Safety assessment of titanium dioxide (E171) as a food additive.
The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO2 nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension < 100 nm. In addition, the Panel noted that constituent particles < 30 nm amounted to less than 1% of particles by number. The Panel therefore considered that studies with TiO2 NPs < 30 nm were of limited relevance to the safety assessment of E 171. The Panel concluded that although gastrointestinal absorption of TiO2 particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E 171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO2 NPs (> 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E 171 and potential neurotoxicity with TiO2 NPs, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO2 particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico-chemical properties of TiO2 particles and the outcome of either in vitro or in vivo genotoxicity assays. A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO2 particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut-off value for TiO2 particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2 NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive.


Differential responses of emergent intertidal coral reef fauna to a large-scale El-Niño southern oscillation event: sponge and coral resilience.
There is a paucity of information on the impacts of the 1997-8 El Niño event and subsequent climatic episodes on emergent intertidal coral reef assemblages. Given the environmental variability intertidal reefs experience, such reefs may potentially be more resilient to climatic events and provide important insights into the adaptation of reef fauna to future ocean warming. Here we report the results of a 17-year (1995-2011) biodiversity survey of four emergent coral reef ecosystems in Bahia, Brazil, to assess the impact of a major El Niño event on the reef fauna, and determine any subsequent recovery. The densities of two species of coral, Favia gravida and Siderastrea stellata, did not vary significantly across the survey period, indicating a high degree of tolerance to the El Niño associated stress. However, there were marked decreases in the diversity of other taxa. Molluscs, bryozoans and ascidians suffered severe declines in diversity and abundance and had not recovered to pre-El Niño levels by the end of the study. Echinoderms were reduced to a single species in 1999, Echinometra lucunter, although diversity levels had recovered by 2002. Sponge assemblages were not impacted by the 1997-8 event and their densities had increased by the study end. Multivariate analysis indicated that a stable invertebrate community had re-established on the reefs after the El Niño event, but it has a different overall composition to the pre-El Niño community. It is unclear if community recovery will continue given more time, but our study highlights that any increase in the frequency of large-scale climatic events to more than one a decade is likely to result in a persistent lower-diversity state. Our results also suggest some coral and sponge species are particularly resilient to the El Niño-associated stress and therefore represent suitable models to investigate temperature adaptation in reef organisms.


Three Types of Adverse Childhood Experiences, and Alcohol and Drug Dependence Among Adults: An Investigation Using Population-Based Data.
There are several gaps in the literature on the link between adverse childhood experiences (ACEs) and substance use, including the impact of less direct forms of abuse, such as witnessing domestic violence, and the role of gender as a moderator of the relationship. To estimate associations between three types of ACEs (sexual abuse, physical abuse, and exposure to parental domestic violence), when mutually adjusted, and two substance dependence outcomes (alcohol and drug dependence), while considering the potential moderating role of gender and the effects of a range of potential explanatory factors. Secondary analysis of the nationally representative Canadian Community Health Survey-Mental Health (2012) using logistic regression (n = 21,554). A series of models were tested separately for each outcome, including ACEs, gender, race, and age. First, gender interactions were tested. Next, potential explanatory factors were entered into the models and the extent of attenuation was noted. These factors included: depression, anxiety, smoking, pain, insomnia, social support, and socioeconomic status All three ACEs are associated with significantly higher odds of alcohol and drug dependence, even when controlling for all factors simultaneously; however, no strong evidence for gender interactions was found. In the fully adjusted model, odds ratios for drug dependence vary from 2.52 (sexual abuse) to 1.34 (exposure to domestic violence). The comparable range for alcohol dependence is 2.13 (physical abuse) to 1.49 (exposure to domestic violence). Three types of ACEs, including direct and indirect forms of violence, are independently related to lifetime drug and alcohol dependence among adult Canadians.


Childhood obesity and school absenteeism: a systematic review and meta-analysis.
Regular school attendance is a key determinant of student's academic achievement and psychosocial development. Obesity may affect children's school attendance through its detrimental impact on their physical and mental health. A literature search was conducted in the PubMed, Web of Science and Cochrane Library for articles published until April 2017 that examined the relationship between unhealthy body weight and school absenteeism among children and adolescents. Thirteen studies total (10 cross-sectional and three longitudinal) conducted in seven countries were identified. The mean and median sample sizes were 24,861 and 3,113, respectively. Ten studies objectively measured children's height and weight, and three were based on parents' self-report. Four studies measured absenteeism using school administrative data, and nine administered questionnaires on children's parents. Among them, 11 reported a statistically significant positive association between childhood overweight/obesity and school absence, whereas two reported null effect. The meta-analysis found that the odds of being absent from school was 27% and 54% higher among children with overweight and obesity than among their normal weight counterparts, respectively. Future studies should adopt an experimental study design and accurate measures on school attendance and delineate the underlining pathways linking childhood obesity to school absenteeism through obesity-related illnesses and psychosocial problems.


Marine natural products.
This review covers the literature published in 2002 for marine natural products, with 579 citations (413 for the period January to December 2002) referring to compounds isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates and echinoderms. The emphasis is on new compounds (677 for 2002), together with their relevant biological activities, source organisms and country of origin. Syntheses that lead to the revision of structures or stereochemistries have been included (114), including any first total syntheses of a marine natural product.


Computed tomographic dimensions of the lacrimal gland in healthy orbits.
The aims of this study were to evaluate the normal range of the dimensions of lacrimal glands in the healthy orbits of Korean subjects and to evaluate their association with clinical findings. A retrospective survey of patients who had visited the Korea University Medical Center and had undergone orbital computed tomographic scan was performed. One hundred eighty Korean patients (90 men and 90 women) who were older than 20 years and without orbital disease were included. Patients with trauma to the orbits or any known lacrimal gland disease were excluded. The length and width of the lacrimal gland were measured in axial and coronal sections using the largest image. The primary outcome was a descriptive analysis of the distribution of dimensions in normal orbits. We analyzed the results and identified associations with age, sex, and laterality and compared our results with a previous study on normal white lacrimal gland dimensions. The mean lacrimal gland axial length was 14.9 mm in the right orbit and 14.7 mm in left orbit. Coronal lengths averaged 20.9 mm in the right orbit and 20.7 mm in the left orbit. The axial width was 4.1 mm in the right orbit and 4.3 mm in the left orbit. The coronal width averaged 3.6 mm in the right orbit and 3.8 mm in the left orbit. A significant inverse linear relationship was observed in both orbits between gland size and age in all dimensions, with the exception of axial width. This study presents a normal range of Korean lacrimal gland dimensions as measured by computed tomography. This range can aid in differentiating diseased and nondiseased lacrimal glands, especially when used in combination with physical examination. These data may also be useful in clinical trials that involve lacrimal gland size.


Mechanical Stress Conditioning and Electrical Stimulation Promote Contractility and Force Maturation of Induced Pluripotent Stem Cell-Derived Human Cardiac Tissue.
Tissue engineering enables the generation of functional human cardiac tissue with cells derived in vitro in combination with biocompatible materials. Human-induced pluripotent stem cell-derived cardiomyocytes provide a cell source for cardiac tissue engineering; however, their immaturity limits their potential applications. Here we sought to study the effect of mechanical conditioning and electric pacing on the maturation of human-induced pluripotent stem cell-derived cardiac tissues. Cardiomyocytes derived from human-induced pluripotent stem cells were used to generate collagen-based bioengineered human cardiac tissue. Engineered tissue constructs were subjected to different mechanical stress and electric pacing conditions. The engineered human myocardium exhibits Frank-Starling-type force-length relationships. After 2 weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility (0.63±0.10 mN/mm2 vs 0.055±0.009 mN/mm2 for no stress), tensile stiffness, construct alignment, and cell size. Stress conditioning also increased SERCA2 (Sarco/Endoplasmic Reticulum Calcium ATPase 2) expression, which correlated with a less negative force-frequency relationship. When electric pacing was combined with static stress conditioning, the tissues showed an additional increase in force production (1.34±0.19 mN/mm2), with no change in construct alignment or cell size, suggesting maturation of excitation-contraction coupling. Supporting this notion, we found expression of RYR2 (Ryanodine Receptor 2) and SERCA2 further increased by combined static stress and electric stimulation. These studies demonstrate that electric pacing and mechanical stimulation promote maturation of the structural, mechanical, and force generation properties of human-induced pluripotent stem cell-derived cardiac tissues.


In vivo distribution and cytopathology of variants of human immunodeficiency virus type 1 showing restricted sequence variability in the V3 loop.
The distribution, cell tropism, and cytopathology in vivo of human immunodeficiency virus (HIV) was investigated in postmortem tissue samples from a series of HIV-infected individuals who died either of complications associated with AIDS or for unrelated reasons while they were asymptomatic. Proviral sequences were detected at a high copy number in lymphoid tissue of both presymptomatic patients and patients with AIDS, whereas significant infection of nonlymphoid tissue such as that from brains, spinal cords, and lungs were confined to those with AIDS. V3 loop sequences from both groups showed highly restricted sequence variability and a low overall positive charge of the encoded amino acid sequence compared with those of standard laboratory isolates of HIV type 1 (HIV-1). The low charge and the restriction in sequence variability were comparable to those observed with isolates showing a non-syncytium-inducing (NSI) and macrophage-tropic phenotype in vitro. All patients were either exclusively infected (six of seven cases) or predominantly infected (one case) with variants with a predicted NSI/macrophage-tropic phenotype, irrespective of the degree of disease progression. p24 antigen was detected by immunocytochemical staining of paraffin-fixed sections in the germinal centers within lymphoid tissue, although little or no antigen was found in areas of lymph node or spleen containing T lymphocytes from either presymptomatic patients or patients with AIDS. The predominant p24 antigen-expressing cells in the lungs and brains of the patients with AIDS were macrophages and microglia (in brains), frequently forming multinucleated giant cells (syncytia) even though the V3 loop sequences of these variants resembled those of NSI isolates in vitro. These studies indicate that lack of syncytium-forming ability in established T-cell lines does not necessarily predict syncytium-forming ability in primary target cells in vivo. Furthermore, variants of HIV with V3 sequences characteristic of NSI/macrophage-tropic isolates form the predominant population in a range of lymphoid and nonlymphoid tissues in vivo, even in patients with AIDS.


CD99 expression in Merkel cell carcinoma: a case series with an unusual paranuclear dot-like staining pattern.
Merkel cell carcinoma (MCC) is a rare neuroendocrine cancer of the skin. The utility of CD99 (MIC-2) in the diagnosis of MCC has been previously studied, with reported rates of expression ranging from 13 to 55%. When specified, a membranous or cytoplasmic staining pattern was considered significant. Recent studies of CD99 have identified a paranuclear dot-like expression pattern in certain non-neuroendocrine pancreatic and colonic lesions. We recently noted paranuclear dot-like staining in several cases of MCC, including cases lacking cytokeratin 20 (CK20) expression. Fourteen cases of MCC were stained with CK20 and CD99 antibody, and the pattern and intensity of staining were recorded. Seven cases of pulmonary small cell carcinoma (PSCC) and one case of primitive neuroectodermal tumor (PNET) were used for comparison. All 14 cases of MCC showed at least focal CD99 staining, with both membranous and paranuclear dot-like staining patterns identified. CK20 staining was present in 12/14 cases, with the characteristic dot-like pattern identified. Four of seven cases of PSCC showed CD99 staining, with two showing a finely granular dot-like staining pattern. We report an unusual pattern of paranuclear dot-like expression of CD99 in 14 cases of MCC, two of which did not express CK20. This previously unrecognized expression pattern may be of use in differentiating MCC from other cutaneous malignancies, especially when CK20 expression is limited or absent.


Protecting Privacy of Users in Brain-Computer Interface Applications.
Machine learning (ML) is revolutionizing research and industry. Many ML applications rely on the use of large amounts of personal data for training and inference. Among the most intimate exploited data sources is electroencephalogram (EEG) data, a kind of data that is so rich with information that application developers can easily gain knowledge beyond the professed scope from unprotected EEG signals, including passwords, ATM PINs, and other intimate data. The challenge we address is how to engage in meaningful ML with EEG data while protecting the privacy of users. Hence, we propose cryptographic protocols based on secure multiparty computation (SMC) to perform linear regression over EEG signals from many users in a fully privacy-preserving (PP) fashion, i.e., such that each individual's EEG signals are not revealed to anyone else. To illustrate the potential of our secure framework, we show how it allows estimating the drowsiness of drivers from their EEG signals as would be possible in the unencrypted case, and at a very reasonable computational cost. Our solution is the first application of commodity-based SMC to EEG data, as well as the largest documented experiment of secret sharing-based SMC in general, namely, with 15 players involved in all the computations.


Hypoglycemia in pregnancy. Occurrence due to adrenocorticotropic hormone and growth hormone deficiency.
Severe symptomatic hypoglycemia (serum glucose level, 24 mg/dL) developed in a 23-year-old, 147.3-cm-tall woman during her late second and third trimesters of pregnancy. Endocrine studies disclosed insulin levels less than 2 microU/mL; growth hormone level less than 3 ng/mL; and cortisol level less than 1 microgram/dL. Hydrocortisone therapy corrected her hypoglycemia, and she was delivered of a healthy female infant. Postpartum, her evaluation included normal thyroid function studies, a normal thyroid-stimulating hormone response to protirelin (thyrotropin-releasing hormone), normal serum and urine gonadotropin levels, normal serum prolactin, normal sella turcica tomograms, and a normal EMI brain scan. Urine 17-hydroxycorticosteroids increased during a four-day cosyntropin infusion, but failed to rise after metyrapone administration. The growth hormone level failed to rise after stimulation with levodopa and propranolol administration. The patient was believed to have idiopathic partial hypopituitarism, with hypoglycemia being due to adrenocorticotropic hormone (ACTH) and growth hormone deficiency and the drain of maternal glucose by the fetus. It is suggested that pregnant women with symptomatic hypoglycemia be treated with glucocorticoids while awaiting the results of their endocrine evaluation.


Single-molecule functionality in electronic components based on orbital resonances.
In recent years, a wide range of single-molecule devices has been realized, enabled by technological advances combined with the versatility offered by synthetic chemistry. In particular, single-molecule diodes have attracted significant attention with an ongoing effort to increase the rectification ratio between the forward and reverse current. Various mechanisms have been investigated to improve rectification, either based on molecule-intrinsic properties or by engineering the coupling of the molecule to the electrodes. In this perspective, we first provide an overview of the current experimental approaches reported in literature to achieve rectification at the single-molecule level. We then proceed with our recent efforts in this direction, exploiting the internal structure of multi-site molecules, yielding the highest rectification ratio based on a molecule-intrinsic mechanism. We introduce the theoretical framework for multi-site molecules and infer general design guidelines from this. Based on these guidelines, a series of two-site molecules have been developed and integrated into devices. Using two- and three-terminal mechanically controllable break junction measurements, we show that depending on the on-site energies, which are tunable by chemical design, the devices either exhibit pronounced negative differential conductance, or behave as highly-efficient rectifiers. Finally, we propose a design of a single-molecule diode with a theoretical rectification ratio exceeding a million.


Effects of augmentative and alternative communication on challenging behavior: a meta-analysis.
The purposes of this review were to (a) use meta-analytic procedures to examine the effectiveness of single-case AAC intervention research on challenging behaviors exhibited by individuals with disabilities, (b) identify study characteristics that moderate intervention effects, and (c) evaluate the quality of research. The authors provided inferential and descriptive analyses of 54 studies representing 111 participants and estimated effect sizes using the Nonoverlap of All Pairs (NAP) method. Overall, AAC interventions were found to be equally effective across a broad spectrum of participants and interventions. AAC interventions were more effective with younger children than with adults. Interventions in which functional behavior assessments (FBA) were used had significantly larger effect sizes than those that did not use FBAs. Further, functional communication training interventions resulted in larger effect sizes than Picture Exchange Communication System interventions. Descriptive analysis revealed that (a) interventions often occurred in atypical environments (e.g., therapy room, experimental room) and with atypical interventionists (e.g., therapists, researchers), and (b) numerous studies did not exhibit quality characteristics of single-case research.


Learning to Write Like a Scientist: A Writing-Intensive Course for Microbiology/Health Science Students.
Learning the tools and conventions of expert communication in the sciences provides multiple benefits to bioscience students, yet often these skills are not formally taught. To address this need, we designed a writing-intensive microbiology course on emerging infectious diseases to provide upper-division students with science-specific writing skills along with disciplinary course content. The course followed the guidelines of our university's Writing Intensive Curriculum (WIC) program. Students wrote a press release, a case study, a controversy/position paper, and a grant prospectus, and revised drafts after feedback. To assess the course, in 2015 and 2016 we administered pre-post surveys and collected writing samples for analysis. Students reported on their experience, training, skills, and knowledge before taking the course. They then rated the extent to which the assignments, lectures, in-class activities, and writing activities contributed to their attainment of the learning outcomes of the course. Students entering the class were inexperienced in tools of science writing and the specific genres covered by the class. Their confidence levels rose in both skills and knowledge. Feedback from instructors was cited as most helpful in the majority of the areas where students reported the most gains. The survey provided evidence that discipline-specific knowledge had been acquired through writing activities. Teaching science writing by allowing the students to write "fiction" (e.g., a case report about a fictional patient) was effective in maintaining a high level of interest, both in learning the conventions of the genre and in seeking out detailed information about emerging infectious diseases. Both the course structure and the specific assignments would be useful at other institutions to teach science writing.


Calibration method for inner product calculation by the volume holographic correlator with randomly interleaved images.
A volume holographic correlator is capable of inner product calculations between the input image and multiple stored images in parallel. The inner product that is the center value of the correlation can provide a scalar measure of change between two images. The inner product values are directly acquired by measuring the intensities of the correlation peaks on the CCD. However, the measured intensities are not exactly equal to the theoretical inner product values due to the redundancy correlation. The structure of the correlation peak for randomly interleaved images is analyzed. It can be regarded as two volumes, one pyramid and one prism. The relative inner product value is only determined by the height of the pyramid. The prism, caused by the redundancy correlation, appears as the background noise, which is the main source of the inner product calculation error. A calibration method is proposed to remove the prism from the measured intensity. Based on the geometric structure of the correlation peak, the theoretical expression of the inner product value for the pyramid is derived. A white image is employed as the input image and the measured correlation peak intensity is used to calibrate the inner product value. The calibration method can effectively eliminate the error caused by the redundancy correlation to achieve a high output accuracy of the volume holographic correlator. Experiments are demonstrated for the validity of the method.


A PET-based nomogram for oropharyngeal cancers.
In the context of locally advanced oropharyngeal cancer (LAOC) treated with definitive radiotherapy (RT) (combined with chemotherapy or cetuximab), the aims of this study were: (1) to identify PET-FDG parameters correlated with overall survival (OS) from a first cohort of patients; then (2) to compute a prognostic score; and (3) finally to validate this scoring system in a second independent cohort of patients. A total of 76 consecutive patients (training cohort from Rennes) treated with chemoradiotherapy or RT with cetuximab for LAOC were used to build a predictive model of locoregional control (LRC) and OS based on PET-FDG parameters. After internal calibration and validation of this model, a nomogram and a scoring system were developed and tested in a validation cohort of 46 consecutive patients treated with definitive RT for LAOC in Lausanne. In multivariate analysis, the metabolic tumour volume (MTV) of the primary tumour and the lymph nodes were independent predictive factors for LRC and OS. Internal calibration showed a very good adjustment between the predicted OS and the observed OS at 24 months. Using the predictive score, two risk groups were identified (median OS 42 versus 14 months, p < 0.001) and confirmed in the validation cohort from Lausanne (median OS not reached versus 26 months, p=0.008). This is the first report of a PET-based nomogram in oropharyngeal cancer. Interestingly, it appeared stronger than the classical prognostic factors and was validated in independent cohorts markedly diverging in many aspects, which suggest that the observed signal was robust.


Low-cost and Scalable Classroom Equipment to Promote Physical Activity and Improve Education.
We tested a low-cost and scalable set of classroom equipment, called Active Classroom Equipment, which was designed to promote physical activity while children learn. We hypothesized the Active Classroom Equipment would be associated with increased physical activity without impairing learning. Fourteen first-grade students in a public elementary school (7 females, 7 males, aged 6.9 ± (SD) 0.4 years, 24 ± 5.4 kg, BMI 15.8 ± 2.6 kg/m2) used the Active Classroom Equipment for 30 minutes each day throughout the school year. Five-day physical activity was measured using validated triaxial accelerometers at baseline (before the intervention began) and on 4 sequential occasions during the 9-month intervention. For the baseline period, 5-day physical activity averaged 157 ± 65 AU/min. When the 14 children accessed the Active Classroom Equipment, their mean 5-day physical activity was 229 ± 103 Acceleration Units (AU)/ min (P < .0001). There were sequential increases in physical activity over the 9-month intervention (Quarter 1: 163 ± 94 AU/min, Quarter 2: 227 ± 108 AU/min, Quarter 3: 278 ± 61 AU/min, Quarter 4: 305 ± 65 AU/min). Students' Dynamic Indicators of Basic Early Literacy Skills (DIBELS) scores improved. Active Classroom Equipment may be one approach to increase physical activity.


A rapid situation assessment of sexual risk behaviour of alcohol users in Lagos, Nigeria.
National sentinel surveys of HIV/AIDS among pregnant women in Nigeria have shown steady rise in prevalence from 1991 (1.8%) to 2001 (5.8%), which may reflect the pattern in the adult population in the country. The roles of known potential risk factors of the HIV/AIDS scourge in Nigeria deserve elucidation. This work aims to study the relationship between alcohol use and sexual risk behaviour. Rapid assessment technique involving qualitative and quantitative methods was employed. A multi-site design which made it possible to compare samples recruited in high and low density settings was used. One hundred and nine of the alcohol users were recruited in the Low Density Area (LDA), while 130 were recruited in the High Density Area (HDA). In the HDA, 49 (53%) of the beer users used alcohol before sex either most or all of the time 21 (22.6%), or occasionally 28 (29.1%). Unlike the beer users less than half, 8 (42.1%), of Palm wine drinkers drank alcohol before sex. Beer users in the HDA used beer after sex with casual partners significantly more than the Palm wine drinkers (P = 0.036). Alcohol users in the LDA were more inclined to casual sex and they (54, 56.8%) believed that it had some or major role in their desire as well as performance of sex compared with users in the HDA (P = 0.005). Irrespective of their socioeconomic class, ethnicity, religion and educational attainment alcohol users in the country indulge in high risk sexual behaviours that predispose them to infection with HIV and other sexually transmitted diseases.


Nerve sheath myxoma (neurothekeoma) of cerebellopontine angle: case report of a rare tumor with brief review of literature.
Nerve sheath myxoma (neurothekeoma) are rare benign nerve sheath tumors, usually arising in the skin of the head and neck region and upper extremities in young females. To the best of author's knowledge only two cases of intracranial neurothekeoma have been published in the English literature. These tumors were located in the parasellar area and in middle cranial fossa. This is the first case report of cerebellopontine angle neurothekeoma and third case report of intracranial neurothekeoma. This patient, a 45-year-old female, presented to us with complaints of right side progressive hearing loss for 12 months and swaying during walking for 8 months. Histologically the tumor had lobular appearance with spindle or stellate cells embedded in abundant myxoid background. The tumor cells were diffusely positive for S100. The patient was symptom free at eight month follow up.


Dry socket: frequency, clinical picture, and risk factors in a palestinian dental teaching center.
The objectives of this study were to find out the frequency, clinical picture, and risk factors of dry socket at the Dental Teaching Center of Al-Quds University in Palestine. Two previously used questionnaires were accomplished in this study over a one year period. The first questionnaire was completed for every patient who had one or more permanent teeth extracted in the Dental Surgery Clinic. The other one was completed for every patient suffered a postoperative pain and was diagnosed with dry socket. There were 1305 dental extractions performed in 805 patients. The overall frequency of dry socket was 3.2%. The incidence of dry socket following non-surgical extractions was 1.7% while it was 15% following surgical extractions (P< 0.005). The incidence of dry socket was significantly higher in smokers (12%) than in non-smokers (4%) (P < 0.005), however, there is a strong association between the amount of smoking and the incidence of dry socket (P < 0.002). The incidence of dry socket was significantly higher in the single extraction cases (13%) than in the multiple extraction cases (5%) (P = 0.005). Age, sex, medical history, extraction site, amount of local anesthesia and experience of operator play no role in the occurrence of dry socket. Smoking, surgical trauma and single extractions are considered predisposing factors in the occurrence of dry socket. On the other hand, factors like: age, sex, medical history, extraction site, amount of anesthesia, and operator experience have no effect on the observation of dry socket.


Visceral Adiposity Predicts Severity of Acute Pancreatitis.
The aim of this study was to determine the association of visceral adiposity with severe outcomes in acute pancreatitis (AP). This retrospective study included consecutive patients with AP admitted to a tertiary care hospital between January 2010 and January 2015 who underwent a computed tomography scan. The visceral adipose tissue (VAT) volume was estimated using the method of Linder and colleagues. Multivariable logistic regression analysis was conducted to assess VAT as a predictor of severe AP compared with other validated predictors of severity. Five hundred and seventy four patients were admitted during the study period, of which 252 had a computed tomography scan available. Patients with severe AP had a larger VAT area compared with those with mild or moderate AP (mean: 184.9 cm vs 79.9 cm, P = 0.006). Patients who developed multisystem organ failure or had acute necrotic collections had a larger VAT area than those who did not (150.6 cm vs 91.0 cm, P = 0.004 and 174.0 cm vs 91.9 cm, P = 0.003, respectively). Visceral adipose tissue area demonstrated superior discrimination of severe AP compared with other severity predictors. Increased VAT area is a strong predictor of severe pancreatitis, necrosis, and multisystem organ failure.


Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.
IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'


Multicenter in vitro thromboelastography and thromboelastometry standardization.
To establish and compare the repeatability and reproducibility of activated thromboelastography (TEG) and thromboelastometry (ROTEM) assays. Multicenter in vitro test standardization. Veterinary academic centers. Test samples were obtained from normal, healthy dogs. Sixty identical 5 mL aliquots of canine platelet-rich plasma collected by apheresis, frozen in 6% dimethyl sulfoxide, were tested initially. Sixty identical 6 mL aliquots of canine fresh frozen plasma with admixed cryoprecipitate were subsequently evaluated. None. Frozen study samples, quality controls, reagents, and consumables were distributed to participating centers (7 TEG and 3 ROTEM). TEG centers analyzed study samples with kaolin and tissue factor activated assays; ROTEM centers ran proprietary ellagic acid activated and tissue factor activated assays. All machines underwent quality control prior to sample analysis. Within- and between-center coefficients of variation (CVs) were calculated and compared using Mann-Whitney tests and calculation of intraclass correlation coefficients. Within and between centers, individual parameters for both TEG and ROTEM assays were comparable. Both within-center and between-center CVs varied markedly (0.7-120.5% and 1.4-116.5%, respectively) with assay type, instrument, and parameter. CVs for equivalent parameters were not significantly different between the 2 platforms. Intraclass correlation coefficients suggested moderate agreement between centers. In general, individual parameter CVs for platelet-rich plasma samples were lower in TEG centers, while CVs for canine fresh frozen plasma with admixed cryoprecipitate samples were lower in ROTEM centers. More variation within and between centers was identified than anticipated, but some parameters such as alpha angle were repeatable and reproducible. Sample types for future multicenter standardization efforts will require further optimization and may need to be adapted separately to each platform. Individual centers using viscoelastic tests for evaluation and management of clinical patients should take steps to minimize preanalytical and analytical sources of variation.


FACILE PREPARATION OF NANOPARTICLES BY INTRAMOLECULAR CROSSLINKING OF ISOCYANATE FUNCTIONALIZED COPOLYMERS.
A new synthetic approach to the preparation of intramolecularly collapsed nanoparticles under mild, room temperature conditions has been developed from commercially available vinyl monomers. Reaction of isocyanate functionalized linear copolymers with a diamine in dilute solution leads to the efficient formation of nanoparticles where the diameter of the nanoparticle can be varied by controlling both the molecular weight and mole percentage of isocyanate repeat units. Physical properties for the intramolecularly collapsed nanoparticles were fully consistent with a three-dimensional structure and analysis of the collapse reaction revealed that approximately 75% of the isocyanate groups along the backbone underwent crosslinking with 25% being available for further reaction with mono-functional amines. This stepwise consumption of the isocyanates allows the chemical and physical properties of the nanoparticles to be further tuned and significantly opens up the range of nanoparticles that can be prepared using this mild and highly efficient chemistry.


The Declaration of Istanbul--early impact and future potential.
The Declaration of Istanbul on Organ Trafficking and Transplant Tourism was adopted at an international meeting held in 2008. The Declaration has been published globally and consists of a preamble, a set of principles and a series of proposals to improve the ethics and expand the benefits of the international organ transplantation endeavor. To promote and monitor the implementation of the Declaration, a Declaration of Istanbul Custodian Group (DICG) has been created. The DICG has provided support for official efforts to ban the sale of organs, restrict transplant tourism and prosecute those who persist in violating the law. Substantial progress has been made thus far in countries that have been the source of transplant tourists and in countries that have been the source of donor organs for trafficking. In China, however, the use of organs from executed prisoners for transplantation purposes continues despite widespread condemnation of this practice.


Testing feedback message framing and comparators to address prescribing of high-risk medications in nursing homes: protocol for a pragmatic, factorial, cluster-randomized trial.
Audit and feedback (AF) interventions that leverage routine administrative data offer a scalable and relatively low-cost method to improve processes of care. AF interventions are usually designed to highlight discrepancies between desired and actual performance and to encourage recipients to act to address such discrepancies. Comparing to a regional average is a common approach, but more recipients would have a discrepancy if compared to a higher-than-average level of performance. In addition, how recipients perceive and respond to discrepancies may depend on how the feedback itself is framed. We aim to evaluate the effectiveness of different comparators and framing in feedback on high-risk prescribing in nursing homes. This is a pragmatic, 2 × 2 factorial, cluster-randomized controlled trial testing variations in the comparator and framing on the effectiveness of quarterly AF in changing high-risk prescribing in nursing homes in Ontario, Canada. We grouped homes that share physicians into clusters and randomized these clusters into the four experimental conditions. Outcomes will be assessed after 6 months; all primary analyses will be by intention-to-treat. The primary outcome (monthly number of high-risk medications received by each patient) will be analysed using a general linear mixed effects regression model. We will present both four-arm and factorial analyses. With 160 clusters and an average of 350 beds per cluster, assuming no interaction and similar effects for each intervention, we anticipate 90% power to detect an absolute mean difference of 0.3 high-risk medications prescribed. A mixed-methods process evaluation will explore potential mechanisms underlying the observed effects, exploring targeted constructs including intention, self-efficacy, outcome expectations, descriptive norms, and goal prioritization. An economic analysis will examine cost-effectiveness analysis from the perspective of the publicly funded health care system. This protocol describes the rationale and methodology of a trial testing manipulations of theory-informed components of an audit and feedback intervention to determine how to improve an existing intervention and provide generalizable insights for implementation science. NCT02979964.


Gaucheromas: When macrophages promote tumor formation and dissemination.
Deficiency of the lysosomal enzyme, β-glucocerebrosidase, and accumulation of its substrate in cells of the reticuloendothelial system affects multiple organ systems in patients with Gaucher disease (GD). Lipid laden macrophages turn into Gaucher cells (GC) which are the pathological characteristic of GD. GC focally accumulate in the liver, spleen and at extraosseous sites to form benign lesions called Gaucheromas. Gaucheromas pose diagnostic and therapeutic challenges. We studied the pathophysiology of extraosseous Gaucheroma formation in a cohort of patients with GD. Among 63 patients followed at a single center, 3 patients with genotypes L444P/L444P and N370S/N370S, were diagnosed with extraosseous Gaucheromas. Flow cytometry revealed a higher expression of CD16+/CCR4+ non-classical monocytes in blood of GD patients who have developed Gaucheromas. A biopsy showed infiltration of GC, which reactivity against CD163, CD68 and VEGF. The cell proliferative marker Ki67 and CCL2, a factor anti-tumor activity, were negative. Our study indicates that extraosseous Gaucheromas are comprised of cellular elements with characteristics of tumor-associated macrophages, the major players in cancer related inflammation. The occurrence of non-classical CD16+/CCR4+ monocytes reflect the underlying cause for the accumulation of the macrophages capable of migrating to distant sites outside the reticuloendotheial system, and giving rise to tumor-like Gaucheromas.


Ischaemic heart disease: trends in mortality in Hong Kong, 1970-89.
To describe the time trends for ischaemic heart disease (IHD) mortality in Hong Kong between 1970 and 1989, and to examine these trends in relation to the risk factors for IHD. A descriptive epidemiological study of time trends using mortality and population data from the Hong Kong Census and Statistics Department. Direct standardisation using the world population was made to adjust for the changing age structure. Log-linear analyses for trends were performed for the whole period and separately for 1970-79 and 1980-89. The cohort effect was studied by regrouping the data into five year groups according to the year of birth. The influences of risk factors, including hypertension, diet, and smoking, on the time trends of IHD were explored. The role of improved hospital treatment of myocardial infarction on the trends of mortality from categories of IHD was also examined. The total Hong Kong population, 1970-89. The substantial and steady decline of IHD mortality seen in most western countries in the past two decades was not observed in Hong Kong, which showed a plateau or slowly decreasing trend only in the past decade for both women and men. The decreasing trends were more apparent in the younger age groups, especially for women. Cohort analysis showed no significant cohort effect in men, but women born more recently had a lower mortality. Trends of risk factors did not show any close relationship with the mortality trends of IHD, except that a decrease in cigarette smoking might have contributed to the slight decrease in IHD mortality in recent years. Better detection and wider availability of treatment for hypertension might also have contributed to the decrease in IHD mortality. Hong Kong started to show a slow decline in IHD mortality during the 1980s, about one to two decades later than in other western countries and with the decreasing trend less pronounced. The reasons for this decline are not clear. More detailed information from systematic, population based surveys on life style and risk factors for IHD among the general population are needed.


Neurohormonal antagonism in heart failure; beneficial effects of vasopressin V(1a) and V(2) receptor blockade and ACE inhibition.
To assess the long-term efficacy of vasopressin (AVP) V(1a) and V(2) receptor blockade with conivaptan, alone and in combination with angiotensin converting enzyme (ACE) inhibition on blood pressure, metabolic and neurohormonal parameters, and cardiovascular structure in a rat model of congestive heart failure (CHF). CHF was induced by left coronary artery ligation. CHF rats received conivaptan (1 mg/kg/day), ACE inhibition (captopril, 50 mg/kg/day), conivaptan and captopril (Combination) or vehicle for 4 weeks. Blood pressure was measured weekly, metabolic caging studies performed at 25 days, and rats killed and blood and tissue collected after 4 weeks treatment. Combination treatment lowered blood pressure (P<0.01), and conivaptan and Combination caused an aquaresis (P<0.01). Combination decreased plasma natriuretic peptide (P<0.05), reduced left and right ventricular mass (P<0.01) and lung mass (P<0.05). In CHF, blockade of vasopressin V(1a) and V(2) receptors was associated with increased water excretion, and the combination of conivaptan with ACE inhibition was the only treatment to reduce blood pressure, natriuretic peptide and pulmonary congestion. These results suggest conivaptan may be a useful addition to ACE inhibitors in the management of vasoconstriction and fluid retention that characterizes CHF.


Tracing photon transmission in dye-doped DNA-CTMA optical nanofibers.
We experimentally demonstrate the novel phenomena of photoluminescence (PL) and fluorescence resonance energy transfer (FRET) assisted three-color PL separating in DNA optical nanofibers consisting of the stretched and connected DNA-cetyltrimethyl ammonium wires. The PL experiments are performed to comparatively trace photon transmission between single dye-doped DNA-CTMA optical nanofiber and PMMA optical nanofiber. A cascade FRET including DNA minor groove binder and DNA intercalators is used to further trace photon transmission inside DNA-CTMA wire. These experimental results will help to intrigue the new applications of DNA-CTMA as molecular waveguide in optobioelectronics area.


Use of three pins in Gamma Knife stereotactic radiosurgery for brain metastases.
We present our institutional experience in treating brain metastases with GK-SRS and a headframe fixed to the skull with only 3 pins to avoid collisions between the headframe and the Gamma Knife (GK) machine. Among 3500 consecutive patients who received GK-SRS in 2011-2017, 50 had 1 of the 2 anterior pins removed immediately before treatment of ≥1 brain lesion. Endpoints were local control, dosimetric parameters, and toxicity. Median follow-up time for the 49 patients with follow-up was 7.0 months (range 0.2-57.0). Median number of lesions treated per session was 6 (range 1-18); a median 1 lesion was treated with 3-pin fixation (range 1-2) and a median 5 lesions treated with 4-pin fixation (range 0-17) during the same session. Lesions treated with 3-pin fixation were in the occipital lobe (n=41), cerebellum (n=9), or temporal lobe (n=1). No local failures were noted. The sole grade 2 toxicity (partial seizure) was attributed to treatment of a 4-pin-fixed lesion. Except for gradient index, dosimetry did not vary for lesions treated with 3-pin versus 4-pin fixation. Treating brain metastases with 3-pin fixation did not compromise treatment outcome and is a good option for posterior brain metastases that cannot otherwise be treated with 4-pin GK-SRS.


Unusual Masses of the Pancreas to Be Aware of.
This paper aims at emphasizing the difficulty in assessing preoperatively the diagnosis of solid masses of the pancreas whatever the initial clinical presentation may be. We illustrate our purpose describing consecutive cases of pancreatic masses of the pancreas we recently had and who were followed according to the internal guidelines of investigation of our referral hospital. Whereas malignant tumors of the pancreas represent the vast majority of solid tumors of the pancreas, other diagnoses must be evoked. We report three cases of pancreatic solid masses that were explored by endoscopic ultrasonography coupled with fine needle aspiration, a method universally considered to be both reliable and accurate but which failed to assess definitive diagnosis due to both cytological pitfalls and sampling error.


Photoinduced C-C reactions on insulators toward photolithography of graphene nanoarchitectures.
On-surface chemistry for atomically precise sp(2) macromolecules requires top-down lithographic methods on insulating surfaces in order to pattern the long-range complex architectures needed by the semiconductor industry. Here, we fabricate sp(2)-carbon nanometer-thin films on insulators and under ultrahigh vacuum (UHV) conditions from photocoupled brominated precursors. We reveal that covalent coupling is initiated by C-Br bond cleavage through photon energies exceeding 4.4 eV, as monitored by laser desorption ionization (LDI) mass spectrometry (MS) and X-ray photoelectron spectroscopy (XPS). Density functional theory (DFT) gives insight into the mechanisms of C-Br scission and C-C coupling processes. Further, unreacted material can be sublimed and the coupled sp(2)-carbon precursors can be graphitized by e-beam treatment at 500 °C, demonstrating promising applications in photolithography of graphene nanoarchitectures. Our results present UV-induced reactions on insulators for the formation of all sp(2)-carbon architectures, thereby converging top-down lithography and bottom-up on-surface chemistry into technology.


Assessing the clinical use of clear cell renal cell carcinoma molecular subtypes identified by RNA expression analysis.
To evaluate the clinical use of recently published RNA-based molecular subtyping algorithms. Patients who undergo surgery for clinically localized clear cell renal cell carcinoma can experience very different outcomes, representing a longstanding challenge for the practicing urologist. Two recent publications suggest that molecular subtyping based on the expression of large panels of genes can help clinically localized clear cell renal cell carcinoma prognostication; however, the analyses was not adjusted for routinely collected clinicopathologic indices. We obtained level 3 RNA-seq RPKM data and corresponding clinicopathologic features from The Cancer Genome Atlas (TCGA) and assigned patients to the TCGA subtypes as well as to the ccA/ccB subtypes. To determine the prognostic ability of molecular subtyping after adjusting for variables that are collected as routine medical care, we used Cox models and adjusted for the composite Mayo stage, size, grade, and necrosis (SSIGN) score. Both the TCGA and the ccA/ccB subtypes are significantly associated with tumor size, category, grade, and presence of necrosis. The association of these subtypes with overall survival is markedly attenuated following adjustment for the composite Mayo SSIGN score. Both the TCGA and the ccA/ccB subtypes are associated with overall survival after adjusting for the Mayo SSIGN score. However, the effect sizes are similar to what has been reported for single markers, and thus the clinical use and cost-effectiveness of these RNA-based whole-genome signatures are questionable.


Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers.
Chromosome deletions are the most common genetic events observed in cancer. These deletions are generally thought to reflect the existence of a tumour suppressor gene within the lost region. However, when the lost region does not precisely coincide with a hereditary cancer locus, identification of the putative tumour suppressor gene (target of the deletion) can be problematic. For example, previous studies have demonstrated that chromosome 18q is lost in over 60% of colorectal as well as in other cancers, but the lost region could not be precisely determined. Here we present a rigorous strategy for mapping and evaluating allelic deletions in sporadic tumours, and apply it to the evaluation of chromosome 18 in colorectal cancers. Using this approach, we define a minimally lost region (MLR) on chromosome 18q21, which contains at least two candidate tumour suppressor genes, DPC4 and DCC. The analysis further suggested genetic heterogeneity, with DPC4 the deletion target in up to a third of the cases and DCC or a neighbouring gene the target in the remaining tumours.


Sharing genetic test results with family members of BRCA, PALB2, CHEK2, and ATM carriers.
This study explored motivators and challenges/barriers to sharing personal genetic test results (GTR) with family members (FM). Semi-structured, in-depth interviews were conducted with 62 women who had a pathogenic or likely pathogenic (P/LP) variant in aBRCA, PALB2, CHEK2, or ATM gene. Selective qualitative data analysis focused on eliciting motivators and challenges/barriers identified by participants when sharing their GTR with FM. Motivators to sharing personal GTR with FM included: health protection and prevention; moral obligation; decisional empowerment; familial ties; written resources; and contextualization for a familial cause for cancer. Challenges/barriers to family sharing included: concern for FM reactions; complexities of information; lack of closeness; perceived relevance; and emotional impact. All motivators and challenges/barriers were identified across BRCA and non-BRCA carriers, demonstrating commonalities in family sharing of GTR among high- to moderate-penetrance hereditary BC (breast cancer) genes. Despite challenges/barriers, participants disclosed their GTR with most close FM, yet restrictions in communication and/or strain on the timing, manner of disclosing, and strategies used varied across certain FM. These findings offer healthcare providers and researchers preliminary practical implications for broadly improving family sharing interventions across P/LP variants in BC risk genes by demonstrating important elements to include in family sharing letters.


Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites.
Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.


Intracerebral functional connectivity-guided neurofeedback as a putative rehabilitative intervention for ameliorating auditory-related dysfunctions.
Electroencephalography (EEG) constitutes one of the most eligible candidates for neurofeedback applications, principally due to its excellent temporal resolution best reflecting the natural dynamics of brain processes. In addition, EEG is easy to use and provides the opportunity for mobile applications. In the present opinion article, we pinpoint the advantages of using intracerebral functional connectivity (IFC) instead of quantitative scalp EEG for interventional applications. In fact, due to the convergence of multiple signals originating from different spatial locations and electrophysiological interactions, miscellaneous scalp signals are too unspecific for therapeutic neurofeedback applications. Otherwise, IFC opens novel perspectives for influencing brain activity in specific dysfunctional small- and large-scale neuronal networks with a reasonable spatial resolution. In the present article, we propose concrete interventional IFC applications that may be used to ameliorate auditory-related dysfunctions such as developmental dyslexia.


Gonioscopy-assisted Transluminal Trabeculotomy (GATT) in Patients With Secondary Open-Angle Glaucoma Following Vitreoretinal Surgery.
To examine the short-term efficacy and safety of gonioscopy-assisted transluminal trabeculotomy (GATT) in a series of patients who developed glaucoma following vitreoretinal surgery. Retrospective case series of consecutive patients aged above 18 years with secondary open-angle glaucoma following vitreoretinal surgery who had undergone GATT between January 2015 and June 2019. Eyes were excluded if there is<1 month of follow-up or glaucoma before vitreoretinal surgery. Eight eyes of 8 patients were included, with age range 18 to 72 years (median 43.5 y). Mean pretreatment intraocular pressure (IOP) was 32.7±5.1 mm Hg with a mean of 4.8±0.9 medications. Following GATT, mean IOP improved to 13.6±1.8 mm Hg (P<0.001) with a reduction to 1.6±1.4 medications after a mean follow-up of 8.6 months (range 1 to 25 mo). Five of the 8 eye (62.5%) had silicone oil in the vitreous cavity during GATT, none of which had concurrent oil removal. GATT is a safe and effective procedure for eyes with secondary open-angle glaucoma following vitreoretinal surgery. Further studies are needed to elucidate long-term benefits of angle surgery on eyes with high pressure following vitreoretinal surgery.


Broadband terahertz transmission within the air channel of thin-wall pipe.
We report broadband transmissions of terahertz radiations through the air channel of thin-wall pipe. The impacts of the wall thickness and of the refractive index of the material on the transmission window bandwidth are investigated. An extension of the bandwidth by at least 5.5 times is reported with a commercial drinking straw. The salient properties of the antiresonant reflecting guiding mechanism are studied with the terahertz time domain spectroscopy method, including the reduction of the attenuation coefficient of the propagated field by 60 times the material absorption coefficient.


Structure and expression of the messenger RNA encoding the murine multidrug resistance protein, an ATP-binding cassette transporter.
In vitro, overexpression of the human multidrug-resistance protein (MRP) causes a form of multidrug resistance similar to that conferred by P-glycoprotein, although the two proteins are only very distantly related. Studies with MRP-enriched membrane vesicles have demonstrated that the protein can bind and transport cysteinyl leukotrienes, as well as some other glutathione conjugates, with high affinity. In contrast, there is no direct evidence of the ability of MRP to bind or transport unmodified forms of the drugs to which it confers resistance. To facilitate studies of the physiological function(s) of MRP and its ability to cause multidrug resistance in vivo, we cloned and characterized the mRNA specifying its murine homolog. The murine MRP mRNA encodes a protein of 1528 amino acids that is 88% identical to human MRP. Although detectable by Northern blotting at variable levels in a wide range of tissues, in situ hybridization experiments revealed that MRP mRNA expression in some tissues is cell-type specific. High levels of the mRNA were detected in epithelia lining bronchi and bronchioles, as well as stage-specific expression in the seminiferous epithelium of the testes. Comparison of the predicted hydropathy profiles of human and murine MRP suggests a highly conserved membrane topology, the most distinctive feature of which is an extremely hydrophobic NH2-terminal region containing five or six potential transmembrane sequences. This structural feature is shared with the sulfonylurea receptor and the yeast cadmium factor 1 but is not present in members of the superfamily, such as the cystic fibrosis transmembrane conductance regulator and P-glycoproteins. Finally, we used overlapping cDNAs to construct an episomally replicating murine MRP expression vector that was stably transfected into HeLa cells. MRP-Transfected cell populations expressed markedly elevated levels of a 180-190-kDa protein that cross-reacted with a polyclonal antiserum raised against a peptide that is completely conserved in murine and human MRPs. The MRP transfectants also displayed increased resistance to vincristine (5-6-fold) and doxorubicin (< 2-fold).


Future etiologic research in occupational cancer.
Research focused on occupational exposure has been one of the cornerstones of epidemiological research into the etiology of cancer. It is appropriate to critically assess the contribution of this research effort and to assess the potential for making significant progress in the future in unraveling the etiology of cancer by studying the occupational environment. The study of the occupational environment has indeed been very fruitful. It is likely that there remain many more carcinogens to be discovered, but we have not deployed adequately sensitive study methods. The two major obstacles to quality research have been inadequate exposure assessment and insufficient sample sizes. Quality exposure assessment requires the participation of trained experts (industrial hygienists, chemists, etc.); it also requires an adequate information base on the exposures that occur in different workplaces. We need structures and career paths that facilitate the participation of exposure experts in epidemiological research. We need active large-scale industrial hygiene surveys to better characterize the U.S. workplace. This will be useful for epidemiological studies and for public health purposes. Community-based case-control studies will need to be much larger than they have been traditionally, with 1000 as a minimum number of cases and controls.


Clinical efficacy and mechanism of bilayered living human skin equivalent (HSE) in treatment of diabetic foot ulcers.
Bilayered living human skin equivalent (HSE) consists of cultured keratinocytes residing on the surface of a fibroblast-populated collagen lattice. Although HSE is FDA-approved for treatment of diabetic foot and venous stasis ulcers, its clinical efficacy remains limited, because the molecular mechanisms underlying its therapeutic effect are not fully understood. It is, therefore, often applied mistakenly as a skin graft. In this report, we delineate a mechanism of HSE biological effect and consequent optimal clinical use in accelerating closure of diabetic foot ulcers. HSE was grafted onto nude mice and the release of various growth factors was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and immunochemistry. Clinical: HSE was grafted onto 11 consecutive patients with diabetes who had 13 non-ischemic foot ulcers and healing was measured as time to 100% closure (e.g., no drainage and 100% epithelialized). HSE cellular components were determined to express 15 different growth factors/cytokine genes known to promote wound healing. Histological evidence from the nude mice showed that the collagen component of HSE underwent remodeling within the first seven days of grafting. Clinical: All diabetic foot ulcers healed in 31.8 12.4 days. Local release of a unique combination of 15 growth factors expressed by HSE keratinocyte and fibroblast components generates closure of diabetic foot ulcers. HSE should be applied with the same surgical conditions for a skin graft (i.e., no cellulitis, no drainage, and negligible bacteria). We hypothesize that bilayered HSE generates its effect by way of the local synthesis and release of multiple growth factors in specific combination and concentration, which improves the impaired reparative process of chronic wounds.


Categorical and coordinate processing in object recognition depends on different spatial frequencies.
Previous studies have suggested that processing categorical spatial relations requires high spatial frequency (HSF) information, while coordinate spatial relations require low spatial frequency (LSF) information. The aim of the present study was to determine whether spatial frequency influences categorical and coordinate processing in object recognition. Participants performed two object-matching tasks for novel, non-nameable objects consisting of "geons" (c.f. Brain Cogn 71:181-186, 2009). For each original stimulus, categorical and coordinate transformations were applied to create comparison stimuli. These stimuli were high-pass/low-cut-filtered or low-pass/high-cut-filtered by a filter with a 2D Gaussian envelope. The categorical task consisted of the original and categorical-transformed objects. The coordinate task consisted of the original and coordinate-transformed objects. The non-filtered object image was presented on a CRT monitor, followed by a comparison object (non-filtered, high-pass-filtered, and low-pass-filtered stimuli). The results showed that the removal of HSF information from the object image produced longer reaction times (RTs) in the categorical task, while removal of LSF information produced longer RTs in the coordinate task. These results support spatial frequency processing theory, specifically Kosslyn's hypothesis and the double filtering frequency model.


Does cancer risk increase with HbA1c, independent of diabetes?
The risks for several cancer types are increased in people with diabetes. Hyperglycaemia, hyperinsulinaemia, inflammation and altered hormonal concentrations are common characteristics between the two diseases and can all be linked to hyperglycaemia. Here, we use glycated haemoglobin (HbA1c) as a biomarker for chronic hyperglycaemia. We explore whether cancer risk increases with HbA1c, independent of diabetes, and, therefore, if risk is already increased below the diabetic HbA1c range, by analysing data from current studies linking HbA1c to risk of several cancer types. The data reveal that chronic hyperglycaemia correlates with increased cancer risk for a number of cancers, except prostate cancer. Evidence is also provided that risk is already increased in the pre-diabetic and normal ranges for several cancers. These results merit urgent investigation into the risks and advantages of updating recommendations for stricter glycaemic control in diabetic and non-diabetic subjects, as this could help reduce the risk of cancer incidence and mortality.


Epidemiologic Trends in Neonatal Intensive Care, 2007-2012.
Neonatal intensive care has been highly effective at improving newborn outcomes but is expensive and carries inherent risks. Existing studies of neonatal intensive care have focused on specific subsets of newborns and lack a population-based perspective. To describe admission rates to neonatal intensive care units (NICUs) for US newborns across the entire continuum of birth weight and how these rates have changed across time, as well as describe the characteristics of infants admitted to NICUs. An epidemiologic time-trend analysis was conducted on April 1, 2015, of live births (≥500 g) from January 1, 2007, to December 31, 2012, to residents of 38 US states and the District of Columbia, recorded using the 2003 revision of the US Standard Certificate of Live Birth (N = 17,896,048). Birth year. Crude, stratified (by birth weight), and adjusted admission rates. Trends in birth weight, gestational age, weight for gestational age, and use of assisted ventilation are presented to describe the cohort of admitted newborns. In 2012, there were 43.0 NICU admissions per 1000 normal-birth-weight infants (2500-3999 g), while the admission rate for very low-birth-weight infants (<1500 g) was 844.1 per 1000 live births. Overall, admission rates during the 6-year study period increased from 64.0 to 77.9 per 1000 live births (relative rate, 1.22; 95% CI, 1.21-1.22 [P < .001]). Admission rates increased for all birth weight categories. Trends in relative rates adjusted for maternal and newborn characteristics showed a similar 23% increase (95% CI, 1.22-1.23 [P < .001]). During the study period, newborns admitted to a NICU were larger and less premature, although no consistent trend was seen in weight for gestational age or the use of assisted ventilation. After adjustment for infant and maternal risk factors, US newborns at all birth weights are increasingly likely to be admitted to a NICU, which raises the possibility of overuse of neonatal intensive care in some newborns. Further study is needed into the causes of the increased use observed in our study as well as its implications for payers, policymakers, families, and newborns.


The Role of Astrocytes in the Generation, Migration, and Integration of New Neurons in the Adult Olfactory Bulb.
In mammals, new neurons in the adult olfactory bulb originate from a pool of neural stem cells in the subventricular zone of the lateral ventricles. Adult-born cells play an important role in odor information processing by adjusting the neuronal network to changing environmental conditions. Olfactory bulb neurogenesis is supported by several non-neuronal cells. In this review, we focus on the role of astroglial cells in the generation, migration, integration, and survival of new neurons in the adult forebrain. In the subventricular zone, neural stem cells with astrocytic properties display regional and temporal specificity when generating different neuronal subtypes. Non-neurogenic astrocytes contribute to the establishment and maintenance of the neurogenic niche. Neuroblast chains migrate through the rostral migratory stream ensheathed by astrocytic processes. Astrocytes play an important regulatory role in neuroblast migration and also assist in the development of a vasculature scaffold in the migratory stream that is essential for neuroblast migration in the postnatal brain. In the olfactory bulb, astrocytes help to modulate the network through a complex release of cytokines, regulate blood flow, and provide metabolic support, which may promote the integration and survival of new neurons. Astrocytes thus play a pivotal role in various processes of adult olfactory bulb neurogenesis, and it is likely that many other functions of these glial cells will emerge in the near future.


The gendered construction and experience of difficulties and rewards in cancer care.
Women cancer carers have consistently been found to report higher levels of distress than men carers. However, there is little understanding of the mechanisms underlying these gender differences in distress, and a neglect of rewarding aspects of care. We conducted in-depth semistructured interviews with 53 informal cancer carers, 34 women and 19 men, to examine difficult and rewarding aspects of cancer care. Thematic analysis was used to analyze the transcripts. Women were more likely to report negative changes in the relationship with the person with cancer; neglect of self, social isolation, and physical health consequences; anxiety; personal strength and growth; and to position caring as a privilege. Men were more likely to report increased relational closeness with the person with cancer, and the burden of additional responsibilities within the home as a difficult aspect of caring. We interpret these findings in relation to a social constructionist analysis of gender roles.


Kidney growth and renal functions under the growth hormone replacement therapy in children.
The aim of this study was to investigate the kidney growth and renal functions in children receiving recombinant human growth hormone (rhGH) treatment. A total of 37 children who received rhGH for 1.5 years before the study was started and 48 healthy controls were included at first evaluation. Hormone levels were determined and kidney sizes were measured by ultrasound. Kidney functions were assessed by serum creatinine and estimated glomerular filtration rate (eGFR). After 3 years of first evaluation, 23 patients were re-assessed. Kidney sizes were found to be lower in rhGH received children compared with controls at first evaluation (p<0.05). Significant positive correlations were found between anthropometric measurements and kidney length and kidney volume (p<0.05). Height was the most significant predictor of kidney volume in rhGH received children (p<0.001). After 3-years of follow-up significantly increases were found in kidney length and volume compared with the first measurements (p<0.05). Increase percentage of body height was similar to increasing percent of kidney length and liver long axis (14.2%, 11.7.1% and 7.7%, respectively, p>0.05). Although no abnormal renal function test results were found at first and second evaluations; rhGH received children had significantly lower eGFR, at first evaluation, compared with controls; however, renal functions significantly increased after 3 years of follow-up (p<0.05). In conclusion, effect rhGH treatment on kidney growth is parallel to growth in body height and other visceral organs. A 3-years rhGH treatment resulted in significant increases in renal functions.


Inhibition of phospholipid signalling and proliferation of Swiss 3T3 cells by the wortmannin analogue demethoxyviridin.
Growth factors and certain oncogenes activate a range of phospholipid-mediated signal transduction pathways resulting in cell proliferation. Demethoxyviridin (DMV), a structural analogue of wortmannin and recently reported as a potent inhibitor of phosphoinositide-3-kinase, inhibited bombesin plus insulin-stimulated increase in cell number in Swiss 3T3 cells, a model of cell proliferation. The drug produced cytostatic effects at concentrations below 1 microM and cytotoxic effects at 10 microM. In intact Swiss 3T3 cells DMV inhibited insulin-stimulated PI 3- and 4-kinases and bombesin-stimulated phospholipases C, D and A2 in the nanomolar range. DMV also inhibited bombesin-stimulated tyrosine phosphorylation of a range of proteins at nM concentrations. This study shows that DMV inhibited multiple stimulated signalling pathways which lead to increased Swiss 3T3 cell proliferation. A stable analogue of DMV may have chemotherapeutic potential.


Native T1-mapping detects the location, extent and patterns of acute myocarditis without the need for gadolinium contrast agents.
Acute myocarditis can be diagnosed on cardiovascular magnetic resonance (CMR) using multiple techniques, including late gadolinium enhancement (LGE) imaging, which requires contrast administration. Native T1-mapping is significantly more sensitive than LGE and conventional T2-weighted (T2W) imaging in detecting myocarditis. The aims of this study were to demonstrate how to display the non-ischemic patterns of injury and to quantify myocardial involvement in acute myocarditis without the need for contrast agents, using topographic T1-maps and incremental T1 thresholds. We studied 60 patients with suspected acute myocarditis (median 3 days from presentation) and 50 controls using CMR (1.5 T), including: (1) dark-blood T2W imaging; >(2) native T1-mapping (ShMOLLI); (3) LGE. Analysis included: (1) global myocardial T2 signal intensity (SI) ratio compared to skeletal muscle; (2) myocardial T1 times; (3) areas of injury by T2W, T1-mapping and LGE. Compared to controls, patients had more edema (global myocardial T2 SI ratio 1.71 ± 0.27 vs.1.56 ± 0.15), higher mean myocardial T1 (1011 ± 64 ms vs. 946 ± 23 ms) and more areas of injury as detected by T2W (median 5% vs. 0%), T1 (median 32% vs. 0.7%) and LGE (median 11% vs. 0%); all p < 0.001. A threshold of T1 > 990 ms (sensitivity 90%, specificity 88%) detected significantly larger areas of involvement than T2W and LGE imaging in patients, and additional areas of injury when T2W and LGE were negative. T1-mapping significantly improved the diagnostic confidence in an additional 30% of cases when at least one of the conventional methods (T2W, LGE) failed to identify any areas of abnormality. Using incremental thresholds, T1-mapping can display the non-ischemic patterns of injury typical of myocarditis. Native T1-mapping can display the typical non-ischemic patterns in acute myocarditis, similar to LGE imaging but without the need for contrast agents. In addition, T1-mapping offers significant incremental diagnostic value, detecting additional areas of myocardial involvement beyond T2W and LGE imaging and identified extra cases when these conventional methods failed to identify abnormalities. In the future, it may be possible to perform gadolinium-free CMR using cine and T1-mapping for tissue characterization and may be particularly useful for patients in whom gadolinium contrast is contraindicated.


Constitutive secretion of a bacterial enzyme by polarized epithelial cells.
The constitutive (or default) pathway for protein secretion was investigated in two epithelial cells, Madin-Darby canine kidney (MDCK) and human colonic adenocarcinoma (Caco-2), using a bacterial enzyme. The choice of a bacterial protein was based on the requirement to identify a protein devoid of sorting signals. The sorting of a bacterial endoglucanase derived from Clostridium thermocellum, endoglucanase E, from stably transfected MDCK and Caco-2 cells was examined. The choice of a bacterial endoglucanase for these studies has advantages of simple, sensitive and quantitative detection, while higher eukaryotic cells do not express endoglucanase activity. Both cell lines secreted a 50 kDa form of the bacterial protein, while smaller intracellular forms were also observed. In polarized layers of MDCK cells the endoglucanase was secreted into both membrane domains in the ratio 62% apical and 38% basolateral. In Caco-2 cells secretion was predominantly, 70%, through the basolateral membrane. These results define the constitutive pathway for protein secretion in these two model epithelial cells.


Oxygen Persufflation in Liver Transplantation Results of a Randomized Controlled Trial.
Oxygen persufflation has shown experimentally to favorably influence hepatic energy dependent pathways and to improve survival after transplantation. The present trial evaluated oxygen persufflation as adjunct in clinical liver preservation. A total of n = 116 adult patients (age: 54 (23-68) years, M/F: 70/46), were enrolled in this prospective randomized study. Grafts were randomized to either oxygen persufflation for ≥2 h (O2) or mere cold storage (control). Only liver grafts from donors ≥55 years and/or marginal grafts after multiple rejections by other centers were included. Primary endpoint was peak-aspartate aminotransferase (AST) level until post-operative day 3. Standard parameters including graft- and patient survival were analyzed by uni- and multivariate analysis. Both study groups were comparable except for a longer ICU stay (4 versus 3 days) of the donors and a higher recipient age (57 versus 52 years) in the O2-group. Serum levels of TNF alpha were significantly reduced after oxygen persufflation (p < 0.05). Median peak-AST values did not differ between the groups (O2: 580 U/l, control: 699 U/l). Five year graft- and patient survival was similar. Subgroup analysis demonstrated a positive effect of oxygen persufflation concerning the development of early allograft dysfunction (EAD), in donors with a history of cardiopulmonary resuscitation and elevated ALT values, and concerning older or macrosteatotic livers. This study favors pre-implantation O2-persufflation in concrete subcategories of less than optimal liver grafts, for which oxygen persufflation can be considered a safe, cheap and easy applicable reconditioning method.


ETM-ANN approach application for thiobenzamide and quinolizidine derivatives.
The structure anti-influenza activity relationships of thiobenzamide and quinolizidine derivatives, being influenza fusion inhibitors, have been investigated using the electronic-topological method (ETM) and artificial neural network (ANN) method. Molecular fragments specific for active compounds and breaks of activity were calculated for influenza fusion inhibitors by applying the ETM. QSAR descriptors such as molecular weight, E(HOMO), E(LUMO), ΔE, chemical potential, softness, electrophilicity index, dipole moment, and so forth were calculated, and it was found to give good statistical qualities (classified correctly 92%, or 48 compounds from 52 in training set, and 69% or 9 compounds from 13 in the external test set). By using multiple linear regression, several QSAR models were performed with the help of calculated descriptors and the compounds activity data. Among the obtained QSAR models, statistically the most significant one is the one of skeleton 1 with R(2) = 0.999.


Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells.
Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8(+) T cells in particular, has been established as a major factor for anti-HER2/neu-mediated tumor regression. However, the role of CD4(+) T cells is still being defined. The purpose of this study was to explore whether and to what extent CD4(+) T cells are involved in mediating the effects of anti-HER2/neu therapy. The role of CD4(+) T cells was examined using a transplant model of the rat HER2/neu-overexpressing cell line TUBO. Tumor-bearing mice were treated with anti-neu therapy in conjunction with CD4 depletion or CD40L blockade. The effects of CD4 depletion on the antitumor response were examined by tumor growth analysis and enzyme-linked immunospot (ELISPOT). In addition to CD8(+) T cells, CD4(+) T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4(+) cells is necessary throughout anti-neu therapy and not limited to helping CD8(+) T cells. Expression of IFN-γ is necessary for anti-neu therapy and IFN-γ induces MHC-II expression in TUBO cells promoting direct recognition by CD4(+) T cells. Furthermore, intratumoral depletion of CD4(+) T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response. This study reveals the essential role of CD4(+) T cell for anti-neu-mediated tumor regression.


Endozoicomonas genomes reveal functional adaptation and plasticity in bacterial strains symbiotically associated with diverse marine hosts.
Endozoicomonas bacteria are globally distributed and often abundantly associated with diverse marine hosts including reef-building corals, yet their function remains unknown. In this study we generated novel Endozoicomonas genomes from single cells and metagenomes obtained directly from the corals Stylophora pistillata, Pocillopora verrucosa, and Acropora humilis. We then compared these culture-independent genomes to existing genomes of bacterial isolates acquired from a sponge, sea slug, and coral to examine the functional landscape of this enigmatic genus. Sequencing and analysis of single cells and metagenomes resulted in four novel genomes with 60-76% and 81-90% genome completeness, respectively. These data also confirmed that Endozoicomonas genomes are large and are not streamlined for an obligate endosymbiotic lifestyle, implying that they have free-living stages. All genomes show an enrichment of genes associated with carbon sugar transport and utilization and protein secretion, potentially indicating that Endozoicomonas contribute to the cycling of carbohydrates and the provision of proteins to their respective hosts. Importantly, besides these commonalities, the genomes showed evidence for differential functional specificity and diversification, including genes for the production of amino acids. Given this metabolic diversity of Endozoicomonas we propose that different genotypes play disparate roles and have diversified in concert with their hosts.


Trends and Causes of Neonatal Mortality in Serbia, 1997-2016
Regardless of the notable reduction in infant deaths worldwide over the last 30 years, the proportion of neonatal mortality in total child mortality is increasing. To perform a trend analysis of neonatal mortality in Serbia. Descriptive observational study. Joinpoint regression was used to analyze neonatal mortality data for the years 1997 to 2016 that were obtained from the Statistical Office of Serbia. The trend in the neonatal mortality rate decreased significantly by -5.6% (95% CI: -6.5 to -4.6) per year from 1997 to 2007, and by -2.6% (95% CI: -3.7 to -1.5) per year from 2007 to 2016. The neonatal mortality rate for certain conditions originating in the perinatal period decreased by -6.2% (95% CI: -7.5 to -4.9) per year during the years from 1997 to 2006, and by -1.9% (95% CI: -3.1 to -0.7) per year from 2006 to 2016. Among these conditions, disorders related to short gestation and low birth weight, not elsewhere classified, showed an upward trend by 8.5% (95% CI: 6.2 to 10.8) per year during the entire study period. From 1997 to 2016, a significant decrease in the neonatal mortality rate was detected in cases of congenital malformations, deformations, and chromosomal abnormalities, by -5.0% (95% CI: -6.1 to -4.0) per year. The neonatal mortality rate for cases of symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified, decreased by -8.1% (95% CI: -11.0 to -5.2) yearly. The neonatal mortality rate in Serbia decreased between 1997 and 2016, excluding deaths due to short gestation and low birth weight. Therefore, prevention of short gestation and low birth weight should be the highest public priority.


Unloaded movement facilitation exercise compared to no exercise or alternative therapy on outcomes for people with nonspecific chronic low back pain: a systematic review.
The purpose of this study was to determine the effect of unloaded movement facilitation exercises on outcomes for people with nonspecific chronic low back pain (NSCLBP). This systematic review was conducted according to Cochrane Back Review Group and Quality of Reporting of Meta-analyses (QUORUM) guidelines. Exercise effects were reported as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Six high-quality randomized controlled trials were included. For NSCLBP effects favored McKenzie therapy over intensive trunk strengthening for pain: SMD: short-term: 0.35 (0.10, 0.59); long-term 0.36 (0.12, 0.61) and short-term function: SMD: 0.45 (0.20, 0.70) and were comparable for medium-term function: SMD: 0.15 (-0.90, 0.40). Effects of favored McKenzie therapy were comparable to specific spinal stabilization exercises for short-term pain: SMD: 0.63 (-0.11, 1.38) and function: SMD: 0.47 (-0.27, 1.20). Pooled effects favored McKenzie therapy over other exercises for short-term pain (pooled SMD: 0.38 (0.14, 0.61)) and were comparable for short-term function: SMD: 0.10 (-0.20, 0.40). Yoga compared to trunk strengthening produced comparable effects for pain: (SMD: short-term: 0.13 (-0.46, 0.71); medium-term 0.51 (-0.08, 1.11)) and function SMD: short-term: 0.51 (-0.08, 1.10); medium-term 0.38 (-0.22, 0.97)). Compared to education, effects of yoga were large for medium-term pain and function (pooled SMDs: 0.92 (0.47, 1.37); 0.95 (0.50, 1.40)). Effects favored unloaded movement facilitation exercises of McKenzie compared to other or no exercise and were comparable for yoga. For NSCLBP, there is strong evidence that unloaded movement facilitation exercise, compared to no exercise, improves pain and function. Compared to other types of exercise, including effort-intensive strengthening and time-intensive stabilization exercise, the effects are comparable. This challenges the role of strengthening for NSCLBP.


Clinical implementation of adaptive helical tomotherapy: a unique approach to image-guided intensity modulated radiotherapy.
Image-guided IMRT is a revolutionary concept whose clinical implementation is rapidly evolving. Methods of executing beam intensity modulation have included individually designed compensators, static multi-leaf collimators (MLC), dynamic MLC, and sequential (serial) tomotherapy. We have developed helical tomotherapy as an innovative solution to overcome some of the limitations of other IMRT systems. The unique physical design of helical tomotherapy allows the realization of the concepts of adaptive radiotherapy and conformal avoidance. In principle, these advances should improve normal tissue sparing and permit dose reconstruction and verification, thereby allowing significant biologically effective dose escalation. Recent radiobiological findings can be translated into altered fractionation schemes that aim to improve the local control and long-term survival. This strategy is being tested at the University of Wisconsin using helical tomotherapy with its highly precise delivery and verification system along with meticulous and practical forms of immobilization. Innovative techniques such optical guidance, respiratory gating, and ultrasound assessments are being designed and tailored for helical tomotherapy use. The intrinsic capability of helical tomotherapy for megavoltage CT (MVCT) imaging for IMRT image-guidance is being optimized. The unique features of helical tomotherapy might allow implementation of image-guided IMRT that was previously impossible or impractical. Here we review the technological, physical, and radiobiological rationale for the ongoing and upcoming clinical trials that will use image-guided IMRT in the form of helical tomotherapy; and we describe our plans for testing our hypotheses in a rigorous prospective fashion.


Frequency and location of prominent left ventricular trabeculations at autopsy in 474 normal human hearts: implications for evaluation of mural thrombi by two-dimensional echocardiography.
The frequency and location of prominent left ventricular trabeculations were studied in 474 autopsy specimens from subjects evenly distributed by sex and age. These structures were observed in 323 (68%) of the hearts, and their frequency was similar in male (72%) and female (65%) subjects. Neither the frequency nor the location varied appreciably with age. Among the 323 hearts with prominent left ventricular trabeculations, 172 (53%) exhibited 2 or more; thus, the total number of trabeculations was 582. Of these 582 trabeculations, 493 (85%) were septoparietal bundles that inserted into both the free wall and the septum. Trabeculations also were observed between two points on the ventricular septum in 37 (6%) of the hearts and between two points along the free wall in 36 (6%). Less common patterns included trabeculations between the ventricular septum and the posteromedial papillary muscle in 10 hearts (2%), the ventricular septum and the anterolateral papillary muscle in 2, the free wall and the posteromedial papillary muscle in 2, the two papillary muscles in 1 and the apex and the ventricular septum in 1. Accordingly, prominent left ventricular trabeculations are considered to be common variants of the normal human heart. Their size, shape and location may lead to their being misinterpreted, possibly as mural thrombi, by two-dimensional echocardiography.


Effect of chronic epinephrine on aqueous humor flow during the day and during sleep in normal healthy subjects.
Epinephrine 2% drops were administered to one eye and a placebo to the fellow eye twice a day for 2 weeks in 18 normal human volunteers. The circadian rhythm of aqueous humor flow was measured by fluorophotometry. Epinephrine (compared with placebo) had no measurable effect on the rate of aqueous flow or the circadian rhythm of aqueous humor flow. These results suggest either that topical application of epinephrine cannot achieve a sustained effect on the mechanism of aqueous formation compared with endogenous epinephrine or that circulating epinephrine is not the sole or principal hormonal messenger that mediates the circadian rhythm of aqueous flow in humans. An experiment in which epinephrine was administered systemically might clarify this ambiguity.


Genome-wide oligonucleotide-based array comparative genome hybridization analysis of non-isolated congenital diaphragmatic hernia.
Non-isolated congenital diaphragmatic hernia (CDH+) is a severe birth defect that is often caused by de novo chromosomal anomalies. In this report, we use genome-wide oligonucleotide-based array comparative genome hybridization (aCGH) followed by rapid real-time quantitative PCR analysis to identify, confirm and map chromosomal anomalies in a cohort of 26 CDH+ patients. One hundred and five putative copy number changes were identified by aCGH in our cohort of CDH+ patients. Sixty-one of these changes (58%) had been previously described in normal controls. Twenty of the remaining 44 changes (45%) were confirmed by quantitative real-time PCR or standard cytogenetic techniques. These changes included de novo chromosomal abnormalities in five of the 26 patients (19%), two of whom had previously normal G-banded chromosome analyses. Data from these patients provide evidence for the existence of CDH-related genes on chromosomes 2q37, 6p22-25 and 14q, and refine the CDH minimal deleted region on 15q26 to an interval that contains COUP-TFII and only eight other known genes. Although COUP-TFII is likely to play a role in the development of CDH in patients with 15q26 deletions, we did not find COUP-TFII mutations in 73 CDH samples. We conclude that the combination of oligonucleotide-based aCGH and quantitative real-time PCR is an effective method of identifying, confirming and mapping clinically relevant copy number changes in patients with CDH+. This method is more sensitive than G-banded chromosome analysis and may find wide application in screening patients with congenital anomalies.


[E. coli DNA polymerase. A study of the mechanism of primer binding using oligothymidylate analogs with ethylated internucleotide phosphate groups].
The following individual diastereomers of oligothymidylate ethyl esters (the alkyl phosphodiester group is asymmetric with R or S configuration) have been prepared: d[(Tr)8Tp'(Et)T] (I), d[(Tp)8Tp''(Et)T] (II), d[(Tp)8Tp'(Et)TpT] (III), d[(Tp)8Tp'' X (Et)TpT] (IV). A totally esterified analogue d[[(Tp(Et)7]T] (V) was obtained as a diastereomeric mixture. All oligothymidylate derivatives revealed substrate activity as primers of DNA polymerase with poly(dA) as a template. The values of the maximal reaction rates were equal to 14; 2,6; 68; 24 and 0,1% for oligothymidylates (I)-(V) with respect to Vm value (100%) for (Tp)9T. Km values of oligothymidylates (I)-(V), 2,7; 2,5; 0,51; 7,2 microM, were obtained in relation to Km for d[(Tp)9T] (0,4 microM). Diastereomers (I) and (II) were not destroyed by Klenow fragment of DNA polymerase I which has only 3'----5' exonuclease activity. However, these derivatives were hydrolyzed by complete DNA polymerase I due to its 5'----3' exonuclease activity, the reaction rate being 3-10 times lower than in case of d[(Tp)9T]. The data suggest an essential contribution to the primer binding from the positive enzyme group interaction with the 3'-end negatively charged phosphate group of oligonucleotide, together with the primer complementary interaction with the template. At least two phosphodiester groups of the oligonucleotide primer are essential for the reaction of polymerization following the correct binding.