Effects of enzyme activities during steeping and sprouting on the solubility and composition of proteins, their bioactivity and relationship with the bread making quality of wheat flour.
The aim was to determine the effect of steeping and sprouting on wheat grain proteins and the functional consequences in this regard. The solubility of proteins and the polypeptide composition of albumins, globulins, gliadins and glutenins were determined, as well as the content of non-protein nitrogen and free sulfhydryl groups (-SH), and the activity of peroxidase (POD) and lipoxygenase (LOX). In addition, the pasting viscosity of flour and protein bioactivity such as antioxidant capacity and immunoreactivity were evaluated. The increase of non-protein nitrogen and free -SH groups by about 62.09 and 96.7%, respectively, as well as the decrease of albumin + globulin polypeptides with a molecular weight over 85.94 kDa and between 85.94-48.00 kDa by about 34 and 8.7%, respectively, were the most notable changes observed in the flour from whole sprouted wheat that clearly point to the intensive protein hydrolysis. The reduction of disulfide bonds and increased concentrations of free -SH groups significantly modify the visco-elastic properties of gliadins and glutenins causing pasting viscosity reduction. However, sprouted wheat flour could be considered as a potential food ingredient because of its improved antioxidant capacity that is a result of protein hydrolysis inter alia. As protein modification induced by steeping may have beneficial effects on the antigenicity of the glutenin fraction, this kind of wheat pretreatment can represent a putative strategy in the dietary modulation of diseases related to glutenin immunoreactivity, e.g. dermatitis herpetiformis.


Well-Being of Child and Family Participants in Phase 1 Pediatric Oncology Clinical Trials.
Pediatric oncology phase 1 clinical trials (P1Ts) are essential to developing new anticancer therapies; however, they raise complex ethical concerns about balancing the need for this research with the well-being of participating children. The purpose of this integrative review was to synthesize and appraise the evidence of how P1T participation, which begins with consent and ends with the transition off the P1T, can affect the well-being (either positively or negatively) of children with cancer. The Resilience in Individuals and Families Affected by Cancer Framework, which has an outcome of well-being, was used to synthesize findings. Articles on the experiences of child (n = 21) and adult (n = 31) P1T participants were identified through systematic searches. Articles were evaluated on rigor and relevance to P1T participant experiences as high, medium, or low. Minimal empirical evidence was found regarding the effect of P1T participation on the well-being of children with cancer. Adult P1T participant experiences provide insights that could also be important to children's P1T experiences. To achieve a balanced approach in P1T consent discussions, nurses and healthcare providers who work with children considering participation in a P1T should share the potential effect of participation on participants' well-being.


Prescription drugs associated with reports of violence towards others.
Violence towards others is a seldom-studied adverse drug event and an atypical one because the risk of injury extends to others. To identify the primary suspects in adverse drug event reports describing thoughts or acts of violence towards others, and assess the strength of the association. From the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we extracted all serious adverse event reports for drugs with 200 or more cases received from 2004 through September 2009. We identified any case report indicating homicide, homicidal ideation, physical assault, physical abuse or violence related symptoms. Disproportionality in reporting was defined as a) 5 or more violence case reports, b) at least twice the number of reports expected given the volume of overall reports for that drug, c) a χ2 statistic indicating the violence cases were unlikely to have occurred by chance (p<0.01). We identified 1527 cases of violence disproportionally reported for 31 drugs. Primary suspect drugs included varenicline (an aid to smoking cessation), 11 antidepressants, 6 sedative/hypnotics and 3 drugs for attention deficit hyperactivity disorder. The evidence of an association was weaker and mixed for antipsychotic drugs and absent for all but 1 anticonvulsant/mood stabilizer. Two or fewer violence cases were reported for 435/484 (84.7%) of all evaluable drugs suggesting that an association with this adverse event is unlikely for these drugs. Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs. Prospective studies to evaluate systematically this side effect are needed to establish the incidence, confirm differences among drugs and identify additional common features.


All-optical technique for modulation format conversion from on-off-keying to alternate-mark-inversion.
We propose and numerically investigate for the first time a novel all-optical on-off-keying to alternate-mark-inversion modulation format converter operating at 40 Gbps employing a semiconductor optical amplifier (SOA)-based Mach-Zehnder interferometer (MZI). We demonstrate that this SOA-MZI operates as a pulse subtractor, and in the absence of patterning will produce perfectly phase inverted pulses regardless of the individual SOA phase excursions. We use a comprehensive computer model to illustrate the impact of patterning on the output phase modulation, which is quantified through the definition of the phase compression factor.


Highlights from the 15th St Gallen International Breast Cancer Conference 15-18 March, 2017, Vienna: tailored treatments for patients with early breast cancer.
The 15th St Gallen International Breast Cancer Conference was held in Vienna for the second time, from 15th-18th March 2017. 4000 people from 105 countries all over the world were invited to take part in the event. The real highlight of the conference was the last day with the International Consensus Session which was chaired by around 50 experts on breast cancer worldwide. With reference to data from scientific research, the consensus panel tried to offer guidelines for the management of breast cancer with the aim of providing patients with optimal treatment. The topics covered focused on the treatment of breast cancer, consideration of surgery, radiotherapy, neo-adjuvant, and adjuvant systemic therapy for breast cancer, as well as genetics and prevention of breast cancer. In particular, in terms of precision medicine, an important topic of the conference was 'is it possible to think that it could become routine in clinical practice to use immunotherapy and targeted therapy based on genetic signatures?' In view of personalised therapy, it is important to take into consideration women's treatment preferences. It is also important not only to offer guidelines which help breast cancer experts all over the world to choose the proper treatment for women with breast cancer but also to discuss the pros and cons of the therapy with the patient. This allows for a better understanding of the disease. 'From the maximum tolerable to the minimum effective treatment: it is essential to escalate treatment when necessary and to de-escalate when unnecessary'. These few words could summarise the meaning of the 15th St Gallen International Breast Cancer Conference. Prof Martine Piccart-Gebhart was awarded with the St Gallen International Breast Cancer Award 2017 for her fundamental clinical research contribution and Prof Giuseppe Curigliano with the Umberto Veronesi Memorial Award which aims to recognise a physician's leading role in advancing the science and care of breast cancer patients. Curigliano, in his lecture, spoke about the revolutionary immunotherapy in the clinical management of breast cancer (BC). For the development of these therapies, it is necessary to identify the genetic determinants of BC immune phenotypes in which The Cancer Genome Atlas (TCGA) has contributed towards this. For example, the T helper (Th-1) phenotype (ICR4), which also exhibits upregulation of immune-regulatory transcripts (eg. PDL1, PD1, FOXP3, IDO1, and CTLA4), was associated with prolonged patients' survival. Chromosome segment 4q21, which includes genes encoding the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favourable phenotype (ICR4). The mutation and neo-antigen load progressively decreased from ICR4 to ICR1 but could not explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favourable phenotype (ICR4). Instead, the presence of MAP3K1 and MAP2K4 mutations were closely associated with an immune unfavourable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates BC according to their immune disposition. These findings suggest that mutational-driven deregulation of MAPK pathways is linked to the negative regulation of intratumoural immune response in BC. The main themes of this congress were: 1) Surgery of the primary tumour and margins; 2) Surgery of the axilla; 3) Radiotherapy: hypofractionated, 'boost' to tumour bed, partial breast, regional node, after mastectomy, advanced technology; 4) Pathology: subtypes, TILs; 5) Multi-gene signatures and therapy; 6) Endocrine therapy: pre- and post-menopausal and duration; 7) Chemotherapy: subtypes, stages; 8) Anti-HER-2 therapy; 9) Neo-adjuvant therapy; 10) Adjuvant bisphosponates; 11) Adjuvant diet and exercise.


Opinions of the Midwives about Enabling Factors of Skin-To-Skin Contact Immediately after Birth: A Descriptive Study.
Despite the benefits of mother-newborn skin-to-skin contact (SSC) immediately after birth, the process has not been universally implemented as routine care for healthy term neonates. The purpose of this study was to determine opinions of the midwives about enabling factors of SSC immediately after birth in Tehran hospitals in 2012- 2013. This study has been conducted in a descriptive method based on PRCEDE-PROCEED model. The samples were 292 midwives from 18 hospitals. We used stratified and then simple random sampling. In this study midwives were working at delivery room; deliveries were conducted by midwives or they were in charge of the newborn immediately after birth. Data collection instrument was a self developed questionnaire concerning the enabling factors in the SSC. We applied face and content validity ratio (CVR), content validity index (CVI) and item impact method for the instrument's validity and Cronbach's Alpha for reliability. Finally, data were analyzed and interpreted using spss-18 through descriptive statistics. The results show that 90.4% of the midwives believed in necessity of a plan, 96.2% believed that good services should be provided to mothers, and 97.9%, 85.3% and 93.8% of them believed there is a need for private space, essential facilities and essential equipment for skin contact process; with Cronbach's Alpha of 0.731, 0.551, 0.501, and 0.600 respectively. Most of the midwives believed that enabling factors concerning the successful SSC are effective. We suggest further studies on other enabling factors effective in SSC from the view point of midwives, gynaecologists and caregivers.


In vitro inhibition of Clostridium difficile and Clostridium perfringens by commercial probiotic strains.
Probiotics have gained importance in human and veterinary medicine to prevent and control clostridial enteric disease. Limited information is available on the ability of different probiotic bacteria used in food products to inhibit Clostridium difficile and Clostridium perfringens. The objective of this study was to examine the in vitro inhibitory effects of selected commercial bacterial strains on pathogenic clostridia and their growth characteristics under simulated gastrointestinal conditions. The inhibitory effects of 17 commercial strains of Lactobacillus (n = 16) and Bifidobacterium (n = 1) on the reference strains of C. difficile and C. perfringens were assessed by an agar well diffusion assay and by a broth culture inhibition assay using cell-free supernatant harvested at different growth phases, with and without pH neutralization. To study growth characteristics, probiotic strains were cultivated in different acid and bile environments, and growth in the modified media was compared to growth in standard medium. In the agar well diffusion assay, supernatant obtained from two probiotic strains inhibited the growth of both reference and clinical strains of C. perfringens. This effect as seen when supernatant was assessed with and without pH neutralization. Supernatants obtained from 10 probiotic strains inhibited C. difficile only when supernatant was added without pH neutralization. In the broth culture inhibition assay, growth of C. perfringens and C. difficile was inhibited by supernatant without pH neutralization from 5 and 10 probiotic strains, respectively. All potential probiotic strains were able to grow at pH 4.0 and in the presence of 0.15% and 0.3% bile but none were able to grow or survive at pH 2.0. Altogether five probiotic strains [Lactobacillus plantarum (n = 2), Lactobacillus rhamnosus (n = 2), Bifidobacterium animalis lactis (n = 1)] were shown to inhibit all strains of C. difficile and C. perfringens. The inhibitory effect was probiotic strain-specific. Two strains showed a pH-independent inhibitory effect likely due to production of either antibiotics or bacteriocins inhibiting C. perfringens only. These strains have favourable growth characteristics for use as probiotics and their efficacy as prophylactic or therapeutic measures against clostridial enteric disease should be further evaluated by clinical trials in animals.


Clinical use of ipilimumab for metastatic melanoma in Spain: towards a more consistent approach.
Ipilimumab has been approved in patients with advanced melanoma by different regulatory bodies worldwide, but its use in clinical practice is not fully consistent among oncologists. We have surveyed a representative sample of Spanish medical oncologists on issues related to the use of ipilimumab. The survey was based on the Delphi method, where experts respond anonymously to two rounds of a questionnaire. Questionnaire consisted of 42 statements divided among the following eight categories: Pathology and Diagnosis; Patterns of Response; Parameters affecting Treatment Selection; Patient Profile; Sequencing of Treatment; Definition of Long-Term Survivors; Quality of Life; Concept of Immuno-oncology. The experts were asked to rate each statement on a scale of 1-9, where 1 meant "completely disagree" and 9 meant "completely agree". Thirty-three oncologists responded to both rounds of the survey (62.3 % of total surveyed). On issues related to pathology and diagnosis, patterns of response, and immuno-oncology, the specialists reached a high level of consensus. There was also a high level of agreement, albeit without consensus on assessment of BRAF mutations before deciding on treatment with ipilimumab. However, there was a lower level of agreement on sequencing treatment with BRAF inhibitors and ipilimumab, on predictive factors, on the use of corticosteroids, and on patient quality of life. The disparity in many of these topics suggests that oncologists need more information on certain aspects of ipilimumab treatment. We need to define generally accepted algorithms of treatment, especially with regard to issues that were shown to be controversial or unclear.


Engagement processes in model programs for community reentry from prison for people with serious mental illness.
Linking prisoners with mental illness with treatment following release is critical to preventing recidivism, but little research exists to inform efforts to engage them effectively. This presentation compares the engagement process in two model programs, each representing an evidence-based practice for mental health which has been adapted to the context of prison reentry. One model, Forensic Assertive Community Treatment (FACT), emphasizes a long-term wrap-around approach that seeks to maximize continuity of care by concentrating all services within one interdisciplinary team; the other, Critical Time Intervention (CTI), is a time-limited intervention that promotes linkages to outside services and bolsters natural support systems. To compare engagement practices, we analyze data from two qualitative studies, each conducted in a newly developed treatment program serving prisoners with mental illness being discharged from prisons to urban communities. Findings show that the working relationship in reentry services exhibits unique features and is furthered in both programs by the use of practitioner strategies of engagement, including tangible assistance, methods of interacting with consumers, and encouragement of service use via third parties such as families and parole officers. Nevertheless, each program exhibited distinct cultures and rituals of reentry that were associated with fundamental differences in philosophy and differences in resources available to each program.


Comparison of hospital performance in nonemergency versus emergency colorectal operations at 142 hospitals.
Quality improvement efforts have demonstrated considerable hospital-to-hospital variation in surgical outcomes. However, information about the quality of emergency surgical care is lacking. The objective of this study was to assess whether hospitals have comparable outcomes for emergency and nonemergency operations. Patients undergoing colorectal resections were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) 2005 to 2007 dataset. Logistic regression models for 30-day morbidity and mortality after emergency and nonemergency colorectal resections were constructed. Hospital risk-adjusted outcomes as measured by observed to expected (O/E) ratios, outlier status, and rank-order differences were compared. Of 25,710 nonemergency colorectal resections performed at 142 ACS NSQIP hospitals, 6,138 (23.9%) patients experienced at least 1 complication, and 492 (1.9%) patients died. There were 5,083 emergency colorectal resections; 2,442 (48%) patients experienced at least 1 complication, and 780 (15.3%) patients died. Outcomes for nonemergency versus emergency operations were weakly correlated for morbidity and mortality (Pearson correlation coefficient: 0.28 versus 0.13). Median differences in hospital rankings based on O/E ratios between nonemergency and emergency performance were 30.5 ranks (interquartile range [IQR] 13 to 59) for morbidity and 34 ranks (interquartile ratio 17 to 61) for mortality. Hospitals with favorable outcomes after nonemergency colorectal resections do not necessarily have similar outcomes for emergency operations. Hospitals should specifically examine their performance on emergency surgical procedures to identify quality improvement opportunities and focus quality improvement efforts appropriately.


Chronic Headache Education and Self-Management Study (CHESS): a process evaluation.
The Chronic Headache Education and Self-Management Study (CHESS) multicentre randomised trial evaluated the impact a group education and self-management support intervention with a best usual care plus relaxation control for people living with chronic headache disorders (tension type headaches or chronic migraine, with or without medication overuse headache). Here we report the process evaluation exploring potential explanations for the lack of positive effects from the CHESS intervention. The CHESS trial included 736 (380 intervention: 356 control) people across the Midlands and London UK. We used a mixed methods approach. Our extensive process evaluation looked at context, reach, recruitment, dose delivered, dose received, fidelity and experiences of participating in the trial, and included participants and trial staff. We also looked for evidence in our qualitative data to investigate whether the original causal assumptions underpinning the intervention were realised. The CHESS trial reached out to a large diverse population and recruited a representative sample. Few people with chronic tension type headaches without migraine were identified and recruited. The expected 'dose'of the intervention was delivered to participants and intervention fidelity was high. Attendance ("dose received") fell below expectation, although 261/380 (69%) received at least at least the pre-identified minimum dose. Intervention participants generally enjoyed being in the groups but there was little evidence to support the causal assumptions underpinning the intervention were realised. From a process evaluation perspective despite our extensive data collection and analysis, we do not have a clear understanding of why the trial outcome was negative as the intervention was delivered as planned. However, the lack of evidence that the intervention causal assumptions brought about the planned behaviour change may provide some insight. Our data suggests only modest changes in managing headache behaviours and some disparity in how participants engaged with components of the intervention within the timeframe of the study. Moving forwards, we need a better understanding of how those who live with chronic headache can be helped to manage this disabling condition more effectively over time. ISRCTN79708100 .


Comparative transcriptomic analysis identifies reprogramming and differentiation genes differentially expressed in UiPSCs and ESCs.
Embryonic stem cells (ESCs) technology has garnered worldwide attention for its therapeutic applications in vivo. Researchers have previously shown that non-viral induced pluripotent stem cells (iPSCs) can be generated from urine. As a potential alternative, Urinary iPSCs (UiPSCs) are highly similar to embryonic stem cells (ESCs) in many aspects such as morphology, expression of pluripotency markers and the capacity to develop into three germ layers in vitro and in vivo. However, the degree of gene expression similarity between iPSCs and ESCs has not been completely elucidated. In the present study, we performed a comparative study on the gene expression profile between UiPSCs and ESCs using microarray technology, and identified 19 differentially expressed genes. Furthermore, four genes associated with reprogramming and differentiation including neuronatin (NNAT), piwilike RNA-mediated gene silencing 2 (PIWIL2), early growth response 1 (EGR1) and TATA-box binding protein associated factor 9b (TAF9B) were validated by quantitative real-time PCR (qRT-PCR) assays. Our results indicate that compared with ESCs, UiPSCs demonstrated a different pathway in reprogramming and differentiation preference from ESCs, and can be used as a potential tool in disease modeling, drug discovery and regenerative medicine.


Acute vestibular migraine treatment with noninvasive vagus nerve stimulation.
To report on the benefits of noninvasive vagus nerve stimulation (nVNS) on acute vestibular migraine (VM) treatment. This was a retrospective chart review of patients with VM treated with nVNS in a single tertiary referral center between November 2017 and January 2019. Eighteen patients (16 women) were identified (mean age 45.7 [±14.8] years); 14 were treated for a VM attack and 4 for bothersome interictal dizziness consistent with persistent perceptual postural dizziness (PPPD). Patients graded the severity of vestibular symptoms and headache using an 11-point visual analog scale (VAS; 0 = no symptoms, 10 = worst ever symptoms) before and 15 minutes after nVNS. In those with acute VM, vertigo improved in 13/14 (complete resolution in 2, at least 50% improvement in 5). The mean vertigo intensity before nVNS was 5.2 (±1.6; median 6), and 3.1 (±2.2; median 3) following stimulation; mean reduction in vertigo intensity was 46.9% (±31.5; median 45%). Five experienced headache with the VM attack; all reported improvement following nVNS. Mean headache severity was 6 (±1.4; median 6) prior to treatment and 2.4 (±1.5; median 3) following nVNS; mean reduction in headache intensity was 63.3% (±21.7; median 50). All 4 treated with nVNS for interictal PPPD reported no benefit. Our study provides preliminary evidence that nVNS may provide rapid relief of vertigo and headache in acute VM, and supports further randomized, sham-controlled studies into nVNS in VM. This study provides Class IV evidence that for patients with acute VM, nVNS rapidly relieves vertigo and headache.


Pair bond formation leads to a sustained increase in global cerebral glucose metabolism in monogamous male titi monkeys (Callicebus cupreus).
Social bonds, especially attachment relationships, are crucial to our health and happiness. However, what we know about the neural substrates of these bonds is almost exclusively limited to rodent models and correlational experiments in humans. Here, we used socially monogamous non-human primates, titi monkeys (Callicebus cupreus) to experimentally examine changes in regional and global cerebral glucose metabolism (GCGM) during the formation and maintenance of pair bonds. Baseline positron emission tomography (PET) scans were taken of thirteen unpaired male titi monkeys. Seven males were then experimentally paired with females, scanned and compared, after one week, to six age-matched control males. Five of the six control males were then also paired and scanned after one week. Scans were repeated on all males after four months of pairing. PET scans were coregistered with structural magnetic resonance imaging (MRI), and region of interest (ROI) analysis was carried out. A primary finding was that paired males showed a significant increase in [18F]-fluorodeoxyglucose (FDG) uptake in whole brain following one week of pairing, which is maintained out to four months. Dopaminergic, "motivational" areas and those involved in social behavior showed the greatest change in glucose uptake. In contrast, control areas changed only marginally more than GCGM. These findings confirm the large effects of social bonds on GCGM. They also suggest that more studies should examine how social manipulations affect whole-brain FDG uptake, as opposed to assuming that it does not change across condition.


Comparative effects of levosimendan and dobutamine on right ventricular function in patients with biventricular heart failure.
Severe heart failure represents a major source of morbidity and mortality. Poor right ventricular function is an independent prognostic marker for mortality in patients with chronic heart failure. In this study, levosimendan (L) and dobutamine (D) in patients with severe chronic biventricular failure were compared. Forty consecutive patients, who were judged for inotropic therapy by their primary physicians, with acutely decompensated systolic heart failure and having moderate-to-severe right ventricular dysfunction with right ventricular fractional area change of <or= 24%m were randomized to L and D in a 2:1 fashion. Echocardiographic parameters including tricuspid annular motion and clinical issues were considered. Mean age and sex distribution were not different between the two groups. After the infusion, ejection fraction improved and systolic pulmonary artery pressure decreased significantly in both arms. Longitudinal systolic function of tricuspid annulus improved significantly better in patients with L compared to patients with D (15%+/-12% vs. 2%+/-6% improvement, P<0.001). Furthermore, L improved both 24-h urine output and creatinine, whereas D showed only a small, but significant improvement in urine output without any improvement in the creatinine levels. Levosimendan seems to offer more beneficial effects compared to dobutamine in a specific group of patients with biventricular failure.


Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling.
Acquisition of planar cell polarity (PCP) in epithelia involves intercellular communication, during which cells align their polarity with that of their neighbors. The transmembrane proteins Frizzled (Fz) and Van Gogh (Vang) are essential components of the intercellular communication mechanism, as loss of either strongly perturbs the polarity of neighboring cells. How Fz and Vang communicate polarity information between neighboring cells is poorly understood. The atypical cadherin, Flamingo (Fmi), is implicated in this process, yet whether Fmi acts permissively as a scaffold or instructively as a signal is unclear. Here, we provide evidence that Fmi functions instructively to mediate Fz-Vang intercellular signal relay, recruiting Fz and Vang to opposite sides of cell boundaries. We propose that two functional forms of Fmi, one of which is induced by and physically interacts with Fz, bind each other to create cadherin homodimers that signal bidirectionally and asymmetrically, instructing unequal responses in adjacent cell membranes to establish molecular asymmetry.


Retinal disorders.
The retina represents part of the central nervous system (CNS). After modifying the neural signal, the axon of the last neuron enters the optic nerve and leaves the eye. In most cases of retinal disease leading to visual loss, the diagnosis will be made by an ophthalmologist after examining the ocular fundus. Some retinal disorders, however, might not be detectable at the time of examination. Those patients will be referred to a neurologist for "unexplained visual loss" when suspecting a lesion behind the optic nerve. Moreover, knowledge of potential retinal abnormalities is useful for the neurologist when seeing patients with CNS disease, which can manifest itself also in the retina. This chapter aims to give an overview about retinal disorders causing no or only few retinal abnormalities, those associated with neurological diseases, as well as the most important retinal diseases involving the tissues of the ocular fundus (vitreous body, retina, pigment epithelium, and the choroid). The most frequently used examination techniques and diagnostic tools are described. Tumors, vascular disease, especially diabetic retinopathy, age-related macular degeneration, chorioretinal inflammatory and toxic disorders, paraneoplastic retinopathies, inherited retinal dystrophies, and retinal involvement in CNS disease such as phakomatoses and multiple sclerosis are discussed.


On the fidelity of DNA replication: use of synthetic oligonucleotide-initiated reactions.
The phi X174 fidelity system provides a biological assay for quantitating the accuracy of DNA polymerases. Expansion of this system to cell extracts and DNA replication complexes from eucaryotes has been limited by the presence of nucleases in these preparations. We have overcome these limitations by priming the phi X template with a synthetic oligodeoxynucleotide, with its free 3'-hydroxyl terminus only a short distance from the amber locus that is the site for determining the frequency of misincorporation. In this paper, this modified phi X system is characterized and compared to that using defined natural DNA restriction fragments as primers. The modified system has been applied to studies on the fidelity of DNA synthesis using different forms of purified DNA polymerase-alpha from calf thymus, as well as crude extracts from human lymphocytes.


Downstream effects of a hydroelectric reservoir on aquatic plant assemblages.
Macrophytes were studied downstream of the Rophémel hydroelectric dam on the River Rance (Côtes d'Armor Department, western France) to assess the effects of hydroelectric functioning on river macrophyte communities. We studied ten representative sections of the hydro-peaking channel on five occasions in 1995 and 1996, on a 15-km stretch of river. Floristic surveys were carried out on sections 50 m in length, and genera of macroalgae, species of bryophyta, hydrophytes, and emergent rhizophytes were identified. For the aquatic bryophytes and spermatophytes section of our study, we compared our results with 19th century floristic surveys, before the dam was built. During the vegetative growth period, the hydro-peaking frequency was low. The plant richness was highest near the dam. The macrophyte communities were highly modified according to the distance to the dam. The frequency and magnitude of hydro-peaking was related to the aquatic macrophyte richness in an Intermediate Disturbance Hypothesis position. However, the results of the eco-historical comparison with 19th century floristic surveys point to the original nature of the flora found at the site. Some floral patterns, seen during both periods and at an interval of 133 years, were indicative of the ubiquity of the aquatic flora and of the plants" adaptability. This demonstrates the importance of taking river basin history into account in such biological surveys.


Bonding of glass ceramic and indirect composite to non-aged and aged resin composite.
Since adhesion of the restorative materials to pre-polymerized or aged resin composites presents a challenge to the clinicians, existing restorations are often removed and remade prior to cementation of fixed dental prostheses (FDPs). This study evaluated bond strength of non-aged and aged resin composite to an indirect resin composite and pressed glass ceramic using two resin cements. Disk-shaped specimens (diameter: 3.5, thickness: 3 mm) (N = 160) produced from a microhybrid resin composite (Quadrant Anterior Shine) were randomly divided into eight groups. While half of the specimens were kept dry at 37°C for 24 h, the other half was aged by means of thermocycling (6000 times, 5°C to 55°C). The non-aged and aged resin composites were bonded to a highly filled indirect composite (Estenia) and a pressed glass ceramic (IPS Empress II) using either a photopolymerizing (Variolink Veneer) or a dual-polymerizing (Panavia F2.0) resin cement. While cementation surfaces of both the direct and indirect composite materials were silica coated (30 µm SiO2, CoJet-Sand) and silanized (ESPE-Sil), ceramic surfaces were conditioned with hydrofluoric acid (20 s), neutralized, and silanized prior to cementation. All specimens were cemented under a load of 750 g. Shear force was applied to the adhesive interface in a universal testing machine (1 mm/min). Failure types of the specimens were identified after debonding. Significant effects of aging (p < 0.05), restorative material (p < 0.05), and cement type (p < 0.05) were observed on the bond strength (3-way ANOVA). Interaction terms were also significant (p < 0.05) (Tukey's test). After aging, in terms of bond strength, indirect composite and pressed glass ceramic in combination with both cements showed no significant difference (p > 0.05). Both indirect composite (24.3 ± 5.1 MPa) and glass ceramic in combination with Variolink (22 ± 9 MPa) showed the highest results on non-aged composites, but were not significantly different from one another (p > 0.05). On the aged composites, indirect composite and glass ceramic showed no significant difference in bond strength within each material group (p > 0.05), with both Panavia (17.2 ± 6 and 15 ± 5.5 MPa, respectively) and Variolink (19 ± 8, 12.8 ± 5.3 MPa, respectively), but in all groups, glass ceramic-Variolink on aged composite revealed the lowest results (12.8 ± 5.3 MPa). Among all groups, predominantly cohesive failures were observed in the indirect resin composite substrate (79 out of 80) as opposed to the ceramic (18 out of 80) (p < 0.05) (Chi square). Regardless of the resin cement type, considering the bond values and the failure types, the adhesion quality of indirect composite cemented to non-aged and aged resin composite was superior with both cements compared to that of pressed glass ceramic.


General practitioners' use of internet-based patient materials for partner notification.
To determine if general practitioners (GPs) would use chlamydia resources for partner notification (PN) when the address to a website was printed on positive results. Two surveys (pre-/postintervention) were sent to GPs before half were exposed to the website address on positive chlamydia results. Of 499 eligible GPs, 233 (48%) returned completed preintervention surveys and 173 of 233 GPs (78%) returned postintervention surveys. Partner letters increased from 13% (10/78) to 36% (28/78) (P = 0.0009) and brochures from 33% (26/78) to 54% (42/78) (P = 0.003) among those exposed to the website. There was no significant change among GPs not exposed to the website. GPs who reported practicing PN all of the time did not change but was greater than 93% in all groups. When a website was provided with useful documents on it, GPs were more likely to provide resources for clients to pass onto partners.


Fluorescence analysis of calmodulin mutants containing tryptophan: conformational changes induced by calmodulin-binding peptides from myosin light chain kinase and protein kinase II.
Peptide-induced conformational changes in five isofunctional mutants of calmodulin (CaM), each bearing a single tryptophan residue either at the seventh position of each of the four calcium-binding loops (i.e., amino acids 26, 62, 99, and 135) or in the central helix (amino acid 81) were studied by using fluorescence spectroscopy. The peptides RS20F and RS20CK correspond to CaM-binding amino acid sequence segments of either nonmuscle myosin light chain kinase (nmMLCK) or calmodulin-dependent protein kinase II (CaMPK-II), respectively. Both steady-state and time-resolved fluorescence data were collected from the various peptide-CaM complexes. Steady-state fluorescence intensity measurements indicated that, in the presence of an excess of calcium, both peptides bind to the calmodulin mutants with a 1:1 stoichiometry. The tryptophans located in loops I and IV exhibited red-shifted emission maxima (356 nm), high quantum yields (0.3), and long average lifetimes (6 ns). They responded in a similar manner to peptide binding, by only slight changes in their fluorescence features. In contrast, the fluorescence intensity of the tryptophans in loops II and III decreased markedly, and their fluorescence spectrum was blue-shifted upon peptide binding. Analysis of the tryptophan fluorescence decay of the last mentioned calmodulins supports a model in which the equilibrium between two (Trp-99) or three (Trp-62) states of these tryptophan residues, each characterized by a different lifetime, was altered toward the blue-shifted short lifetime component upon peptide binding. Taken together, these data provide new evidence that both lobes of calmodulin are involved in peptide binding. Both peptides induced similar changes in the fluorescence properties of the tryptophan residues located in the calcium-binding loops, with the exception of calmodulin with Trp-135. For this last mentioned calmodulin, slight differences were observed. Tryptophan in the central helix responded differently to RS20F and RS20CK binding. RS20F binding induced a red-shift in the emission maximum of Trp-81 while RS20CK induced a blue-shift. The quenching rate of Trp-81 by iodide was slightly reduced upon RS20CK binding, while RS20F induced a 2-fold increase. These results provide evidence that the environment of Trp-81 is different in each case and are, therefore, consistent with the hypothesis that the central helix can play a differential role in the recognition of, or response to, CaM-binding structures.


Direct interaction of beta-amyloid with Na,K-ATPase as a putative regulator of the enzyme function.
By maintaining the Na(+) and K(+) transmembrane gradient mammalian Na,K-ATPase acts as a key regulator of neuronal electrotonic properties. Na,K-ATPase has an important role in synaptic transmission and memory formation. Accumulation of beta-amyloid (Aβ) at the early stages of Alzheimer's disease is accompanied by reduction of Na,K-ATPase functional activity. The molecular mechanism behind this phenomenon is not known. Here we show that the monomeric Aβ(1-42) forms a tight (Kd of 3 μM), enthalpy-driven equimolar complex with α1β1 Na,K-ATPase. The complex formation results in dose-dependent inhibition of the enzyme hydrolytic activity. The binding site of Aβ(1-42) is localized in the "gap" between the alpha- and beta-subunits of Na,K-ATPase, disrupting the enzyme functionality by preventing the subunits from shifting towards each other. Interaction of Na,K-ATPase with exogenous Aβ(1-42) leads to a pronounced decrease of the enzyme transport and hydrolytic activity and Src-kinase activation in neuroblastoma cells SH-SY5Y. This interaction allows regulation of Na,K-ATPase activity by short-term increase of the Aβ(1-42) level. However prolonged increase of Aβ(1-42) level under pathological conditions could lead to chronical inhibition of Na,K-ATPase and disruption of neuronal function. Taken together, our data suggest the role of beta-amyloid as a novel physiological regulator of Na,K-ATPase.


Effects of carbon dioxide on the searching behaviour of the root-feeding clover weevil Sitona lepidus (Coleoptera: Curculionidae).
The respiratory emission of CO2 from roots is frequently proposed as an attractant that allows soil-dwelling insects to locate host plant roots, but this role has recently become less certain. CO2 is emitted from many sources other than roots, so does not necessarily indicate the presence of host plants, and because of the high density of roots in the upper soil layers, spatial gradients may not always be perceptible by soil-dwelling insects. The role of CO2 in host location was investigated using the clover root weevil Sitona lepidus Gyllenhall and its host plant white clover (Trifolium repens L.) as a model system. Rhizochamber experiments showed that CO2 concentrations were approximately 1000 ppm around the roots of white clover, but significantly decreased with increasing distance from roots. In behavioural experiments, no evidence was found for any attraction by S. lepidus larvae to point emissions of CO2, regardless of emission rates. Fewer than 15% of larvae were attracted to point emissions of CO2, compared with a control response of 17%. However, fractal analysis of movement paths in constant CO2 concentrations demonstrated that searching by S. lepidus larvae significantly intensified when they experienced CO2 concentrations similar to those found around the roots of white clover (i.e. 1000 ppm). It is suggested that respiratory emissions of CO2 may act as a 'search trigger' for S. lepidus, whereby it induces larvae to search a smaller area more intensively, in order to detect location cues that are more specific to their host plant.


S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model.
Hepatocellular carcinoma (HCC) remains a common cancer worldwide that lacks effective chemoprevention or treatment. Chronic liver disease often leads to impaired hepatic S-adenosylmethionine (SAMe) biosynthesis, and mice with SAMe deficiency develop HCC spontaneously. SAMe is antiapoptotic in normal hepatocytes but proapoptotic in cancerous hepatocytes. The present study investigated SAMe's effectiveness in prevention and treatment of HCC. Two weeks after injecting 2.5 million H4IIE cells into the liver parenchyma of ACI rats, they typically form a 1-cm tumor. When SAMe (150 mg/kg/day) was delivered through continuous intravenous infusion, hepatic SAMe levels reached 0.7 mM (over 10-fold) 24 hours later. This regimen, started 1 day after injecting H4IIE cells and continued for 10 days, was able to reduce tumor establishment and growth. However, if intravenous SAMe was started after HCC had already developed, it was ineffective in reducing tumor growth for 24 days. Although plasma SAMe levels remained elevated, hepatic SAMe levels were minimally increased (30% higher). Chronic SAMe administration led to induction of hepatic methyltransferases, which prevented SAMe accumulation. To see if SAMe's preventive effect on tumor establishment involves angiogenesis, the effect of SAMe on angiogenesis genes was studied. SAMe treatment of H4IIE cells altered the expression of several genes with the net effect of inhibiting angiogenesis. These changes were confirmed at the protein level and functionally in human umbilical vein endothelial cells. SAMe is effective in preventing HCC establishment but ineffective in treating established HCC because of induction of hepatic methyltransferases, which prevents SAMe level to reach high enough to kill liver cancer cells. SAMe's chemopreventive effect may be related to its proapoptotic action and its ability to inhibit angiogenesis.


HIF-1-Dependent IL-6 Activation in Articular Chondrocytes Initiating Synovitis in Femoral Head Ischemic Osteonecrosis.
Ischemic osteonecrosis of the femoral head in children is associated with chronic hip synovitis and increased levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in the synovial fluid due to unknown mechanisms. The purpose of this study was to investigate hypoxia-inducible factor-1 (HIF-1) activation as a molecular mechanism linking the induction of ischemic osteonecrosis to IL-6 production and the initiation of hip synovitis. Ischemic osteonecrosis was surgically induced in the right femoral head of 6 piglets. A histologic score, synovial fluid volume, and IL-6 level were used to assess hip synovitis. IL-6 immunostaining of articular cartilage and synovial tissue was performed as well. To study the role of HIF-1 in IL-6 activation, in vitro experiments using an HIF-1α activator (deferoxamine) and inhibitor (HIF-1 small interfering-RNA [siRNA]) were carried out. Synovial cell responses to hypoxic chondrocyte-conditioned media with and without an IL-6 receptor blocker (tocilizumab) were assessed on the basis of IL-1β and tumor necrosis factor-alpha (TNF-α) gene expressions and with a synovial cell-proliferation assay. Induction of ischemic osteonecrosis produced hip synovitis and increased IL-6 levels in the synovial fluid. Immunostaining and protein analysis demonstrated articular chondrocytes as a source of increased IL-6 production. When articular chondrocytes were cultured under hypoxic conditions, significantly increased HIF-1α and IL-6 expressions were observed. Under hypoxic culture conditions, IL-6 gene expression was significantly increased by HIF-1α activation using deferoxamine and inhibited by HIF-1α inhibition using HIF-1 siRNA. Synovial cells exposed to hypoxic chondrocyte-conditioned medium showed significant increases in IL-1β and TNF-α gene expressions and cell proliferation, which were inhibited by the IL-6 receptor blocker tocilizumab. Induction of ischemic osteonecrosis results in IL-6 production in the articular cartilage through an HIF-1-dependent pathway. IL-6 produced by hypoxic articular chondrocytes stimulates inflammatory cytokine responses in synovial cells, which were significantly decreased by tocilizumab. This study provides new insight into the inherent relationship between the induction of ischemia and the initiation of hip synovitis following ischemic osteonecrosis and suggests a potential therapeutic target in the treatment of the synovitis.


Effect of codon adaptation on codon-level and gene-level translation efficiency in vivo.
There is a significant difference between synonymous codon usage in many organisms, and it is known that codons used more frequently generally showed efficient decoding rate. At the gene level, however, there are conflicting reports on the existence of a correlation between codon adaptation and translation efficiency, even in the same organism. To resolve this issue, we cultured Escherichia coli under conditions designed to maintain constant levels of mRNA and protein and subjected the cells to ribosome profiling (RP) and mRNA-seq analyses. We showed that the RP results correlated more closely with protein levels generated under similar culture conditions than with the mRNA abundance from the mRNA-seq. Our result indicated that RP/mRNA ratio could be used as a measure of translation efficiency at gene level. On the other hand, the RP data showed that codon-specific ribosome density at the decoding site negatively correlated with codon usage, consistent with the hypothesis that preferred codons display lower ribosome densities due to their faster decoding rate. However, highly codon-adapted genes showed higher ribosome densities at the gene level, indicating that the efficiency of translation initiation, rather than higher elongation efficiency of preferred codons, exerted a greater effect on ribosome density and thus translation efficiency. These findings indicate that evolutionary pressure on highly expressed genes influenced both codon bias and translation initiation efficiency and therefore explains contradictory findings that codon usage bias correlates with translation efficiency of native genes, but not with the artificially created gene pool, which was not subjected to evolution pressure.


Posterior cortical atrophy.
Five patients had progressive dementia heralded by disorders of higher visual function. All eventually developed alexia, agraphia, visual agnosia, and components of Balint's, Gerstmann's, and transcortical sensory aphasia syndromes. Memory, insight, and judgment were relatively preserved until late in the course. Predominant parieto-occipital atrophy was demonstrated on both computed tomography and magnetic resonance imaging in two of the patients; posterior circulation was normal by angiography in the three studied. To date, no pathologic specimen is available for study; speculations on the underlying pathologic condition include an atypical clinical variant of Alzheimer's disease, a lobar atrophy analogous to Pick's disease, or some previously unrecognized entity.


Regenerative medicine as applied to solid organ transplantation: current status and future challenges.
In the last two decades, regenerative medicine has shown the potential for "bench-to-bedside" translational research in specific clinical settings. Progress made in cell and stem cell biology, material sciences and tissue engineering enabled researchers to develop cutting-edge technology which has lead to the creation of nonmodular tissue constructs such as skin, bladders, vessels and upper airways. In all cases, autologous cells were seeded on either artificial or natural supporting scaffolds. However, such constructs were implanted without the reconstruction of the vascular supply, and the nutrients and oxygen were supplied by diffusion from adjacent tissues. Engineering of modular organs (namely, organs organized in functioning units referred to as modules and requiring the reconstruction of the vascular supply) is more complex and challenging. Models of functioning hearts and livers have been engineered using "natural tissue" scaffolds and efforts are underway to produce kidneys, pancreata and small intestine. Creation of custom-made bioengineered organs, where the cellular component is exquisitely autologous and have an internal vascular network, will theoretically overcome the two major hurdles in transplantation, namely the shortage of organs and the toxicity deriving from lifelong immunosuppression. This review describes recent advances in the engineering of several key tissues and organs.


Induction and rejoining of DNA double-strand breaks in bladder tumor cells.
The induction and rejoining of radiation-induced double-strand breaks (DSBs) in cells of six bladder tumor cell lines (T24, UM-UC-3, TCC-SUP, RT112, J82, HT1376) were measured using the neutral comet assay. Radiation dose-response curves (0-60 Gy) showed damage (measured as mean tail moment) for five of the cell lines in the same rank order as cell survival (measured over 0-10 Gy), with the least damage in the most radioresistant cell line. Damage induction correlated well with clonogenic survival at high doses (SF10) for all six cell lines. At the clinically relevant dose of 2 Gy, correlation was good for four cell lines but poor for two (TCC-SUP and T24). The rejoining process had a fast and slow component for all cell lines. The rate of these two components of DNA repair did not correlate with cell survival. However, the time taken to reduce the amount of DNA damage to preirradiated control levels correlated positively with cell survival at 10 Gy but not 2 Gy; radioresistant cells rejoined the induced DSBs to preirradiation control levels more quickly than the radiosensitive cells. Although the results show good correlation between SF10 and DSBs for all six cell lines, the lack of correlation with SF2 for TCC-SUP and T24 cells would suggest that a predictive test should be carried out at the clinically relevant dose. At present the neutral comet assay cannot achieve this.


Synergism between Medihoney and rifampicin against methicillin-resistant Staphylococcus aureus (MRSA).
Skin and chronic wound infections caused by highly antibiotic resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) are an increasing and urgent health problem worldwide, particularly with sharp increases in obesity and diabetes. New Zealand manuka honey has potent broad-spectrum antimicrobial activity, has been shown to inhibit the growth of MRSA strains, and bacteria resistant to this honey have not been obtainable in the laboratory. Combinational treatment of chronic wounds with manuka honey and common antibiotics may offer a wide range of advantages including synergistic enhancement of the antibacterial activity, reduction of the effective dose of the antibiotic, and reduction of the risk of antibiotic resistance. The aim of this study was to investigate the effect of Medihoney in combination with the widely used antibiotic rifampicin on S. aureus. Using checkerboard microdilution assays, time-kill curve experiments and agar diffusion assays, we show a synergism between Medihoney and rifampicin against MRSA and clinical isolates of S. aureus. Furthermore, the Medihoney/rifampicin combination stopped the appearance of rifampicin-resistant S. aureus in vitro. Methylglyoxal (MGO), believed to be the major antibacterial compound in manuka honey, did not act synergistically with rifampicin and is therefore not the sole factor responsible for the synergistic effect of manuka honey with rifampicin. Our findings support the idea that a combination of honey and antibiotics may be an effective new antimicrobial therapy for chronic wound infections.


Circulating adiponectin concentrations during the transition from pregnancy to lactation in high-yielding dairy cows: testing the effects of farm, parity, and dietary energy level in large animal numbers.
Dairy cows experience a negative energy balance due to increasing energy demands and insufficient voluntary feed intake in the transition from late pregnancy to early lactation. For supplying sufficient energy toward the conceptus and the mammary gland, insulin sensitivity in peripheral tissues is reduced leading to adipose tissue mobilization. Adiponectin, an insulin-sensitizing adipokine, is presumably related to energy metabolism and could play an important role in these metabolic adaptations. We hypothesize (1) that primiparous cows would differ from pluriparous cows in their circulating adiponectin concentrations during the transition from late pregnancy to early lactation and (2) that feeding different energy levels would affect the adiponectin concentrations during early lactation in dairy cows. For the first hypothesis, we examined 201 primiparous and 456 pluriparous Holstein dairy cows on three experimental farms. Ante partum, primiparous cows had lower adiponectin and greater NEFA concentrations than pluriparous cows, but vice versa post partum. Hence, adiponectin might be involved in the energy partitioning in primiparous cows (conceptus and lactation vs other still growing body tissues) with changing priorities from pregnancy to lactation. For the second hypothesis, 110 primiparous and 558 pluriparous Holstein and Simmental dairy cows in six experimental farms received either roughage with 6.1 or 6.5 MJ NEl/kg dry matter (adjusted with different amounts of wheat straw) ad libitum, combined with either 150 or 250 g concentrates/kg energy corrected milk. Greater amounts of concentrate lead to greater milk yield, but did not affect the blood variables. The higher energy level in the roughage led to greater glucose and IGF-1 but lower adiponectin in pluriparous cows. Further studies are needed to elucidate the mechanisms behind the roughage effect and its metabolic consequences.


Unusual presentation of chromoblastomycosis due to Cladophialophora carrionii in a renal and pancreas transplant recipient patient successfully treated with posaconazole and surgical excision.
Chromoblastomycosis is a chronic, tropical and subtropical, subcutaneous mycosis caused by inoculation of dematiaceous molds. This disease is uncommonly reported in patients who have undergone solid organ transplantation. We describe a case of chromoblastomycosis caused by Cladophialophora carrionii that occurred 7 years after transplantation in a 58-year-old male renal and pancreatic transplant recipient. Diagnosis was based on histopathology and isolation of multiple colonies of the dematiaceous mold in pure culture. Identification was achieved by sequencing of the internal transcribed spacer regions of the rRNA. The patient was successfully treated with posaconazole and surgical excision of a residual lesion.


Cue conditions and wayfinding in older and younger women.
This study examined how varying the salience and complexity of environmental cues affects place learning in older versus younger women. Place learning is a critical cognitive function for wayfinding in new or changed environments that becomes impaired with age in many people. Environments such as nursing homes and assisted living facilities typically have poorly differentiated environments. Environmental modifications that influence how older adults learn places more effectively are not known. It was hypothesized that salient cues (prominent and distinctive) are particularly important to place learning. The Computer-Generated Arena was used to test this hypothesis in 20 healthy older (age 65+) women and 6 healthy younger (ages 18 to 35) women. Analyses of the data showed differences in place learning with respect to cue salience, complexity, and age, with younger women being much more proficient in the place learning task and with the best overall learning in the salient and complex cue conditions.


Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism.
Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.


Aldehyde oxidation in human placenta. Purification and properties of 1-pyrroline-5-carboxylate dehydrogenase.
The human placenta contains a considerable amount of 1-pyrroline-5-carboxylate dehydrogenase (23 +/- 6 micrograms/g; n = 12), about 25% of the concentration present in liver. The enzyme is the only form in placenta that oxidizes short- and medium-chain aldehydes, which facilitates its purification from this organ. It can be purified to homogeneity by successive chromatographies on DEAE-cellulose, 5'-AMP-Sepharose and Sephacryl S-300. From 500 g of tissue, about 2.1 units of enzyme can be obtained with a 12% yield. Placental 1-pyrroline-5-carboxylate dehydrogenase is a dimer of Mr-63,000 subunits. It exhibits a pI of 6.80-6.65, and is specific for 1-pyrroline-5-carboxylate, the cyclic form of glutamate gamma-semialdehyde (Km = 0.17 mM, kcat. = 870 min-1), although it also oxidizes short-chain aliphatic aldehydes such as propionaldehyde (Km = 24 mM, kcat. = 500 min-1). These properties are very close to those of the liver enzyme, indicating a strong similarity between the enzyme forms from both organs. The enzyme is highly sensitive to temperature, showing 50% inhibition after incubation for 0.8 min at 45 degrees C or after 23 min at 25 degrees C. It is irreversibly inhibited by disulfiram, and a molar ratio inhibitor: enzyme of 60:1 produced 50% inhibition after incubation for 10 min. A subcellular-distribution study indicates that the enzyme is located in two compartments: the mitochondria, with 60% of the total activity, and the cytosol, with 40% activity. The physiological role of the enzyme in placental amino acid metabolism is discussed.


Epidemiological evaluation of the multifactorial aetiology of abfractions.
The purpose of this study was to determine risk indicators for the aetiology of abfractions (cervical wedge-shaped defects) on teeth using dental and medical variables obtained in a population-based sample of the cross-sectional epidemiological 'Study of Health in Pomerania' (SHIP). Medical history, dental, and sociodemographic parameters of 2707 representatively selected subjects 20-59 years of age with more than four natural teeth were checked for associations with the occurrence of abfractions using a two-level logistic regression model on a tooth and a subject level. The estimated prevalence of developing abfractions generally increased with age. The following independent variables were associated with the occurrence of abfractions: buccal recession of the gingiva, odds ratio (OR) = 6.7; occlusal wear facets of scores 1, 2 and 3, OR = 1.5, 1.9, 1.9; tilted teeth, OR = 1.4; inlays, OR = 1.6; toothbrushing behaviour, OR = 1.9 to 2.0 (two and three times a day versus once a day). First premolars had the highest estimated risk for developing abfractions, followed by the second premolars. Maxillary and mandibular teeth behaved similarly in terms of abfractions, with the exception of mandibular canines, which had a much lower estimated risk of incurring abfractions than did maxillary canines. The results of this analysis indicated that abfractions are associated with occlusal factors, like occlusal wear, inlay restorations, altered tooth position and tooth brushing behaviour. This study delivers further evidence for a multifactorial aetiology of abfractions.


A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1.
Phospholipase C-gamma (PLC-gamma) is a substrate of the fibroblast growth factor receptor (FGFR; encoded by the flg gene) and other receptors with tyrosine kinase activity. It has been demonstrated that the src homology region 2 (SH2 domain) of PLC-gamma and of other signalling molecules such as GTPase-activating protein and phosphatidylinositol 3-kinase-associated p85 direct their binding toward tyrosine-autophosphorylated regions of the epidermal growth factor or platelet-derived growth factor receptor. In this report, we describe the identification of Tyr-766 as an autophosphorylation site of flg-encoded FGFR by direct sequencing of a tyrosine-phosphorylated tryptic peptide isolated from the cytoplasmic domain of FGFR expressed in Escherichia coli. The same phosphopeptide was found in wild-type FGFR phosphorylated either in vitro or in living cells. Like other growth factor receptors, tyrosine-phosphorylated wild-type FGFR or its cytoplasmic domain becomes associated with intact PLC-gamma or with a fusion protein containing the SH2 domain of PLC-gamma. To delineate the site of association, we have examined the capacity of a 28-amino-acid tryptic peptide containing phosphorylated Tyr-766 to bind to various constructs containing SH2 and other domains of PLC-gamma. It is demonstrated that the tyrosine-phosphorylated peptide binds specifically to the SH2 domain but not to the SH3 domain or other regions of PLC-gamma. Hence, Tyr-766 and its flanking sequences represent a major binding site in FGFR for PLC-gamma. Alignment of the amino acid sequences surrounding Tyr-766 with corresponding regions of other FGFRs revealed conserved tyrosine residues in all known members of the FGFR family. We propose that homologous tyrosine-phosphorylated regions in other FGFRs also function as binding sites for PLC-gamma and therefore are involved in coupling to phosphatidylinositol breakdown.


Differences in frequency of ERG oncoprotein expression between index tumors of Caucasian and African American patients with prostate cancer.
To systematically evaluate the ETS-related gene (ERG) alterations in the multifocal tumor context using whole-mount prostatectomy specimens from African and Caucasian American patients matched for age, pathologic grade and stage. Oncogenic activation of the ERG is the most common early genomic alteration in patients with prostate cancer (CaP) in Western countries. However, ERG alterations have not been systematically examined in African American patients with a known greater risk of CaP incidence and mortality. ERG oncoprotein expression was analyzed in 91 Caucasian and 91 African American patients with CaP, who were matched for age, Gleason score, and pathologic stage. A unique aspect of the present study was the evaluation of ERG in whole-mount prostatectomy sections, minimizing sampling bias and allowing the careful assessment of the ERG in the multifocal tumor context of CaP. The frequency of ERG-positive prostate tumors was significantly greater among Caucasian Americans than among African Americans when assessed in all tumor foci (41.9% vs 23.9%, P < .0001). A markedly greater frequency of ERG oncoprotein expression was noted between the index tumors of the Caucasian Americans (63.3%) and those of the African Americans (28.6%). Also, in the African American patients, the higher grade index tumors were predominantly ERG negative. ERG typing of CaP established a major difference between the index tumors of Caucasian and African American patients. ERG-negative index tumors might indicate a less favorable outcome for African American patients. The results of the present study underscore that typing of CaP for the ERG could enhance our understanding of the biologic differences between the examined ethnic groups.


Long-term maternal effect on offspring immune response in song sparrows Melospiza melodia.
Knowledge of the causes of variation in host immunity to parasitic infection and the time-scales over which variation persists, is integral to predicting the evolutionary and epidemiological consequences of host-parasite interactions. It is clear that offspring immunity can be influenced by parental immune experience, for example, reflecting transfer of antibodies from mothers to young offspring. However, it is less clear whether such parental effects persist or have functional consequences over longer time-scales, linking a parent's previous immune experience to future immune responsiveness in fully grown offspring. We used free-living song sparrows (Melospiza melodia) to quantify long-term effects of parental immune experience on offspring immune response. We experimentally vaccinated parents with a novel antigen and tested whether parental vaccination influenced the humoral antibody response mounted by fully grown offspring hatched the following year. Parental vaccination did not influence offspring baseline antibody titres. However, offspring of vaccinated mothers mounted substantially stronger antibody responses than offspring of unvaccinated mothers. Antibody responses did not differ between offspring of vaccinated and unvaccinated fathers. These data demonstrate substantial long-term effects of maternal immune experience on the humoral immune response of fully grown offspring in free-living birds.


Deaf Individuals Show a Leftward Bias in Numerical Bisection.
Consistent evidence suggests that deaf individuals conceive of numerical magnitude as a left-to-right-oriented mental number line, as typically observed in hearing individuals. When accessing this spatial representation of numbers, normally hearing individuals typically show an attentional bias to the left (pseudoneglect), resembling the attentional bias they show in physical space. Deaf individuals do not show pseudoneglect in representing external space, as assessed by a visual line bisection task. However, whether deaf individuals show attentional biases in representing numerical space has never been investigated before. Here we instructed groups of deaf and hearing individuals to quickly estimate (without calculating) the midpoint of a series of numerical intervals presented in ascending and descending order. Both hearing and deaf individuals were significantly biased toward lower numbers (i.e., the leftward side of the mental number line) in their estimations. Nonetheless, the underestimation bias was smaller in deaf individuals than in the hearing when bisecting pairs of numbers given in descending order. This result may depend on the use of different strategies by deaf and hearing participants or a less pronounced lateralization of deaf individuals in the control of spatial attention.


Simulation-Based Mastery Learning Improves Medical Student Performance and Retention of Core Clinical Skills.
Simulation-based mastery learning (SBML) improves procedural skills among medical trainees. We employed an SBML method that includes an asynchronous knowledge acquisition portion and a hands-on skill acquisition portion with simulation to assess senior medical student performance and retention of the following 6 core clinical skills: (a) ultrasound-guided peripheral intravenous placement, (b) basic skin laceration repair, (c) chest compressions, (d) bag-valve mask ventilation, (e) defibrillator management, and (f) code leadership. Seven emergency medicine (EM) faculty members developed curricula, created checklists, and set minimum passing standards (MPSs) to test mastery of the 6 skills. One hundred thirty-five students on an EM clerkship were pretested on all 6 skills, viewed online videos asynchronously followed by a multiple choice computer-based skill-related quiz, received one-on-one hands-on skill training using deliberate practice with feedback, and were posttested until MPS was met. We compared pretest and posttest performance. We also retested, unannounced, a convenience sample (36%) of students from 1 to 9 months postintervention to assess skill retention. All students passed each quiz. The percentage of students who reached each MPS increased significantly (P < 0.001) from pretest to posttest for all 6 clinical skills. Ninety-eight percent of the students scored at or above the MPS when retested 1 to 9 months later. There was no significant decrease in mean score for any of the 6 skills between posttest and retention testing. Simulation-based mastery learning using a substantial asynchronous component is an effective way for senior medical students to learn and retain EM clinical skills. This method can be adapted to other skill training necessary for residency readiness.


Prevalence of human coronaviruses in adults with acute respiratory tract infections in Beijing, China.
Human coronaviruses (HCoVs) are a common etiological agent of acute respiratory tract infections. HCoV infections, especially those caused by the two HCoVs identified most recently, NL63 and HKU-1, have not been characterized fully. To evaluate the prevalence and clinical presentations of HKU1 and NL63 in adults with acute respiratory tract infections, an investigation of HCoV infections in Beijing, China from 2005 to 2009 was performed by using reverse transcriptase PCR assays and sequencing analysis. Among 8,396 respiratory specimens studied, 87 (1%) clinical samples were positive for HCoVs, of which 50 samples (0.6% of the total) were positive for HCoV-OC43, 15 (0.2%) for HCoV-229E, 14 (0.2%) for HCoV-HKU1, and 8 (0.1%) for HCoV-NL63. The prevalence of HCoV infection in adults exhibited distinct seasonal fluctuations during the study period. In addition, patients positive for HCoV-229E infections were more likely to be co-infected with other respiratory viruses. Enterovirus, rhinovirus, and parainfluenza virus type 3 were the most common viruses found in patients with HCoV infections. The demographic and clinical data present in this study of HCoV infections in adults with acute respiratory tract infections should improve our understanding of the pathogenesis of HCoVs.


Oral contraceptives and liver cancer. Results of the Multicentre International Liver Tumor Study (MILTS).
Many, but not all, previous epidemiological studies indicated a greater risk of hepatocellular cancer (HCC) in women who have used combined oral contraceptives for a long period of time, but no one has analyzed this risk based upon use of different formulations. It was decided to analyze specifically the risk of OC containing cyproterone acetate (CPA) after toxicological experiments in animals found hints for a potential genotoxicity. This report describes the risk associated with ever having used combined oral contraceptives (OC) among 317 cases of primary hepatocellular cancer (HCC) in women under age 65, compared with 1060 age-matched hospital and 719 population controls in a case-control study, which was conducted in six European countries. The adjusted odds ratio (unconditional logistic regression) for ever having used any OC was found to be 0.75 (0.54 to 1.03) when all cases were compared with all controls, and compared to hospital and population controls separately: 1.13 (0.86 to 1.48) and 0.78 (0.59 to 1.03), respectively. The adjusted odds ratios for OC containing all progestins of the CPA group were 0.89 (0.49 to 1.61); and 0.89 (0.37 to 2.18) for OC containing only CPA. There was no increase in risk for HCC with increasing duration of OC use among the different groups of OCs in the total group of cases with pooled controls. The risk estimates were not related to time since first or last use of any of the types of OCs considered. The most important risk factors for HCC were confirmed as a prior history of hepatitis B and C (adjusted odds ratio 3.1 (2.2; 4.3) and 37.9 (20.2; 70.9) for HBV and HCV, respectively). In the small subgroup of HCC cases without liver cirrhosis and with negative serology for HBV and HCV, there was evidence of an association with duration of OC use. No such trend was observed for the CPA group of OCs. Altogether, there is no evidence for an increased risk of HCC associated with CPA or CPA-like OCs. Oral contraceptives in the aggregate may enhance the risk of liver carcinomas not associated with HBV or HCV infection, but if so, this is an extremely rare adverse effect of their use.


An Exploration of Deep-Learning Based Phenotypic Analysis to Detect Spike Regions in Field Conditions for UK Bread Wheat.
Wheat is one of the major crops in the world, with a global demand expected to reach 850 million tons by 2050 that is clearly outpacing current supply. The continual pressure to sustain wheat yield due to the world's growing population under fluctuating climate conditions requires breeders to increase yield and yield stability across environments. We are working to integrate deep learning into field-based phenotypic analysis to assist breeders in this endeavour. We have utilised wheat images collected by distributed CropQuant phenotyping workstations deployed for multiyear field experiments of UK bread wheat varieties. Based on these image series, we have developed a deep-learning based analysis pipeline to segment spike regions from complicated backgrounds. As a first step towards robust measurement of key yield traits in the field, we present a promising approach that employ Fully Convolutional Network (FCN) to perform semantic segmentation of images to segment wheat spike regions. We also demonstrate the benefits of transfer learning through the use of parameters obtained from other image datasets. We found that the FCN architecture had achieved a Mean classification Accuracy (MA) >82% on validation data and >76% on test data and Mean Intersection over Union value (MIoU) >73% on validation data and and >64% on test datasets. Through this phenomics research, we trust our attempt is likely to form a sound foundation for extracting key yield-related traits such as spikes per unit area and spikelet number per spike, which can be used to assist yield-focused wheat breeding objectives in near future.


Specific and covalent targeting of conjugating and deconjugating enzymes of ubiquitin-like proteins.
Modification of proteins by ubiquitin (Ub)-like proteins (UBLs) plays an important role in many cellular processes, including cell cycle progression, nuclear transport, and autophagy. Protein modification occurs via UBL-conjugating and -deconjugating enzymes, which presumably exert a regulatory function by determining the conjugation status of the substrate proteins. To target and identify UBL-modifying enzymes, we produced Nedd8, ISG15, and SUMO-1 in Escherichia coli and equipped them with a C-terminal electrophilic trap (vinyl sulfone [VS]) via an intein-based method. These C-terminally modified UBL probes reacted with purified UBL-activating (E1), -conjugating (E2), and -deconjugating enzymes in a covalent fashion. Modified UBLs were radioiodinated and incubated with cell lysates prepared from mouse cell lines and tissues to allow visualization of polypeptides reactive with individual UBL probes. The cell type- and tissue-specific labeling patterns observed for the UBL probes reflect distinct expression profiles of active enzymes, indicating tissue-specific functions of UBLs. We identify Ub C-terminal hydrolase L1 (UCH-L1) and DEN1/NEDP1/SENP8, in addition to UCH-L3, as proteases with specificity for Nedd8. The Ub-specific protease isopeptidase T/USP5 is shown to react with ISG15-VS. Furthermore, we demonstrate that the desumoylation enzyme SuPr-1 can be modified by SUMO-1-VS, a modification that is dependent on the SuPr-1 active-site cysteine. The UBL probes described here will be valuable tools for the further characterization of the enzymatic pathways that govern modification by UBLs.


Aggregation in Polysphondylium.
Dense aggregating fields of P. violaceum and P. pallidum exhibit propagated waves which may be analogous to those seen in Dictyostelium discoideum. As in D. discoideum the wave velocity is determined by an intracellular delay between stimulation and response, rather than by the diffusion coefficient of the acrasin. The frequency of the propagated wave overlaps that of aggregating D. discoideum, so that absence of coaggregation reported by Raper & Thom is unlikely to be based on specificity of the propagated wave parameters, but rather on a difference in the chemical acrasin itself, as argued on independent evidence by Bonner. Despite this difference in the chemical nature of the acrasin, the presence of propagated waves in Polysphondylium with frequencies similar to those in D. discoideum, taken together with evidence for a diffusible acrasin, suggests that the mechanism of aggregation is substantially the same in both genera.


Atomistic electrodynamics simulations of bare and ligand-coated nanoparticles in the quantum size regime.
The optical properties of metallic nanoparticles with nanometre dimensions exhibit features that cannot be described by classical electrodynamics. In this quantum size regime, the near-field properties are significantly modified and depend strongly on the geometric arrangements. However, simulating realistically sized systems while retaining the atomistic description remains computationally intractable for fully quantum mechanical approaches. Here we introduce an atomistic electrodynamics model where the traditional description of nanoparticles in terms of a macroscopic homogenous dielectric constant is replaced by an atomic representation with dielectric properties that depend on the local chemical environment. This model provides a unified description of bare and ligand-coated nanoparticles, as well as strongly interacting nanoparticle dimer systems. The non-local screening owing to an inhomogeneous ligand layer is shown to drastically modify the near-field properties. This will be important to consider in optimization of plasmonic nanostructures for near-field spectroscopy and sensing applications.


Aspergillus osteomyelitis: epidemiology, clinical manifestations, management, and outcome.
The epidemiology, pathogenesis, diagnosis, and management of Aspergillus osteomyelitis are not well understood. Protocol-defined cases of Aspergillus osteomyelitis published in the English literature were reviewed for comorbidities, microbiology, mechanisms of infection, clinical manifestations, radiological findings, inflammatory biomarkers, antifungal therapy, and outcome. Among 180 evaluable patients, 127 (71%) were males. Possible predisposing medical conditions in 103 (57%) included pharmacological immunosuppression, primary immunodeficiency, and neutropenia. Seventy-three others (41%) had prior open fracture, trauma or surgery. Eighty (44%) followed a hematogenous mechanism, 58 (32%) contiguous infections, and 42 (23%) direct inoculation. Aspergillus osteomyelitis was the first manifestation of aspergillosis in 77%. Pain and tenderness were present in 80%. The most frequently infected sites were vertebrae (46%), cranium (23%), ribs (16%), and long bones (13%). Patients with vertebral Aspergillus osteomyelitis had more previous orthopedic surgery (19% vs 0%; P = 0.02), while those with cranial osteomyelitis had more diabetes mellitus (32% vs 8%; P = 0.002) and prior head/neck surgery (12% vs 0%; P = 0.02). Radiologic findings included osteolysis, soft-tissue extension, and uptake on T2-weighted images. Vertebral body Aspergillus osteomyelitis was complicated by spinal-cord compression in 47% and neurological deficits in 41%. Forty-four patients (24%) received only antifungal therapy, while 121 (67%) were managed with surgery and antifungal therapy. Overall mortality was 25%. Median duration of therapy was 90 days (range, 10-772 days). There were fewer relapses in patients managed with surgery plus antifungal therapy in comparison to those managed with antifungal therapy alone (8% vs 30%; P = 0.006). Aspergillus osteomyelitis is a debilitating infection affecting both immunocompromised and immunocompetent patients. The most common sites are vertebrae, ribs, and cranium. Based upon this comprehensive review, management of Aspergillus osteomyelitis optimally includes antifungal therapy and selective surgery to avoid relapse and to achieve a complete response.


Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group.
Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the second and third European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as 'normal', 'suggestive of', or 'diagnostic of' MDS. An FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis, if at least two abnormalities are evidenced. The working group is dedicated to initiate further studies to establish robust diagnostic and prognostic FC panels in MDS. An ultimate goal is to refine and improve diagnosis and prognostic scoring systems. Finally, the working group stresses that FC should be part of an integrated diagnosis rather than a separate technique.


Na+,K(+)-ATPase expression in maleic-acid-induced Fanconi syndrome in rats.
Na+,K(+)-ATPase activity and its alpha 1 subunit protein and mRNA in kidney cortex were monitored in rats developing Fanconi syndrome after the administration of maleate. Na+,K(+)-ATPase activity was significantly lower than in saline-injected controls, although this was partially mediated by a general, non-specific decrease in the cortex protein content. 2. The low activity of the sodium pump correlated with low abundance of alpha 1 subunit mRNA and protein levels. Hsp60 protein levels were also decreased in kidney cortex from maleate-treated rats. 3. Kidney cortex brush-border membrane vesicles from maleate-treated rats showed a marked decrease in Na(+)-dependent alanine and glucose transport, which was not dependent on the Na(+)-transmembrane gradient itself, a finding which is consistent with a more stable effect at the plasma membrane level. 4. The effect of maleate may be partially non-specific and involve a great variety of proteins, but seems to be restricted to selected tissues because alpha 1 subunit Na+,K(+)-ATPase and hsp60 protein amounts were not significantly modified in livers from rats developing Fanconi syndrome. 5. These results show that maleate administration induces a low activity of selected concentrative transport systems and a decrease in Na+,K(+)-ATPase activity and expression. The combination of both effects may explain the increased excretion of most organic solutes present in rats developing Fanconi syndrome.


Volatile organic compounds in tartu office buildings.
The volatile organic compounds (VOCs) that are emitted by many materials and activities are common indoor air pollutants. It is believed that VOCs might contribute to many adverse health effects, but there is scant evidence to support this. The difficulties involved in assessing the effects of VOCs involve both the chemistry of indoor air and the physiological responses in varying physical conditions. Inconsistent results of experimental studies and difficulties in performing longitudinal epidemiological studies have led to the conclusion that only higher concentrations (in the range of 1-25mg/m3) of VOCs in indoor air should be considered to relate to higher health risks. This pilot study provides evidence that there is no such risk in Estonian offices.


Evaluation of the morphological features of the uterine tubes during postnatal development in West African Dwarf goats (Capra hircus).
The objective of this study was to highlight the postnatal development of the uterine tubes of the West African Dwarf goat from birth to 28 weeks of age by gross examination and light microscopy. There was a caudal migration of the paired uterine tubes from behind the paired kidneys at birth to the pelvic inlet at week 8 of age. Each uterine tube exhibited three segments namely; infundibulum, ampulla and isthmus. A marked flexure, the utero-tubal junction, was the point at which the uterine tubes joined the uterine horns. The length and absolute weight of the uterine tubes increased from 4.95 ± 0.28 cm and 0.02 ± 0.01 g at birth to 14.98 ± 2.79 cm and 0.22 ± 0.03 g at week 28 of age, respectively. The mucosa of the infundibulum and the ampulla showed long, branched and anastomosing primary, secondary and tertiary mucosal folds which decreased in height towards the isthmus. The mucosal folds within the isthmus were short and lacked the anastomosing pattern. The epithelia of all three segments were pseudostratified columnar. Numerous secretory blebs and extruded nuclei became apparent from week 16 of age. The thickness of the tunica muscularis varied with the segments.


An update on the association of vitamin D deficiency with common infectious diseases.
Vitamin D plays an important role in modulating the immune response to infections. Deficiency of vitamin D is a common condition, affecting both the general population and patients in health care facilities. Over the last decade, an increasing body of evidence has shown an association between vitamin D deficiency and an increased risk for acquiring several infectious diseases, as well as poorer outcomes in vitamin D deficient patients with infections. This review details recent developments in understanding the role of vitamin D in immunity, the antibacterial actions of vitamin D, the association between vitamin D deficiency and common infections (like sepsis, pneumonia, influenza, methicillin-resistant Staphylococcus aureus, human immunodeficiency virus type-1 (HIV), and hepatitis C virus (HCV)), potential therapeutic implications for vitamin D replacement, and future research directions.


A qualitative study of the pre-operative preparation of children, young people and their parents' for planned continence surgery: experiences and expectations.
The aim of this study is to explore children's, young people's and parents' pre-operative experiences of continent stoma formation. Current research investigating continent stoma surgery focuses on surgical outcomes including complication rates, adherence to management regimes, self-management practices and levels of continence achieved. Despite reports of pre-operative anxiety in families undergoing continent stoma surgery, there has been a lack of research exploring pre-operative experiences, information needs or decision-making processes in this group. A qualitative study. Forty-nine semi-structured interviews were conducted with 17 children, young people and their parents. Data were collected at key points in the surgical process that aimed to represent a longitudinal perspective of continent stoma formation. The interviews suggested that children's, young people's and parents' information needs in relation to the long-term implications of surgery and for their day-to-day lives were not being adequately met. The preparation process was described as being positively influenced by contact with a nurse specialist, being given time to make the decision and having access to different sources of information. Decisions regarding life-long planned surgery can be challenging. The individual involvement and information needs of children, young people and their parents need to be recognised during pre-operative preparation. Health professionals need to discuss the holistic implications of continent stoma surgery and provide families with the time and opportunity to consider surgery and access relevant sources of information pre-operatively.


Effect of sampling rates on the quantification of forces, durations, and rates of loading of simulated side posture high-velocity, low-amplitude lumbar spine manipulation.
Quantification of chiropractic high-velocity, low-amplitude spinal manipulation (HVLA-SM) may require biomechanical equipment capable of sampling data at high rates. However, there are few studies reported in the literature regarding the minimal sampling rate required to record the HVLA-SM force-time profile data accurately and precisely. The purpose of this study was to investigate the effect of different sampling rates on the quantification of forces, durations, and rates of loading of simulated side posture lumbar spine HVLA-SM delivered by doctors of chiropractic. Five doctors of chiropractic (DCs) and 5 asymptomatic participants were recruited for this study. Force-time profiles were recorded during (i) 52 simulated HVLA-SM thrusts to a force transducer placed on a force plate by 2 DCs and (ii) 12 lumbar side posture HVLA-SM on 5 participants by 3 DCs. Data sampling rate of the force plate remained the same at 1000 Hz, whereas the sampling rate of the force transducer varied at 50, 100, 200, and 500 Hz. The data were reduced using custom-written MATLAB (Mathworks, Inc, Natick, MA) and MathCad (version 15; Parametric Technologies, Natick, MA) programs and analyzed descriptively. The average differences in the computed durations and rates of loading are smaller than 5% between 50 and 1000 Hz sampling rates. The differences in the computed preloads and peak loads are smaller than 3%. The small differences observed in the characteristics of force-time profiles of simulated manual HVLA-SM thrusts measured using various sampling rates suggest that a sampling rate as low as 50 to 100 Hz may be sufficient. The results are applicable to the manipulation performed in this study: manual side posture lumbar spine HVLA-SM.


High-fidelity spatially resolved multiphoton counting for quantum imaging applications.
We present a method for spatially resolved multiphoton counting based on an intensified camera with the retrieval of multimode photon statistics fully accounting for nonlinearities in the detection process. The scheme relies on one-time quantum tomographic calibration of the detector. Faithful, high-fidelity reconstruction of single- and two-mode statistics of multiphoton states is demonstrated for coherent states and their statistical mixtures. The results consistently exhibit classical values of the Mandel parameter and the noise reduction factor in contrast to raw statistics of camera photo-events. Detector operation is reliable for illumination levels up to the average of one detected photon per an event area-substantially higher than in previous approaches to characterize quantum statistical properties of light with spatial resolution.


Training software using virtual-reality technology and pre-calculated effective dose data.
This paper describes the development of a software package, called VR Dose Simulator, which aims to provide interactive radiation safety and ALARA training to radiation workers using virtual-reality (VR) simulations. Combined with a pre-calculated effective dose equivalent (EDE) database, a virtual radiation environment was constructed in VR authoring software, EON Studio, using 3-D models of a real nuclear power plant building. Models of avatars representing two workers were adopted with arms and legs of the avatar being controlled in the software to simulate walking and other postures. Collision detection algorithms were developed for various parts of the 3-D power plant building and avatars to confine the avatars to certain regions of the virtual environment. Ten different camera viewpoints were assigned to conveniently cover the entire virtual scenery in different viewing angles. A user can control the avatar to carry out radiological engineering tasks using two modes of avatar navigation. A user can also specify two types of radiation source: Cs and Co. The location of the avatar inside the virtual environment during the course of the avatar's movement is linked to the EDE database. The accumulative dose is calculated and displayed on the screen in real-time. Based on the final accumulated dose and the completion status of all virtual tasks, a score is given to evaluate the performance of the user. The paper concludes that VR-based simulation technologies are interactive and engaging, thus potentially useful in improving the quality of radiation safety training. The paper also summarizes several challenges: more streamlined data conversion, realistic avatar movement and posture, more intuitive implementation of the data communication between EON Studio and VB.NET, and more versatile utilization of EDE data such as a source near the body, etc., all of which needs to be addressed in future efforts to develop this type of software.


Curcumin improves bone microarchitecture and enhances mineral density in APP/PS1 transgenic mice.
Alzheimer's disease and osteoporosis are often observed to co-occur in clinical practice. The present study aimed to evaluate the bone microarchitecture and bone mineral density (BMD) of the proximal tibia in APP/PS1 transgenic mice by micro-computed tomography (micro-CT), and to search for evidence that curcumin can be used to reduce bone mineral losses and treat osteoporosis after senile dementia in these transgenic mice. Three-month-old female mice were divided into the following groups (n=9 per group): wild-type mice (WT group); APP/PS1 transgenic mice (APP group); and APP/PS1 transgenic mice with curcumin treatment (APP+Cur group). Between 9 and 12 months of age, the APP+Cur group were administered curcumin orally (600ppm). CT scans of the proximal tibia were taken at 6, 9 and 12 months. At 6 months, there were little differences in the structural parameters. At 9 months, the APP groups displayed loss of bone volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and connectivity density (Conn.D) and increases in trabecular separation (Tb.Sp) and geometric degree of anisotropy (DA) (P<0.05 or P<0.01), with significant changes in the BMD parameters. At 12 months, curcumin treatment led to constant increases in the trabecular bone mass of the metaphysis and clearly improved the BMD. By the same time, we measured the TNF-α and IL-6 in the serum among the different groups at 6, 9 and 12 months by enzyme-linked immunoassay(ELISA). These results suggest that APP/PS1 transgenic mice are susceptible to osteoporosis, and that curcumin can prevent further deterioration of the bone structure and produce beneficial changes in bone turnover. The change of inflammation cytokine, including TNF-α and IL-6, may play an important role in the mechanisms of action of curcumin, but the detail mechanism remains unknown.