabetics.
In order to find that the outcome of vitrectomy could be predicted in diabetics with very low visual acuity (finger counting at 3 m--approximately 20/400--or less), flash electroretinograms (ERG) and visual evoked cortical potentials (VECP) were simultaneously recorded from about 300 patients within one month before the operation. From this series two groups were formed, based on the outcome of surgery. One group (30 patients) had improved visual acuity, with finger counting at 0.1 to 1.0 m (20/200-20/20). The other group (29 patients) was unimproved by surgery. The groups were matched with regard to age, duration of diabetes, preoperative visual acuity and occurrence of cataract and previous panretinal photocoagulation. All patients had dense vitreal opacities, precluding inspection of the ocular fundus. Only patients without surgical and postoperative complications were included. There was a statistically significant (P less than 0.05) difference between the groups in ERG amplitude, but not in VECP latency or amplitude. Based on ERG amplitude, the outcome of vitrectomy could be predicted correctly in 36 of 59 patients (61%) and in 35 of 56 patients (63%) based on VECP latency. The VECP amplitude or the combination of ERG and VECP parameters did not improve the prediction rate. Thus, preoperative flash ERG and VECP can not safely predict the outcome of vitrectomy in diabetics with very low visual acuity.


Frequency of human leukocyte antigens class II-DR alleles (HLA-DRB1) in Argentinian patients with early arthritis.
Patients with rheumatoid arthritis (RA) or undifferentiated arthritis (UA) in the CONAART database (Argentine Consortium for Early Arthritis) were assessed for genetic risk factors for RA, specifically for HLA-DRB1 alleles and the PTPN22 rs2476601 polymorphism associated with progression to RA. This is a case-control study. Blood samples were obtained to determine HLA-DRB1 genotypes by PCR-SSO Luminex and PTPN22 (rs2476601) polymorphism by allelic discrimination. A control group of individuals from the general Argentinian population were obtained from the national register of cadaveric organ donors. A total of 1859 individuals were included in this analysis: 399 patients from the CONAART database (347 patients with RA at study end and 52 patients with UA at study end, mean follow-up time 25 ± 18 months) and 1460 individuals from the general Argentinian population. Compared with the controls, the HLA-DRB1*04 and DRB1*09 alleles were more commonly detected in patients with RA diagnosis (OR (95% CI) 2.23 (1.74-2.85) and 1.89 (1.26-2.81)) respectively. Both patients with UA and the general population showed higher frequency of DRB1*07, DRB1*11 and DRB1*15 alleles than patients with RA. PTPN22 rs2476601 polymorphism frequency was higher in RA and UA vs the general population; however, this was significantly different only for RA vs control group (OR [95% CI] = 1.81 [1.10-3.02], P = 0.018. HLA-DRB1 typing and PTPN22 allelic discrimination could distinguish between patients with UA, patients with early RA, and the general population in Argentina. This is the first study of HLA-DRB1 alleles and PTPN22 polymorphism associations with progression to early RA in an Argentinian population.


Reduced activation of superior temporal gyrus during auditory comprehension in young offspring of patients with schizophrenia.
Smaller Superior Temporal Gyrus (STG) and reduced activation with language tasks have been found in schizophrenia emphasizing the involvement of parts of language network. Recently, we reported smaller STG in individuals at risk for psychosis. In this study, we examined the brain activation for auditory comprehension using fMRI in a group of young offspring of schizophrenia patients (HR) with a hypothesis that HR subjects will not activate STG as well as comparison subjects. Fifteen HR (7M, 8F, mean age 15.9±3.1) and 17 comparison subjects (9M and 8F, mean age 14.5±3.5) participated. BOLD fMRI images were obtained using a 4 Tesla scanner with a multi echo-planar imaging sequence. The participants were asked to listen to 30 sec blocks of a story alternated with blocks of the same reading played backwards. The data were analyzed using Statistical Parametric Mapping (SPM5) and a BOLD activation exceeding a threshold of T>2.58 (p<0.01, uncorrected) was considered significant. The HR showed significantly lower BOLD activation at the STG bilaterally compared to normal controls (left STG; x=-64, y=-48, z=12, Z=2.95, right STG; x=62, y=-50, z=-16, Z=2.77). The effect was more pronounced in males and on left STG. These data suggest that adolescents at risk for schizophrenia show reduced activation of the STG compared to control subjects during a language related task (listening). This finding adds support to the idea that abnormal development of the language related cortex is a marker of increased susceptibility to schizophrenia and that such deviant development may be mediated by familial/genetic factors.


[Expert Consensus for Thermal Ablation of Pulmonary Subsolid Nodules (2021 Edition)].
"The Expert Group on Tumor Ablation Therapy of Chinese Medical Doctor Association, The Tumor Ablation Committee of Chinese College of Interventionalists, The Society of Tumor Ablation Therapy of Chinese Anti-Cancer Association and The Ablation Expert Committee of the Chinese Society of Clinical Oncology" have organized multidisciplinary experts to formulate the consensus for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The expert consensus reviews current literatures and provides clinical practices for thermal ablation of GGN. The main contents include: (1) clinical evaluation of GGN, (2) procedures, indications, contraindications, outcomes evaluation and related complications of thermal ablation for GGN and (3) future development directions. .


Harnessing the full potential of hospital-based data to support surgical quality improvement.
Surgical departments commonly rely on third-party quality improvement registries. As electronic health data become increasingly integrated and accessible within an institution, alternatives to these platforms arise. We present the conceptualization and implementation of an in-house quality improvement platform that provides real-time reports, is less onerous on clinicians and is tailored to an institution's priorities of care.


Cord-Age-Gender Connections Shape the Pathophysiology of Multiple Sclerosis Progressive Forms.
There is increasing evidence that sex hormones, aging, and the occurrence of spinal cord (SC) tissue alterations exert combined effects on the development and outcome of multiple sclerosis (MS) progressive forms [...].


Atrial fibrillation is associated with central sleep apnea in clinic patients undergoing diagnostic polysomnography.
Sleep apnea is highly prevalent in patients with atrial fibrillation (AF). Obstructive sleep apnea (OSA) is the most common type, and best studied in the context of AF. However, recent investigations have indicated that central sleep apnea (CSA) may be a risk factor for incident AF. We evaluated the burden of CSA events in patients referred for diagnostic polysomnography (PSG) and whether AF is associated with CSA. We identified patients with and without a history of AF who underwent clinically indicated PSG in a matched manner. OSA was defined as obstructive apnea-hypopnea index (AHI) ≥15/h, and CSA was defined as central apnea index (CAI) ≥5/h. The association between AF and CSA was evaluated using multivariable logistic regression. Among 465 patients included, mean AHI was 25.5/h, and mean CAI was 1.7/h. OSA prevalence was 53.3%, while CSA prevalence was 8.4%. The prevalence of OSA in the AF and non-AF groups (54.7% vs 52.0%, P = .56) was similar. CSA was more common in the AF group (12.3% vs 4.4%, P = .002). In multivariable analysis, AF (OR: 2.19 [1.02, 5.03], P = .05), male gender (OR: 2.5 [1.17, 5.84], P = .02), and older age (OR: 2.44, [1.16, 5.46], P = .02) were associated with CSA. Though CSA is much less common than OSA in patients with AF, the presence of AF is independently associated with CSA.


The embodied CO2 transfer across sectors of cities in Jing-Jin-Ji region: combining multi-regional input-output analysis with complex network analysis.
The CO2 emission transfer at city level, especially across sectors of cities, has not yet been sufficiently quantified. This paper analyzes the embodied CO2 transfer across sectors of 13 cities in Jing-Jin-Ji region (Beijing-Tianjin-Hebei in China) combining multi-regional input-output analysis with complex network analysis. The results show that (1) most embodied CO2 transfers are concentrated in a few sectors and emission reduction effects on these sectors can be quickly extended to the entire embodied CO2 transfer network (ECTN). (2) The electricity and hot water production and supply sector in Beijing have the most embodied CO2 export partners and the strongest control over embodied CO2 transfer. The construction sector in Beijing has the most embodied CO2 import partners and greatest influence on the ECTN. (3) At city level, 90% of embodied CO2 transfers occur within the city, and the general direction of embodied CO2 transfer across cities is from resource-rich cities, Tangshan and Handan, to developed cities, Beijing and Tianjin. At sector level, the largest embodied CO2 transfer path is electricity and hot water production and supply → metallurgy → construction sector. (4) Embodied CO2 transfers of sectors in the same or adjacent cities are denser. Collection of sectors in Beijing and Tianjin is the densest embodied CO2 transfer community.


Promoting Early Literacy Using Digital Devices: A Pilot Randomized Controlled Trial.
To determine feasibility and explore effects of literacy promotion using e-books versus board books on the home reading environment, book reading, television use, and child development. Randomized controlled trial comparing digital literacy promotion (DLP) using e-books to standard literacy promotion (SLP) using board books among Medicaid-eligible infants. DLP participants received e-books on home digital devices, while SLP participants received board books at well visits between 6 and 12 months of age. Differences in StimQ Read Subscale (StimQ-Read) scores, parent-reported reading and television use, and Bayley Scales of Infant Development-3rd Edition (Bayley-3) scores between groups were assessed using intention-to-treat analysis. A total of 104 Medicaid-eligible infants were enrolled and randomized from 3 pediatric practices. There were no differences in sociodemographic characteristics between groups at baseline. Children in the DLP group initially had lower StimQ-Read scores but showed similar increases in StimQ-Read scores over time as children in the SLP group. Parents in the DLP group reported greater use of digital devices to read or engage their child (65% vs 23%, P < .001) but similar board book reading and television viewing. There were no differences between groups in cognitive or motor scale scores, but DLP participants had marginally lower language scales scores (DLP 85.7 vs SLP 89.7; P = .10) at the 6-month follow-up. Literacy promotion using e-books was feasible and associated with greater e-book usage but no difference in board book reading, television viewing, or home reading environment scores. A potential adverse impact of e-books on language development should be confirmed in future study.


Environmental exposure to manganese and health risk assessment from personal sampling near an industrial source of airborne manganese.
Manganese (Mn), despite being a trace element necessary in small quantities for the correct functioning of the organism, at higher concentrations can induce health disorders, mainly in motor and cognitive functions, even at levels found in non-occupational environments. For this reason, US EPA guidelines define safe reference doses/concentrations (RfD/RfC) for health. In this study, the individualised health risk of exposure to Mn through different media (air, diet, soil) and routes of entry into the organism (inhalation, ingestion and dermal absorption) was assessed according to the procedure defined by the US EPA. Calculations related to Mn present in ambient air were made on the basis of data obtained from size-segregated particulate matter (PM) personal samplers carried by volunteers recruited in a cross-sectional study conducted in the Santander Bay (northern Spain), where an industrial source of airborne Mn is located. Individuals residing in the vicinity of the main Mn source (within 1.5 km) were found to have a hazard index (HI) higher than 1, indicating that there is a potential risk for these subjects to develop health alterations. Also, people living in Santander, the capital of the region, located 7-10 km from the Mn source, may have some risk (HI > 1) under some wind conditions (SW). In addition, a preliminary study of media and routes of entry into the body confirmed that inhalation of PM2.5-bound Mn is the most important route contributing to the overall non-carcinogenic health risk related to environmental Mn.


The relationship between gross motor function impairment in cerebral palsy and sleeping issues of children and caregivers.
To investigate, among children and adolescents with cerebral palsy (CP), the relationship between impairment of the gross motor function and: (i) child sleep disorders; (ii) the need for nocturnal support; and (iii) the quality of sleep of their caregivers. For children, we considered their scores on the gross motor function measure (GMFM-88) and on the sleep disturbance scale for children (SDSC), besides analyzing qualitative features about their sleep. For caregivers, we considered their scores in the Pittsburgh sleep quality index (PSQI). Our sample was comprised of 87 participants with mean age of 11.4 years old (±3.4). We observed correlations between GMFM-88 and disorders of initiating and maintaining sleep (DIMS) (r = -0.22; p = 0.039), sleep-wake transition disorders (SWTD) (r = 0.26; p = 0.017) and disorders of arousal (DA) (r = 0.23; p = 0.033). Children receiving nocturnal support presented lower scores in the GMFM-88 (p = 0.001) and higher scores in the SDSC (p = 0.029). For the caregivers, we found no correlation between GMFM-88 and PSQI. Nonetheless, their PSQI scores correlated with the SDSC scores (r = 0.24; p = 0.027). Impairment of the gross motor function correlated with DIMS and the need for nocturnal support but might not have an impact on the caregivers' sleep, which in turn correlated with child sleep disorders.


The perceived effectiveness of traditional and faith healing in the treatment of mental illness: a systematic review of qualitative studies.
This work complements a quantitative review by Nortje et al. (Lancet Psychiatry 3(2):154-170, 2016) by exploring the qualitative literature in regard to the perceived effectiveness of traditional and faith healing of mental disorders. Qualitative studies focusing specifically on traditional and/or faith healing practices for mental illness were retrieved from eight databases. Data were extracted into basic coding sheets to facilitate the assessment of the quality of eligible papers using the COREQ. Sixteen articles met the inclusion criteria. Despite methodological limitations, there was evidence from the papers that stakeholders perceived traditional and/or faith healing to be effective in treating mental illness, especially when used in combination with biomedical treatment. Patients will continue to seek treatment from traditional and/or faith healers for mental illness if they perceive it to be effective regardless of alternative biomedical evidence. This provides opportunities for collaboration to address resource scarcity in low to middle income countries.


Human Microbiome: Composition and Role in Inflammatory Skin Diseases.
This review focuses on recent evidences about human microbiome composition and functions, exploring the potential implication of its impairment in some diffuse and invalidating inflammatory skin diseases, such as atopic dermatitis, psoriasis, hidradenitis suppurativa and acne. We analysed current scientific literature, focusing on the current evidences about gut and skin microbiome composition and the complex dialogue between microbes and the host. Finally, we examined the consequences of this dialogue for health and skin diseases. This review highlights how human microbes interact with different anatomic niches modifying the state of immune activation, skin barrier status, microbe-host and microbe-microbe interactions. It also shows as most of the factors affecting gut and skin microorganisms' activity have demonstrated to be effective also in modulating chronic inflammatory skin diseases. More and more evidences demonstrate that human microbiome plays a key role in human health and diseases. It is to be expected that these new insights will translate into diagnostic, therapeutic and preventive measures in the context of personalized/precision medicine.


Isovitexin modulates autophagy in Alzheimer's disease via miR-107 signalling.
Alzheimer's disease (AD) is an ultimately fatal, degenerative brain disease in the elderly people. In the current work, we assessed the defensive capability of isovitexin (IVX) through an intracerebroventricular injection of streptozotocin (STZ)-induced AD mouse model. Mice were separated into four cohorts: sham-operated control mice; STZ-intoxicated Alzheimer's mice; IVX cohort, IVX + STZ; and Ant-107 cohort, antagomiR-107 + IVX/STZ as in the IVX cohort. The outcomes indicated that IVX administration ameliorated spatial memory loss and blunted a cascade of neuro-noxious episodes - including increased amyloid-beta (Aβ) and degraded myelin basic protein burden, neuroinflammation (represented by elevated caspase-1, TNF-α and IL-6 levels) and autophagic dysfunction (represented by altered LC3-II, Atg7 and beclin-1 expressions) - via the inhibition of PI3K/Akt/mTOR signalling axis. We considered the question of whether the epigenetic role of microRNA-107 (miR-107) has any impact on these events, by using antagomiR-107. This probing underscored that miR-107 could be a pivotal regulatory button in the activation of molecular signals linked with the beneficial autophagic process and anti-inflammatory activities in relation to IVX treatment. Hence, this report exemplifies that IVX could guard against Aβ toxicity and serve as an effectual treatment for patients afflicted with AD.


Utility of an in-house mycobacteriophage-based assay for rapid detection of rifampin resistance in Mycobacterium tuberculosis clinical isolates.
A rapid in-house mycobacteriophage-based assay to identify multidrug resistance by detecting the rifampin susceptibility of Mycobacterium tuberculosis in a microtiter plate format was evaluated. The sensitivity, specificity, and overall accuracy of the assay were 100%. This test is rapid to perform and suitable for widespread implementation.


Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain.
Questions have been raised about the potential neurotoxicity of the neuraxial use of ketamine although ketamine and its active enantiomer S(+)-ketamine have been used intrathecally and epidurally (caudally) for the management of perioperative pain and in a variety of chronic pain syndromes. Clinical experience following neuraxial administration of S(+)-ketamine has been documented without reference to local central nervous system toxicity following this approach. In addition, there are no preclinical safety data regarding stability, compatibility, and neurotoxicity on intrathecal use of single S(+)-ketamine or combinations of S(+)-ketamine, morphine, bupivacaine, and clonidine. In the present case, the continuous intrathecal administration of S(+)-ketamine, in combination with morphine, bupivacaine, and clonidine resulted in adequate pain relief in a patient suffering from intractable neuropathic cancer pain. However, postmortem observation of the spinal cord and nerve roots revealed severe histological abnormalities including central chromatolysis, nerve cell shrinkage, neuronophagia, microglial upregulation, and gliosis. Based on our results, neuraxial administration of S (+)-ketamine cannot be recommended for clinical practise before a systematic study of toxicology of neuraxial S(+)-ketamine in animals or humans has been performed.


Phenytoin-Induced Gingival Overgrowth with Predominant Involvement of Hard Palate and Floor of Oral Cavity: A Case Report and Review of Literature.
Drug-induced gingival overgrowth (DIGO) secondary to chronic phenytoin intake for seizure control is a well-recognized phenomenon. Phenytoin-induced gingival overgrowth (PIGO) usually resolves gradually following cessation of phenytoin intake. It is usually seen throughout the dentate regions of the maxillary and mandibular dental arches, but more severely affect their anterior portions exposed to atmosphere. We report a rare case of PIGO predominantly involving hard palate and floor of oral cavity, which has not been reported in English literature till date.


Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey.
Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children. Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was "useful", i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence. Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %). Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study.


Analysis of flow-based adhesion in vitro.
To be able to visualize real time leukocyte - endothelial cell interactions in vitro opens up the possibility of exploring the complex cascade of events that culminate in leukocyte recruitment and diapedesis in a much more detailed and controlled way. Techniques have been developed whereby fluorescently labeled leukocytes are perfused over an endothelial substrate in a controlled manner. Interactions can then be visualized and, using motion tracking software, the movement of cells characterized. Dynamic flow based adhesion assay protocols build on previous static assays of leukocyte adhesion in better modeling the environment in which these interactions actually take place in vivo.


Modelling, designing, and implementing a family-based health record prototype.
Within the arising and fast growing trend of the personalized healthcare, the promising Personalized Health Informatics (PHI) asks to be understood, modelled, implemented, and tested. The central idea of "keeping healthy lifestyle", that grounds the development of PHI systems, needs to be extended to the digital family group, where the middle generation (the "parents") manages the responsibility of taking care and improving the health of the weaker members (children and grandparents). The family environment is also a fundamental indicator of disease risk. We modelled, designed, and implemented a prototype for the health data management in a multigenerational family environment.


Correction to "Synthesis, Evaluation, and Characterization of an Ergotamine Imprinted Styrene-Based Polymer for Potential Use as an Ergot Alkaloid Selective Adsorbent".
[This corrects the article DOI: 10.1021/acsomega.1c02158.].


The new classification of hemorrhoids: PATE 2000-Sorrento. History of the scientific debate.
The history of our proposal for a new classification of hemorrhoids is very old: 7 years of scientific debate had a big impact for the study and the definition of hemorrhoids. Nowadays many things have changed mainly in the field of treatment of hemorrhoids. New medical and surgical tools are available for the modern proctologist. The new classification of the disease seems to fit the necessity of introducing these modern opportunities. Many authors recognize the fundamental role and claim for the routine use of a new classification, named PATE 2000 Sorrento. Nevertheless many problems are on debate. Their resolution needs the cooperation of all the experts in order to choose the best version of the classification. For these reasons the authors analyse all the work carried out till now in order to see what we still need to introduce a new classification of the disease.


Expression of substance P, neurokinin 1 receptor, Ki-67 and pyruvate kinase M2 in hormone receptor negative breast cancer and evaluation of impact on overall survival.
Chronic inflammation is a hallmark of cancer, and it can be stimulated by many factors. Substance P (SP), through binding to neurokinin 1 receptor (NK1R), and pyruvate kinase M2 (PKM2) play critical roles in cancer development and progression via modulating the tumor microenvironment. This study aimed to investigate the prognostic significance of SP and PKM2 in combination with NK1R and Ki-67 in hormone receptor negative (HR-ve) breast cancer. Immunohistochemical expression levels of SP, NK1R, PKM2, and Ki-67 were measured in 144 paraffin-embedded breast cancer tissues (77 h -ve and 67 h + ve). SP, NK1R, and PKM2 were scored semiquantitatively, while Ki-67 was obtained by the percentage of total number of tumor cells with nuclear staining. The optimal cutoff value for SP, NK1R, PKM2, and Ki-67 were assessed by Cutoff Finder. High SP expression in HR -ve breast cancer was associated with TNM stage (p = 0.020), pT stage (p = 0.035), pN stage (p = 0.002), axillary lymph node metastasis (p = 0.003), and NK1R expression level (p = 0.010). In HR + ve breast cancer, SP expression was associated with HER2 status (p = 0.001) and PKM2 expression level (p = 0.012). Regarding PKM2 expression level, it significantly associated with HER2 status (p = 0.001) and history of DCIS (p = 0.046) in HR-ve tumors, and with HER2 status (p < 0.001) and SP expression level (p = 0.012) in HR + ve tumors. Survival analysis revealed that high SP level negatively impacted overall survival in HR-ve tumors that had low NK1R level (p = 0.021). Moreover, high SP negatively impacted overall survival in HR-ve tumors that had low Ki-67 level (p = 0.005). High PKM2 negatively impacted overall survival in HR-ve cases with low SP (p = 0.047). Combined expression levels of SP with NK1R or Ki-67, and PKM2 with SP could be used to predict survival in breast cancer patients with HR-ve tumors. Our findings suggest a role of SP/NK1R pathway and PKM2 in HR-ve breast cancer pathogenesis which should be further investigated to unveil the underlying molecular mechanisms.


Does the quality of prenatal care matter in promoting skilled institutional delivery? A study in rural Mexico.
To determine if the quality of prenatal care predicts skilled institutional delivery, a primary means of reducing maternal mortality. The probability of skilled institutional delivery is predicted among 4173 rural low-income women of reproductive age in seven Mexican states, as a function of maternal retrospective reports about prenatal care services received in 1997-2003. Women who received most prenatal care procedures were more likely to have a skilled institutional delivery (OR 2.29, 95% CI 1.18, 4.44). Women who received less than the 75th percentile of prenatal care procedures were not significantly different from those who received no prenatal care. Policies promoting increased access to prenatal services should be linked to the promotion of practice standards to impact health and behavioral outcomes.


On taming the effect of transcript level intra-condition count variation during differential expression analysis: A story of dogs, foxes and wolves.
The evolution of RNA-seq technologies has yielded datasets of scientific value that are often generated as condition associated biological replicates within expression studies. With expanding data archives opportunity arises to augment replicate numbers when conditions of interest overlap. Despite correction procedures for estimating transcript abundance, a source of ambiguity is transcript level intra-condition count variation; as indicated by disjointed results between analysis tools. We present TVscript, a tool that removes reference-based transcripts associated with intra-condition count variation above specified thresholds and we explore the effects of such variation on differential expression analysis. Initially iterative differential expression analysis involving simulated counts, where levels of intra-condition variation and sets of over represented transcripts are explicitly specified, was performed. Then counts derived from inter- and intra-study data representing brain samples of dogs, wolves and foxes (wolves vs. dogs and aggressive vs. tame foxes) were used. For simulations, the sensitivity in detecting differentially expressed transcripts increased after removing hyper-variable transcripts, although at levels of intra-condition variation above 5% detection became unreliable. For real data, prior to applying TVscript, ≈20% of the transcripts identified as being differentially expressed were associated with high levels of intra-condition variation, an over representation relative to the reference set. As transcripts harbouring such variation were removed pre-analysis, a discordance from 26 to 40% in the lists of differentially expressed transcripts is observed when compared to those obtained using the non-filtered reference. The removal of transcripts possessing intra-condition variation values within (and above) the 97th and 95th percentiles, for wolves vs. dogs and aggressive vs. tame foxes, maximized the sensitivity in detecting differentially expressed transcripts as a result of alterations within gene-wise dispersion estimates. Through analysis of our real data the support for seven genes with potential for being involved with selection for tameness is provided. TVscript is available at: https://sourceforge.net/projects/tvscript/.


Different behavior of type I and type I-trimer collagen in neutral sodium chloride solutions.
Type I and type I-trimer collagen, isolated from ductal infiltrating carcinoma of the human breast, have been tested for their behavior in neutral NaCl solutions. Evident diversities in their rate of precipitation at different saline concentrations have been found, since type I-trimer collagen precipitates at low NaCl molarity while type I collagen is mostly recovered in 2.6-3.6 M NaCl solutions. The native conformation of homotrimer collagen is proved by its ability to produce segment long-spacing crystallites and native-type fibrils.


The dynamical foundations of motion pattern formation: stability, selective adaptation, and perceptual continuity.
A dynamical model is used to show that global motion pattern formation for several different apparent motion stimuli can be embodied in the stable distribution of activation over a population of concurrently activated, directionally selective motion detectors. The model, which is based on motion detectors being interactive, noisy, and self-stabilizing, accounts for such phenomena as bistability, spontaneous switching, hysteresis, and selective adaptation. Simulations show that dynamical solutions to the motion correspondence problem for a bistable stimulus (two qualitatively different patterns are formed) apply as well to the solution for a monostable stimulus (only one pattern is formed) and highlight the role of interactions among sequentially stimulated detectors in establishing the state dependence and, thereby, the temporal persistence of percepts.


Longitudinal Associations between Physical Fitness and Academic Achievement in Youth.
Data from clinical trials have justified the promotion of fitness as a means to enhance facets of cognitive control and academic achievement in youth. However, such associations, when tested under real-world conditions, are equivocal. The purpose of this study, therefore, was to evaluate longitudinal associations between aerobic capacity (AC), weight status, and academic achievement within a large urban county. Longitudinal data were obtained from a sample of third, fifth, and seventh grade students in schools within an urban county in Georgia. Data on body mass index (BMI) were available from 11,639 students; AC data from 5735 students. Data on both indicators were obtained through the established FitnessGram assessment battery with 2-yr changes calculated using standardized Z scores. Academic achievement data were available from three subjects (math, science, and reading) for third, fifth, and seventh grade students, and 2-yr changes were computed using changes in Z scores for each test. Data were analyzed using generalized logistic models to test associations between change in BMI and AC in relation to changes in academic achievement. Positive associations were observed between improvements in weight status and academic achievement for the fifth grade boys and girls ([reading] odds ratio [OR], 1.47; 95% confidence interval [CI], 1.25-1.72; [science] OR, 1.22; 95% CI, 1.04-1.42). Maintaining weight status was associated with improved scores in the third grade ([math] OR, 1.16; 95% CI, 1.012-1.327; [reading] OR, 1.47; 95% CI, 1.25-1.72) and fifth grade cohorts (math OR, 1.20; 95% CI, 1.00.1.43). For AC, no significant associations were found for any age cohort. Modest associations between improvements in weight status, AC, and academic achievement are noteworthy, despite the lack of statistical significance for AC. The results provide a robust evaluation of associations between fitness and academic achievement.


Lunasin Peptide is a Modulator of the Immune Response in the Human Gastrointestinal Tract.
Lunasin is a soybean bioactive peptide with a variety of beneficial properties against chronic disorders. However, its effect in human primary intestinal cells remains unknown. Hence, this study aims to characterize its ex vivo biological activity in the human intestinal mucosa. Human intestinal biopsies, obtained from healthy controls, are ex vivo conditioned with lunasin both in the presence/absence of lipopolysaccharide (LPS). Peptide maintains its stability during biopsy culture by HPLC-MS/MS analysis. Lunasin is bioactive in the human mucosa, as it induces IL-1β, TNF-α, IL-17A, CCL2, and PGE2/COX-2 gene expression together with an increased expression of tolerogenic IL-10 and TGFβ, while it also downregulates the expression of iNOS and subunit p65 from NF-κB. Indeed, lunasin also abrogates the LPS-induced pro-inflammatory response, downregulating IL-17A, IFNγ, and IL-8 expression, and inducing IL-10 and TGFβ expression. These results are also mirrored in the cell-free culture supernatants at the protein level by Multiplex. Moreover, lunasin further induces a regulatory phenotype and function on human intestinal conventional dendritic cell and macrophage subsets as assessed by flow cytometry. We hereby have characterized lunasin as an immunomodulatory peptide with potential capacity to prevent immune and inflammatory-mediated disorders in the human gastrointestinal tract.


Variability in expression of the human MDR1 drug efflux transporter and genetic variation of the ABCB1 gene: implications for drug-resistant epilepsy.
Among individuals diagnosed with epilepsy, as many as one in three develop resistance to antiepileptic drugs (AEDs) thus rendering their seizures refractory to treatment. Despite current antiepileptic drugs (AEDs) having a variety of modes of action, seizures in drug-resistant individuals often persist even after treatment with two or more drugs. The underlying cause of this broad resistance is currently under debate, but two dominant theories have emerged and have been widely studied. Here we discuss current literature investigating the "transporter theory", the idea that individuals present with drug resistance due to genetic variability in the ABCB1 gene encoding the efflux transporter multidrug resistance protein 1 (MDR1). Results of in vitro and in vivo studies suggest that variability in the expression of the MDR1 transporter may be closely tied to drug resistance. While there is much support for this hypothesis from molecular and mechanistic studies, population-based studies of ABCB1 polymorphisms are divergent in their conclusions, and there is need for additional investigations.


Diagnosis of occlusal caries lesions in deciduous molars by coherent light scattering pattern speckle.
This study presents the correlation between laser speckle images and detection of incipient caries lesions from changs in the microstructure of the surface of tooth enamel. We used 30 healthy deciduous molar teeth collected from the Biobank Human Teeth, Faculty of Dentistry, University of São Paulo who had carious lesions induced by the pH cycling method. The samples were evaluated for the diagnosis of caries by two methods ICDAS and speckle pattern of coherent light scattering after 5, 10 and 15days and the results were statistically analyzed using α=0.05 significance level. A significant difference was observed between the image of the speckle scattering of healthy and injured areas within the 3 study groups, but not when comparing the three groups, showing us that it is an innovative technique that needs further study, but can be used as a diagnostic method for the detection of early caries lesions. It can be concluded that the analysis of scattering speckle pattern is a diagnostic technique that provides information on the microstructure of the surface of tooth enamel which has sensitivity for detection of incipient caries lesions.


Inherited glucosephosphate isomerase deficiency. A review of known variants and some aspects of the pathomechanism of the deficiency.
Since the first report of GPI deficiency in 1967 many patients from all over the world have been described. The patients suffer from a typical nonspherocytic hemolytic anemia with hemolytic crises during acute infections. The disease is inherited as an autosomal recessive, half of the patients are homozygotic, the others are double heterozygotes. The biochemical properties of the deficient enzymes vary widely. Thus, many well characterized enzymes have been designated as different variants. The modification of physicochemical properties surpasses kinetic aberrations. All defective variants are more or less unstable. The activity diminishes progressively, leading to a rise in G6P concentration and in red cells after aging in vitro to a dramatic impairment of glycolysis and concomittant hemolysis. The cause of the metabolic block is the diminished GPI activity itself and not an inhibition of hexokinase by the high G6P.


Clinical manifestations of IgE hypogammaglobulinemia.
Although IgE has been shown to play a role in the expulsion of intestinal parasites in experimental animals, its overall contribution to host defense in humans remains a subject of controversy. In order to clarify the potential role of IgE in host defense, we have studied the clinical characteristics of patient with serum IgE levels of < 2.5 IU/mL, using patients with normal or elevated IgE levels as controls. To determine the clinical characteristics of IgE deficiency. Serum IgE levels were measured in 420 adult patients seen in our Allergy-Immunology Clinic over a period extending from January, 1990 to March, 1996. All subjects were examined by one of the authors (JKS or GHK) using a standardized history and physical examination form. Patients with IgE levels of < 2.5 IU/mL also had measurements of serum IgG, IgG subclasses, IgA and IgM. All IgE-deficient patients and 73% of those with normal to elevated IgE levels underwent RAST and/or skin testing for Type I hypersensitivity, and, where clinically indicated, had serum drawn for autoimmune serologic profiles. Infectious complications were documented by culture. The American Rheumatology Association criteria were used to establish a diagnosis of autoimmune disease. Forty-four patients were found to have IgE levels of < 2.5 IU/mL; 57% of these had depressed serum levels of other immunoglobulins, and 43% had isolated IgE deficiencies. Respiratory symptoms were equally common in IgE-deficient patients and in patients with normal to elevated IgE levels. IgE-deficient patients, however, were more likely to complain of arthralgias (P < .0001), chronic fatigue (P < .0001), and symptoms suggestive of airway infection (P = .0119). Compared with controls, patients with IgE deficiency had a higher prevalence of autoimmune disease (46% versus 15%) (P < .0001) and nonallergic reactive airway disease (73% versus 20%) (P < .0001). There was no difference in the prevalence of these disease in patients with selective IgE deficiency as compared with those with IgE deficiency complicated by deficits in other immunoglobulin classes. IgE-deficient patients with multiple immunoglobulin deficiencies, however, were more likely to have serious infection involving both the upper and lower respiratory tract than those with isolated IgE deficiency. IgE-deficient patients have an increased prevalence of multiple immunoglobulin deficits, autoimmune disease, and nonallergic reactive airway disease when compared with a clinic population of patients with normal to elevated IgE levels.