Possible mechanisms for the cariostatic effect of xylitol.
Xylitol appears to be the only known cariostatic natural carbohydrate which meets most of the desiderata for a sweetener in the human diet. Possible mechanisms for this cariostatic action can be derived from a consideration of the factors which may be operating at a molecular and microbiological level. These include: a) Molecular size and e.g. the short, open-chain structure and absence of reducing groups b) Absence or relative lack in most oral microorganisms of xylitol-binding factors in dental plaque c) Lack of bacterial genes coding for xylitol-utilizing enzymes or of inducible or de-repressible genes for this purpose d) Inhibition of enzymes involved in cariogenesis (competitive in case of some isomerases) e) Enzyme specificity requirements f) Higher osmotic pressure exerted by xylitol as compared to hexoses and disaccharides g) Ability of xylitol to produce a favourable electrolyte concentration in the saliva without lowering plaque pH h) Ability of xylitol to increase the secretion and activity of salivary lactoperoxidase and certain other (muco) proteins. Xylitol may enhance the adsorption of glycoproteins on the tooth surfaces and strengthen the acquired pellicle.


The diagnosis and management of dry eye: a twenty-five-year review.
To review the advances in the diagnosis, pathogenesis, and management of dry eye disease in the past 25 years. Literature review. The preocular tear film is a hydrated mucus gel that contains soluble antimicrobial proteins and growth factors that protect and support the ocular surface. The final common pathway in dry eye is a perturbation of the integrated ocular surface/lacrimal gland reflex unit. Diagnostic tests evaluating tear composition and clearance appear to show stronger correlation with the severity of ocular irritation symptoms and keratoconjunctivitis sicca (KCS) than the conventional Schirmer tests. KCS is a condition of abnormal differentiation and mucus production by the ocular surface epithelium that results in a poorly lubricated, abnormally permeable ocular surface that has increased susceptibility to environmental insults. Chronic subclinical ocular surface inflammation appears to play a key role in the pathogenesis of KCS. New therapeutic strategies are aimed at reducing the ocular surface inflammation of dry eye disease. There has been a tremendous increase in knowledge regarding dry eye disease in the past 25 years that has resulted in improved diagnostic classification and new targeted therapies.


A general formula for computing maximum proportion correct scores in various psychophysical paradigms with arbitrary probability distributions of stimulus observations.
Proportion correct (Pc) is a fundamental measure of task performance in psychophysics. The maximum Pc score that can be achieved by an optimal (maximum-likelihood) observer in a given task is of both theoretical and practical importance, because it sets an upper limit on human performance. Within the framework of signal detection theory, analytical solutions for computing the maximum Pc score have been established for several common experimental paradigms under the assumption of Gaussian additive internal noise. However, as the scope of applications of psychophysical signal detection theory expands, the need is growing for psychophysicists to compute maximum Pc scores for situations involving non-Gaussian (internal or stimulus-induced) noise. In this article, we provide a general formula for computing the maximum Pc in various psychophysical experimental paradigms for arbitrary probability distributions of sensory activity. Moreover, easy-to-use MATLAB code implementing the formula is provided. Practical applications of the formula are illustrated, and its accuracy is evaluated, for two paradigms and two types of probability distributions (uniform and Gaussian). The results demonstrate that Pc scores computed using the formula remain accurate even for continuous probability distributions, as long as the conversion from continuous probability density functions to discrete probability mass functions is supported by a sufficiently high sampling resolution. We hope that the exposition in this article, and the freely available MATLAB code, facilitates calculations of maximum performance for a wider range of experimental situations, as well as explorations of the impact of different assumptions concerning internal-noise distributions on maximum performance in psychophysical experiments.


[Enzyme activity of Bacillus polymyxa 153, the producer of polymyxin B, during sporulation and biosynthesis].
Metabolic properties of Bacillus polymyxa 153 were studied during vegetative growth, polymyxin B biosynthesis and active sporulation. In the cell extracts there was detected activity of exoproteases, endoproteases, tricarboxylic acid cycle dehydrogenases and pyruvate dehydrogenase. The enzymes activity in the cells growing into spores was higher than that in the cells of the vegetative developmental type. The activity of the enzymes depended on the culture age.


Cloning the promoter for transforming growth factor-beta type III receptor. Basal and conditional expression in fetal rat osteoblasts.
Transforming growth factor-beta binds to three high affinity cell surface molecules that directly or indirectly regulate its biological effects. The type III receptor (TRIII) is a proteoglycan that lacks significant intracellular signaling or enzymatic motifs but may facilitate transforming growth factor-beta binding to other receptors, stabilize multimeric receptor complexes, or segregate growth factor from activating receptors. Because various agents or events that regulate osteoblast function rapidly modulate TRIII expression, we cloned the 5' region of the rat TRIII gene to assess possible control elements. DNA fragments from this region directed high reporter gene expression in osteoblasts. Sequencing showed no consensus TATA or CCAAT boxes, whereas several nuclear factors binding sequences within the 3' region of the promoter co-mapped with multiple transcription initiation sites, DNase I footprints, gel mobility shift analysis, or loss of activity by deletion or mutation. An upstream enhancer was evident 5' proximal to nucleotide -979, and a silencer region occurred between nucleotides -2014 and -2194. Glucocorticoid sensitivity mapped between nucleotides -687 and -253, whereas bone morphogenetic protein 2 sensitivity co-mapped within the silencer region. Thus, the TRIII promoter contains cooperative basal elements and dispersed growth factor- and hormone-sensitive regulatory regions that can control TRIII expression by osteoblasts.


The Impact of Hospital Health Network Affiliation on Discharge Communication Preferences of Primary Care Providers.
Primary care physicians (PCPs) experience differential postdischarge access to electronic health records, depending upon affiliation with the discharging hospital's health network. To better understand whether this affiliation impacts discharge communication preferences, we surveyed a convenience sample of PCPs in and out of our hospital's health network. We also surveyed hospitalists and compared PCPs' and hospitalists' responses. We found that PCP discharge communication preferences differed by hospital health network affiliation. In addition, PCPs and hospitalists reported different expectations of responsibility for pending laboratory test follow-up. More inclusive communication strategies and standardization of responsibility for pending laboratory results may improve discharge communication quality.


Development and Validation of a Postpartum Care Mobile Application for First-time Mothers.
The aims of the study were to develop mobile application for postpartum care of first-time mothers and to validate it's effect. Using a nonequivalent control group pretest-posttest design, 52 first-time mothers were recruited (26 each in experimental and control) and the experimental group used the mobile application for 6 weeks after delivery. Postpartum self-care knowledge and confidence, infant care knowledge and confidence, and postpartum depressive mood (Edinburgh Postnatal Depression Scale) were measured before discharge from the hospital and 6 weeks later. Women who have used the postpartum care mobile application reported higher levels of postpartum self-care knowledge (p=.030) and confidence (p=.023) infant care knowledge (p=.001) and confidence (p=.004), while scores of postpartum depression (p=.021) were lower than those in the control group. The postpartum-care mobile application developed in this research may be effective in reinforcing knowledge and confidence for postpartum self-care and infant care and in reducing postpartum depressive mood.


Recommendations for bone mineral density reporting in Canada.
To propose a set of recommendations for optimal bone mineral density (BMD) reporting in postmenopausal women and older men and to provide clinicians with both a BMD diagnostic category and a useful tool to assess an individual's risk of osteoporotic fracture. The current methods of BMD reporting were reviewed. In this document, we propose that an individual's 10-year absolute fracture risk, rather than BMD alone, be used for fracture risk categorization. Consequently, age, sex, BMD, fragility fracture history, and glucocorticoid use are the basis for the approach outlined in this document. An optimal BMD report as proposed in this document will provide clinicians with both a BMD diagnostic category and a useful tool to assess an individual's risk of osteoporotic fracture. A BMD report format, a checklist, and a patient questionnaire are meant to further encourage its use. All recommendations were developed using a consensus from clinicians and experts in the field of BMD testing and a standard method for the evaluation and citation of the supporting evidence. These recommendations were developed by a multidisciplinary working group under the auspices of the Scientific Advisory Council of the Osteoporosis Society of Canada and the Canadian Association of Radiologists. BENEFITS, HARM, AND COSTS: Optimal BMD reports help the practitioner to assess an individual's risk for osteoporotic fracture and to decide whether medical therapy is warranted. The BMD report should include: patient identifiers. Dual-energy X-ray absorptiometry (DXA) scanner identifier. BMD results expressed in absolute values (g/cm2; 3 decimal places) and T-score (1 decimal place) for lumbar spine; proximal femur (total hip, femoral neck, and trochanter); and an alternate site (forearm BMD preferred: 1/3 radius, 33% radius or proximal radius) if either hip or spine is not valid. A statement about any limitations due to artifacts, if present. The fracture risk category (low, moderate, or high) as determined by using Tables 3 and 4 and by including major clinical factors that modify absolute fracture risk probability (with an indication of the corresponding absolute 10-year fracture risk of <10%, 10-20%, or >20%). A statement as to whether the change is statistically significant or not for serial measurements. The BMD centre's least significant change for each skeletal site (in g/cm2) should be included. Recommendations were based on consensus opinion. Since these are the first Canadian recommendations integrating clinical risk factors in a quantitative fracture risk assessment, it is anticipated that these "Recommendations for BMD Reporting in Canada" will be a work in progress and will be updated periodically to accommodate advances in this field.


SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics.
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.


Biomechanical modelling of a direct vertebral translation instrumentation system: preliminary results.
Many new spine instrumentation concepts were introduced in recent years, like the incremental direct vertebral translation. The objective was to develop a biomechanical model in order to analyze the biomechanics of this instrumentation system. The patient-specific spine model was built using the 3D reconstruction based on bi-planar radiographs of a scoliotic patient (thoraco-lumbar Cobb: 49 degrees ). The mechanical properties were derived from literature, experiments on cadaver spines and patient's side bending radiographs. Each screw construct was modelled by four rigid bodies connected each other by kinematic joints. The screw-vertebra flexible joint was represented by 3 experimentally derived non-linear springs, and the rods by non-linear flexible elements. The correction manoeuvres were simulated by lowering the rod, tightening the crimps (incremental segmental translation) and applying secondary correction manoeuvres (direct vertebra derotation, compression, distraction and construct tightening). The simulations showed that the system allows a good force distribution among implants. The long post pushing and pulling contributed, to a great extent, to a global correction in the coronal plane, while the crimp tightening had more important effect in the sagittal plane. The preliminary results illustrated the effectiveness of local correction by a direct vertebra translation technique. Our next step is to validate the model and compare the performance of this strategy with other spinal instrumentation systems.


Cost-effectiveness of opportunistic screening and minimal contact psychotherapy to prevent depression in primary care patients.
Depression causes a large burden of disease worldwide. Effective prevention has the potential to reduce that burden considerably. This study aimed to investigate the cost-effectiveness of minimal contact psychotherapy, based on Lewinsohn's 'Coping with depression' course, targeted at opportunistically screened individuals with sub-threshold depression. Using a Markov model, future health effects and costs of an intervention scenario and a current practice scenario were estimated. The time horizon was five years. Incremental cost-effectiveness ratios were expressed in euro per Disability Adjusted Life Year (DALY) averted. Probabilistic sensitivity analysis was employed to study the effect of uncertainty in the model parameters. From the health care perspective the incremental cost-effectiveness ratio was € 1,400 per DALY, and from the societal perspective the intervention was cost-saving. Although the estimated incremental costs and effects were surrounded with large uncertainty, given a willingness to pay of € 20,000 per DALY, the probability that the intervention is cost-effective was around 80%. This modelling study showed that opportunistic screening in primary care for sub-threshold depression in combination with minimal contact psychotherapy may be cost-effective in the prevention of major depression.


Providing interoperability of eHealth communities through peer-to-peer networks.
Providing an interoperability infrastructure for Electronic Healthcare Records (EHRs) is on the agenda of many national and regional eHealth initiatives. Two important integration profiles have been specified for this purpose, namely, the "Integrating the Healthcare Enterprise (IHE) Cross-enterprise Document Sharing (XDS)" and the "IHE Cross Community Access (XCA)." IHE XDS describes how to share EHRs in a community of healthcare enterprises and IHE XCA describes how EHRs are shared across communities. However, the current version of the IHE XCA integration profile does not address some of the important challenges of cross-community exchange environments. The first challenge is scalability. If every community that joins the network needs to connect to every other community, i.e., a pure peer-to-peer network, this solution will not scale. Furthermore, each community may use a different coding vocabulary for the same metadata attribute, in which case, the target community cannot interpret the query involving such an attribute. Yet another important challenge is that each community may (and typically will) have a different patient identifier domain. Querying for the patient identifiers in the target community using patient demographic data may create patient privacy concerns. In this paper, we address each of these challenges and show how they can be handled effectively in a superpeer-based peer-to-peer architecture.


Familial amyloid polyneuropathy--clinical report of a family.
This paper reports a familial amyloid polyneuropathy (FAP) family in China. This family being investigated had 69 members of five generations. From the third generation, there have been 16 patients. The age of onset was about 3 to 5 decades. The initial symptoms were autonomic nerve symptoms, such as impotence, dyspepsia and diarrhoea, associated with the sensory loss of lower extremities. As the disease progressed, the upper extremities and motor ability were also involved. The duration of disease course was about 8-10 years, most patients died of infection and cachexia. Sural biopsy in 3 patients had showed positive Congo red staining. From the clinical view, this FAP family is similar to FAP I found in Japan. The true classification, however, should be confirmed by further genetic analysis.


Trends in US Vascular Access Use, Patient Preferences, and Related Practices: An Update From the US DOPPS Practice Monitor With International Comparisons.
Since the bundled end-stage renal disease prospective payment system began in 2011 in the United States, some hemodialysis practices have changed substantially, raising the question of whether vascular access practice also has changed. We describe monthly US vascular access use from August 2010 to August 2013 with international comparisons, and other aspects of US vascular access practice. Prospective observational cohort study of vascular access. Maintenance hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor (DPM) in the United States (N=3,442; US patients) and 19 other nations (N=8,478). Country, patient demographics, time period. Vascular access use, pre-end-stage renal disease access timing of first nephrologist care and arteriovenous access placement, patient self-reported vascular access preferences (United States only), treatment practices as stated by medical directors. In the United States from August 2010 to August 2013, arteriovenous fistula (AVF) use increased from 63% to 68%, while catheter use declined from 19% to 15%. Although AVF use did not differ greatly across age groups, arteriovenous graft use was 2-fold higher among black (26%) versus nonblack US patients (13%) in 2013. Across 20 countries in 2013, AVF use ranged from 49% to 92%, whereas catheter use ranged from 1% to 45%. Patient-reported vascular access preferences differed by sex and race, with 16% to 20% of patients feeling uninformed regarding benefits/risks of different vascular access types. Among new (incident) US hemodialysis patients, AVF use remains low, with ∼70% initiating hemodialysis therapy with a catheter (60% starting with catheter when having ≥4 months of predialysis nephrology care). In the United States, longer typical times to first AVF cannulation were reported. Noncompletion of surveys may affect the generalizability of findings to the wider hemodialysis population. AVF use has increased, with catheter use decreasing among prevalent US hemodialysis patients since the introduction of the prospective payment system. However, AVF use at dialysis therapy initiation remains low, suggesting that reforms affecting predialysis care may be necessary to incentivize improvements in fistula rates at dialysis therapy initiation as achieved for prevalent hemodialysis patients.


Overlapping Autoimmune Neurological Syndrome: A Case Report of Triple-Positive Antibody.
The presentation of several autoimmune neurological disorders in a single patient is rare and often debilitating. However, early diagnosis and efficacious treatment can lead to a significant recovery. Here, we present an interesting case of a triple antibody-positive autoimmune neurological syndrome patient who manifested the clinical features of neuromyelitis optica (NMO) spectrum disorder (NMOSD), N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis, and myasthenia gravis (MG). Hence, the patient manifested both central and peripheral nervous system immune-mediated neurological syndromes. A middle-aged female with a history of seropositive aquaporin-4 (AQP4) NMOSD on mycophenolate 1 g twice daily presented with severe fatigue and right eye ptosis (three months since NMOSD diagnosis) and tested positive for acetylcholine receptor (AchR) binding antibody, consistent with MG. Six months after the patient's NMOSD diagnosis, she began to experience subacute progressive cognitive decline, behavioral changes, imbalance, anxiety/panic attacks, and paranoid delusions. NMDAR encephalitis was suspected, and she tested positive for cerebrospinal fluid NMDAR antibodies. After treatment with steroids failed, she was given two doses of rituximab 1 g, two weeks apart, and reported improvement in her symptoms shortly after the second dose.


Effects of corticosteroids on the soluble creatine phosphokinase of the skeletal muscle of rats of various ages.
Effects of adrenalectomy, hydrocortisone and cortisone on the activity of creatine phosphokinase of the skeletal muscle of 7-, 30-, and 80-week old male rats were studied. The specific activity of the enzyme was the highest in the young and decreased in adult and old rats. However, its activity increased with age when expressed as units/mg DNA. Adrenalectomy decreased the activity in the young, but not in the adult and old rats. Hydrocortisone induced it in the young and old rats, but not in the adults rats. Cortisone induced it in the young and to some extent in the adult rats, but not in the old rats. The magnitude of induction was higher in the young rats with both hormones. Induction of enzyme was actinomycin D sensitive.


Fungus-mediated green synthesis of nano-silver using Aspergillus sydowii and its antifungal/antiproliferative activities.
Due to the increasing demand for eco-friendly, cost-effective and safe technologies, biosynthetic metal nanoparticles have attracted worldwide attention. In this study, silver nanoparticles (AgNPs) were extracellularly biosynthesized using the culture supernatants of Aspergillus sydowii. During synthesis, color change was preliminarily judge of the generation of AgNPs, and the UV absorption peak at 420 nm further confirms the production of AgNPs. Transmission electron microscopy and X-ray diffraction were also used to identify the AgNPs. The results shows that AgNPs has crystalline cubic feature and is a polydisperse spherical particle with size between 1 and 24 nm. Three main synthesis factors (temperature, pH and substrate concentration) were optimized, the best synthesis conditions were as follows 50 °C, 8.0 and 1.5 mM. In the biological application of AgNPs, it shows effective antifungal activity against many clinical pathogenic fungi and antiproliferative activity to HeLa cells and MCF-7 cells in vitro. Our research finds a new path to biosynthesis of AgNPs in an eco-friendly manner, and bring opportunity for biomedical applications in clinic.


Histological studies of gene-ablated mice support important functional roles for natural killer cells in the uterus during pregnancy.
Maternal lymphocytes having a large and granulated morphology accumulate at healthy implantation sites in normal mice. Insight into the functions of these cells has come from a previous study of two independent lines of mice deficient in natural killer (NK) cells. In pregnant Tg epsilon 26 mice, vascular pathology was found that led to the major complications of either fetal death or intrauterine growth retardation. In pregnant p56lck null x IL-2R beta null mice, extensive distension of the decidua was observed that separated the placenta from the myometrium and appeared to be interstitial edema. To strengthen assignment of uterine large granulated lymphocytes to the NK cell lineage and to understand which aspects of NK cell biology may be important for a uterine-based, pregnancy-associated subset, mid-gestation implantation sites from a new series of mice having gene deletions which alter NK cells (IL-2R gamma null, Stat4 null, IL-12 p40 null, beta 7 integrin null and Muc-1 null) have been examined histologically. The findings support the assignment of pregnancy-associated large granulated cells of mice to the NK cell lineage and suggest that the primary functions of these tissue-based NK cells are to support normal development of the decidua and/or its vasculature using pathways that involve IL-12 mediated signal transduction.


Low-moisture food matrices as probiotic carriers.
To exert a beneficial effect on the host, adequate doses of probiotics must be administered and maintaining their viability until consumption is thus essential. Dehydrated probiotics exhibit enhanced long-term viability and can be incorporated into low-moisture food matrices, which also possess high stability at refrigeration and ambient temperature. However, several factors associated with the desiccation process, the physicochemical properties of the matrix and the storage conditions can affect probiotic survival. In the near future, an increased demand for probiotics based on functionally dominant members of the gut microbiome ('next-generation probiotics', NGP) is expected. NGPs are very sensitive to oxygen and efficient encapsulation protocols are needed. Strategies to improve the viability of traditional probiotics and particularly of NGPs involve the selection of a suitable carrier as well as proper desiccation and protection techniques. Dehydrated probiotic microcapsules may constitute an alternative to improve the microbial viability during not only storage but also upper gastrointestinal tract passage. Here we review the main dehydration techniques that are applied in the industry as well as the potential stresses associated with the desiccation process and storage. Finally, low- or intermediate-moisture food matrices suitable as carriers of traditional as well as NGPs will be discussed.


Metabolically engineered soybean seed with enhanced threonine levels: biochemical characterization and seed-specific expression of lysine-insensitive variants of aspartate kinases from the enteric bacterium Xenorhabdus bovienii.
Threonine (Thr) is one of a few limiting essential amino acids (EAAs) in the animal feed industry, and its level in feed rations can impact production of important meat sources, such as swine and poultry. Threonine as well as EAAs lysine (Lys) and methionine (Met) are all synthesized via the aspartate family pathway. Here, we report a successful strategy to produce high free threonine soybean seed via identification of a feedback-resistant aspartate kinase (AK) enzyme that can be over-expressed in developing soybean seed. Towards this goal, we have purified and biochemically characterized AK from the enteric bacterium Xenorhabdus bovienii (Xb). Site-directed mutagenesis of XbAK identified two key regulatory residues Glu-257 and Thr-359 involved in lysine inhibition. Three feedback-resistant alleles, XbAK_T359I, XbAK_E257K and XbAK_E257K/T359I, have been generated. This study is the first to kinetically characterize the XbAK enzyme and provide biochemical and transgenic evidence that Glu-257 near the catalytic site is a critical residue for the allosteric regulation of AK. Furthermore, seed-specific expression of the feedback-resistant XbAK_T359I or XbAK_E257K allele results in increases of free Thr levels of up to 100-fold in R(1) soybean seed when compared to wild-type. Expression of feedback-sensitive wild-type AK did not substantially impact seed Thr content. In addition to high Thr, transgenic seed also showed substantial increases in other major free amino acid (FAA) levels, resulting in an up to 3.5-fold increase in the total FAA content. The transgenic seed was normal in appearance and germinated well under greenhouse conditions.


Clinical features of Crimean-Congo haemorrhagic fever in the United Arab Emirates.
Crimean-Congo haemorrhagic fever (C-CHF) re-emerged recently in the United Arab Emirates. The clinical outcome of 11 cases of viral haemorrhagic fever patients admitted to hospital between June 1994 and January 1995 is described. Four cases were laboratory confirmed retrospectively as C-CHF, the other patients were diagnosed likely to have the same disease on epidemiological and clinical grounds. In 72.7% of the patients, infection was fatal. Symptoms started 3.5 days before hospitalization. On admission, 81.8% of patients had high fever, 45.5% were vomiting, 63.6% had diarrhoea, 45.5% had haemorrhagic signs, and 18.2% had throat pain. Fatalities occurred 6.8 days after admission. Survivors were hospitalized for 9.3 days. Nosocomial transmission was not observed.


A luminescent Pt2Fe spin crossover complex.
A heterotrinuclear [Pt2Fe] spin crossover (SCO) complex was developed and synthesized employing a ditopic bridging bpp-alkynyl ligand L and alkynyl coordinated PtII terpy units: [FeII(L-PtII)2]2(BF4)2 (1). We identified two different types of crystals of 1 which differ in their molecular packing and the number of co-crystallized solvent molecules: 1H (1·3.5CH2Cl2 in P1[combining macron]) and 1L (1·10CH2Cl2 in C2/c); while 1L shows a reversible SCO with a transition temperature of 268 K, the analogous compound 1H does not show any SCO and remains blocked in the HS state. The temperature-dependent magnetic properties of 1H and 1L were complementarily studied by Mössbauer spectroscopy. It has been shown that 1L performs thermal spin crossover and that 1L can be excited to a LIESST state. The vibrational properties of 1 were investigated by experimental nuclear resonance vibrational spectroscopy. The experimentally determined partial density of vibrational states (pDOS) was compared to a DFT-based simulation of the pDOS. The vibrational modes of the different components were assigned and visualized. In addition, the photophysical properties of 1 and L-Pt were investigated in the solid state and in solution. The ultrafast transient absorption spectroscopy of 1 in solution was carried out to study the PL quenching channel via energy transfer from photoexcited PtII terpy units to the FeII-moiety.


In the Eye of the Covid-19 Storm: A Web-Based Survey of Psychological Distress Among People Living in Lombardy.
In March 2020, the World Health Organization announced the Covid-19 outbreak a pandemic and restrictive measures were enacted by the Governments to fight the spread of the virus. In Italy, these measures included a nationwide lockdown, with limited exceptions including grocery shopping, certain work activities, and healthcare. Consistently with findings from previous studies investigating the psychological impact of similar pandemics [e.g., Severe Acute Respiratory Syndrome (SARS)], there is evidence that Covid-19 is associated with negative mental health outcomes. Given this background, we conducted a cross-sectional study aimed at investigating the impact of the Covid-19 pandemic and the subsequent restrictive measures imposed by the Government on the psychological health of Italian men and women aged = 18 years and living in Lombardy, one of the worst-hit regions. The study also aimed at identifying what factors are associated with specific psychological outcomes. Thus, we developed an online survey that included a researcher-made questionnaire to collect sociodemographic, household, general health, and pandemic-related information. The Generalized Anxiety Disorder-7, the Patient Health Questionnaire-9 and the Perceived Stress Scale were used to assess anxiety, depression, and perceived stress, respectively. We found that younger age, greater concerns about the pandemic, female gender, being unmarried, not having children, and being a student were associated with worse psychological health. These findings may provide further insight into the risk factors associated with negative psychological outcomes during the current pandemic, with identification of vulnerable groups. This body of evidence may help professionals implement targeted psychosocial treatment and prevention programs.


Iron requirements of broiler breeder hens.
A study was conducted to investigate Fe requirements of broiler breeders. One-hundred-fifty-six Cobb 500 broiler breeder hens were individually placed in electrostatically painted cages at 22 weeks. The study was composed of an adaptation phase, in which hens were fed corn-soy-wheat bran diets until 35 wks. An Fe deficient mash diet (24.6 ppm Fe) was provided from 35 to 46 wk in order to induce a partial body Fe depletion. A production phase followed from 47 to 70 wk when hens were fed 6 diets with increasing Fe sulfate supplementation, which, upon analyses had 24.6, 48.6, 74.3, 99.6, 125.6, and 148.2 ppm Fe. Thirty hatching eggs from each treatment were randomly collected in the last wk of each production period and incubated. Hemoglobin and hematocrit were analyzed from 6 hens as well as all hatched chicks per treatment. Analyses of production and hatching data were conducted using quadratic polynomial (QP), broken-line (BL), and exponential asymptotic (EA) models. Effects of dietary Fe were observed for total eggs and total hatching eggs, egg yolk Fe content, and hen and chick hematocrit and hemoglobin (P < 0.05). These responses to added Fe were optimized when dietary Fe were 96.8, 97.1, 130.6, 122.6, 120.0, and 125.0 ppm (QP) and 76.4, 89.3, 135.0, 128.4, 133.8, and 95.0 ppm (BL) for total hatching eggs, egg yolk Fe content, and hen and chick hematocrit and hemoglobin, respectively. Optimization with the EA model was obtained for total hatching eggs, egg yolk Fe, and hen and chick hemoglobin at 97.9, 111.0, 77.9, and 96.3 ppm Fe for total hatching eggs, egg yolk Fe, and hen and chick hemoglobin, respectively. Adequate Fe levels are needed to maintain egg production as well as hatching chicks' indexes. Fe concentration in the yolk and diet are positively influenced. The average of all Fe requirement estimates obtained in the present study was 106 ppm total Fe, whereas averaged values for BL, QP, and EA models were 107, 113, and 97 ppm Fe, respectively.


Multifocal hepatocellular carcinoma and precancerous lesions in a patient with autoimmune hepatitis-related cirrhosis.
A 44-year-old woman with a 29-year history of autoimmune hepatitis (AIH) received a living donor liver transplant for multifocal hepatocellular carcinoma (HCC) and cirrhosis in 2007. Her initial laboratory workup at our institution in 1996 revealed a positive antismooth muscle antibody with a titer of 1:640. Serum electrophoresis showed a monoclonal gamma globulin spike with elevated IgG, IgA, and IgM. The patient was negative for hepatitis B and hepatitis C (HCV) by serology and serum polymerase chain reaction. She was treated with corticosteroids and azathioprine, but her disease progressed. In 1997, a liver needle biopsy revealed cirrhosis and a focus of small cell change. In 2004, a 2-cm exophytic mass was detected on magnetic resonance imaging. Follow-up imaging in 2005 and 2006 showed growth of the exophytic mass and development of new tumors. The exophytic mass was treated with ethanol ablation and she received a transplant. Examination of the explant revealed multiple high-grade dysplastic nodules and four moderately differentiated HCCs, one of which is arising in a high-grade dysplastic nodule. We believe this to be the first case in the English literature documenting the presence of preneoplastic lesions in an HCV-negative patient with AIH who developed HCC.


Brain tumors enhance plasmatic coagulation: the role of hemeoxygenase-1.
Patients with brain tumors suffer significant thrombotic morbidity and mortality. In addition to increased thrombin generation via tumor release of tissue factor-bearing microparticles and hyperfibrinogenemia, brain tumors and surrounding normal brain likely generate endogenous carbon monoxide (CO) via the hemeoxygenase-1 (HO-1) system. CO has been shown to enhance plasmatic coagulation via formation of carboxyhemefibrinogen (COHF). Thus, our goals in this study were to determine whether patients with brain tumors had increased HO-1 upregulation/CO production, plasmatic hypercoagulability, and formation of COHF. Patients with brain tumors (N = 20) undergoing craniotomy had blood collected for determination of carboxyhemoglobin as a marker of HO-1 activity, plasmatic hypercoagulability (defined as clot strength > 95% confidence interval value of normal subject plasma), and COHF formation (determined with a thrombelastograph-based assay). Plasma obtained from commercially available normal subjects (N = 30) was used for comparison with brain tumor patient samples. Brain tumor patients had carboxyhemoglobin concentrations of 1.5% ± 0.5% (mean ± SD), indicative of HO-1 upregulation. Compared with normal subject plasma, brain tumor patient plasma had significantly (P < 0.0001) greater clot formation velocity (5.2 ± 1.5 vs 9.5 ± 2.3 dynes/cm/s, respectively) and significantly (P = 0.00016) stronger final clot strength (166 ± 28 vs 230 ± 78 dynes/cm, respectively). Ten of the brain tumor patients had plasma clot strength that exceeded the 95% confidence interval value observed in normal subjects, and 12 of the brain tumor patients had COHF formation. Five of the brain tumor patients in the hypercoagulable subgroup had COHF formation. Last, 5 of the hypercoagulable patients had primary brain tumors, whereas the other 5 patients had metastatic tumors or an inflammatory mass lesion. A subset of patients with brain tumors has increased endogenous CO production, plasmatic hypercoagulability, and COHF formation. Future investigation of the role played by HO-1 derived CO in the pathogenesis of brain tumor-associated thrombophilia is warranted.


Early 1,25-Dihydroxyvitamin D3 Supplementation Effectively Lowers the Incidence of Type 2 Diabetes Mellitus via Ameliorating Inflammation In KK-Ay Mice.
Few studies have been performed to investigate the effect of vitamin D supplementation and T2DM in type 2 diabetic animal models. The present study aimed to explore the relationship between early 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the incidence of T2DM and determine whether early 1,25(OH)2D3 supplementation was associated with inflammation in KK-Ay mice. The KK-Ay mice were divided into 4 vitamin D treatment groups, the low-dose vitamin D supplementation group (VDS-L, 1.5 μg/kg 1,25(OH)2D3), moderate-dose vitamin D supplementation group (VDS-M, 3.0 μg/kg 1,25(OH)2D3), high-dose vitamin D supplementation group (VDS-H, 6.0 μg/kg 1,25(OH)2D3) and the model control group (MC). C57BL/6J mice were used as the controls. The treatment period lasted for 9 wk. During this treatment period, fasting blood glucose (FBG) level of the mice was measured on a weekly basis. The levels of lipid profile, insulin and inflammation biomarkers were determined after 9 wk of 1,25(OH)2D3 intragastric gavage. After 9 wk of 1,25(OH)2D3 intragastric gavage, FBG level was significantly decreased in the vitamin D treatment groups compared with the MC group. The number of T2DM incidence in the VDS-L group (n=7), VDS-M group (n=5) and VDS-H group (n=3) was lower than those in the MC group (n=10) on week 9. Moreover, serum C-reactive protein (CRP) and interleukin-6 (IL-6) in the vitamin D treatment groups were significantly suppressed by 1,25(OH)2D3 administration compared with the MC group. Early 1,25(OH)2D3 supplementation could effectively lower the incidence of T2DM via ameliorating inflammation in KK-Ay mice.


Mutual information measures applied to EEG signals for sleepiness characterization.
Excessive daytime sleepiness (EDS) is one of the main symptoms of several sleep related disorders with a great impact on the patient lives. While many studies have been carried out in order to assess daytime sleepiness, the automatic EDS detection still remains an open problem. In this work, a novel approach to this issue based on non-linear dynamical analysis of EEG signal was proposed. Multichannel EEG signals were recorded during five maintenance of wakefulness (MWT) and multiple sleep latency (MSLT) tests alternated throughout the day from patients suffering from sleep disordered breathing. A group of 20 patients with excessive daytime sleepiness (EDS) was compared with a group of 20 patients without daytime sleepiness (WDS), by analyzing 60-s EEG windows in waking state. Measures obtained from cross-mutual information function (CMIF) and auto-mutual-information function (AMIF) were calculated in the EEG. These functions permitted a quantification of the complexity properties of the EEG signal and the non-linear couplings between different zones of the scalp. Statistical differences between EDS and WDS groups were found in β band during MSLT events (p-value < 0.0001). WDS group presented more complexity than EDS in the occipital zone, while a stronger nonlinear coupling between occipital and frontal zones was detected in EDS patients than in WDS. The AMIF and CMIF measures yielded sensitivity and specificity above 80% and AUC of ROC above 0.85 in classifying EDS and WDS patients.


Evaluation of the Acute Flaccid Paralysis Surveillance System in Polio-Free Jordan, 2012-2016: Retrospective Secondary Analysis.
As part of the polio-eradication strategy, the World Health Organization (WHO) has established a global acute flaccid paralysis (AFP) surveillance system. AFP surveillance has successfully helped Jordan achieve polio-free certification. However, there is a substantial risk of polio importation from neighboring countries including Syria and Iraq. This study aimed to evaluate the AFP surveillance in Jordan and identify areas that need improvement. This retrospective study is a secondary analysis of data that were routinely collected between 2012 and 2016 by Jordan's Expanded Program on Immunization. The WHO's minimum performance indicators were used to evaluate the AFP surveillance. Cumulatively, 328 AFP cases had been reported. Almost half (n=168, 51.3%) of the patients were aged 1-5 years, and 55.8% (n=183) were male. All cases were discarded (classified as a nonpolio case). The most common cause of AFP was Guillain-Barre Syndrome (n=115, 35.1%). The annualized nonpolio AFP rate increased from 1.4/100,000 children below 15 years of age in 2012 to 4.3 in 2016. National and subnational sensitivities were not met in 2012 and 2013. Adequacy of stool specimens and timeliness of specimens arriving at and processed in the laboratory were constantly above the minimum target. Timeliness of the investigation met the expected target but with a decreasing trend. The nonpolio enterovirus isolation rate was below the target, except in 2016. The AFP surveillance system in Jordan is performing well; however, additional efforts are needed to strengthen the subnational sensitivity. The cold chain from sample collection to laboratory testing has to be maintained to ensure the reliability of stool specimens required for isolation of the nonpolio enterovirus.


Oral thymoquinone administration ameliorates: the effect of cisplatin on brush border membrane enzymes, energy metabolism, and redox status in rat kidney.
Therapeutic use of cisplatin (CP), an effective anticancer drug, is limited by dose dependent nephrotoxicity. Thymoquinone (TQ), the major Nigella sativa seed oil constituent has been shown to prevent progression of various renal disorders. The present study investigates the protective effect of TQ on CP-induced nephrotoxicity. Rats were divided into six groups viz. control, CP, CPTQ1, CPTQ2, CPTQ3, and TQ alone group. Animals in CP and TQ combination groups were administered TQ (0.5, 1.5, and 3 mg/kg bwt, orally) with single intraperitoneal dose of CP (6 mg/kg bwt). The effect of TQ administration was determined on CP-induced alterations in various serum/urine parameters and on the enzymes of brush border membrane enzyme (BBM), carbohydrate metabolism, and antioxidant defense system in renal cortex and medulla. Oral administration of TQ in all the three doses prior to and following a single dose CP treatment caused significant recovery of serum creatinine and blood urea nitrogen levels; however, maximum recovery was seen in CPTQ2 group. TQ administration averted CP-induced decline in BBM activities, both in the cortical and medullary homogenates and in isolated BBM vesicles. TQ administration also ameliorated CP-induced impairments in renal metabolic and antioxidant status. Histopathological studies supported these biochemical findings. TQ ameliorates CP-induced oxidative damage owing to its intrinsic antioxidant properties.


Network flow model of force transmission in unbonded and bonded granular media.
An established aspect of force transmission in quasistatic deformation of granular media is the existence of a dual network of strongly versus weakly loaded particles. Despite significant interest, the regulation of strong and weak forces through the contact network remains poorly understood. We examine this aspect of force transmission using data on microstructural fabric from: (I) three-dimensional discrete element models of grain agglomerates of bonded subspheres constructed from in situ synchrotron microtomography images of silica sand grains under unconfined compression and (II) two-dimensional assemblies of unbonded photoelastic circular disks submitted to biaxial compression under constant volume. We model force transmission as a network flow and solve the maximum flow-minimum cost (MFMC) problem, the solution to which yields a percolating subnetwork of contacts that transmits the "maximum flow" (i.e., the highest units of force) at "least cost" (i.e., the dissipated energy from such transmission). We find the MFMC describes a two-tier hierarchical architecture. At the local level, it encapsulates intraconnections between particles in individual force chains and in their conjoined 3-cycles, with the most common configuration having at least one force chain contact experiencing frustrated rotation. At the global level, the MFMC encapsulates interconnections between force chains. The MFMC can be used to predict most of the force chain particles without need for any information on contact forces, thereby suggesting the network flow framework may have potential broad utility in the modeling of force transmission in unbonded and bonded granular media.


Neurodevelopmental disorders among young adults and the risk of sickness absence and disability pension: a nationwide register linkage study.
Objectives Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and learning disabilities (LD) have an early onset and often persist into adulthood, although their relative contribution to incapacity for work is unclear. We examined this issue among young adults with ADHD, ASD or LD taking into account socioeconomic factors and comorbid mental disorders. Methods Recorded diagnoses between the ages of 10-35 years between 2001 and 2010 were derived from nationwide inpatient and specialized outpatient hospital registers in Sweden. We identified 15 632 individuals with a main diagnosis of ADHD, 8238 with ASD, and 1038 with LD, and the matched control group without recorded mental disorders (N=124 536). The outcome was the number of register-based sickness absence and work disability pension (SA-DP) days during a maximum of three years follow-up. Results Among men, the rate ratio (RR) of SA-DP was 11.17 [95% confidence interval (CI) 9.89-12.60] for ADHD, 35.59 (95% CI 30.30-41.81) for ASD, and 9.20 (95% CI 5.76-14.70) for LD, in comparison to those in the reference group. The corresponding risks among women were RR 12.05 (95% CI 10.30-14.09) for ADHD, RR 28.36 (95% CI 22.96-35.02) for ASD, and RR 9.60 (95% CI 5.83-15.81) for LD. The findings were, to a large extent, similar when individuals on DP at baseline were excluded. Comorbid mental disorders further increased the risk of SA-DP. Educational differences were smaller among the patients than in the reference group. Conclusions Early-onset neurodevelopmental disorders, particularly with comorbidity, have a far-reaching impact on adult life in terms of SA and DP.


Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach.
Protein arginine methyltransferases (PRMTs) are important therapeutic targets, playing a crucial role in the regulation of many cellular processes and being linked to many diseases. Yet, there is still much to be understood regarding their functions and the biological pathways in which they are involved, as well as on the structural requirements that could drive the development of selective modulators of PRMT activity. Here we report a deconstruction-reconstruction approach that, starting from a series of type I PRMT inhibitors previously identified by us, allowed for the identification of potent and selective inhibitors of PRMT4, which regardless of the low cell permeability show an evident reduction of arginine methylation levels in MCF7 cells and a marked reduction of proliferation. We also report crystal structures with various PRMTs supporting the observed specificity and selectivity.


Probing surface mediated configurations of nonplanar regioisomeric adsorbates using ultrahigh vacuum tip-enhanced Raman spectroscopy.
The ability to directly probe the adsorption configurations of organic regioisomeric molecules, specifically nonplanar isomers, on well-defined substrates holds promise to revolutionize fields dependent on nanoscale processes, such as catalysis, surface science, nanotechnology and modern day electronic applications. Herein, the adsorption configurations and surface sensitive interactions of two nonplanar regioisomer, trans- and cis-tetrakispentafluorophenylporphodilactone (trans- and cis-H2F20TPPDL), molecules on (100) surfaces of Ag, Cu and Au were studied and investigated using high resolution scanning tunneling microscopy (STM), combined with ultrahigh vacuum tip-enhanced Raman spectroscopy (UHV-TERS). Depending on molecule-substrate interactions, similar "phenyl-up" configurations were observed for these molecules on Ag(100) and Au(100), while a "phenyl-flat" configuration was discovered on a Cu(100) surface. With the help of surface selection rules of TERS, we explain the spectral discrepancies recorded on the Ag and Cu substrate. Furthermore, the intermolecular interactions were addressed using STM analysis on these surfaces after the configurations were determined by TERS. This study sheds light on the distinct configurations of regioisomeric porphodilactone systems (at interfaces) for near-infrared (NIR) photosensitizers and molecular electronics in the near future.


A novel cytochrome P450 mono-oxygenase from Streptomyces platensis resembles activities of human drug metabolizing P450s.
Cytochrome P450 mono-oxygenases (P450) are versatile enzymes which play essential roles in C-source assimilation, secondary metabolism, and in degradations of endo- and exogenous xenobiotics. In humans, several P450 isoforms constitute the largest part of phase I metabolizing enzymes and catalyze oxidation reactions which convert lipophilic xenobiotics, including drugs, to more water soluble species. Recombinant human P450s and microorganisms are applied in the pharmaceutical industry for the synthesis of drug metabolites for pharmacokinetics and toxicity studies. Compared to the membrane-bound eukaryotic P450s, prokaryotic ones exhibit some advantageous features, such as high stability and generally easier heterologous expression. Here, we describe a novel P450 from Streptomyces platensis DSM 40041 classified as CYP107L that efficiently converts several commercial drugs of various size and properties. This P450 was identified by screening of actinobacterial strains for amodiaquine and ritonavir metabolizing activities, followed by genome sequencing and expression of the annotated S. platensis P450s in Escherichia coli. Performance of CYP107L in biotransformations of amodiaquine, ritonavir, amitriptyline, and thioridazine resembles activities of the main human metabolizing P450s, namely CYPs 3A4, 2C8, 2C19, and 2D6. For application in the pharmaceutical industry, an E. coli whole-cell biocatalyst expressing CYP107L was developed and evaluated for preparative amodiaquine metabolite production.


GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors.
Glycogen synthase kinase 3α/β (GSK3α/β) is a serine/threonine kinase that plays a critical role in cancer. In this study, we evaluated the effects of the specific GSK3α/β inhibitor AR-A014418 in vitro to gain novel insights into GSK3α/β signaling in neuroendocrine tumors (NETs). Human NET cell lines (BON1, QGP1, H727, and GOT1) were treated with different concentrations of AR-A014418 alone and in combination with lovastatin, everolimus, 5-fluorouracil (5-FU), and γ-irradiation. AR-A014418 significantly dose- and time-dependently decreased cell viability in all 4 NET cell lines through inhibition of epithelial growth factor receptor and mTORC1/p70S6K signaling, as well as cyclin D3 downregulation and induction of pChk1. In all cell lines tested, FACS analysis showed an AR-A014418-induced increase in the sub-G1 phase, reflecting cell death. Apoptosis induction was observed in H727, GOT1 and QGP1 cells, but not in BON1 cells. Furthermore, significant antimigratory effects upon GSK3α/β inhibition were found and were associated with β-catenin downregulation in all cell lines tested. Compensatory upregulation of pAkt and pERK in response to GSK3α/β inhibition was prevented by combining AR-A014418 with the ERK and Akt inhibitor lovastatin. Accordingly, the lovastatin/AR-A014418 combination was synergistic in BON1 and QGP1 cells. Moreover, AR-A014418 displayed promising chemosensitizing effects on 5-FU in QGP1 and slight radiosensitizing properties in BON1 and QGP1 cells. Our data provide new insights into the role of GSK3α/β in NETs and suggest that GSK3α/β inhibition could be a novel therapeutic option in NETs, especially in combination with lovastatin or 5-FU, depending on tumor entity.


[Mental health care systems and provisions in the immediate and acute phase of the Great East Japan Earthquake: situational and support activities in Miyagi Prefecture].
The Great East Japan Earthquake on March 11, 2011, which measured 9.0 on the Richter scale, was followed by a huge tsunami that caused catastrophic damage to the area extending from the Tohoku to Kanto regions. It was also accompanied by the meltdown of the Fukushima Daiichi Nuclear Power Station. Mental health service provisions were hit equally hard by the disaster, with a wide range of support and relief activities being implemented. This article reviews damage that was inflicted and support activities that were carried out in the mental health field in Miyagi Prefecture in the immediate aftermath and acute phase of the disaster, and also examines future challenges. Almost all mental health institutions in Miyagi Prefecture were affected by the disaster, and experienced difficulties such as feeding inpatients and securing necessary medication. Mental health institutions in the coastal area, in particular, were severely hit. Three hospitals-were seriously damaged by the tsunami, which forced them to make arrangements for the transfer of 300 inpatients. In the aftermath of the earthquake, it became difficult to access medical institutions, and confusion ensued regarding the provision of mental health services. Many municipalities in Miyagi Prefecture were seriously affected by the disaster, and information-gathering was crippled due to the disruption of communication and transport networks. Consequently, the administrative function regarding mental health service provisions was significantly impaired. Through official, private, and academic channels, volunteers in the field of mental health were sent to the affected areas in the immediate aftermath of the disaster. It was very difficult to coordinate these volunteers because of the confusion in gathering-information and in the chain of command for support activities. The number of support teams working in the affected areas peaked one to two months after the earthquake, but it became clear that continuous and long-term support in mental health service provisions by external support teams was necessary in some remote areas. Measures were taken to care for the elderly and children, to tackle alcohol-related problems, and provide support for volunteers, but many challenges remain. When a disaster hits, measures appropriate to the nature and size of the disaster become necessary, and the need arises to construct a model to facilitate such responses. It is now necessary to integrate mental health measures with a municipality's plan for medical care in a disaster, along with develop a permanent system to provide support for mental health care at the time of a disaster.


"Derived spectra" software tools for detecting spatial and spectral features in spectrum images.
A spectrum image is recorded as an x-y array of beam locations at each of which a spectrum of radiation is recorded as stimulated by the beam. The large database or "datacube" that results from a single image presents a significant challenge to the analyst to recover information efficiently, especially in the case where a true unknown is examined. This paper describes a class of "derived spectra" software tools that can aid the analyst in recognizing both common and rare features within the datacube. A derived spectrum tool creates a spectrum-like display (intensity vs. channel number) in which the intensity (e.g., x-ray counts) at a particular channel (e.g., x-ray photon energy) is calculated from all of or a subset of the pixel intensities measured for that channel. Derived spectra tools considered include the SUM, MAXIMUM PIXEL, RUNNING SUM, and RUNNING MAXIMUM. The SUM-derived spectrum is useful for recognizing common features of the datacube, while the MAXIMUM PIXEL-and RUNNING MAXIMUM-derived spectra can locate rare, unanticipated features, which may occur as infrequently as being present at a single pixel in the original datacube.


Time trends in incidence of pathological and etiological stroke subtypes during 16 years: the Erlangen Stroke Project.
Population-based data, which continuously monitors time trends in stroke epidemiology are limited. We investigated the incidence of pathological and etiological stroke subtypes over a 16 year time period. Data were collected within the Erlangen Stroke Project (ESPro), a prospective, population-based stroke register in Germany covering a total study population of 105,164 inhabitants (2010). Etiology of ischemic stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Between January 1995 and December 2010, 3,243 patients with first-ever stroke were documented. The median age was 75 and 55% were females. The total stroke incidence decreased over the 16 year study period in men (Incidence Rate Ratio 1995-1996 vs. 2009-2010 (IRR) 0.78; 95% CI 0.58-0.90) but not in women. Among stroke subtypes, a decrease in ischemic stroke incidence (IRR 0.73; 95% CI 0.57-0.93) and of large artery atherosclerotic stroke (IRR 0.27; 95% CI 0.12-0.59) was found in men and an increase of stroke due to small artery occlusion in women (IRR 2.33; 95% CI 1.39-3.90). Variations in time trends of pathological and etiological stroke subtypes were found between men and women that might be linked to gender differences in the development of major vascular risk factors in the study population.


Origin and fate of IgE-bearing lymphocytes. I. Peyer's patches as differentiation site of cells. Simultaneously bearing IgA and IgE.
Peyer's patches (PP) from adult conventionally raised (C) and germ-free (GF) rats of the same age differed strikingly in the distributions of cells bearing membrane-bound immunoglobulin of the different isotypes. High concentrations of cells with membrane-bound IgE (approximately 20% of total cells determined by indirect immunofluorescence) were found in PP of rats, whereas IgE+ cells were absent from PP of C rats. The numbers of IgA+ cells were almost threefold higher in PP of GF rats when compared with C rats. In contrast, PP of GF rats had greatly reduced numbers of IgM-bearing cells (4%) when compared with C rats (23%); in some experiments virtually no IgM-bearing cells were detected. The levels of IgA- and IgE-bearing cells in spleen of GF rats were increased (to 11% and 7%, respectively). Of the IgE-bearing cells in PP and spleen of GF rats, approximately one-half were simultaneously positive for IgA. When these PP cells were treated with pronase to remove membrane bound immunoglobulins and maintained in culture, both IgE and IgA reappeared within 12 h. The proportion of doubly labeled cells was similar to that of the untreated population. No IgE+ cells were detected in bone marrow of C of GF rats at any time, in agreement with the findings of Ishizaka et al., although up to 20% of bone marrow cells bore other immunoglobulin isotypes, suggesting that IgE-bearing cells arise in the PP either de novo or by switching from precursors carrying IgM or IgA.


Maternal exposure to caffeine and risk of congenital anomalies: a systematic review.
Caffeine is teratogenic in animal studies when administered at high concentrations. Previous review articles have concluded that maternal caffeine consumption does not influence the risk of congenital anomalies. These reviews were narrative rather than systematic. The objective of the current systematic review is to provide a critical appraisal of epidemiologic evidence. A search of the MEDLINE/PUBMED database (1966-October 2004) was conducted for all published epidemiologic studies with maternal intake of caffeine as an exposure and major malformations as an outcome. Study characteristics were abstracted, internal validity evaluated, and study findings summarized. Twenty-five papers met the initial criteria for inclusion, of which 18 were subsequently excluded as a result of other limitations. Effect estimates for the remaining 7 studies were generally close to null. Specific subgroup analyses were summarized across studies (associations between coffee and cardiovascular malformations, coffee and oral clefts, and tea and cardiovascular malformations). Summary point estimates ranged from 1.0 to 1.2; the upper limits of all confidence intervals were less than 1.7. There is no evidence to support a teratogenic effect of caffeine in humans. Current epidemiologic evidence is not adequate to assess the possibility of a small change in risk of congenital anomalies resulting from maternal caffeine consumption.


Transcatheter aortic valve replacement: establishing a comprehensive program model for hybrid cardiac catheterization laboratories in the Department of Veterans Affairs.
Aortic valve disease, especially aortic stenosis, becomes progressively debilitating and carries a high mortality risk if it is categorized as severe and symptomatic (J Thorac Cardiovas Surg. 2012;144(3):e29-e84). In the past, the only treatment for aortic stenosis was surgical aortic valve replacement. Surgical treatment may require several hours of cardioplegia, and if the patient has comorbidities, such as renal failure or chronic obstructive pulmonary disease, their operative mortality percentage increases.In 2011, the US Food and Drug Administration approved the use of a transcatheter aortic valve replacement (TAVR) procedure for patients who were deemed high risk or inoperative for the routine surgical aortic valve replacement surgery. More than 20, 000 TAVRs have been performed in patients worldwide since 2002 when Dr Alain Cribier performed the first-in-man TAVR (Arch Cardiovasc Dis. 2012;105(3):145-152). The Edwards Lifesciences SAPIEN XT valve and the Medtronic CoreValve are commercially available.The clinical findings and economic statistic have supported the expansion of the TAVR procedure. However, there has been considerable controversy over where the procedure is to occur and who is directly responsible for directing the TAVR care. This debate has identified barriers to the implementation of a TAVR program. The operating rooms and a cardiac catheterization laboratory are underprepared for the hybrid valve replacement therapy. Because of the barriers identified, the Department of Veterans Affairs determined a need for a systematic approach to review the programs that applied for this structural heart disease program. A centralized team was developed to ensure room readiness and staff competency. The use of the Health Failure Mode and Effects Analysis can define high-risk clinical processes and conduct a hazard analysis. Worksheets can show potential failure modes and their probabilities, along with actions and outcome measures, team collaboration, extensive screening, and selection process. The TAVR program begins implementation with data entry with each case into CART-CL (Cardiovascular Assessment, Reporting and Tracking System for Cath Labs, Veteran Administration database for interventional cardiology procedures). If an untoward event occurs, within 24 hours the CART-CL Quality Assessment Team is activated to begin the review process. This provides real-time review and feedback to the local facility in an expeditious manner. Cardiac catheterization laboratories have been inundated with rapidly changing technological advances in the past decade. The era for structural heart repair is rapidly mobilizing from a surgical/operating room setting to a transcatheter/hybrid catheterization laboratory suite. The use of the new hybrid catheterization laboratories will continue to expand as the approval of future transcatheter therapies evolve. Editor's note: Due to the volume of important information presented in each table, only the first table is included in the print version of the article, however, all tables may be viewed in their entirety free of charge on the online version of this article: http://journals.lww.com/dccnjournal/pages/default.aspx.


Isoflurane regulates atypical type-A γ-aminobutyric acid receptors in alveolar type II epithelial cells.
Volatile anesthetics act primarily through upregulating the activity of γ-aminobutyric acid type A (GABAA) receptors. They also exhibit antiinflammatory actions in the lung. Rodent alveolar type II (ATII) epithelial cells express GABAA receptors and the inflammatory factor cyclooxygenase-2 (COX-2). The goal of this study was to determine whether human ATII cells also express GABAA receptors and whether volatile anesthetics upregulate GABAA receptor activity, thereby reducing the expression of COX-2 in ATII cells. The expression of GABAA receptor subunits and COX-2 in ATII cells of human lung tissue and in the human ATII cell line A549 was studied with immunostaining and immunoblot analyses. Patch clamp recordings were used to study the functional and pharmacological properties of GABAA receptors in cultured A549 cells. ATII cells in human lungs and cultured A549 cells expressed GABAA receptor subunits and COX-2. GABA induced currents in A549 cells, with half-maximal effective concentration of 2.5 µM. Isoflurane (0.1-250 µM) enhanced the GABA currents, which were partially inhibited by bicuculline. Treating A549 cells with muscimol or with isoflurane (250 µM) reduced the expression of COX-2, an effect that was attenuated by cotreatment with bicuculline. GABAA receptors expressed by human ATII cells differ pharmacologically from those in neurons, exhibiting a higher affinity for GABA and lower sensitivity to bicuculline. Clinically relevant concentrations of isoflurane increased the activity of GABAA receptors and reduced the expression of COX-2 in ATII cells. These findings reveal a novel mechanism that could contribute to the antiinflammatory effect of isoflurane in the human lung.


Detection of 6K1 as a mature protein of 6 kDa in plum pox virus-infected Nicotiana benthamiana.
The RNA genome of Plum pox virus (PPV) encodes one large polyprotein that is subsequently cleaved into mature viral proteins. One of the products of proteolytic processing, the 6K1 protein, has not yet been identified in vivo for any member of the genus Potyvirus. In this study, 6K1-specific polyclonal antiserum was raised against PPV 6K1 expressed in Escherichia coli as a translational fusion with the N terminus of avian troponin C and an unusual metal-binding cluster of troponin T-1. For detection of 6K1 in vivo, a pPPV-H6K1-NAT infectious clone was constructed, enabling concentration of histidine-tagged 6K1 by affinity chromatography. Affinity-purified 6K1 was detected in locally infected Nicotiana benthamiana leaves at 4, 7 and 14 days post-inoculation (d.p.i.) and, in addition, in systemically infected leaves at 14 d.p.i., 6K1 was detected exclusively as a protein of 6 kDa and no polyprotein precursors were identified with the raised anti-6K1 antiserum.


Association between Psychosocial Stress and Cardiovascular Disease in Relation to Low Consumption of Fruit and Vegetables in Middle-Aged Men.
Stress has been reported to affect dietary intake and chronic disease. This study aimed to investigate the association between psychosocial stress and cardiovascular disease (CVD) in relation to dietary intake. This cross-sectional analysis was performed on 23,792 men enrolled in the Korean Genome and Epidemiology Study from 2004 to 2013. Stress was assessed by the Psychosocial Well-Being Index. Stress level was positively associated with the risks of CVD (odds ratio (OR) for quartile 4 compared to quartile 1 = 1.30 (95% confidence interval 1.24-1.37), p-trend < 0.0001), including hypertension (OR = 1.26 (1.20-1.33), p-trend < 0.0001), heart disease (OR = 1.55 (1.34-1.80), p-trend = 0.0001), and cerebrovascular disease (OR = 2.47 (1.97-3.09), p-trend < 0.0001). As the level of stress increased, the intake of fruits and vegetables, as well as antioxidant nutrients, was decreased. Stress level showed an inverse association with dietary variety score (p-trend = 0.0001). In addition, dietary variety score was inversely associated with fruits and vegetables consumption (p-trend < 0.0001). These results suggest that the CVD risks for those with higher stress levels may be partially related to the decreased consumption of fruits and vegetables and dietary variety score.


Biomimetic calcium phosphate coatings on Ti6AI4V: a crystal growth study of octacalcium phosphate and inhibition by Mg2+ and HCO3-.
The biomimetic approach for coating metal implants allows the deposition of new calcium phosphate (Ca-P) phases. Films elaborated at physiological conditions might have structures closer to bone mineral than hydroxylapatite (HA) plasma-sprayed coatings. In this study, different Ca-P coatings have been deposited through a two-step procedure. After cleaning and etching, Ti6Al4V plates were pretreated by soaking in a simulated body fluid (SBF), i.e., a solution containing inorganic components in concentration more or less similar to body fluids: a thin amorphous carbonated Ca-P layer precipitated on the metal substrate. Second, by soaking these thinly coated metal substrates in another SBF, with different concentrations, the thin amorphous carbonated Ca-P layer led to the fast precipitation of a second and thick Ca-P layer. Different SBF solutions were used in order to investigate the influence of magnesium and carbonate ions. From SBF containing only Ca2+ and HPO4(2-) ions, an octacalcium phosphate layer grew epitaxially on the substrate. When Mg2+ was added into this SBF, the coating was composed of Ca-deficient apatite crystals, while the addition of HCO3- in SBF led to the formation of a B-carbonated apatite layer. Magnesium and carbonate acted as inhibitors of crystal growth. The three phases obtained by our biomimetic process are closer to bone mineral structure than plasma-sprayed HA. Therefore, the obtained results may be particularly relevant for the development of biomimetic Ca-P coatings with optimal bioactivity.


Chapter 20: Issues in planning cervical cancer screening in the era of HPV vaccination.
Human Papillomavirus (HPV) vaccines will likely have an impact as a preventive strategy for cervical cancer. Screening for precancerous lesions cannot be discontinued because vaccination will not protect against HPV types not included in the first generation of vaccines. Moreover, protection for the target types, 16 and 18, which are responsible for most cases of cervical precancerous lesions and cancer, and 6 and 11, which are responsible for a substantial proportion of low-grade lesions, cannot be expected to be absolute, and the likely implementation of HPV vaccination in young women will not impact older groups initially. Cervical cancer control programs will need to be re-evaluated because the addition of HPV vaccination will make the existing approach of high-frequency screening by cytology too costly and inefficient for most public health budgets. Simply making cytology screening less frequent may not be a viable strategy in light of potential problems that may plague cytology performance in conditions of low lesion prevalence. HPV testing has the performance characteristics that would make it an ideal primary screening test in such conditions. Cytology should be reserved for triage of HPV-positive cases because it is more likely to perform with sufficient accuracy in high-prevalence conditions. Another advantage of using HPV testing as a primary screening tool is the opportunity to create infection registries that can link test results from the same women over time, thus allowing an efficient and low-cost strategy to monitor long-term protection among vaccinated women.


Antiplatelet Therapy, Abdominal Aortic Aneurysm Progression, and Clinical Outcomes.
Preclinical studies suggest a potential role for aspirin in slowing abdominal aortic aneurysm (AAA) progression and preventing rupture. Evidence on the clinical benefit of aspirin in AAA from human studies is lacking. To investigate the association of aspirin use with aneurysm progression and long-term clinical outcomes in patients with AAA. This was a retrospective, single-center cohort study. Adult patients with at least 2 available vascular ultrasounds at the Cleveland Clinic were included, and patients with history of aneurysm repair, dissection, or rupture were excluded. All patients were followed up for 10 years. Data were analyzed from May 2022 to July 2023. Clinical outcomes were time-to-first occurrence of all-cause mortality, major bleeding, or composite of dissection, rupture, and repair. Multivariable-adjusted Cox proportional-hazard regression was used to estimate hazard ratios (HR) for all-cause mortality, and subhazard ratios competing-risk regression using Fine and Gray proportional subhazards regression was used for major bleeding and composite outcome. Aneurysm progression was assessed by comparing the mean annualized change of aneurysm diameter using multivariable-adjusted linear regression and comparing the odds of having rapid progression (annual diameter change >0.5 cm per year) using logistic regression. A total of 3435 patients (mean [SD] age 73.7 [9.0] years; 2672 male patients [77.5%]; 120 Asian, Hispanic, American Indian, or Pacific Islander patients [3.4%]; 255 Black patients [7.4%]; 3060 White patients [89.0%]; and median [IQR] follow-up, 4.9 [2.5-7.5] years) were included in the final analyses, of which 2150 (63%) were verified to be taking aspirin by prescription. Patients taking aspirin had a slower mean (SD) annualized change in aneurysm diameter (2.8 [3.0] vs 3.8 [4.2] mm per year; P = .001) and lower odds of having rapid aneurysm progression compared with patients not taking aspirin (adjusted odds ratio, 0.64; 95% CI, 0.49-0.89; P = .002). Aspirin use was not associated with risk of all-cause mortality (adjusted HR [aHR], 0.92; 95% CI, 0.79-1.07; P = .32), nor was aspirin use associated with major bleeding (aHR, 0.88; 95% CI, 0.76-1.03; P = .12), or composite outcome (aHR, 1.16; 95% CI, 0.93-1.45; P = .09) at 10 years. In this retrospective study of a clinical cohort of 3435 patients with objectively measured changes in aortic aneurysm growth, aspirin use was significantly associated with slower progression of AAA with a favorable safety profile.


Covariate selection in high-dimensional propensity score analyses of treatment effects in small samples.
To reduce bias by residual confounding in nonrandomized database studies, the high-dimensional propensity score (hd-PS) algorithm selects and adjusts for previously unmeasured confounders. The authors evaluated whether hd-PS maintains its capabilities in small cohorts that have few exposed patients or few outcome events. In 4 North American pharmacoepidemiologic cohort studies between 1995 and 2005, the authors repeatedly sampled the data to yield increasingly smaller cohorts. They identified potential confounders in each sample and estimated both an hd-PS that included 0-500 covariates and treatment effects adjusted by decile of hd-PS. For sensitivity analyses, they altered the variable selection process to use zero-cell correction and, separately, to use only the variables' exposure association. With >50 exposed patients with an outcome event, hd-PS-adjusted point estimates in the small cohorts were similar to the full-cohort values. With 25-50 exposed events, both sensitivity analyses yielded estimates closer to those obtained in the full data set. Point estimates generally did not change as compared with the full data set when selecting >300 covariates for the hd-PS. In these data, using zero-cell correction or exposure-based covariate selection allowed hd-PS to function robustly with few events. hd-PS is a flexible analytical tool for nonrandomized research across a range of study sizes and event frequencies.


Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old.
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. To identify distinct molecular mechanisms for early HCC we developed a rat model of liver regeneration post-hepatectomy, as well as liver cells undergoing malignant transformation and compared them to normal liver using a microarray approach. Subsequently, we performed cross-species comparative analysis coupled with copy number alterations (CNA) of independent early human HCC microarray studies to facilitate the identification of critical regulatory modules conserved across species. We identified 35 signature genes conserved across species, and shared among different types of early human HCCs. Over 70% of signature genes were cancer-related, and more than 50% of the conserved genes were mapped to human genomic CNA regions. Functional annotation revealed genes already implicated in HCC, as well as novel genes which were not previously reported in liver tumors. A subset of differentially expressed genes was validated using quantitative RT-PCR. Concordance was also confirmed for a significant number of genes and pathways in five independent validation microarray datasets. Our results indicated alterations in a number of cancer related pathways, including p53, p38 MAPK, ERK/MAPK, PI3K/AKT, and TGF-beta signaling pathways, and potential critical regulatory role of MYC, ERBB2, HNF4A, and SMAD3 for early HCC transformation. The integrative analysis of transcriptional deregulation, genomic CNA and comparative cross species analysis brings new insights into the molecular profile of early hepatoma formation. This approach may lead to robust biomarkers for the detection of early human HCC.


GmLecRlk, a Lectin Receptor-like Protein Kinase, Contributes to Salt Stress Tolerance by Regulating Salt-Responsive Genes in Soybean.
Soybean [Glycine max (L.) Merr.] is an important oil crop that provides valuable resources for human consumption, animal feed, and biofuel. Through the transcriptome analysis in our previous study, GmLecRlk (Glyma.07G005700) was identified as a salt-responsive candidate gene in soybean. In this study, qRT-PCR analysis showed that the GmLecRlk gene expression level was significantly induced by salt stress and highly expressed in soybean roots. The pCAMBIA3300-GmLecRlk construct was generated and introduced into the soybean genome by Agrobacterium rhizogenes. Compared with the wild type (WT), GmLecRlk overexpressing (GmLecRlk-ox) soybean lines had significantly enhanced fresh weight, proline (Pro) content, and catalase (CAT) activity, and reduced malondialdehyde (MDA) and H2O2 content under salt stress. These results show that GmLecRlk gene enhanced ROS scavenging ability in response to salt stress in soybean. Meanwhile, we demonstrated that GmLecRlk gene also conferred soybean salt tolerance when it was overexpressed alone in soybean hairy root. Furthermore, the combination of RNA-seq and qRT-PCR analysis was used to determine that GmLecRlk improves the salt tolerance of soybean by upregulating GmERF3, GmbHLH30, and GmDREB2 and downregulating GmGH3.6, GmPUB8, and GmLAMP1. Our research reveals a new mechanism of salt resistance in soybean, which exposes a novel avenue for the cultivation of salt-resistant varieties.


In Vivo Evaluation of Magnetic Targeting in Mice Colon Tumors with Ultra-Magnetic Liposomes Monitored by MRI.
The development of theranostic nanocarriers as an innovative therapy against cancer has been improved by targeting properties in order to optimize the drug delivery to safely achieve its desired therapeutic effect. The aim of this paper is to evaluate the magnetic targeting (MT) efficiency of ultra-magnetic liposomes (UML) into CT26 murine colon tumor by magnetic resonance imaging (MRI). Dynamic susceptibility contrast MRI was applied to assess the bloodstream circulation time. A novel semi-quantitative method called %I0.25, based on the intensity distribution in T2*-weighted MRI images was developed to compare the accumulation of T2 contrast agent in tumors with or without MT. To evaluate the efficiency of magnetic targeting, the percentage of pixels under the intensity value I0.25 (I0.25 = 0.25(Imax - Imin)) was calculated on the intensity distribution histogram. This innovative method of processing MRI images showed the MT efficiency by a %I0.25 that was significantly higher in tumors using MT compared to passive accumulation, from 15.3 to 28.6 %. This methodology was validated by ex vivo methods with an iron concentration that is 3-fold higher in tumors using MT. We have developed a method that allows a semi-quantitative evaluation of targeting efficiency in tumors, which could be applied to different T2 contrast agents.


Association of systemic lupus erythematosus clinical features with European population genetic substructure.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10(-4)), oral ulcers (P = 6.9×10(-4)) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.


Ginseng increases Klotho expression by FoxO3-mediated manganese superoxide dismutase in a mouse model of tacrolimus-induced renal injury.
The antioxidant function of Klotho is well-documented as a regulatory factor implicated in countering the aging process. This study investigated whether ginseng upregulates Klotho and its antiaging signaling in a setting of calcineurin inhibitor-induced oxidative stress. Although tacrolimus treatment reduced Klotho level in the serum and kidney, ginseng treatment was found to reverse the levels. Tacrolimus-induced oxidative stress was reduced by ginseng treatment, with functional and histological improvements. Effect of ginseng on Klotho-induced manganese superoxide dismutase signaling pathway during tacrolimus treatment in mice revealed that ginseng suppressed phosphatidylinositol 3-kinase/serine-threonine kinase Akt-mediated phosphorylation of forkhead box protein O3a and promoted the binding of forkhead box protein O3a to manganese superoxide dismutase promoter. In the mitochondria, ginseng reduced mitochondrial reactive oxygen species production, mitochondrial membrane potential, and oxygen consumption rate, whereas blocking phosphatidylinositol 3-kinase activity with LY294002 enhanced them. These findings together suggested that ginseng attenuated tacrolimus-induced oxidative stress via signaling between Klotho and the phosphatidylinositol 3-kinase/serine-threonine kinase Akt/forkhead box protein O3a-related antioxidant pathway.


Microwave-assisted synthesis of water-soluble, fluorescent gold nanoclusters capped with small organic molecules and a revealing fluorescence and X-ray absorption study.
Colourless solutions of blue light-emitting, water-soluble gold nanoclusters (AuNC) were synthesized from gold colloids under microwave irradiation using small organic molecules as ligands. Stabilized by 1,3,5-triaza-7-phosphaadamantane (TPA) or L-glutamine (GLU), fluorescence quantum yields up to 5% were obtained. AuNC are considered to be very promising for biological labelling, optoelectronic devices and light-emitting materials but the structure-property relationships have still not been fully clarified. To expand the knowledge about the AuNC apart from their fluorescent properties they were studied by X-ray absorption spectroscopy elucidating the oxidation state of the nanoclusters' gold atoms. Based on curve fitting of the XANES spectra in comparison to several gold references, optically transparent fluorescent AuNC are predicted to be ligand-stabilized Au5(+) species. Additionally, their near edge structure compared with analogous results of polynuclear clusters known from the literature discloses an increasing intensity of the feature close to the absorption edge with decreasing cluster size. As a result, a linear relationship between the cluster size and the X-ray absorption coefficient can be established for the first time.


Pharmacological Prophylaxis for Venous Thromboembolism Among Hospitalized Patients With Acute Medical Illness: An Electronic Medical Records Study.
Patients hospitalized with acute medical illness have an elevated risk of venous thromboembolism (VTE). American College of Chest Physicians guidelines list various chronic illnesses, sepsis, advanced age, history of VTE, and immobility as risk factors and recommend prophylactic anticoagulation using fondaparinux, low-molecular weight heparin, or low-dose unfractionated heparin. The objectives of this study were to examine pharmacological prophylaxis against VTE among hospitalized medically ill patients and to assess demographic and clinical correlates related to VTE prophylaxis. A retrospective (1999-2010) electronic medical records study included patients aged 40 years and older hospitalized for at least 3 days, with significant medical illness or with a VTE hospitalization 30-365 days before admission. Each patient's first qualifying hospitalization was analyzed. Exclusions were if VTE treatment was started within 1 day of admission, or if warfarin (and not heparin or enoxaparin) was used. Prophylaxis was defined if the first inpatient dose of subcutaneous heparin or enoxaparin was at prophylaxis levels (lower than treatment levels). Multivariable logistic regression was used to examine factors associated with VTE prophylaxis. Among 12,980 patients, 22.1% received prophylaxis (11.8% with enoxaparin, 10.3% with heparin). VTE prophylaxis was positively associated with year of hospitalization, subcutaneous heparin in the month before admission, aspirin, self-pay status, age, and sepsis. VTE prophylaxis was negatively associated with smoking, alcohol, warfarin in the past 30 days, and primary diagnoses of stroke, infectious disease, or inflammatory bowel disease. Pharmacological VTE prophylaxis has increased significantly over the past 12 years but is still largely underused in patients hospitalized with acute medical illness. Multiple demographic, behavioral, and clinical factors are associated with inpatient VTE prophylaxis.


Perceptual and motor learning underlies human stick-balancing skill.
We investigated the acquisition of skill in balancing a stick (52 cm, 34 g) on the fingertip in nine participants using three-dimensional motion analysis. After 3.5 h of practice over 6 wk, the participants could more consistently balance the stick for longer durations with greatly reduced magnitude and speed of stick and finger movements. Irrespective of level of skill, the balanced stick behaved like a normal noninverted pendulum oscillating under greater-than-gravity torque with simple harmonic motion about a virtual pivot located at the radius of gyration above the center of mass. The control input parameter was the magnitude ratio between the torque applied on the stick by the participant and the torque due to gravity. The participants utilized only a narrow range of this parameter, which did not change with practice, to rotate the stick like a linear mass-spring system. With increased skill, the stick therefore maintained the same period of oscillation but showed marked reductions in magnitude of both oscillation and horizontal translation. Better balancing was associated with 1) more accurate visual localization of the stick and proprioceptive localization of the finger and 2) reduced cross-coupling errors between finger and stick movements in orthogonal directions; i.e., finger movements in the anteroposterior plane became less coupled with stick tip movements in the mediolateral plane, and vice versa. Development of this fine motor skill therefore depended on perceptual and motor learning to provide improved estimation of sensorimotor state and precision of motor commands to an unchanging internal model of the rotational dynamics.


Effect of childhood nutrition counselling on intelligence in adolescence: a 15-year follow-up of a cluster-randomised trial.
The present study aimed to assess the effects of an early childhood nutrition counselling intervention on intelligence (as measured by the intelligence quotient (IQ)) at age 15-16 years. A single-blind, cluster-randomised trial. In 1998, in Southern Brazil, mothers of children aged 18 months or younger were enrolled in a nutrition counselling intervention (n 424). Counselling included encouragement and promotion of exclusive breast-feeding until 6 months of age and continued breast-feeding supplemented by protein-, lipid- and carbohydrate-rich foods after age 6 months up to age 2 years. The control group received routine feeding advice. In 2013, the fourth round of follow-up of these individuals, at the age of 15-16 years, was undertaken. IQ was assessed using the short form of the Wechsler Adult Intelligence Scale (WAIS-III). Mental disorders (evaluated using the Development and Well-Being Assessment (DAWBA)) and self-reported school failure, smoking and alcohol use were also investigated. Adjusted analyses were conducted using a multilevel model in accordance with the sampling process. Adolescents, mean (sd) age of 15·4 (0·5) years (n 339). Mean (sd) total IQ score was lower in the intervention group than the control group (93·4 (11·4) and 95·8 (11·2), respectively) but the association did not persist after adjustment. The prevalence of any mental disorders was similar between intervention and control groups (23·1 and 23·5 %, respectively). There were no differences between groups regarding school failure, smoking and alcohol use. Nutrition counselling intervention in early childhood had no effect on intelligence measured during adolescence.


Regulation of tyrosinase processing and trafficking by organellar pH and by proteasome activity.
Pigmentation of the hair, skin, and eyes of mammals results from a number of melanocyte-specific proteins that are required for the biosynthesis of melanin. Those proteins comprise the structural and enzymatic components of melanosomes, the membrane-bound organelles in which melanin is synthesized and deposited. Tyrosinase (TYR) is absolutely required for melanogenesis, but other melanosomal proteins, such as TYRP1, DCT, and gp100, also play important roles in regulating mammalian pigmentation. However, pigmentation does not always correlate with the expression of TYR mRNA/protein, and thus its function is also regulated at the post-translational level. Thus, TYR does not necessarily exist in a catalytically active state, and its post-translational activation could be an important control point for regulating melanin synthesis. In this study, we used a multidisciplinary approach to examine the processing and sorting of TYR through the endoplasmic reticulum (ER), Golgi apparatus, coated vesicles, endosomes and early melanosomes because those organelles hold the key to understanding the trafficking of TYR to melanosomes and thus the regulation of melanogenesis. In pigmented cells, TYR is trafficked through those organelles rapidly, but in amelanotic cells, TYR is retained within the ER and is eventually degraded by proteasomes. We now show that TYR can be released from the ER in the presence of protonophore or proton pump inhibitors which increase the pH of intracellular organelles, after which TYR is transported correctly to the Golgi, and then to melanosomes via the endosomal sorting system. The expression of TYRP1, which facilitates TYR processing in the ER, is down-regulated in the amelanotic cells; this is analogous to a hypopigmentary disease known as oculocutaneous albinism type 3 and further impairs melanin production. The sum of these results shows that organellar pH, proteasome activity, and down-regulation of TYRP1 expression all contribute to the lack of pigmentation in TYR-positive amelanotic melanoma cells.


Effects of Shift Work on the Eating Behavior of Police Officers on Patrol.
Recent studies indicate that the timing of food intake can significantly affect metabolism and weight management. Workers operating at atypical times of the 24-h day are at risk of disturbed feeding patterns. Given the increased risk of weight gain, obesity and metabolic syndrome in shift working populations, further research is required to understand whether their eating behavior could contribute to these increased metabolic risks. The objective of this study was to characterize the dietary patterns of police officers across different types of shifts in their natural environments. Thirty-one police officers (six women; aged 32.1 ± 5.4 years, mean ± SD) from the province of Quebec, Canada, participated in a 28- to 35-day study, comprising 9- to 12-h morning, evening, and night shifts alternating with rest days. Sleep and work patterns were recorded with actigraphy and diaries. For at least 24 h during each type of work day and rest day, participants logged nutrient intake by timestamped photographs on smartphones. Macronutrient composition and caloric content were estimated by registered dieticians using the Nutrition Data System for Research database. Data were analyzed with linear mixed effects models and circular ANOVA. More calories were consumed relative to individual metabolic requirements on rest days than both evening- and night-shift days (p = 0.001), largely sourced from increased fat (p = 0.004) and carbohydrate (trend, p = 0.064) intake. Regardless, the proportions of calories from carbohydrates, fat, and protein did not differ significantly between days. More calories were consumed during the night, between 2300 h and 0600 h, on night-shift days than any other days (p < 0.001). Caloric intake occurred significantly later for night-shift days (2308 h ± 0114 h, circular mean ± SD) than for rest days (1525 h ± 0029 h; p < 0.01) and was dispersed across a longer eating window (13.9 h ± 3.1 h vs. 11.3 h ± 1.8 h, mean ± SD). As macronutrient proportions were similar and caloric intake was lower, the finding of later meals times on night-shift days versus rest days is consistent with emerging hypotheses that implicate the biological timing of food intake-rather than its quantity or composition-as the differentiating dietary factor in shift worker health.