Measurements and model of the cat middle ear: evidence of tympanic membrane acoustic delay.
In order to better understand the mechanics of tympanic membrane (TM) transduction at frequencies above a few kHz, the middle-ear (ME) impedance measured near the tympanic membrane is studied for three anesthetized cat ears after widely opening the ME cavities (MEC). Three conditions were measured: intact ossicles, drained cochlea, and disarticulated stapes. When the cochlear load is removed from the ME by disarticulating the stapes, the impedance magnitude varies by about +/- 25 dB in the 5- to 30-kHz range, with peaks and valleys at intervals of approximately 5 kHz. These measurements suggest middle-ear standing waves. It is argued that these standing waves reside in the TM. In contrast, the magnitude of the impedance for the intact case varies by less than +/- 10 dB, indicating that for this case the standing waves are damped by the cochlear load. Since the measurements were made within 2 mm of the TM, standing waves in the ear canal can be ruled out at these frequencies. Although the ME cavities were widely opened, reflections from the ME cavity walls or surrounding structures could conceivably result in standing waves. However, this possibility is ruled out by model predictions showing that such large standing waves in the ME cavity space would also be present in the intact case, in disagreement with the observation that standing waves are damped by cochlear loading. As a first-order approximation, the standing waves are modeled by representing the TM as a lossless transmission line with a frequency-independent delay of 36 microseconds. The delay was estimated by converting the impedance data to reflectance and analyzing the reflectance group delay. In the model the ossicles are represented as lumped-parameter elements. In contrast to previous models, the distributed and lumped parameter model of the ME is consistent with the measured impedance for all three conditions in the 200-Hz to 30-kHz region. Also in contrast with previous models, the ear-canal impedance is not mass dominated for frequencies above a few kHz. Finally, the present model is shown to be consistent, at high frequencies, with widely accepted transfer functions between (i) the stapes displacement and ear-canal pressure, (ii) the vestibule pressure and ear-canal pressure, and (iii) the umbo velocity and ear-canal volume velocity. An improved understanding of TM mechanics is important to improve hearing aid transducer design, ear-plug design, as well as otoacoustic emissions research.


TAML/H2O2 Oxidative Degradation of Metaldehyde: Pursuing Better Water Treatment for the Most Persistent Pollutants.
The extremely persistent molluscicide, metaldehyde, widely used on farms and gardens, is often detected in drinking water sources of various countries at concentrations of regulatory concern. Metaldehyde contamination restricts treatment options. Conventional technologies for remediating dilute organics in drinking water, activated carbon, and ozone, are insufficiently effective against metaldehyde. Some treatment plants have resorted to effective, but more costly UV/H2O2. Here we have examined if TAML/H2O2 can decompose metaldehyde under laboratory conditions to guide development of a better real world option. TAML/H2O2 slowly degrades metaldehyde to acetaldehyde and acetic acid. Nuclear magnetic resonance spectroscopy ((1)H NMR) was used to monitor the degradation-the technique requires a high metaldehyde concentration (60 ppm). Within the pH range of 6.5-9, the reaction rate is greatest at pH 7. Under optimum conditions, one aliquot of TAML 1a (400 nM) catalyzed 5% degradation over 10 h with a turnover number of 40. Five sequential TAML aliquots (2 μM overall) effected a 31% removal over 60 h. TAML/H2O2 degraded metaldehyde steadily over many hours, highlighting an important long-service property. The observation of metaldehyde decomposition under mild conditions provides a further indication that TAML catalysis holds promise for advancing water treatment. These results have turned our attention to more aggressive TAML activators in development, which we expect will advance the observed technical performance.


Wave localization at the boundary of disordered photonic lattices.
We report on the experimental observation of reduced light-energy transport and disorder-induced localization close to a boundary of a truncated 1D disordered photonic lattice. Our observations uncover that a higher level of disorder near the boundary is required to obtain similar localization than in the bulk.


Increased expression of macrophage migration inhibitory factor in aorta of patients with coronary atherosclerosis.
The aim of the present study was to investigate the changes of macrophage migration inhibitory factor (MIF) in the aorta of patients with coronary atherosclerosis and to evaluate the relationship between aortic expression levels of MIF and atherosclerotic risk factors. We collected discarded aortic specimens from patients (N.=36) undergoing coronary artery bypass graft surgery (CABG), and studied the presence and distribution of MIF by immunohistochemistry. The arterial tissues from 10 subjects without known atherosclerosis through the kidney donation program were taken as control group. The preoperative serum triglycerides, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A, apolipoprotein B, total bilirubin, direct bilirubin, and indirect bilirubin levels of patients were examined and the coronary angiography was performed in order to assess the severity of atherosclerotic lesions. MIF was detectable in aorta from CABG patients. The aortic MIF expression was elevated in smokers, and patients with hypertension or diabetes. In addition, the aortic MIF expression was associated with the levels of triglycerides, total cholesterol, low density lipoprotein cholesterol, lipoprotein (a), apolipoprotein B, total bilirubin, direct bilirubin, indirect bilirubin and coronary severity scores in simple regression analysis. However, the expression of MIF was only correlated to coronary severity scores in multiple regression analysis. MIF is overexpressed in aorta from patients with coronary atherosclerosis and the aortic MIF expression is correlated with the severity of coronary artery disease.


Right Prefrontal TMS Disrupts Interregional Anticipatory EEG Alpha Activity during Shifting of Visuospatial Attention.
Visual attention can be shifted in space without moving the eyes. Amplitude decrease of rhythmical brain activity around 10 Hz (so called alpha activity) at contralateral posterior sites has been reported during covered shifts of visuospatial attention to one visual hemi-field. Alpha amplitude increase, on the other hand, can be found at ipsilateral visual cortex. There is some evidence suggesting an involvement of prefrontal brain areas during the control of attention-related anticipatory alpha amplitude asymmetry. This open question has been studied in detail using a multimodal approach combining transcranial magnetic stimulation (TMS) and multichannel electroencephalography (EEG) in healthy humans. Slow (1 Hz) repetitive TMS leading to reduced excitability of the stimulation site was delivered either to right frontal eye field (FEF) or a control site (vertex). Subsequently, participants had to perform a spatial cuing task in which covert shifts of attention were required to either the left or the right visual hemi-field. After stimulation at the vertex (control condition) a pattern of anticipatory, attention-related ipsilateral alpha increase/contralateral alpha decrease over posterior recording sites could be obtained. Additionally, there was pronounced coupling between (in particular right) FEF and posterior brain sites at EEG alpha frequency. When, however, right prefrontal cortex had been virtually lesioned preceding the task, these EEG correlates of visuospatial attention were attenuated. Notably, the effect of TMS at the right FEF on interregional fronto-parietal alpha coupling predicted the effect of TMS on response times. This suggests that visual attention processes associated with posterior EEG alpha activity are at least partly top-down controlled by the prefrontal cortex.


Inhibition of neuroinflammation by cinnamon and its main components.
Uncontrolled activation of microglia contributes to neuroinflammation, which is highly involved in the development of neurodegenerative diseases. Although cinnamon has neuro-protective properties, its capacity to inhibit neuroinflammation has not been investigated and its active compounds remain unclear. Therefore, the composition of cinnamon extract was analysed by LC-MS and the ability of cinnamon and its main constituents to inhibit neuroinflammation was evaluated using a lipopolysaccharide (LPS)-activated BV2 microglia culture system. In total, 50 μg/mL cinnamon extract decreased significantly the production and expression of nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in LPS-activated BV2 microglia. Blocking of nuclear factor-κB (NF-κB) activation was the most likely mechanism responsible for inhibition by cinnamon of neuroinflammation. Among the eight tested compounds, cinnamaldehyde had the greatest anti-neuroinflammatory capacity. Experimental results suggest that cinnamon may have a potential therapeutic effect against neurodegenerative diseases and its potent anti-neuroinflammatory capacity was primarily attributed to cinnamaldehyde.


New genetic variants of LATS1 detected in urinary bladder and colon cancer.
LATS1, the large tumor suppressor 1 gene, encodes for a serine/threonine kinase protein and is implicated in cell cycle progression. LATS1 is down-regulated in various human cancers, such as breast cancer, and astrocytoma. Point mutations in LATS1 were reported in human sarcomas. Additionally, loss of heterozygosity of LATS1 chromosomal region predisposes to breast, ovarian, and cervical tumors. In the current study, we investigated LATS1 genetic variations including single nucleotide polymorphisms (SNPs), in 28 Egyptian patients with either urinary bladder or colon cancers. The LATS1 gene was amplified and sequenced and the expression of LATS1 at the RNA level was assessed in 12 urinary bladder cancer samples. We report, the identification of a total of 29 variants including previously identified SNPs within LATS1 coding and non-coding sequences. A total of 18 variants were novel. Majority of the novel variants, 13, were mapped to intronic sequences and un-translated regions of the gene. Four of the five novel variants located in the coding region of the gene, represented missense mutations within the serine/threonine kinase catalytic domain. Interestingly, LATS1 RNA steady state levels was lost in urinary bladder cancerous tissue harboring four specific SNPs (16045 + 41736 + 34614 + 56177) positioned in the 5'UTR, intron 6, and two silent mutations within exon 4 and exon 8, respectively. This study identifies novel single-base-sequence alterations in the LATS1 gene. These newly identified variants could potentially be used as novel diagnostic or prognostic tools in cancer.


[Voronoi s Diagram for defining catchment areas for public hospitals in the Municipality of Rio de Janeiro].
One of the most important pieces of information for health resources planning is the definition of catchment areas for health units. Voronoi Diagrams are a potential technique for this purpose. They are polygons with the property whereby adjacent polygons have their borders located within the same distance of the respective generator points. One possible adjustment to the catchment areas thus defined is the use of weighted Voronoi Diagrams, which result in an improved representation of a health unit's actual capacity. In this study, the 21 public general hospitals in the city of Rio de Janeiro, Brazil, were used as generator points for Voronoi Diagrams. Non-weighted Voronoi Diagrams were initially implemented and then used as the basis for obtaining weighted Voronoi Diagrams, using as weights the annual admission rates estimated for each unit. In the classic Voronoi Diagram case, some catchment areas had similar sizes, although their respective health units had different characteristics. In the weighted case the areas were modified in a way that appeared closer to the actual functioning of the units. The method appeared simple to implement, used easy-to-access data, and did not rely on geopolitical considerations such as existing administrative areas. It thus provided a more realistic picture of a unit's capacity to support basic health programs.


Effect of anthelmintic treatment on leptin, adiponectin and leptin to adiponectin ratio: a randomized-controlled trial.
Emerging evidence suggests that helminths might confer protection against the development of type 2 diabetes. We aimed to assess the role of adipokines in mediating the effect of helminths on insulin resistance. Serum samples were obtained from a randomized-controlled trial of anthelmintic treatment in an area endemic for soil-transmitted helminths (STH), Flores Island, Indonesia. In STH-infected subjects, anthelmintic treatment significantly increased the ratio of leptin to adiponectin (treatment effect factor (95% confidence interval (CI)), P-value for interaction: 1.20 (1.06-1.35), P=0.010), which largely stemmed from a significant reduction in adiponectin (0.91 (0.85-0.98), P=0.020) and a trend for an increase in leptin level (1.10 (1.00-1.21), P=0.119). No significant effect on resistin level was observed. This increase in leptin to adiponectin ratio seemed to contribute to the observed effect of deworming on increased insulin resistance (IR) as adjustment for leptin to adiponectin ratio attenuated the effect on IR from 1.07 (1.01-1.14, P=0.023) to 1.05 (0.99-1.11, P=0.075). Anthelmintic treatment in STH-infected subjects increases leptin to adiponectin ratio which may in small part contribute to the modest increase in IR. Further studies will be needed to assess the effect of the changes in adipokine levels on the host immune response and metabolism.


Anthropometrics, Athletic Abilities and Perceptual-Cognitive Skills Associated With Baseball Pitching Velocity in Young Athletes Aged Between 10 and 22 Years Old.
Objective assessments of players performance and individual characteristics are increasingly used in baseball. However, evidence linking individual characteristics to players' performance are scarce. The purpose of the study was to identify across ages, in younger males and females, and to compare, in younger males, the anthropometrics, athletic abilities and perceptual-cognitive skills associated with baseball pitcher's ball velocity. A cross-sectional design was used to conduct this study. Male and female athletes completed a sociodemographic questionnaire followed by anthropometric, athletic ability, perceptual-cognitive skill and pitching velocity assessments. Athletes were categorized by their age categories (11U, 13U, 15U, 18U, 21U). To evaluate the athletes' anthropometrics, height and weight, BMI, waist circumference, arms segmental length and girth were measured. Athletic abilities were assessed using athletes' grip strength, upper body power, vertical jump height, sprint, change of direction, and dynamic balance. Perceptual-cognitive skills performance was assessed with the Neurotracker platform. Pitching performance assessment was completed using the athletes' average fastball velocity. Kendall Tau's correlation coefficient was used to assess relationships between variables and pitching velocity in male athletes (p < 0.05). A 1-way ANOVA was performed to identify differences between age categories for all variables in male athletes (p < 0.05). In male athletes, without age categories discrimination, all anthropometric, athletic ability and perceptual-cognitive skill factors were associated with pitching velocity with associations ranging from τ = 0.185 for perceptual-cognitive skills to τ = 0.653 for left arm grip strength. The results showed that significant differences exist between age categories for anthropometric, athletic ability and perceptual-cognitive skill assessments. The study showed that associations between anthropometrics and pitching velocity, and athletic abilities and pitching velocity vary across age categories. Descriptive data of female athletes results regarding anthropometrics, athletic abilities, perceptual-cognitive skills and pitching velocity are also presented. Gender differences should be investigated in future studies exploring baseball pitching performance.


Sympathetic Overactivity in Chronic Kidney Disease: Consequences and Mechanisms.
The incidence of chronic kidney disease (CKD) is increasing worldwide, with more than 26 million people suffering from CKD in the United States alone. More patients with CKD die of cardiovascular complications than progress to dialysis. Over 80% of CKD patients have hypertension, which is associated with increased risk of cardiovascular morbidity and mortality. Another common, perhaps underappreciated, feature of CKD is an overactive sympathetic nervous system. This elevation in sympathetic nerve activity (SNA) not only contributes to hypertension but also plays a detrimental role in the progression of CKD independent of any increase in blood pressure. Indeed, high SNA is associated with poor prognosis and increased cardiovascular morbidity and mortality independent of its effect on blood pressure. This brief review will discuss some of the consequences of sympathetic overactivity and highlight some of the potential pathways contributing to chronically elevated SNA in CKD. Mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and to date, not completely understood. Identification of the mechanisms and/or signals leading to sympathetic overactivity in CKD are crucial for development of effective therapeutic targets to reduce the increased cardiovascular risk in this patient group.


IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model.
The immunosuppression and immune dysregulation that follows severe injury includes type 2 immune responses manifested by elevations in interleukin (IL) 4, IL5, and IL13 early after injury. We hypothesized that IL33, an alarmin released early after tissue injury and a known regulator of type 2 immunity, contributes to the early type 2 immune responses after systemic injury. Blunt trauma patients admitted to the trauma intensive care unit of a level I trauma center were enrolled in an observational study that included frequent blood sampling. Dynamic changes in IL33 and soluble suppression of tumorigenicity 2 (sST2) levels were measured in the plasma and correlated with levels of the type 2 cytokines and nosocomial infection. Based on the observations in humans, mechanistic experiments were designed in a mouse model of resuscitated hemorrhagic shock and tissue trauma (HS/T). These experiments utilized wild-type C57BL/6 mice, IL33-/- mice, B6.C3(Cg)-Rorasg/sg mice deficient in group 2 innate lymphoid cells (ILC2), and C57BL/6 wild-type mice treated with anti-IL5 antibody. Severely injured human blunt trauma patients (n = 472, average injury severity score [ISS] = 20.2) exhibited elevations in plasma IL33 levels upon admission and over time that correlated positively with increases in IL4, IL5, and IL13 (P < 0.0001). sST2 levels also increased after injury but in a delayed manner compared with IL33. The increases in IL33 and sST2 were significantly greater in patients that developed nosocomial infection and organ dysfunction than similarly injured patients that did not (P < 0.05). Mechanistic studies were carried out in a mouse model of HS/T that recapitulated the early increase in IL33 and delayed increase in sST2 in the plasma (P < 0.005). These studies identified a pathway where IL33 induces ILC2 activation in the lung within hours of HS/T. ILC2 IL5 up-regulation induces further IL5 expression by CXCR2+ lung neutrophils, culminating in early lung injury. The major limitations of this study are the descriptive nature of the human study component and the impact of the potential differences between human and mouse immune responses to polytrauma. Also, the studies performed did not permit us to make conclusions about the impact of IL33 on pulmonary function. These results suggest that IL33 may initiate early detrimental type 2 immune responses after trauma through ILC2 regulation of neutrophil IL5 production. This IL33-ILC2-IL5-neutrophil axis defines a novel regulatory role for ILC2 in acute lung injury that could be targeted in trauma patients prone to early lung dysfunction.


SMS for disease control in developing countries: a systematic review of mobile health applications.
Mobile phones provide a low cost method of addressing certain health system needs in developing countries. We examined SMS-supported interventions for prevention, surveillance, management and treatment compliance of communicable and non-communicable diseases in developing countries. We searched both peer-reviewed and grey literature reporting the use of SMS messages for disease prevention, surveillance, self-management and compliance in developing countries. A total of 98 applications fulfilled the inclusion criteria (33 prevention, 19 surveillance, 29 disease management and 17 patient compliance applications). In 31 projects, the SMS applications were evaluated. The majority of applications focused on HIV/AIDS and were located in India, South Africa and Kenya. Most used bulk (push) messaging. In general, they were well accepted by the population. The review provides further evidence that mobile phones are an appropriate and promising tool for disease control interventions in developing countries.


[Congenital nephrogenic diabetes insipidus: a difficult diagnosis?].
In five patients (a boy aged 10 years, a boy aged 3 months, his brother aged 1 week, the brother of the mother of the last-mentioned two boys who had died at the age of one, and a girl of kindergarten age) congenital nephrogenic diabetes insipidus was diagnosed. This rare syndrome (prevalence 1:500,000) is caused by renal insensitivity to the antidiuretic hormone arginine vasopressin. In infancy the symptoms of this disorder are aspecific, and the main symptoms of the disease, polyuria and polydipsia, often remain unnoticed at this young age. A simple anamnesis and a few laboratory tests should suggest the diagnosis. Early diagnosis and genetic counselling are possible as the molecular effects involved have been elucidated.


The lived experiences of emotionally insecure nursing students: A qualitative study.
Research shows that students who feel emotionally insecure are at risk of dropping out of nursing educational program. It is, therefore, important to support student resilience in the international nursing education. The aim of this study was to investigate the lived experiences of undergoing a nursing education as an emotionally insecure student. The method was conducted within a phenomenological-hermeneutic approach, inspired by the French philosopher Paul Ricoeur's theory of narrative and interpretation, which is conducted in a three-phased structure: Naïve reading, structural analysis and critical interpretation and discussion. Seven participants were included in the study. The findings show that feeling emotionally insecure can be linked to not feeling good enough and feeling misunderstood - yet, with hidden resources. Nurse educators must be aware that emotionally insecure students can easily feel shame, must be willing to help clear up potential misunderstandings and should be curious about resources that might be hidden, such as competence awareness. Hidden resources might be related to protective factors and resilience. The study points to ways in which the relation between nurse educators and students can affect resilience, and that students are not solely either resilient or emotionally insecure; resilience may exist within vulnerability.


Expression of transforming growth factor-beta1, activin A, and their receptors in thyroid follicle cells: negative regulation of thyrocyte growth and function.
Thyroid growth and function are intricately regulated by both positive and negative factors. In the present study, we have investigated the expression of transforming growth factor-beta (TGF-beta) super-family members and their receptors in normal porcine thyroid follicle cells. In tissue sections of porcine thyroids, we observed an expression of TGF-beta1, activin A, and bone morphogenetic protein (BMP)-7 proteins. The staining was localized to the follicular epithelium. In affinity cross-linking experiments, TGF-beta1 was found to bind to heteromeric complexes of TGF-beta type I and type II receptors, and activin A bound most efficiently to heteromeric complexes of activin type IB and type II receptors. We were unable to detect any BMP receptors (BMPRs) in attempts to perform affinity cross-linking with BMP-7. However, expression of BMPR-IA and BMPR-II messenger RNA (mRNA) was detected by Northern blot analysis. Both TGF-beta1 and activin A, but not BMP-7, increased the phosphorylation of Smad2, induced nuclear translocation of Smad2, Smad3, and Smad4, and inhibited thyrocyte cell growth as well as TSH-stimulated cAMP response. TGF-beta1 was more potent, compared with activin A, to induce these cellular responses. Taken together, our findings indicate a role for several members of the TGF-beta family in regulation of thyroid growth and function.


Effects of quercetin on methotrexate-induced nephrotoxicity in rats.
This experimental study was conducted to elucidate the possible protective/therapeutic effects of quercetin against methotrexate (Mtx)-induced kidney toxicity with biochemical and histopathological studies. Twenty-four adult male rats were randomly divided into four groups, as follows: control group (saline intraperitoneally (i.p.), 9 days), Mtx group (20 mg/kg i.p., single dose), Mtx + quercetin group (50 mg/kg quercetin was orally administered 2 days before and 6 days after Mtx administration) and only quercetin group (50 mg/kg oral, 9 days). Structural changes were evaluated by hematoxylin-eosin and periodic acid-Schiff stainings. Apoptotic changes were investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and caspase-3 antibody. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured in tissue and plasma samples. Mtx compared with the control group, there was significant increase in nephrotoxic tissue damage findings, in addition to apoptotic index (APOI) and caspase-3 expression ( p < 0.05). Mtx + quercetin group revealed significantly lower histopathological damage and APOI and caspase-3 expression decreased when compared to Mtx group. MDA levels were increased in Mtx group compared to others, and by the use of quercetin, this increase was significantly reduced. SOD levels were higher in Mtx group than others. This increase was evaluated as a relative increase arising from oxidative damage caused by Mtx. As a result, Mtx administration may involve oxidative stress by causing structural and functional damage in kidney tissue in rats. Quercetin reduced the Mtx-induced oxidative stress through its antioxidant properties and so quercetin may be promising to alleviate Mtx-induced renal toxicity.


The nature of prophage in lysogenic Bacillus megatherium.
1. By complement-fixation tests it has been shown that the lysogenic and sensitive strains of B. megatherium share one or more antigenic components which are serologically related but not identical. 2. Bacilli of the lysogenic strain of B. megatherium, when grown under conditions such that little extracellular phage is produced, fail to evoke antibodies in rabbits which react either in complement-fixation or neutralization tests with purified megatherium T phage. From this it must be concluded either that prophage is not antigenic or that any antibody which it might elicit does not react with the antigens of the mature virus. The observations reported in this communication accord with the hypothesis that prophage is a genetic structure.


Pathway- and expression level-dependent effects of oncogenic N-Ras: p27(Kip1) mislocalization by the Ral-GEF pathway and Erk-mediated interference with Smad signaling.
Overactivation of Ras pathways contributes to oncogenesis and metastasis of epithelial cells in several ways, including interference with cell cycle regulation via the CDK inhibitor p27(Kip1) (p27) and disruption of transforming growth factor beta (TGF-beta) anti-proliferative activity. Here, we show that at high expression levels, constitutively active N-Ras induces cytoplasmic mislocalization of murine and human p27 via the Ral-GEF pathway and disrupts TGF-beta-mediated Smad nuclear translocation by activation of the Mek/Erk pathway. While human p27 could also be mislocalized via the phosphatidylinositol 3-kinase/Akt pathway, only Ral-GEF activation was effective for murine p27, which lacks the Thr157 Akt phosphorylation site of human p27. This establishes a novel role for the Ral-GEF pathway in regulating p27 localization. Interference with either Smad translocation or p27 nuclear localization was sufficient to disrupt TGF-beta growth inhibition. Moreover, expression of activated N-Ras or specific effector loop mutants at lower levels using retroviral vectors induced p27 mislocalization but did not inhibit Smad2/3 translocation, indicating that the effects on p27 localization occur at lower levels of activated Ras. These findings have important implications for the contribution of activated Ras to oncogenesis and for the conversion of TGF-beta from an inhibitory to a metastatic factor in some epithelial tumors.


Effect of chewing gum containing sodium bicarbonate on human interproximal plaque pH.
The effect of chewing sorbitol gum containing sodium bicarbonate on interproximal plaque pH was determined by use of an ion-sensitive field-effect transistor (ISFET) electrode system with four human volunteers. Plaque pH was lowered by 2 min of chewing of a sucrose-containing toffee. After 20 min, either sodium bicarbonate or control gum was chewed for 10 min, and the pH was followed for an additional 20 min. The minimum pH after toffee chewing was elevated by both the control gum (4.5 +/- 0.3 to 5.2 +/- 0.5) and the sodium-bicarbonate-containing product (4.3 +/- 0.3 to 6.1 +/- 0.6) to levels which were significantly different (p less than 0.01). The rate of rise in pH was 2.6 times faster with the gum containing buffer compared with the control gum. In comparison with the control gum, the sodium bicarbonate gum caused the pH to remain at a higher level, approximately 0.5 pH units, for 20 min after gum chewing. The addition of sodium bicarbonate to gum containing sorbitol markedly enhanced its capacity to cause and maintain an elevation of interproximal plaque pH previously lowered by exposure to fermentable carbohydrate. Sodium bicarbonate may be useful in products designed to reduce the acidogenic challenge to the teeth following food ingestion.


Nanoscopic analyses of cell-adhesive protein adsorption on poly(2-methoxyethyl acrylate) surfaces.
Regulation of protein adsorption on the surface of biomaterials is important for modulating cell adhesion. Two important proteins in this regard are fibrinogen and fibronectin. Poly(2-methoxyethyl acrylate) (PMEA) and its derivatives have been developed as promising coating materials for biomaterial surfaces. Previous studies have highlighted that PMEA-coated substrates suppress thrombogenicity but promote cell adhesiveness. However, it was unclear what was responsible for these differences in adhesion. In this study, we focused on the correlation between protein adsorption and the nanometer-scale structures on the surfaces of the PMEA substrates. An atomic force microscope using protein- or antibody-conjugated cantilevers was used to perform nanoscopic analyses of the adsorption forces and conformational changes in fibrinogen and fibronectin adsorbed on the nanometer-scale PMEA structures. The adsorption force of fibronectin in the polymer-poor region was higher than that of fibrinogen, whereas the polymer-rich region showed a negligible difference in adsorption force between the two proteins. Interestingly, a greater conformational change in the adsorbed fibronectin was induced in the polymer-poor region than that in fibronectin in the polymer-rich region or fibrinogen in either regions, resulting in the induction of cell adhesion. Nanoscopic analyses of protein adsorption on biomaterial surfaces provide promising insights into the design of novel biomaterials that control protein adsorption and cell adhesion.


Effects of circadian rhythm disorders on wound healing and strength of bowel anastomosis in rats.
Many body systems, especially the immune system, are affected by circadian rhythm disorders (CRDs). This study investigated the effects of shift lag on wound healing and bowel anastomosis in rats. Forty-five rats were randomly divided into 3 groups: placebo, control, and experimental. Circadian rhythm was disturbed with altered light/dark cycles. Colon anastomosis was performed in rats with and without disturbed circadian rhythms. Serum melatonin levels and bowel anastomosis bursting pressures were measured. Tissue samples were used to measure tissue hydroxyproline levels and for histological assessment. In the groups with an altered circadian rhythm, the bowel bursting pressures, tissue hydroxyproline levels, and fibrosis were greater than the control group. This study found that a CRD, simulated by altered light/dark cycles, positively affected the anastomotic bursting pressure. This suggests that cytokines such as interleukin (IL)-1, IL-6, transforming growth factor α, and stress hormones affect fibroblasts and thereby increase collagen synthesis in the proliferative phase. More studies are necessary to understand the effects of CRDs. .


MR monitoring of MR-guided radiofrequency thermal ablation of normal liver in an animal model.
The purpose of this study was to determine the suitability of MRI to accurately detect radiofrequency (RF) thermoablative lesions created under MR guidance. In vivo RF lesions were created in the livers of six New Zealand White rabbits using a 2-mm-diameter titanium alloy RF electrode with a 20-mm exposed tip and a 50-W RF generator. This was performed using a 0.2T clinical C-arm MR imager for guidance and monitoring. Each animal was sacrificed and gross evaluation was performed. Histologic correlation was performed on the first two animals. The MR-compatible RF electrode was easily identified on rapid gradient-echo images used to guide electrode placement. A single lesion was created in each rabbit liver. Lesions ranged from approximately 10 to 17 mm in diameter (mean, 13.5 mm). T2-weighted and short T1 inversion recovery (STIR) images demonstrated lesions ranging in diameter from 12 to 18 mm (mean, 14.6 mm). Lesion dimensions determined from images closely correlated with those determined at gross examination with the discrepancy never exceeding 2 mm, for an r2 value of .87. MRI performed at the time of MR-guided RF ablation accurately demonstrated created lesions. This modality may provide a new option for the treatment of local and regional neoplastic disease.


The slow S to M rise of chlorophyll a fluorescence reflects transition from state 2 to state 1 in the green alga Chlamydomonas reinhardtii.
The green alga Chlamydomonas (C.) reinhardtii is a model organism for photosynthesis research. State transitions regulate redistribution of excitation energy between photosystem I (PS I) and photosystem II (PS II) to provide balanced photosynthesis. Chlorophyll (Chl) a fluorescence induction (the so-called OJIPSMT transient) is a signature of several photosynthetic reactions. Here, we show that the slow (seconds to minutes) S to M fluorescence rise is reduced or absent in the stt7 mutant (which is locked in state 1) in C. reinhardtii. This suggests that the SM rise in wild type C. reinhardtii may be due to state 2 (low fluorescence state; larger antenna in PS I) to state 1 (high fluorescence state; larger antenna in PS II) transition, and thus, it can be used as an efficient and quick method to monitor state transitions in algae, as has already been shown in cyanobacteria (Papageorgiou et al. 1999, 2007; Kaňa et al. 2012). We also discuss our results on the effects of (1) 3-(3,4-dichlorophenyl)-1,4-dimethyl urea, an inhibitor of electron transport; (2) n-propyl gallate, an inhibitor of alternative oxidase (AOX) in mitochondria and of plastid terminal oxidase in chloroplasts; (3) salicylhydroxamic acid, an inhibitor of AOX in mitochondria; and (4) carbonyl cyanide p-trifluoromethoxyphenylhydrazone, an uncoupler of phosphorylation, which dissipates proton gradient across membranes. Based on the data presented in this paper, we conclude that the slow PSMT fluorescence transient in C. reinhardtii is due to the superimposition of, at least, two phenomena: qE dependent non-photochemical quenching of the excited state of Chl, and state transitions.


The purification and properties of yeast proteinase B from Candida albicans.
A serine proteinase (ycaB) from the yeast Candida albicans A.T.C.C. 10261 was purified to near homogeneity. The enzyme was almost indistinguishable from yeast proteinase B (EC 126.96.36.199), and an Mr of 30,000 for the proteinase was determined by SDS/polyacrylamide-gel electrophoresis. The initial site of hydrolysis of the oxidized B-chain of insulin, by the purified proteinase, was the Leu-Tyr peptide bond. The preferential degradation at this site, analysed further with N-blocked amino acid ester and amide substrates, demonstrated that the specificity of the proteinase is determined by an extended substrate-binding site, consisting of at least three subsites (S1, S2 and S'1). The best p-nitrophenyl ester substrates were benzyloxycarbonyl-Tyr p-nitrophenyl ester (kcat./Km 3,536,000 M-1 X S-1), benzyloxycarbonyl-Leu p-nitrophenyl ester (kcat./Km 2,250,000 M-1 X S-1) and benzyloxycarbonyl-Phe p-nitrophenyl ester (kcat./Km 1,000,000 M-1 X S-1) consistent with a preference for aliphatic or aromatic amino acids at subsite S1. The specificity for benzyloxycarbonyl-Tyr p-nitrophenyl ester probably reflects the binding of the p-nitrophenyl group in subsite S'1. The presence of S2 was demonstrated by comparison of the proteolytic coefficients (kcat./Km) for benzyloxycarbonyl-Ala p-nitrophenyl ester (825,000 M-1 X S-1) and t-butyloxycarbonyl-Ala p-nitrophenyl ester (333,000 M-1 X S-1). Cell-free extracts contain a heat-stable inhibitor of the proteinase.


Pins composed of poly(L-lactic acid)/poly(3- hydroxybutyrate-co-hydroxyvalerate) PLLA/PHBV blends: Degradation in vitro.
Bioabsorbable polymers have shown good clinical success in the fixation and stabilization of bone fractures. Understanding and controlling polymer prosthetic degradation and the effect of the degradation products in vivo are crucial for successful implant developments. In this study, pins made from blends of PLLA/PHBV of varying compositions were degraded in phosphate buffer and characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and scanning electron microscopy (SEM). The PLLA/PHBV blends were found to be immiscible. PLLA began to degrade after approximately 12 weeks, whereas PHBV showed some degradation only after 53 weeks. The crystallinity of the blends increased with degradation. In conclusion, PHBV improved the thermal properties of PLLA and reduced the brittleness of the blends tested. The 40/60 PLLA/PHBV blend had the best properties for use in orthopedics since it degraded quicker than pure PHBV, and yet maintained its crystallinity for longer than PLLA; in addition, this blend did not have the brittleness of PLLA. (Journal of Applied Biomaterials and Biomechanics 2005; 3: 50-60).


New mitochondrial carriers: an overview.
The transport of metabolites, nucleotides and cofactors across the mitochondrial inner membrane is performed by members of mitochondrial carrier family (MCF). These proteins share marked structural features that have made feasible the functional characterization of numerous MCs in the last years. The MCs responsible for transport activities in mitochondria known for decades such as glutamate uptake or ATP-Mg/Pi exchange have recently been identified as well as novel carriers such as those involved in S-adenosylmethionine or thiamine pyrophosphate uptake. Here, after a brief review of the novel data on structural characteristics and import mechanisms of MCF members, we present an exhaustive compilation of human MC sequences, including previously characterized carriers, together with their respective Saccharomyces cerevisiae orthologues, ordered according to the phylogenetic analysis of el Moualij and co-workers [Yeast (1997) 13: 573-581]. We have detected the existence of at least 49 human MC sequences, including those of yet unknown function. An overview of novel MCF members functionally characterized in recent years in mammals and in yeast genomes is presented.


Malabsorptive gastric bypass in patients with superobesity.
Weight loss in superobese patients has been problematic after conventional gastric restrictive operations including conventional Roux-en-Y gastric bypass (RYGB). The goal of the present study was to compare weight loss in patients with superobesity (body mass index > or =50 kg/m(2)) using a distal RYGB (D-RY) in which the Roux-en-Y anastomosis was performed 75 cm proximal to the ileocecal junction (N = 47) vs. patients who had Roux limbs of 150 cm (N = 152) and 50 to 75 cm (N = 99). All operations incorporated the same gastric restrictive parameters. Minimum follow-up was 3 years and ranged to 16 years. Weight loss and reduction in body mass index were significantly greater after D-RY vs. both RYGB-150 cm and short RYGB and in RYGB-150 cm vs. short RYGB through 5 years. Mean percentage of excess weight loss peaked at 64% after DRY, at 61% after RYGB-150 cm, and at 56% after short RYGB. Weight loss maintenance through 5 years was correlated with Roux limb length with D-RY greater than RYGB-150 cm greater than short RYGB. More than 95% of obesity-related comorbid conditions improved or resolved with weight loss. There was no difference in the early postoperative morbidity rates: 9% after D-RY; 8% after RYGB-150 cm; and 2% after short RYGB with one death (0.3%). All D-RY patients had at least one postoperative metabolic abnormality. Anemia was significantly more common after D-RY vs. the shorter RYGB with no difference in the incidence of metabolic sequelae between RYGB-150 cm and short RYGB. No operations were reversed or modified for nutritional complications. Two D-RY patients required total parenteral nutrition for protein malnutrition. These results show that Roux limb length is correlated with weight loss in superobese patients. However, the greater incidence of metabolic sequelae after D-RY vs. RYGB-150 cm calls into question its routine use in superobese patients undergoing bariatric surgery. We conclude that some degree of malabsorption should be incorporated into bariatric operations performed in superobese patients to achieve satisfactory long-term weight loss.


Comparison of resting distal to aortic coronary pressure with angiography-based quantitative flow ratio.
Quantitative flow ratio (QFR) is a novel, adenosine-free method for functional coronary lesion interrogation, which is based on 3-dimensional quantitative coronary angiography and computational algorithms. Data on QFR in all-comer patients with intermediate coronary lesions are scarce, and the diagnostic performance in comparison to resting distal to aortic coronary pressure (Pd/Pa) ratio unknown. A total of 436 patients with 516 vessels undergoing FFR measurements were included in the analysis. Diagnostic performance of QFR, distal to aortic coronary pressure (Pd/Pa) ratio, and anatomic indices versus FFR was assessed. FFR ≤0.80 was measured in 19.4% of interrogated vessels. QFR significantly correlated with FFR (r = 0.82, p < 0.001) with good agreement between QFR and FFR (mean difference 0.011, 95% CI 0.008-0.015). The AUC for an FFR ≤0.80 was 0.86 (95% CI 0.83-0.89, p < 0.001) for QFR, 0.76 (0.72-0.80, p < 0.001) for resting Pd/Pa ratio, and 0.63 (0.59-0.67, p < 0.001) for diameter stenosis. The diagnostic accuracy for identifying an FFR ≤0.80 was 93.4% for QFR, 84.3% for resting Pd/Pa ratio, and 80.4% for diameter stenosis. QFR provides a novel diagnostic tool for functional coronary lesion assessment with superior diagnostic accuracy as compared with resting Pd/Pa ratio and anatomic indices. Future studies are needed to determine the non-inferiority of QFR analysis to FFR assessment with respect to clinical outcomes.


[Energy support and the contractile capacity of glycerinized myocardial fibers in experimental informational neurosis].
Experiments in dogs revealed that in informational neurosis the ability of myocardial contractile protein system (myocardial glycerinized filament bundles) to develop tension and produce work as well as the power of the contractile process are considerably reduced. Obviously, the energy production is not disturbed as a lower myocardial content of ATP (by 12%) and particularly of CP (by 54%) is caused by 8-9-month hypokinesia. Analogous shifts seem to occur in the human heart in informational neurosis which, in combination with the reduced intensity of the calcium transport by sarcoplasmic reticulum and mitochondria, may underlie the development of heart weakness.


Improved Calibration of Voltammetric Sensors for Studying Pharmacological Effects on Dopamine Transporter Kinetics in Vivo.
The distribution and density of neurons within the brain poses many challenges when making quantitative measurements of neurotransmission in the extracellular space. A volume neurotransmitter is released into the synapse during chemical communication and must diffuse through the extracellular space to an implanted sensor for real-time in situ detection. Fast-scan cyclic voltammetry is an excellent technique for measuring biologically relevant concentration changes in vivo; however, the sensitivity is limited by mass-transport-limited adsorption. Due to the resistance to mass transfer in the brain, the response time of voltammetric sensors is increased, which decreases the sensitivity and the temporal fidelity of the measurement. Here, experimental results reveal how the tortuosity of the extracellular space affects the response of the electrode. Additionally, a model of mass-transport-limited adsorption is utilized to account for both the strength of adsorption and the magnitude of the diffusion coefficient to calculate the response time of the electrode. The response time is then used to determine the concentration of dopamine released in response to salient stimuli. We present the method of kinetic calibration of in vivo voltammetric data and apply the method to discern changes in the KM for the murine dopamine transporter. The KM increased from 0.32 ± 0.08 μM (n = 3 animals) prior to drug administration to 2.72 ± 0.37 μM (n = 3 animals) after treatment with GBR-12909.


Enhancing single-wall carbon nanotube properties through controlled endohedral filling.
Chemical control of the endohedral volume of single-wall carbon nanotubes (SWCNTs) via liquid-phase filling is established to be a facile strategy to controllably modify properties of SWCNTs in manners significant for processing and proposed applications. Encapsulation of over 20 different compounds with distinct chemical structures, functionalities, and effects is demonstrated in SWCNTs of multiple diameter ranges, with the ability to fill the endohedral volume based on the availability of the core volume and compatibility of the molecule's size with the cross-section of the nanotube's cavity. Through exclusion of ingested water and selection of the endohedral chemical environment, significant improvements to the optical properties of dispersed SWCNTs such as narrowed optical transition linewidths and enhanced fluorescence intensities are observed. Examples of tailoring modified properties towards applications or improved processing by endohedral passivation are discussed.


Reproducibility of macular ganglion cell-inner plexiform layer thickness measurement with cirrus HD-OCT in normal, hypertensive and glaucomatous eyes.
To evaluate the intraobserver and interobserver reproducibility of macular retinal ganglion cell-inner plexiform layer (GC-IPL) thickness measurement by automated detection on Optical Coherence Tomography (OCT) images in normal, hypertensive (ocular hypertensive (OHT)) and glaucomatous eyes. A total of 138 eyes were enrolled in three groups: 69 normal, 35 OHT and 34 primary open-angle glaucoma eyes. All patients underwent a complete ocular examination, 24-2 automated perimetry, biometry and pachymetry. Macular imaging was performed in each eye using the Cirrus HD-OCT 4000 with software V.6.0. (Carl Zeiss Meditec, Dublin, California, USA) three times on the same day by each of two observers, and the GC analysis (GCA) algorithm provided parameters expressed as average, minimum and six sectoral GC-IPL thicknesses. Reproducibility was assessed by intraclass correlation coefficient (ICC), coefficient of variation (CV) and test-retest variability (TRTV) calculated as 1.96 times the SD. Mean GC-IPL thickness was 82.27 ± 7.37 μm, 76.84 ± 7.01 μm and 66.16 ± 11.16 μm in normal, OHT and glaucoma groups, respectively. GC-IPL thickness was significantly lower in glaucomatous eyes than in normal and OHT eyes (p<0.0001 for all parameters). In all groups, ICC ranged from 96.4 to 99.9% and 92.5 to 99.8%, CV ranged from 0.41 to 2.24% and 0.55 to 1.67%, and TRTV ranged from 0.61 to 2.64 μm and 0.83 to 2.22 μm for intraobserver and interobserver reproducibility, respectively. To the best of our knowledge, this is the first study of GCA algorithm reproducibility in normal, OHT and glaucomatous eyes. The reproducibility of GC-IPL thickness measurements using the Cirrus HD-OCT GCA algorithm was found to be highly satisfactory. GC-IPL thickness may be a promising new OCT parameter for analysis of ganglion cell damage in glaucoma.


Occurrence and formation of the N epsilon-methyl-lysines in myosin and the myofibrillar proteins.
1. Adult rabbit skeletal-muscle myosin has been shown to contain 1.0 residue of mono-N(in)-methyl-lysine and 3.3 residues of tri-N(in)-methyl-lysine per molecule of molecular weight 500000. 2. The methyl-lysines appear to be located in the subfragment 1 portion of the myosin molecule. 3. Methyl-lysines are not present in actin, tropomyosin, inhibitory factor and calcium-sensitizing factor. 4. Enzymic methylation of histidine and lysine residues of myosin has been demonstrated in vitro. 5. The methylation of histidine and lysine of the total myofibrillar protein occurs after peptide-bond synthesis. 6. Although methylated lysines and 3-methyl-histidine could not be detected by analysis of hydrolysates, radiochemical evidence is provided for the presence of these residues in the soluble-protein fraction of rabbit skeletal muscle.


Validation of Specific and Reliable Genetic Tools to Identify, Label, and Target Cardiac Pericytes in Mice.
Background In the myocardium, pericytes are often confused with other interstitial cell types, such as fibroblasts. The lack of well-characterized and specific tools for identification, lineage tracing, and conditional targeting of myocardial pericytes has hampered studies on their role in heart disease. In the current study, we characterize and validate specific and reliable strategies for labeling and targeting of cardiac pericytes. Methods and Results Using the neuron-glial antigen 2 (NG2)DsRed reporter line, we identified a large population of NG2+ periendothelial cells in mouse atria, ventricles, and valves. To examine possible overlap of NG2+ mural cells with fibroblasts, we generated NG2DsRed; platelet-derived growth factor receptor (PDGFR) αEGFP pericyte/fibroblast dual reporter mice. Myocardial NG2+ pericytes and PDGFRα+ fibroblasts were identified as nonoverlapping cellular populations with distinct transcriptional signatures. PDGFRα+ fibroblasts expressed high levels of fibrillar collagens, matrix metalloproteinases, tissue inhibitor of metalloproteinases, and genes encoding matricellular proteins, whereas NG2+ pericytes expressed high levels of Pdgfrb, Adamts1, and Vtn. To validate the specificity of pericyte Cre drivers, we crossed these lines with PDGFRαEGFP fibroblast reporter mice. The constitutive NG2Cre driver did not specifically track mural cells, labeling many cardiomyocytes. However, the inducible NG2CreER driver specifically traced vascular mural cells in the ventricle and in the aorta, without significant labeling of PDGFRα+ fibroblasts. In contrast, the inducible PDGFRβCreER line labeled not only mural cells but also the majority of cardiac and aortic fibroblasts. Conclusions Fibroblasts and pericytes are topographically and transcriptomically distinct populations of cardiac interstitial cells. The inducible NG2CreER driver optimally targets cardiac pericytes; in contrast, the inducible PDGFRβCreER line lacks specificity.


Global Impact of COVID-19 Pandemic on Physical Activity Habits of Competitive Runners: An Analysis of Wearable Device Data.
The COVID-19 pandemic resulted in government restrictions that altered the lifestyle of people worldwide. Studying the impact of these restrictions on exercise behaviors will improve our understanding of the environmental factors that influence individuals' physical activity (PA). We conducted a retrospective analysis using an stringency index of government pandemic policies developed by Oxford University and digitally-logged PA data from more than 7000 runners collected using a wearable exercise-tracking device to compare the relationship between strictness of lockdowns and exercise habits on a global scale. Additionally, the time-of-day of PA globally, and activity-levels of PA in 14 countries, are compared between the pre-pandemic year of 2019 and the first pandemic year of 2020. We found that during the pandemic year there was a major shift in the time-of-day that runners exercised, with significantly more activity counts logged during standard working hours on workdays (p < 0.001) and fewer activities during the same time frame on weekends (p < 0.001). Of the countries examined, Italy and Spain had among the most strict lockdowns and suffered the largest decreases in activity counts, whereas France experienced a minimal decrease in activity counts despite enacting a strict lockdown with certain allowances. This study suggests that there are several factors affecting PA of dedicated runners, including government policy, workplace policy, and cultural norms.


Hotels re-explored: Experience and influence of reciprocity and social normative appeals.
In this paper we report two high-powered and pre-registered experiments, testing the robustness and conceptual development of reciprocity and social norm appeals. Both experiments assessed both psychological processes for complying with these appeals and pro-environmental behavioral intention in tourism settings. In Experiment 1 (N = 2004), participants reported lower psychological reactance levels after learning that the hotel engaged in resource conservation (i.e., indirect homeomorphic reciprocity). No statistically significant effect was obtained for either obligatory motivation, prosocial motivation, skepticism, or behavioral intentions to reuse hotel towels. Importantly, high baseline intention of reusing hotel towels might have limited the effect of appeals. Therefore, we targeted meat consumption in Experiment 2 (n = 2540). Results first showed stronger obligatory and prosocial motivation for all three reciprocity appeals, compared to the standard appeal. No statistically significant results were found for either reactance or skepticism. Finally, after learning that the hotel had made a financial contribution to an environmental organization (i.e., indirect heteromorphic reciprocity) participants showed reduced meat consumption intentions compared to the standard appeal. Overall, the results provide initial evidence for conceptually refining the norm of reciprocity to encourage pro-environmental behaviors and for understanding the underlying psychological processes.


Shape-dependent antibacterial effects of non-cytotoxic gold nanoparticles.
Gold nanoparticles (AuNPs) of various shapes (including spheres, stars and flowers), with similar dimensions, were synthesized and evaluated for their antibacterial effects toward Staphylococcus aureus, a bacterium responsible for numerous life-threatening infections worldwide. Optical growth curve measurements and Gompertz modeling showed significant AuNP shape- and concentration-dependent decreases in bacterial growth with increases in bacterial growth lag time. To evaluate prospective use in in vivo systems, the cytotoxicity of the same AuNPs was evaluated toward human dermal fibroblasts in vitro by 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) viability assays and confocal microscopy. No indication of any mammalian cell toxicity or morphological effects was found. Additionally, it was observed that the AuNPs were readily internalized in fibroblasts after 4 days of incubation. Most importantly, the results of the present study showed that gold nanoflowers in particular possessed the most promising non-cytotoxic mammalian cell behavior with the greatest shape-dependent antibacterial activity-promising properties for their future investigation in a wide range of anti-infection applications.


Evaluation of caregiver-friendly workplace policy (CFWPs) interventions on the health of full-time caregiver employees (CEs): implementation and cost-benefit analysis.
Current Canadian evidence illustrating the health benefits and cost-effectiveness of caregiver-friendly workplace policies is needed if Canadian employers are to adopt and integrate caregiver-friendly workplace policies into their employment practices. The goal of this three-year, three study research project is to provide such evidence for the auto manufacturing and educational services sectors. The research questions being addressed are: What are the impacts for employers (economic) and workers (health) of caregiver-friendly workplace policy intervention(s) for full-time caregiver-employees? What are the impacts for employers, workers and society of the caregiver-friendly workplace policy intervention(s) in each participating workplace? What contextual factors impact the successful implementation of caregiver-friendly workplace policy intervention(s)? Using a pre-post-test comparative case study design, Study A will determine the effectiveness of newly implemented caregiver-friendly workplace policy intervention(s) across two workplaces to determine impacts on caregiver-employee health. A quasi-experimental pre-post design will allow the caregiver-friendly workplace policy intervention(s) to be tested with respect to potential impacts on health, and specifically on caregiver employee mental, psychosocial, and physical health. Framed within a comparative case study design, Study B will utilize cost-benefit and cost-effectiveness analysis approaches to evaluate the economic impacts of the caregiver-friendly workplace policy intervention(s) for each of the two participating workplaces. Framed within a comparative case study design, Study C will undertake an implementation analysis of the caregiver-friendly workplace policy intervention(s) in each participating workplace in order to determine: the degree of support for the intervention(s) (reflected in the workplace culture); how sex and gender are implicated; co-workers' responses to the chosen intervention(s), and; other nuances at play. It is hypothesized that the benefits of the caregiver-friendly workplace policy intervention(s) will include improvements in caregiver-employees' mental, psychosocial and physical health, as well as evidence of cost-benefit and cost-effectiveness for the employer. The expected project results will provide the research evidence for extensive knowledge translation work, to be carried out in collaboration with our knowledge transition partners, to the employer/human resources and occupational health/safety target populations. ISRCTN16187974 Registered August 25, 2016.


Microarray blob-defect removal improves array analysis.
New generation Affymetrix oligonucleotide microarrays often have blob-like image defects that will require investigators to either repeat their hybridization assays or analyze their data with the defects left in place. We investigated the effect of analyzing a spike-in experiment on Affymetrix ENCODE tiling arrays in the presence of simulated blobs covering between 1 and 9% of the array area. Using two different ChIP-chip tiling array analysis programs (Affymetrix tiling array software, TAS, and model-based analysis of tiling arrays, MAT), we found that even the smallest blob defects significantly decreased the sensitivity and increased the false discovery rate (FDR) of the spike-in target prediction. We introduced a new software tool, the microarray blob remover (MBR), which allows rapid visualization, detection and removal of various blob defects from the .CEL files of different types of Affymetrix microarrays. It is shown that using MBR significantly improves the sensitivity and FDR of a tiling array analysis compared to leaving the affected probes in the analysis. The MBR software and the sample array .CEL files used in this article are available at: http://liulab.dfci.harvard.edu/Software/MBR/MBR.htm


A finite element analysis of masticatory stress hypotheses.
Understanding how the skull transmits and dissipates forces during feeding provides insights into the selective pressures that may have driven the evolution of primate skull morphology. Traditionally, researchers have interpreted masticatory biomechanics in terms of simple global loading regimes applied to simple shapes (i.e., bending in sagittal and frontal planes, dorsoventral shear, and torsion of beams and cylinders). This study uses finite element analysis to examine the extent to which these geometric models provide accurate strain predictions in the face and evaluate whether simple global loading regimes predict strains that approximate the craniofacial deformation pattern observed during mastication. Loading regimes, including those simulating peak loads during molar chewing and those approximating the global loading regimes, were applied to a previously validated finite element model (FEM) of a macaque (Macaca fascicularis) skull, and the resulting strain patterns were compared. When simple global loading regimes are applied to the FEM, the resulting strains do not match those predicted by simple geometric models, suggesting that these models fail to generate accurate predictions of facial strain. Of the four loading regimes tested, bending in the frontal plane most closely approximates strain patterns in the circumorbital region and lateral face, apparently due to masseter muscle forces acting on the zygomatic arches. However, these results indicate that no single simple global loading regime satisfactorily accounts for the strain pattern found in the validated FEM. Instead, we propose that FE models replace simple cranial models when interpreting bone strain data and formulating hypotheses about craniofacial biomechanics.


Twisted elliptical multi-Gaussian Schell-model beams and their propagation properties.
We introduce a new kind of partially coherent source whose cross-spectral density (CSD) function is described as the incoherent superposition of elliptical twisted Gaussian Schell-model sources with different beam widths and transverse coherence widths, named twisted elliptical multi-Gaussian Schell-model (TEMGSM) beams. Analytical expression for the CSD function propagating through a paraxial ABCD optical system is derived with the help of the generalized Collins formula. Our results show that the TEMGSM beam is capable of generating a flat-topped elliptical beam profile in the far field, and the beam spot during propagation exhibits clockwise/anti-clockwise rotation with respect to its propagation axis. In addition, the analytical expressions for the orbital angular momentum (OAM) and the propagation factor are also derived by means of the Wigner distribution function. The influences of the twisted factor and the beam index on the OAM and the propagation factor are studied and discussed in detail.


Growth in some physical dimensions in relation to adolescent growth spurt among rural Indian children.
Measurements other than weight and height are rarely used in adolescent growth assessment. It is necessary to examine changes in other physical dimensions especially in relation to spurt in height as stature growth has a significance in the assessment of adolescent growth. The present study, therefore, reports data on four such measurements viz. foot length, sitting height, leg length and shoulder width along with height in a semilongitudinal growth study carried out over a 3 year period, on rural Indian boys (n = 587) and girls (n = 433), to examine the occurrence of their maximum increments in relation to spurt in height. Our analysis shows that the sequence of spurt in these physical dimensions is the same in the case of boys and girls, viz. spurt in foot length and leg length occurs before age at peak height velocity (14.3 yr--boys, 12.1 yr--girls) while that for sitting height and shoulder width occurs after attaining the peak height velocity. While foot length is the first one to reach peak (14 yr--boys, 11 yr--girls), shoulder width is the last one (16 yr--boys, 14 yr--girls) in this sequence. Thus the duration between the first spurt and the last spurt was observed to be larger in case of girls (3 yr) as compared to boys (2 yr) and apart from biological differences it could be partly due to the differential treatment received by rural girls. Sitting heights and leg lengths of rural children were significantly (p < 0.01) lower compared to Indian well-off and British children suggest that undernutrition prevailing in rural community affects all components of linear growth.


In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients.
HIV-1 infection is characterized by a progressive decline in CD4(+) T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4(+) counts beyond that observed with antiretroviral therapy. Recent phase III trials revealed that despite a sustained increase in CD4(+) counts, IL-2-treated patients did not experience a better clinical outcome [Abrams D, et al. (2009) N Engl J Med 361(16):1548-1559]. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4(+) T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4(+)CD25(+) T cell populations (CD4(+)CD25(lo)CD127(lo)FOXP3(+) and CD4(+)CD25(hi)CD127(lo)FOXP3(hi)) that shared phenotypic markers of Treg but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4(+)CD25(+) T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to those of natural regulatory CD4(+)CD25(hi)FOXP3(+) T cells (Treg) from healthy donors, an immunosuppressive T cell subset critically important for the maintenance of self-tolerance. We propose that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4(+) T cells had a higher relative risk of clinical progression to AIDS.


Effect of iron on leukocyte function: inactivation of H2O2 BY IRON.
We investigated the effect of FeSO4 on phagocytosis-associated, increased oxidative metabolism via the hexose monophosphate shunt, with special attention to its effect on H2O2 levels. The availability of glutathione eroxidase and glutathione reductase for H2O2 disposal and hexose monophosphate shunt stimulation also are evaluated. The results show an impairment of phagocytosis-associated hexose monophosphate shunt activity together with an increase both of resting and phagocytosing formate oxidation. These apparently paradoxical findings are resolved by demonstrating a direct enhancement of formate oxidation by FeSO4 in a cell-free system. In addition, measurement of H2O2 concentrations via scopoletin fluorescence shows reduction of H2O2 by Feso4. There is no effect on either glutathione peroxidase or glutathione reductase activities. These data suggest that one mechanism of FeSO4 imairment of microbicidal activity is by its removal of H2O2.


Variational calculation of second-order reduced density matrices by strong N-representability conditions and an accurate semidefinite programming solver.
The reduced density matrix (RDM) method, which is a variational calculation based on the second-order reduced density matrix, is applied to the ground state energies and the dipole moments for 57 different states of atoms, molecules, and to the ground state energies and the elements of 2-RDM for the Hubbard model. We explore the well-known N-representability conditions (P, Q, and G) together with the more recent and much stronger T1 and T2(') conditions. T2(') condition was recently rederived and it implies T2 condition. Using these N-representability conditions, we can usually calculate correlation energies in percentage ranging from 100% to 101%, whose accuracy is similar to CCSD(T) and even better for high spin states or anion systems where CCSD(T) fails. Highly accurate calculations are carried out by handling equality constraints and/or developing multiple precision arithmetic in the semidefinite programming (SDP) solver. Results show that handling equality constraints correctly improves the accuracy from 0.1 to 0.6 mhartree. Additionally, improvements by replacing T2 condition with T2(') condition are typically of 0.1-0.5 mhartree. The newly developed multiple precision arithmetic version of SDP solver calculates extraordinary accurate energies for the one dimensional Hubbard model and Be atom. It gives at least 16 significant digits for energies, where double precision calculations gives only two to eight digits. It also provides physically meaningful results for the Hubbard model in the high correlation limit.


Current dietary advice and challenges for adolescents.
The major risk factors driving the global burden of disease are diet related. Adolescence presents a window of opportunity for establishing healthy dietary trajectories. Yet around the world, adolescents experience many barriers that prevent them from consuming diets that would give them the foundation for long, healthy and productive adult lives. A narrative literature search of most relevant original, review and meta-analyses, restricted to English was conducted in Medline, Web of Science and PubMed up to December 2019 together with published papers known to the author concerning the current dietary advice and challenges for adolescent nutrition. Adolescence is a critical period of growth and development and adequate nutrition is essential. Sufficient population data indicate adolescents are not meeting dietary recommendations and are a vulnerable population group for malnutrition in all its forms. Despite extensive studies on dietary risk factors and the global burden of disease and population data demonstrating inadequate nutritional intake in adolescent populations, few effective interventions and policies have been scaled up to support adolescent nutrition. Improving the diets of adolescents, especially vulnerable adolescents from low- and middle-income countries and socioeconomically disadvantaged backgrounds, has the potential to impact individuals, societies and economies. Future research should focus on vulnerable adolescent populations by addressing food environments, food insecurity and ensuring effective programmes and strategies are integrated within broader adolescent health strategies and implemented into government policies.


Gastric Ischemic Conditioning Prior to Esophagectomy Is Associated with Decreased Stricture Rate and Overall Anastomotic Complications.
Gastric ischemic conditioning prior to esophagectomy can increase neovascularization of the new conduit. Prior studies of ischemic conditioning have only investigated reductions in anastomotic leaks. Our aim was to analyze the association between gastric conditioning and all anastomotic outcomes as well as overall morbidity in our cohort of esophagectomy patients. We performed a retrospective review of patients undergoing esophagectomy from 2010 to 2015 in a National Cancer Institute designated center. Ischemic conditioning (IC) was performed on morbidly obese patients, those with cardiovascular disease or uncontrolled diabetes, and those requiring feeding jejunostomy and active tobacco users. IC consisted of transection of the short gastric vessels and ligation of the left gastric vessels. Primary outcomes consisted of all postoperative anastomotic complications. Secondary outcomes were overall morbidity. Two-hundred and seven esophagectomies were performed with an average follow-up of 19 months. Thirty-eight patients (18.4%) underwent conditioning (IC). This group was similar to patients not conditioned (NIC) in age, preoperative pathology, and surgical approach. Five patients in the ischemic conditioning group (13.2%) and 57 patients (33.7%) in the NIC experienced anastomotic complications (p = 0.011). Ischemic conditioning significantly reduced the postoperative stricture rate fourfold (5.3 vs. 20.7% p = 0.02). IC patients experienced significantly fewer complications overall (36.8 vs. 56.2% p = 0.03). Gastric ischemic conditioning is associated with fewer overall anastomotic complications, fewer strictures, and less morbidity. Randomized studies may determine optimal selection criteria to determine whom best benefits from ischemic conditioning.


Long-term pulmonary sequelae after treatment of childhood Hodgkin's disease.
Pulmonary sequelae have been reported in patients treated for Hodgkin's disease (HD). Few data are available about patients treated for childhood HD followed over several years. In a cross-sectional study carried out for 76 months (median time) after treatment completion, we evaluated the lung function abnormalities and respiratory symptoms in 27 patients (16 males and 11 females) with HD diagnosed between 1983 and 1994 (median age at diagnosis 11 years, range 2-16 years). They had been treated with chemotherapy and radiotherapy according to current protocol AIEOP-MH 83 (n = 14) or AIEOP-MH 89 (n = 13). At the time of the study, 26 patients were in first complete remission and one in second remission. Of the 27 patients, 19 had had mediastinal irradiation at a dose of 20 Gy (n = 5) or 20.8-44 Gy (n = 14). Forced vital capacity (FVC), functional residual capacity (FRC), forced expiratory volume in one second (FEV1), FEV1/FVC ratio, and maximal expiratory flow at 25% of FVC were registered; diffusion capacity for carbon monoxide (DLCO) was determined. Data were expressed as standard deviation (SD) score. Four patterns of respiratory function abnormalities were defined: restrictive, obstructive, isolated bronchiolar impairment, isolated diffusing impairment. Twelve patients (44%) were asymptomatic and showed completely normal pulmonary function tests. Three patients reported dyspnea on exertion, and one of them also cough and phelgm: out of these symptomatic subjects, only 1 had functional abnormality (isolated DLCO impairment). A restrictive pattern was found in 5 patients (18%), including 2 who also had a pathological DLCO SD score. Eight additional patients (30%) had isolated diffusing impairment. Oxygen saturation was normal in all patients. Forty-seven percent of patients with normal DLCO had had lower dose irradiation (20 Gy) compared to 10% of patients with impaired DLCO (P = 0.054). Similarly, patients with normal DLCO had had significantly less chemotherapy as compared to patients with abnormal DLCO (P = 0.003). Occurrence of lung abnormalities was not significantly associated with sex, age at treatment, mediastinal irradiation, and time elapsed from treatment completion. Adolescents and young adults treated for childhood HD are at risk for lung function abnormalities, significantly more frequent in patients who received more intense treatment, as mediastinal irradiation at a higher dose (> 20 Gy) and more chemotherapy blocks. Long-term follow-up should be offered to these patients because of their possible limited potential for pulmonary function and possible lesser resistance to adverse agents such as smoke, pollution, infections and aging.


A comparison of hypoxic burden algorithms using three different methods for calculating baseline oxygen saturation for predicting cardiovascular death in the Sleep Heart Health Study.
Respiratory event related oxygen desaturation area measures have recently shown merit as novel predictors of cardiovascular disease (CVD) outcomes. In this study, we investigate one such measure (hypoxic burden (HB)) and investigate how three different ways of calculating the SpO2 baseline of the HB algorithm impact its ability to predict cardiovascular mortality. The three baseline estimation steps include a pre-event baseline, a record-based baseline, and a fixed baseline. Pulse oximetry signals from the Sleep Heart Health Study and the corresponding CVD outcomes were analyzed. The performance of each baseline method was compared using adjusted Cox proportional hazard regression analysis. Results show that HB with the record-based baseline method returned the best performing results with a hazard ratio (HR) of 1.83 (95% CI: 1.03-3.27, p<0.05) in the fully adjusted model, compared to HB with the pre-event baseline method (HR: 1.60, 95%CI: 0.86-3.00, p>0.05) and HB with the fixed baseline method (HR: 1.73, 95%CI: 0.93-3.22, p>0.05).


Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.
In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of inhibitors targeting a unique pocket on EcDHFR.


Relating improvisational music therapy with severely and multiply disabled children to communication development.
The effect of different levels of preintentional and intentional communication development on musical interaction with children with severe and multiple disabilities has not been explored in the music therapy literature. Aside from stage of communication development, what are the particular influences of disability on musical interaction with children who have preintentional and early intentional communication? A qualitative research project explored these issues. Ten school-aged children with severe and multiple disabilities participated in the project. The most common medical diagnosis was cerebral palsy. Analysis of video recordings and other data confirmed that the children's level of communication development was reflected in individual music therapy. Specifically, children at different levels of communication development varied in their abilities to initiate, anticipate, and sustain participation in turn taking, and to maintain attention to and engagement in the interaction. Both turn taking and playing and singing together were found to be important forms of communication during music therapy. Communication problems related to disability included: difficulties in using objects as a focus of joint attention, difficulties in interpreting the interactive environment, being sufficiently motivated to communicate, severely limited means of interaction, attaining and maintaining an appropriate level of arousal, and lack of interest in interaction and the outside environment. Further study of how music therapy can be related to general issues in communication for individuals with severe and multiple disabilities is recommended.


The Impact of Focus and Context Visualization Techniques on Depth Perception in Optical See-Through Head-Mounted Displays.
Estimating the depth of virtual content has proven to be a challenging task in Augmented Reality (AR) applications. Existing studies have shown that the visual system makes use of multiple depth cues to infer the distance of objects, occlusion being one of the most important ones. The ability to generate appropriate occlusions becomes particularly important for AR applications that require the visualization of augmented objects placed below a real surface. Examples of these applications are medical scenarios in which the visualization of anatomical information needs to be observed within the patient's body. In this regard, existing works have proposed several focus and context (F+C) approaches to aid users in visualizing this content using Video See-Through (VST) Head-Mounted Displays (HMDs). However, the implementation of these approaches in Optical See-Through (OST) HMDs remains an open question due to the additive characteristics of the display technology. In this article, we, for the first time, design and conduct a user study that compares depth estimation between VST and OST HMDs using existing in-situ visualization methods. Our results show that these visualizations cannot be directly transferred to OST displays without increasing error in depth perception tasks. To tackle this gap, we perform a structured decomposition of the visual properties of AR F+C methods to find best-performing combinations. We propose the use of chromatic shadows and hatching approaches transferred from computer graphics. In a second study, we perform a factorized analysis of these combinations, showing that varying the shading type and using colored shadows can lead to better depth estimation when using OST HMDs.


Mechanism of degradation of immunogenic gluten epitopes from Triticum turgidum L. var. durum by sourdough lactobacilli and fungal proteases.
As shown by R5 antibody-based sandwich and competitive enzyme-linked immunosorbent assay (ELISA), selected sourdough lactobacilli, in combination with fungal proteases, hydrolyzed gluten (72 h at 37 degrees C) of various cultivars of Triticum turgidum L. var. durum to less than 20 ppm. Complementary electrophoretic, chromatography, and mass spectrometry techniques were used to characterize the gluten and epitope hydrolysis. Nine peptidases were partially purified from the pooled cytoplasmic extract of the sourdough lactobacilli and used to hydrolyze the 33-mer epitope, the most immunogenic peptide generated during digestion of Triticum species. At least three peptidases (general aminopeptidase type N [PepN], X-prolyl dipeptidyl aminopeptidase [PepX], and endopeptidase PepO) were necessary to detoxify the 33-mer without generation of related immunogenic epitopes. After 14 h of incubation, the combination of all or at least six different peptidases totally hydrolyzed the 33-mer (200 mM) into free amino acids. The same results were found for other immunogenic epitopes, such as fragments 57-68 of alpha 9-gliadin, 62-75 of A-gliadin, and 134-153 of gamma-gliadin. When peptidases were used for fermentation of durum wheat semolina, they caused the hydrolysis of gluten to ca. 2 ppm. The in vivo digestion was simulated, and proteins/peptides extracted from pepsin-trypsin (PT) digestion of durum wheat semolina fermented with selected sourdough lactobacilli induced the expression of gamma interferon and interleukin 2 at levels comparable to those of the negative control. Durum wheat semolina fermented with sourdough lactobacilli was freeze-dried and used for making Italian-type pasta. The scores for cooking and sensory properties for this pasta were higher that those of conventional gluten-free pasta.


Impaired serotonin synthesis in hippocampus of murine lupus represents an early neuropsychiatric event.
Despite significant progress in understanding the mechanisms underlying hippocampal involvement in neuropsychiatric systemic lupus erythematosus (NPSLE), our understanding of how neuroinflammation affects the brain neurotransmitter systems is limited. To date, few studies have investigated the role of neurotransmitters in pathogenesis of NPSLE with contradictory results. Hippocampal tissue from NZB/W-F1 lupus-prone mice and age-matched control strains were dissected in both pre-nephritic (3-month-old) and nephritic (6-month-old) stages. High-Performance Liquid Chromatography (HPLC) was used to evaluate the level of serotonin (5-HT), dopamine (DA), and their metabolites 5-HIAA and DOPAC, respectively, in mouse hippocampi. Lupus mice exhibit decreased levels of serotonin at the early stages of the disease, along with intact levels of its metabolite 5-HIAA. The 5-HT turnover ratio (5-HIAA/5-HT ratio) was increased in the hippocampus of lupus mice at pre-nephritic stage suggesting that low hippocampal serotonin levels in lupus are attributed to decreased serotonin synthesis. Both DA and DOPAC levels remained unaffected in lupus hippocampus at both early and late stages. Impaired hippocampal serotonin synthesis in the hippocampus of lupus-prone mice represents an early neuropsychiatric event. These findings may have important implications for the use of symptomatic therapy in diffuse NPSLE.


Community as client: environmental issues in the real world. A SimCity computer simulation.
The ability to think critically has become a crucial part of professional practice and education. SimCity, a popular computer simulation game, provides an opportunity to practice community assessment and interventions using a systems approach. SimCity is an interactive computer simulation game in which the player takes an active part in community planning. SimCity is supported on either a Windows 95/98 or a Macintosh platform and is available on CD-ROM at retail stores or at www.simcity.com. Students complete a tutorial and then apply a selected scenario in SimCity. Scenarios consist of hypothetical communities that have varying types and degrees of environmental problems, e.g., traffic, crime, nuclear meltdown, flooding, fire, and earthquakes. In problem solving with the simulated scenarios, students (a) identify systems and subsystems within the community that are critical factors impacting the environmental health of the community, (b) create changes in the systems and subsystems in an effort to solve the environmental health problem, and (c) evaluate the effectiveness of interventions based on the game score, demographic and fiscal data, and amount of community support. Because the consequences of planned intervention are part of the simulation, nursing students are able to develop critical-thinking skills. The simulation provides essential content in community planning in an interesting and interactive format.


Immediate adverse reactions to intravenous immunoglobulin in children: a single center experience.
Intravenous immunoglobulin (IVIG) is commonly used in primary and secondary immunodeficiency diseases as well as autoimmune conditions as immunomodulatator treatment. Immediate adverse events which are generally mild and occur during infusion are seen in 6 hours. Reported immediate adverse events are in a wide range from 1%-40% in pediatric patients. 115 patients who received IVIG (except newborns) were included into this crosssectional study. IVIG was given to patients for primary immunodeficiencies (n=8), ITP (n=65), Kawasaki disease (n=11), secondary immunosupression (n=28), and passive immunization (n=3). 5%, 10% IVIG preparations and pentaglobin were used. Headache, fever, chills, nausea, rash, arthralgia, myalgia and back pain were accepted as mild immediate events. There were 62 (54%) boys and 53 (46%) girls aged 1 month-18 years. Mean age of the group was 7.4±4.6 years. Immediate adverse events due to IVIG infusions were seen in 29 (25.2%) of all patients. Gender and types of the disease were not different in significance regarding the presence of adverse events. The rate of adverse events did not change with receiving pre-medication. The most common reaction was fever/chills. Immediate reactions were seen in first 6 hours in 7 patients and during infusion in the remaining. They were treated with slowing of the infusion rate and infusion was stopped in 3 patients because of moderate events. Because of the increasingly use of IVIG therapy, it is important to know the side effects. High doses, high infusion rates, accompanying infection may worsen the adverse effects especially in primary immunodeficiency diseases.


Genotoxicity and diabetic embryopathy: impaired expression of developmental control genes as a cause of defective morphogenesis.
Since the advent of insulin therapy for diabetes mellitus, the survival of mothers with diabetes prior to pregnancy and their offspring has greatly improved. Nevertheless, the observation that the earliest stages of organogenesis can be impaired in the offspring of women with diabetes raises the question of how abnormal fuel metabolism disturbs embryogenesis. Research into this process has been made possible in recent years by advances in molecular biology which makes it possible to study gene expression in early embryos, and by the availability of genetically engineered mutant mouse strains. Using these approaches, a model is emerging in which elevated glucose, by disturbing expression of genes which regulate embryonic development and cell cycle progression, causes premature cell death of emerging organ structures, thereby causing defective morphogenesis. Investigation into the signaling mechanisms by which excess glucose metabolism exhibits toxic effects on embryo gene expression will explain how diabetic embryopathy occurs on a molecular and cellular level, as well as increase our understanding of the role of metabolic homeostasis in proper embryonic development.


The Use of Nanoneedles in Drug Delivery: an Overview of Recent Trends and Applications.
Nanoneedles (NN) are growing rapidly as a means of navigating biological membranes and delivering therapeutics intracellularly. Nanoneedle arrays (NNA) are among the most potential resources to achieve therapeutic effects by administration of drugs through the skin. Although this is based on well-established approaches, its implementations are rapidly developing as an important pharmaceutical and biological research phenomenon. This study intends to provide a broad overview of current NNA research, with an emphasis on existing approaches, applications, and types of compounds released by these systems. A nanoneedle-based delivery device with great spatial and temporal accuracy, minimal interference, and low toxicity could transfer biomolecules into living organisms. Due to its vast potential, NN has been widely used as a capable transportation system of many therapeutic active substances, from cancer therapy, vaccine delivery, cosmetics, and bio-sensing nanocarrier drugs to genes. The use of nanoneedles for drug delivery offers new opportunities for the rapid, targeted, and exact administration of biomolecules into cell membranes for high-resolution research of biological systems, and it can treat a wide range of biological challenges. As a result, the literature has analyzed existing patents to emphasize the status of NNA in biological applications.


Sexual Activity and Weekly Contraceptive Discontinuation and Selection Among Young Adult Women in Michigan.
Understanding young women's contraceptive and pregnancy prevention behaviors is important for helping women and their partners control if and when they have children. Prior research on associations between patterns of sexual activity and contraceptive behaviors is limited. We assessed the influence of recent sexual activity on discontinuation and selection of specific contraceptive methods. We used weekly data from the Relationship Dynamics and Social Life (RDSL) study, a longitudinal 2.5-year population-based project that sampled woman ages 18 and 19 (N = 1,003) in one Michigan county. We estimated logistic and multinomial regression models that accounted for clustering of weekly observations within partnerships and women. Weekly discontinuation of longer-acting methods declined with increasing sexual activity in the past month, as did discontinuation of shorter-acting hormonal methods. Sexual activity was associated with decreased selection of condoms relative to other methods. Future research into life events that lead to changes in the frequency of sexual activity may provide insight into times when women are at risk of contraceptive discontinuation. These findings underscore the importance of anticipatory guidance in contraceptive counseling so that when women change their contraceptive behavior they are equipped in advance with resources to make safe transitions between methods.


Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei.
Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.


[Excessive oral administration of iron to sheep. 1. Digestibility of rations, results of fattening and carcass yields].
4 digestibility trials (4 male sheep per group) and 2 growth trials were carried out with 24 (V 1) and 32 (V 2) fattening lambs to investigate the effect of abundant oral Fe doses on the digestibility of crude nutrients in a ration of barley + dried green feed and on the results of fattening and carcass yields. Fe supplementation (less than 1400 mg per sheep/day) did not significantly change the digestibility coefficients of crude nutrients. Increasing Fe levels in the concentrates decreased the rates of liveweight increase and food consumption in both growth trials. Well-established statistical evidence was provided for the decline in absolute carcass yields resulting from the lower weight of the lambs at the end of the fattening period after Fe supplementation.


Long-Term Treatment With Sacubitril/Valsartan in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction - Open-Label Extension of the PARALLEL-HF Study.
The PARALLEL-HF study assessed the efficacy and safety of sacubitril/valsartan vs. enalapril in Japanese patients with chronic heart failure with reduced ejection fraction (HFrEF). This open-label extension (OLE) assessed long-term safety with sacubitril/valsartan.Methods and Results: This study enrolled 150 patients who received sacubitril/valsartan 50 or 100 mg, b.i.d., in addition to optimal background heart failure (HF) therapy. A dose level of sacubitril/valsartan 200 mg, b.i.d., was targeted by Week 8. At OLE baseline, higher concentrations of B-type natriuretic peptide (BNP) and urine cGMP, and lower concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), were observed in the sacubitril/valsartan core group (patients who received sacubitril/valsartan in both the core and extension study) than in the enalapril core group (patients who received enalapril in the core study and were then transitioned to sacubitril/valsartan). The mean exposure to study drug was 98.9%. There was no trend of worsening of HF at Month 12. No obvious changes in cardiac biomarkers were observed, whereas BNP and urine cGMP increased and NT-proBNP decreased in the enalapril core group, which was evident at Weeks 2-4 and sustained to Month 12. Long-term sacubitril/valsartan at doses up to 200 mg, b.i.d., has a positive risk-benefit profile; it was safe and well tolerated in Japanese patients with chronic HFrEF.