Long non-coding RNA AC122108.1 promotes lung adenocarcinoma brain metastasis and progression through the Wnt/β-catenin pathway by directly binding to aldolase A.
Brain metastasis (BM) is a major pathological subtype of lung adenocarcinoma (LAD), but the pathogenic mechanisms of BM remain unclear. The potential prognostic biomarkers and therapeutic targets for BM of LAD urgently need to be identified. AC122108.1 is a recently discovered new long non-coding ribonucleic acid (RNA). AC122108 was found to be overexpressed in a LAD BM cell model, and upregulated in 64.52% of LAD BM tissues. AC122108 is an independent factor of BM during LAD development; however, the molecular mechanisms and clinical significance of AC122108.1 in LAD have not yet been established. Additionally, in vitro and in vivo experiments showed that the direct binding of AC122108.1 with aldolase A (ALDOA) enhanced the proliferation, apoptosis, invasiveness, migration, and metastasis of LAD cells. This RNA-protein complex decreased the stability of the β-catenin destruction complex, leading to the accumulation of β-catenin in the cytoplasm and ultimately its translocation into the nucleus to activate Wnt(wingless/integrated)/β-catenin signaling. Overall, AC122108.1 promotes LAD BM and its progression through the Wnt/β-catenin pathway by directly binding to ALDOA. This study provides insights into the regulatory mechanism of the LAD BM. AC122108.1 may serve as a potential therapeutic target and prognostic biomarker of LAD.


Description of the transfer function of an optical system with wavelet transforms.
According to the wavefront filtering idea of wavelet optics, the transfer function of an optical system is described with a wavelet scale function. In the transfer function described with a wavelet scale function, different scale parameters a,c and shift parameters b,d correspond to different subtransfer functions, which correspond to different situations of the optical system. According to the request of the optical system, by adjusting all these scale parameters, not only can we obtain the optical images under different conditions, but we can also obtain the singular points under this scale parameter; hence a more ideal output can be obtained by such processing. The transfer function described with a wavelet scale function can be adjusted according to the request of the optical system, which makes the described transfer function self-adjustable. According to all types of disturbing effects to the system, by adjusting the scale and shift parameters, the practical form of the transfer function of an optical system can be confirmed, which satisfies the request of the self-adjustability of the optical imaging system. The result of our analysis shows that describing the transfer function of an optical system with a wavelet scale function is not only feasible but also satisfies the request of the self-adjustability of the optical imaging system, and different optical systems can be described by different wavelet scale parameters. This work breaks from the formal additional describing mode of the transfer function of an optical system and makes description of the transfer function of an optical system convenient.


Hearing loss and use of health services: a population-based cross-sectional study among Finnish older adults.
Older adults with hearing difficulties face problems of communication which may lead to underuse of health services. This study investigated the association of hearing loss and self-reported hearing difficulty with the use of health services and unmet health care needs in older adults. Data on persons aged 65 and older (n = 2144) drawn from a population-based study, Health 2000, were analyzed. Hearing loss was determined with screening audiometry (n = 1680). Structured face-to-face interviews were used to assess self-reported hearing difficulty (n = 1962), use of health services (physician and nurse visits, health examinations, mental health services, physical therapy, health promotion groups, vision test, hearing test, mammography, PSA test) and perceived unmet health care needs. Multivariable logistic regression analyses were used. After adjusting for socio-economic and health-related confounders, persons with hearing loss (hearing level of better ear 0.5-2 kHz > 40 dB) were more likely to have used mental health services than those with non-impaired hearing (OR = 3.2, 95 % CI 1.3-7.9). Self-reported hearing difficulty was also associated with higher odds for mental health service use (OR = 2.1 95 % CI 1.2-3.5). Hearing was not associated with use of the other health services studied, except presenting for a hearing test. Persons with self-reported hearing difficulty were more likely to perceive unmet health care needs than those without hearing difficulty (OR = 1.7, 95 % CI 1.4-2.1). Older adults with hearing loss or self-reported hearing difficulty are as likely to use most health services as those without hearing loss. However, self-reported hearing difficulty is associated with experiencing unmet health care needs. Adequate health services should be ensured for older adults with hearing difficulties.


Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma.
Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells appears to be a promising immunotherapeutic strategy. CAR combines the specificity of antibody and cytotoxicity of cytotoxic T lymphocytes, enhancing T cells' ability to specifically target antigens and to effectively kill cancer cells. Recent efforts have been made to integrate the costimulatory signals in the CAR to improve the antitumor efficacy. Epidermal growth factor receptor variant III (EGFRvIII) is an attractive therapeutic target as it frequently expresses in glioma and many other types of cancers. Our current study aimed to investigate the specific and efficient antitumor effect of T cells modified with CAR containing inducible costimulator (ICOS) signaling domain. A second generation of EGFRvIII/CAR was generated and it contained the EGFRvIII single chain variable fragment, ICOS signaling domain and CD3ζ chain. Lentiviral EGFRvIII/CAR was prepared and human CD3+ T cells were infected by lentivirus encoding EGFRvIII/CAR. The expression of EGFRvIII/CAR on CD3+ T cells was confirmed by flow cytometry and Western blot. The functions of EGFRvIII/CAR+ T cells were evaluated using in vitro and in vivo methods including cytotoxicity assay, cytokine release assay and xenograft tumor mouse model. Chimeric EGFRvIIIscFv-ICOS-CD3ζ (EGFRvIII/CAR) was constructed and lentiviral EGFRvIII/CAR were made to titer of 106 TU/ml. The transduction efficiency of lentiviral EGFRvIII/CAR on T cells reached around 70% and expression of EGFRvIII/CAR protein was verified by immunoblotting as a band of about 57 kDa. Four hour 51Cr release assays demonstrated specific and efficient cytotoxicity of EGFRvIII/CAR+ T cells against EGFRvIII expressing U87 cells. A robust increase in the IFN-γ secretion was detected in the co-culture supernatant of the EGFRvIII/CAR+ T cells and the EGFRvIII expressing U87 cells. Intravenous and intratumor injection of EGFRvIII/CAR+ T cells inhibited the in vivo growth of the EGFRvIII expressing glioma cells. Our study demonstrates that the EGFRvIII/CAR-modified T cells can destroy glioma cells efficiently in an EGFRvIII specific manner and release IFN-γ in an antigen dependent manner. The specific recognition and effective killing activity of the EGFRvIII-directed T cells with ICOS signaling domain lays a foundation for us to employ such approach in future cancer treatment.


Music Training, and the Ability of Musicians to Harmonize, Are Associated With Enhanced Planning and Problem-Solving.
Music training is associated with enhanced executive function but little is known about the extent to which harmonic aspects of musical training are associated with components of executive function. In the current study, an array of cognitive tests associated with one or more components of executive function, was administered to young adult musicians and non-musicians. To investigate how harmonic aspects of musical training relate to executive function, a test of the ability to compose a four-part harmony was developed and administered to musicians. We tested the working hypothesis that musicians would outperform non-musicians on measures of executive function, and that among musicians, the ability to harmonize would correlate positively with measures of executive function. Results indicate that musicians outperformed non-musicians on the Tower of London task, a measure of planning and problem-solving. Group differences were not detected on tasks more selective for inhibitory control, conflict resolution, or working memory. Among musicians, scores on the harmony assessment were positively correlated with performance of the Tower of London task. Taken together, the current results support a strong relationship between musicianship and planning and problem solving abilities, and indicate that the ability to harmonize is associated with components of executive function contributing to planning and problem solving.


Rationale for using aromatase inhibitors to manage benign prostatic hyperplasia. Experimental studies.
Today, human benign prostatic hyperplasia (BPH) is considered primarily to be a disease of the stroma, in which estrogens are thought to play a considerable causative or permissive role. The growing incidence of BPH with increasing age coincides with a shift in the androgen:estrogen ratio in favor of estrogens, not only in terms of serum hormone values, but also in the prostate itself. Furthermore, evidence has been provided for a preferential accumulation of estrogens in the stroma of human hyperplastic tissue, and the presence of an estrogen receptor satisfying the classical criteria of high affinity and low capacity has been demonstrated. Also, animal studies have emphasized the potential role of estrogens in the pathogenesis of BPH. Experimentally, stimulation of the stroma, particularly of smooth muscle, can be induced by aromatizable substrates, such as androstenedione, in the prostates of beagles and cynomolgus monkeys. These effects can be antagonized by aromatase inhibitors, such as atamestane. In addition, the increase in intraprostatic estrogen concentrations and immunohistochemically detectable estrogen receptor content induced by androstenedione in intact dogs is completely reversed by simultaneous treatment with atamestane. In conclusion, clinical data, as well as that from animal models, emphasize an important role for estrogens in the development of BPH. Estrogen deprivation might, therefore, represent a useful treatment for human BPH.


Evaluating the utility of the HTRF Transcreener ADP assay technology: a comparison with the standard HTRF assay technology.
The HTRF (homogeneous time-resolved fluorescence) Transcreener ADP assay is a new kinase assay technology marketed by Cis-Bio International (Bagnols-Cèze, France). It measures kinase activity by detecting the formation of ADP using a monoclonal antibody and HTRF detection principles. In this article, we compare this technology with a standard HTRF kinase assay using EGFR [L858R/T790M] mutant enzyme as a case study. We demonstrate that the HTRF Transcreener ADP assay generated similar kinetic constants and inhibitor potency compared with the standard HTRF assay. However, the smaller dynamic window and lower Z' factor of the HTRF Transcreener ADP assay make this format less preferable for high-throughput screening. Based on the assay principle, the HTRF Transcreener ADP assay can detect both kinase and ATPase activities simultaneously. The ability to probe ATPase activity opens up new avenues for assaying kinases with intrinsic ATPase activity without the need to identify substrates, and this can speed up the drug discovery process. However, caution must be exercised because any contaminating ATPase activity will result in an invalid assay. The inability to tolerate high concentrations of ATP in the assay will also limit the application of this technology, especially in compound mechanistic studies such as ATP competition. Overall, the HTRF Transcreener ADP assay provides a new alternative tool to complement existing assay technologies for drug discovery.


Hierarchical cluster analysis of environmental pollutants through P450 induction in cultured hepatic cells.
Environmental pollutants are classically associated with increased drug metabolism. Cultures of rat hepatocytes, quail hepatocytes, and human hepatoma (Hep G2) cells were used to study the effects of pesticides on drug-metabolizing enzymes. Membrane integrity and mitochondrial activity were evaluated and induction of ethoxycoumarin-O-deethylase and ethoxyresorufin-O-deethylase activities were measured. Induced P450s were identified by immunoblotting. Pentachlorophenol and lindane appeared as the strongest inducers. On the immunoblots, specific antibodies revealed induced CYP1A1 in fetal rat hepatocytes, CYP2B in quail hepatocytes, and CYP3A7 in Hep G2 cells. Pesticide effects on these different activities in each type of cultured cells were compared by cluster analysis. Results obtained under similar conditions with reference inducers phenobarbital (PB) and benzo[a]anthracene and other environmental pollutants (polychlorobiphenyls) were added to previous data prior to multivariate analysis. The tested products fell into four major groups: a first group with pentachlorophenol, identified as a CYP3A inducer; a second group containing the methylcholanthrene-type inducers that increase CYP1A-related activities; a third class represented by dieldrin, a PB-type inducer; a fourth group including inert compounds or weak inducers. Lindane shares the criteria of the second and third groups and seems to induce both CYP1A and CYP2B activities. The current study results highlight the advantage of using several types of cultured hepatocytes to evaluate the short-term toxicity of environmental pollutants in vitro and constitute a useful model for predicting the potential toxicity of pesticides in humans (Hep G2 cells) and wildlife (fetal quail hepatocytes).


Contribution of the sensory innervation of the spine in low back pain: review and clinical commentary.
Few validated tests allow a precise aetiological diagnosis of Low Back Pain (LBP), and the difficulty of clinical evaluations could be one of the reasons to explain the lack of effectiveness in the therapeutic management of chronic LBP. However, an implication of a sensory impairment in the control of sensorimotor circuits could be suggested. Interactive and specific responses between nociceptive nerve fibres and the paraspinal musculature motor control could have clinical implications, in particular through kinematic evaluation. Following an introduction to the link between the sensory innervation of the spine and pain, we then summarise the maladaptive movement in LBP at the kinematic and neuropathological level. A clinical objectification of these kinematic adaptations at the lumbar spine level, would clarify the aetiological diagnosis causes of chronic LBP, and so help optimising therapeutic strategies by proposing a relevant and precise clinical model of this painful condition.


Accuracy of single intravenous access iohexol GFR in children is hampered by marker contamination.
Measurement of glomerular filtration rate (GFR) in children by iohexol injection and blood sampling from the contralateral arm is widely used. A single intravenous access for iohexol injection and subsequent blood sampling has the obvious advantages of being less painful and easier to perform. The purpose of our study was to determine if blood samples drawn from the injection access are feasible and accurate for iohexol GFR (iGFR) measurements. Thirty-one children, median age 10.5 (range 6-17) years, with chronic kidney disease were given a bolus of iohexol followed by extended saline flushing and subsequent venous blood samples collected from the injection access as well as from a cannula in the contralateral arm, the latter serving as the reference method. Paired venous blood samples were collected at four time points (2, 3, 3.5 and 4 h) after the iohexol bolus. Blood sample discarding preceded and saline flushing followed each blood sampling to avoid marker contamination. iGFR based on samples drawn from the injection access at 2 and 3 h showed significantly lower iGFR than measurement from the contralateral arm (p < 0.01). Singlepoint iGFR did not differ significantly after 3-4 repeated procedures of blood discarding and saline flusing (3.5 and 4 h). Despite thorough saline flushing there is still a relatively high risk of falsely low iGFR due to marker contamination in blood samples from the injection site. Hence, blood sampling from a second intravenous access is recommended for routine iohexol GFR measurements in children.Clinical trial registration: ClinicalTrials.gov, Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2 .


Lessons without limit: how free-choice learning is transforming science and technology education.
Societies are becoming nations of lifelong learners supported by a vast infrastructure of learning organizations. The centers of this learning revolution are not schools, but a network of organizations and media (museums, libraries, television, books, and increasingly the Internet) supporting the public's ever-growing demand for free-choice learning - learning guided by a person's needs and interests. Science learning is an important part of this revolution. Traditional boundaries and roles distinguishing groups of science educators and institutions are disappearing. To not understand and embrace these changes will impede our ability to enhance science learning worldwide.


High-Throughput Single-Particle Analysis of Metal-Enhanced Fluorescence in Free Solution Using Ag@SiO2 Core-Shell Nanoparticles.
Metal-enhanced fluorescence (MEF) based on localized surface plasmon resonance (LSPR) is an effective strategy to increase the detection sensitivity in biotechnology and biomedicine. Because plasmonic nanoparticles are intrinsically heterogeneous, high-throughput single-particle analysis of MEF in free solution are highly demanded for the mechanistic understanding and control of this nanoscale process. Here, we report the application of a laboratory-built high-sensitivity flow cytometer (HSFCM) to investigate the fluorescence-enhancing effect of individual plasmonic nanoparticles on nearby fluorophore molecules. Ag@SiO2 core-shell nanoparticles were used as the model system which comprised a silver core, a silica shell, and an FITC-doped thin layer of silica shell. FITC-doped silica nanoparticles of the same particle size but without silver core were used as the counterparts. Both the side scattering and fluorescence signals of single nanoparticles in suspension were measured simultaneously by the HSFCM at a speed of thousands of particles per minute. The roles of silver core size (40-100 nm) and fluorophore-metal distance (5-30 nm) were systematically examined. Fluorescence enhancement factor exceeding 30 was observed at silver core size of 70 nm and silica shell thickness of 5 nm. Compared with ensemble-averaged spectrofluorometric measurements, our experimental observation at the single-particle level was well supported by the finite difference time domain (FDTD) calculation. It allows us to achieve a fundamental understanding of MEF, which is important to the design and control of plasmonic nanostructures for efficient fluorescence enhancement.


Incorporation of functionalized single-wall carbon nanotubes in dye-sensitized TiO2 solar cells.
Effects of incorporation of acid-treated single-wall carbon nanotubes (a-SWCNs) in TiO(2) film and of anchorage of dye-linked, a-SWCNs (hereafter dye-SWCNs) to the TiO(2)/electrolyte interface on photocurrent-voltage characteristics of dye-sensitized solar cells were studied. Compared with an unmodified cell, the modified cell with the a-SWCNs in TiO(2) film showed a 25% increase in short-circuit photocurrent (J(sc)). The J(sc) increase is correlated with improved connectivity between the a-SWCNs and the TiO(2) particles and with enhanced light scattering by TiO(2) clusters formed in the presence of the a-SWCNs. In the case of anchoring dye-SWCNs to the TiO(2)/electrolyte interface, the open-circuit voltage (V(oc)) increased by as much as 0.1 V, possibly due to the basicity of the TiO(2) surface from NH groups of ethylenediamine moieties of the anchored dye-SWCNs.


Evaluation of the predisposing factors and involved outcome of surgical treatment in bisphosphonate-related osteonecrosis of the jaw cases including bone biopsies.
This study examined the statistical relevance of whether the systemic predisposing factors affect the prognosis of surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ). All cases had undergone bone biopsies to determine the characteristics of the mechanisms of BRONJ by optical microscopy. The data included 54 BRONJ cases who underwent surgery and in whom bone biopsies were performed. The results of surgery were evaluated and the results were classified into 3 categories: normal recovery, delayed recovery, and recurrence after surgery. The medical history, such as diabetes mellitus, medication of steroids, malignancies on other sites was investigated for an evaluation of the systemic predisposing factors in relation to the prognosis. The three factors involved with the medication of bisphosphonate (BP) were the medication route, medication period, and drug holiday of BP before surgery. The serum C-terminal cross-linking telopeptide (CTX) value and presence of microorganism colony in bone biopsy specimens were also checked. Statistical analysis was then carried out to determine the relationship between these factors and the results of surgery. The group of patients suffering from diabetes and on steroids tended to show poorer results after surgery. Parenteral medication of BP made the patients have a poorer prognosis after surgery than oral medication. In contrast, the medication period and drug holiday of BP before surgery did not have significance with the results of surgery nor did the serum CTX value and presence of microorganism colony. Necrotic bone specimens in this study typically showed disappearing new bone formation around the osteocytic lacunae and destroyed Howship's lacunae. Although many variables exist, this study could in part, predict the prognosis of surgical treatment of BRONJ by taking the patient's medical history.


[Clinical features of pyogenic liver abscess according to age group].
Pyogenic liver abscess remains a major diagnostic and therapeutic challenge, despite advances in diagnostic technology and new strategies for treatment. This study was conducted to compare the differences in clinical features and outcomes of pyogenic liver abscess according to age. In total, 166 patients were enrolled and included 63 (<65 years old, group I), 62 (65-74 years old, group II), 41 (>75 years old, group III) patients in each group. We reviewed the medical records retrospectively including etiology, underlying diseases, characteristics of the liver abscess, laboratory and microbiologic findings, treatment, and outcome of the patients. Group I had higher prevalence rates of male patients and chronic alcoholics, but lower prevalence rates of biliary disease, hypertension, and malignancy. In laboratory findings, group II had higher incidence of thrombocytopenia, elevated blood urea nitrogen and creatinine. There were no differences in symptoms and microbiologic findings in blood and pus among the three groups. Liver abscesses were more common in right liver in Group I. The lengths of stay and the treatment modalities were similar in three groups. Although there were differences in sex ratio, etiology, underlying disease among the different age groups, they did not cause difference in treatment and clinical outcome of pyogenic liver abscess. Thus, we recommend active treatments in patients of all age.


Evaluation of breast stiffness measured by ultrasound and breast density measured by MRI using a prone-supine deformation model.
This study evaluated breast tissue stiffness measured by ultrasound elastography and the percent breast density measured by magnetic resonance imaging to understand their relationship. Magnetic resonance imaging and whole breast ultrasound were performed in 20 patients with suspicious lesions. Only the contralateral normal breasts were analyzed. Breast tissue stiffness was measured from the echogenic homogeneous fibroglandular tissues in the central breast area underneath the nipple. An automatic, computer algorithm-based, segmentation method was used to segment the whole breast and fibroglandular tissues on three dimensional magnetic resonanceimaging. A finite element model was applied to deform the prone magnetic resonance imaging to match the supine ultrasound images, by using the inversed gravity loaded transformation. After deformation, the tissue level used in ultrasound elastography measurement could be estimated on the deformed supine magnetic resonance imaging to measure the breast density in the corresponding tissue region. The mean breast tissue stiffness was 2.3 ± 0.8 m/s. The stiffness was not correlated with age (r = 0.29). Overall, there was no positive correlation between breast stiffness and breast volume (r = - 0.14), or the whole breast percent density (r = - 0.09). There was also no correlation between breast stiffness and the local percent density measured from the corresponding region (r = - 0.12). The lack of correlation between breast stiffness measured by ultrasound and the whole breast or local percent density measured by magnetic resonance imaging suggests that breast stiffness is not solely related to the amount of fibroglandular tissue. Further studies are needed to investigate whether they are dependent or independent cancer risk factors.


The potential of resilient carbon dynamics for stabilizing crop reproductive development and productivity during heat stress.
Impaired carbon metabolism and reproductive development constrain crop productivity during heat stress. Reproductive development is energy intensive, and its requirement for respiratory substrates rises as associated metabolism increases with temperature. Understanding how these processes are integrated and the extent to which they contribute to the maintenance of yield during and following periods of elevated temperatures is important for developing climate-resilient crops. Recent studies are beginning to demonstrate links between processes underlying carbon dynamics and reproduction during heat stress, consequently a summation of research that has been reported thus far and an evaluation of purported associations are needed to guide and stimulate future research. To this end, we review recent studies relating to source-sink dynamics, non-foliar photosynthesis and net carbon gain as pivotal in understanding how to improve reproductive development and crop productivity during heat stress. Rapid and precise phenotyping during narrow phenological windows will be important for understanding mechanisms underlying these processes, thus we discuss the development of relevant high-throughput phenotyping approaches that will allow for more informed decision-making regarding future crop improvement.


Teasing apart the impacts of curriculum and professional development on teaching assistants' teaching practices.
Teaching assistants (TAs) often lead courses using curricula they did not design. Therefore, examining how curriculum and professional development (PD) interact to influence TAs' teaching practices is critical. This study describes the effects of a curriculum and PD intervention in two contexts: when TAs are teaching curriculum that is explicitly linked to PD, and when teaching curriculum that is not linked to PD. The Intervention curriculum featured structured opportunities for reform-oriented teaching practices. The Intervention PD was situated in the context of these specific curriculum activities and modelled the desired teaching practices. TAs that participated in the intervention implemented more student-centered teaching practices than TAs that did not participate in the intervention, even when teaching curriculum that was not designed to be student-centered and was not linked to PD. A linear model of TAs' teaching practices that included PD type, task cognitive demand and curriculum type indicates that cognitive demand has the largest relationship with teaching practices, followed by PD type. These results have implications for policy. They suggest that investment in curriculum-linked TA PD can be effective even when teaching curricula that is not linked to PD. Additionally, investment in development of higher-cognitive-demand tasks may be an effective strategy to support implementation of student-centered practices.


[Study of the consequences to the health of the Urkutsk Region's population from nuclear explosions at the Semipalatinsk testing site].
Analysis of archival records on the activity of diurnal plane-tables from the region's weather stations revealed local radioactive fall-out in the near-Baikal areas from the nuclear weapon tests carried out at the Semipalatinsk testing site. Examination of mortality rates in the settlements exposed to the tests showed that the maximum rates of overall and lung malignancy mortalities were observed in 1960-1979; the mean radiation dose in the exposed settlements were estimated to be 580-850 MeV.


Evaluating a Decision Aid for Improving Decision Making in Patients with Early-stage Breast Cancer.
Early-stage breast cancer patients face a series of complex treatment decisions, with the first typically being choice of locoregional treatment. There is a need for tools to support patients in this decision-making process. We developed an innovative, online locoregional treatment tool based on International Patient Decision Aids Standards criteria. We evaluated its impact on patient knowledge about treatment and appraisal of decision making in a pilot study using a clinical sample of newly diagnosed, breast cancer patients who were randomized to view the decision aid website first or complete a survey prior to viewing the decision aid. Differences in knowledge and decision appraisal between the two groups were compared using t-tests and chi-square tests. Computer-generated preferences for treatment were compared with patients' stated preferences using chi-square tests. One hundred and one newly diagnosed patients were randomized to view the website first or take a survey first. Women who viewed the website first had slightly higher, though not significantly, knowledge about surgery (p = 0.29) and reconstruction (p = 0.10) than the survey-first group. Those who viewed the website first also appraised their decision process significantly more favorably than did those who took the survey first (p < 0.05 for most decision outcomes). There was very good concordance between computer-suggested and stated treatment preferences. This pilot study suggests that an interactive decision tool shows promise for supporting early-stage breast cancer patients with complicated treatment decision making.


A Prognostic Nomogram Combining Immune-Related Gene Signature and Clinical Factors Predicts Survival in Patients With Lung Adenocarcinoma.
The existence of tumor heterogeneity and complex carcinogenic mechanisms in lung adenocarcinoma (LUAD) make the most commonly used TNM staging system unable to well-interpret the prognosis of patients. Using transcriptome profiling and clinical data from The Cancer Genome Atlas (TCGA) database, we constructed an immune signature based on a multivariate Cox analysis (stepwise model). We estimated the half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs in patients according to the pRRophetic algorithm. Gene-set variation analysis (GSVA) was used to reveal pathway enrichment between groups. Moreover, immune microenvironment landscape was described by single-sample gene-set enrichment analysis (ssGSEA) and CIBERSORT and systematically correlated with genomic of these patients. A prognostic nomogram combining the immune signature and TNM stage to predict the prognosis was developed by multivariate Cox regression. The novel signature with four immune-related genes (MAL, MS4A1, OAS1, and WFDC2) had good robustness, which can accurately distinguish between high- and low-risk patients. Compared with low-risk patients, high-risk patients with a worse prognosis (5-year OS: 46.5 vs. 59.4%, p = 0.002) could benefit more from immunotherapy and the application of common chemotherapeutic agents such as cisplatin and paclitaxel (Wilcoxon test, all p < 0.05). There were significant differences in tumor immune microenvironment and metabolic pathways between the two groups. Additionally, the constructed nomogram had reliable predictive performance with the C-index of 0.725 (95% CI = 0.668-0.781) in the development set (n = 500), 0.793 (95% CI = 0.728-0.858) in the internal validation set (n = 250) and 0.679 (95% CI = 0.644-0.714) in the external validation set (n = 442). The corresponding calibration curves also showed good consistency. To sum up, we developed an immune-related gene signature and comprehensively evaluated LUAD immune landscape and metabolic pathways. Effective differentiation of high- and low-risk patients and accurate construction of nomogram would be helpful to the development of individualized treatment strategies.


Effects of various combinations of benzodiazepines with buprenorphine on arterial blood gases in rats.
Fatalities have been attributed to combinations of high-dose buprenorphine with benzodiazepines. In rats, high-dose buprenorphine combined with midazolam was shown to induce sustained respiratory acidosis, while buprenorphine alone did not. However, the effects of buprenorphine combined with pharmacological doses of benzodiazepines remain unknown. Our objective was to compare the acute effects of four selected benzodiazepines used intravenously at equi-efficacious doses in rats, alone and in combination with buprenorphine on sedation, respiratory rate and arterial blood gases. Buprenorphine (30 mg/kg) did not significantly modify sedation level or respiratory rate, but induced mild and transient effects on pH and PaCO(2) (P < 0.05). Similarly, despite having no effects on respiratory rate, nordiazepam (10 mg/kg), bromazepam (1 mg/kg) and oxazepam (12 mg/kg) mildly and transiently altered pH and PaCO(2) (P < 0.05), whereas clonazepam (5 mg/kg) did not. Buprenorphine combined with each benzodiazepine induced no significant effects on respiratory rate or blood gases, in comparison with buprenorphine alone. However, combinations of oxazepam or nordiazepam with buprenorphine significantly deepened sedation. While both combinations reduced respiratory rate, buprenorphine + 30 mg/kg clonazepam significantly increased PaCO(2) and buprenorphine + 30 mg/kg nordiazepam decreased PaO(2). In conclusion, not all benzodiazepines induce significant respiratory depression at therapeutic doses. We were unable to demonstrate significant effects on rat ventilatory parameters of buprenorphine combined with equi-efficacious pharmacological doses of benzodiazepines in comparison with buprenorphine alone. Our results may suggest that effects of these combinations are rather mild. Respiratory failure may, however, result from the association of buprenorphine with elevated doses of benzodiazepines.


Low-dose hormone replacement therapy: effects on bone.
Hormone replacement therapy (HRT) is considered the mainstay for postmenopausal osteoporosis prevention. However, at the standard doses, HRT preparations can induce bothersome hormone-related side-effects, in both sequential and continuous combined regimens. Lower-dose HRT schedules are reported to be highly effective in the relief of climacteric symptoms, inducing minimal endometrial stimulation with very low rates of unscheduled bleeding. Moreover, low-dose HRT associated with an adequate calcium supplement can spare bone by preventing the increase in bone turnover and the resultant bone loss in postmenopausal women. Low-dose regimens may be considered as a starting dose not only in elderly subjects, but also in early postmenopausal women to allow for adjustment to HRT. In older women, these may minimize the occurrence of side-effects and improve compliance, while preventing the long-term consequences of estrogen deprivation.


Tension pneumothorax: a pulmonary complication secondary to regional anesthesia from brachial plexus interscalene nerve block.
Interscalene brachial plexus anesthesia is often used for surgeries involving the shoulder and upper arm. This method of regional anesthesia decreases pain, nausea, and vomiting associated with general anesthesia. One infrequent complication of interscalene brachial plexus block is tension pneumothorax. Recognition of early signs and symptoms of tension pneumothorax and expeditious treatment for rapid decompression before physiologic decompensation is mandatory. This article discusses the interscalene brachial plexus block procedure leading to the pathogenesis, clinical presentation, diagnosis, and treatment of tension pneumothorax.


Microbial protein formation of different carbohydrates in vitro.
The aim of this study was to investigate the microbial protein yield of different pure carbohydrates to contribute to a more precise prediction of the microbial protein formed in the rumen. In a first experiment, sucrose, wheat starch, microcrystalline cellulose and citrus pectin were incubated for 8 and 24 hr in the modified Hohenheim gas test (HGT) system (3 runs × 2 syringes) including gas production, ammonia and short-chain fatty acid concentration measurements. Ammonia values were used for estimation of the microbial protein formation. In a second experiment, the same substrates were incubated for 96 hr in the HGT system (2 runs × 3 syringes) and gas production was measured after 2, 4, 6, 8, 12, 16, 24, 30, 36, 48, 60, 72 and 96 hr of incubation to obtain the fermentation kinetics and the time of half-maximal gas production (t1/2 ) of the substrates. The substrates differed considerably in their fermentation kinetics, and therefore, comparison on the basis of t1/2 was chosen as the most meaningful. At t1/2 , microbial protein yield [g/kg dry matter] was higher for cellulose than for sucrose and pectin and higher for starch than for sucrose. The microbial protein expressed in g/L gas production was higher for starch and cellulose than for sucrose and pectin at t1/2 . Effects of carbohydrates related to ruminal pH may remain undetected in in vitro trials.


Explaining Medicare to caregivers.
In addition to providing help with tasks such as bathing, dressing and preparing meals, many caregivers also assist with health-care decision making, including making choices about Medicare. Caregivers therefore may require education about issues related to Medicare benefits. In this brief we explore the special Medicare education needs of caregivers.


Effects of combined treatment with imipramine and metyrapone in the forced swimming test in rats. Behavioral and pharmacokinetic studies.
In the present study, we examined the effects of imipramine (IMI) and metyrapone (MET) given alone or in combination of IMI and MET in the forced swimming test in rats. We also measured pharmacokinetic parameters: the level of IMI and its metabolite, desipramine (DMI), in the rat plasma and brain (1 h after the forced swimming test). The present studies indicate that MET (50 mg/kg) reduced immobility time. Combined treatment with MET (50 mg/kg) and IMI (5 or 10 mg/kg) produced stronger antidepressant-like effect than either of drugs given alone. Sulpiride (dopamine D2/3 antagonist), or WAY 100635 (5-HT1A antagonist) but not prazosin, (alpha1-adrenergic antagonist), at doses ineffective in the forced swimming test, inhibited an antidepressant-like effect induced by co-administration of IMI with MET. The active behaviors in that test did not reflect an increase in general activity, since combined administration of IMI and MET failed to alter the locomotor activity of rats, measured in the open field test. MET elevated the concentrations of IMI and DMI in plasma, and the total drug concentration (IMI + DMI) was doubled by MET. In the brain, MET enhanced the concentration of IMI, but decreased that of DMI, consequently, the brain IMI/DMI ratio increased twice. The total drug concentration in the brain (IMI + DMI) was not changed significantly by MET treatment. The obtained results suggest that dopamine D2/3 and 5-HT1A receptors may contribute to the mechanism of synergistic action of IMI and MET in the forced swimming test in rats, and that pharmacokinetic interaction should not have a substantial impact on the MET-induced potentiation of IMI effect, observed in vivo. These findings may be of particular importance to pharmacotherapy of drug-resistant depression.


The chronic injury glucose error grid: a tool to reduce diabetes complications.
Traditional glucose error grids provide error limits for glucose meters. These criteria help to assess the meter's suitability to prevent acute injury. We present a rationale for an error grid that provides a different set of error limits to help prevent chronic injury in diabetes. For example, glucose values in the no treatment zone of a traditional error grid could be harmful in diabetic retinopathy. The same method comparison data informs both the acute and chronic injury error grids. All of the data are used in an acute injury error grid, whereas only long-term biases populate a chronic injury error grid. These biases can be due to reagent lots and patient specific interferences. An example of a chronic injury glucose error grid is provided using simulated data.


Management of an intracanal separated instrument: a case report.
Instrument fracture within the root canal during root canal treatment is an unwanted and frustrating complication. The fractured segment may hinder cleaning and shaping procedures with potential impact on prognosis of treatment. Fracture of endodontic instrument often results from incorrect use or overuse. If breakage occurs clinically, the patient should be informed of the incident and consideration should be given whether to remove the fragment or not. When managed properly, the presence of a broken fragment per se may not adversely affect the outcome of root canal treatment. This article reports management of an intracanal separated instrument. Masserann kit along with gates glidden drills were used to remove the intracanal broken instrument.


Acceptability and adherence: findings from a Phase II study of a candidate vaginal microbicide, 'Praneem polyherbal tablet', in Pune, India.
Acceptability and adherence in clinical trials of microbicides may possibly predict their acceptance by the community. In this study, we investigated the acceptability and adherence of Praneem polyherbal tablet, a candidate microbicide, among 100 HIV-uninfected participants of a Phase II randomised, double-blind, placebo-controlled trial in Pune, India, conducted between June 2004 and February 2006 involving 6 months of coitally-dependent product use. The relationship between five acceptability domains and adherence to product use during the study period was explored. Acceptability and adherence were assessed among 95 study participants completing all study follow-ups. One hundred percent adherence (product use during each sex act for the study period) was reported by 67 participants (70.5%). The majority of participants reported acceptability towards all product characteristics. Product odour was reported to be a concern both in the placebo and Praneem arms. Participants from the Praneem arm [adjusted odds ratio (AOR)=3.8; 95% CI 1.4-10.8] and participants reporting lower acceptability for experience of product use during the sex act (AOR=4.2; 95% CI 1.0-17.3) were more likely to have partial adherence. In conclusion, the study product was acceptable to the majority of participants. However, barriers to adherence attributable to undesirable sexual experiences need to be addressed.


[CAP system methods versus FAST methods in immunologic monitoring of specific immunotherapy in pollen allergy].
The aim was to study the value of the CAP system (Pharmacia) in comparison with the FAST method (Bio Whittaker) in determination of total IgE, specific IgE and IgG4 during specific immunotherapy (sIT). The studies were carried out on a group of 67 patients with pollinosis treated with various pollen allergen extracts. The immunological studies were performed before and after several courses of sIT. A higher reproducibility and sensitivity of the CAP System was shown. The values of specific IgE were somewhat higher on using the CAP system than using the FAST method. The CAP system seems to be of great value in diagnostics and monitoring sIT, especially in birch pollen allergy.


Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the "Variant" Biochemical Phenotype of Niemann-Pick Type C1 Disease.
Niemann-Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder caused by autosomal recessive mutations in the NPC1 gene. Patients display a wide spectrum on the clinical as well as on the molecular level, wherein a so-called "variant" biochemical phenotype can be observed. Here, we report an in vitro analysis of fibroblasts obtained from an NP-C1 patient carrying the undescribed compound heterozygous mutation p.V1023Sfs*15/p.G992R. Since NP-C1 is a neurovisceral disease and the patient suffers from severe neurological as well as hepatic symptoms, we extended our study to neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells. We detected slightly increased intracellular cholesterol levels compared to the control cell line in fibroblasts, neural differentiated and hepatocyte-like cells, suggesting a "variant" biochemical phenotype. Furthermore, the total NPC1 protein, as well as post-ER glycoforms of the NPC1 protein, tended to be reduced. In addition, colocalization analysis revealed a mild reduction of the NPC1 protein in the lysosomes. The patient was diagnosed with NP-C1 at the age of 34 years, after an initial misdiagnosis of schizophrenia. After years of mild and unspecific symptoms, such as difficulties in coordination and concentration, symptoms progressed and the patient finally presented with ataxia, dysarthria, dysphagia, vertical supranuclear gaze palsy, and hepatosplenomegaly. Genetic testing finally pointed towards an NP-C1 diagnosis, revealing the so-far undescribed compound heterozygous mutation p.V1023Sfs*15/p.G992R in the NPC1 gene. In light of these findings, this case provides support for the p.G992R mutation being causative for a "variant" biochemical phenotype leading to an adult-onset type of NP-C1 disease.


The nuclear tubular invaginations are dynamic structures inside the nucleus of HeLa cells.
Nuclear tubules (NTs) were found in the nucleus of HeLa cells. Although no function has been ascribed to these structures, our previous data has shown that they are the sites of Ca(2+) release with mitochondria shuttled around. In the present study, we further characterized these NTs through different fluorescent dye-labeling and red fluorescent protein transfection experiments. We found that doxorubicin (Dox) is a good indicator to demonstrate the NTs since Dox is fluorescent and DNA is able to quench its fluorescence. By using confocal and electron microscopy, we show that the number and nature of the NTs in HeLa vary from cell to cell, ranging from tubular to intricately branched structures. Additionally, these NTs are double-membrane invaginations of the nuclear envelope and usually lie close to nucleolus. At rest, NTs appeared to be stable and their mouths are always closed. Upon Ca(2+) ionomycin stimulation, various forms of dynamism, including membrane protrusion to the nucleus, enlargement and shrinkage of the NTs, and distortion of the nuclear envelope and NTs were observed over a time scale of minutes. These observations suggest that the NT represents a specialized and dynamic compartment inside the nucleus under the control of Ca(2+).


Isolates belonging to CDC group II-i belong predominantly to Sphingobacterium mizutaii Yabuuchi et al. 1983: emended descriptions of S. mizutaii and of the genus Sphingobacterium.
Two clinical strains, NF 296 and NF 931, present in our collection, were identified biochemically as members of CDC group II-i. Determination of the 16S rRNA gene sequence revealed highest similarity with strains of Sphingobacterium mizutaii. Because these strains produced indole, whereas S. mizutaii has been described as indole-negative, we also investigated the type strain and a reference strain of S. mizutaii, LMG 8340(T) (=CCUG 15907(T)) and LMG 8341 (=CCUG 15908), and found both strains also to be positive for indole production. These data warrant inclusion of some of the CDC group II-i strains into S. mizutaii and emended descriptions of Sphingobacterium mizutaii as indole-production-positive and of the genus Sphingobacterium as variable for indole production.


Two siblings with phenotypes mimicking peroxisomal disorders but with discordant biochemical findings.
The authors present a report on two sibling with a nearly identical phenotype mimicking peroxisomal disorder but with totally discordant biochemical findings. In an attempt to confirm the diagnosis of a peroxisomal disorder, plasma levels of very long chain fatty acids (VLCFA) and phytanic acid were determined. In addition, fibroblasts profile of VLCFA and plasmalogen levels were evaluated for Case 2. Pathomorphological examinations represented by lymph node and kidney biopsies as well as postmortem examinations of liver, adrenals and brain were performed in Case 1. The phenotypes of both siblings showed marked resemblance to those observed in children with Zellweger syndrome. The results of biochemical tests performed in Case 1, together with abundant peroxisomes in the liver and the wide spectrum of clinical abnormalities suggest pseudo-Zellweger or Zellweger-like syndromes, but no conclusive data have been found. The plasmalogen level in fibroblasts as well as the fibroblasts profile of VLCFA noted in Case 2 were within the normal range, thus excluding the possibility of a peroxisomal disorder. The striking phenotype resemblance of the siblings mimicking Zellweger, together with discordant biochemical findings, are difficult to explain on the basis of currently available tests.


Effect of ring substitution on the S-H bond dissociation enthalpies of thiophenols. An experimental and computational study.
There are conflicting reports on the origin of the effect of Y substituents on the S-H bond dissociation enthalpies (BDEs) in 4-Y-substituted thiophenols, 4-YC(6)H(4)S-H. The differences in S-H BDEs, [4-YC(6)H(4)S-H] - [C(6)H(5)S-H], are known as the total (de)stabilization enthalpies, TSEs, where TSE = RSE - MSE, i.e., the radical (de)stabilization enthalpy minus the molecule (de)stabilization enthalpy. The effects of 4-Y substituents on the S-H BDEs in thiophenols and on the S-C BDEs in phenyl thioethers are expected to be almost identical. Some S-C TSEs were therefore derived from the rates of homolyses of a few 4-Y-substituted phenyl benzyl sulfides, 4-YC(6)H(4)S-CH(2)C(6)H(5), in the hydrogen donor solvent 9,10-dihydroanthracene. These TSEs were found to be -3.6 +/- 0.5 (Y = NH(2)), -1.8 +/- 0.5 (CH(3)O), 0 (H), and 0.7 +/- 0.5 (CN) kcal mol(-1). The MSEs of 4-YC(6)H(4)SCH(2)C(6)H(5) have also been derived from the results of combustion calorimetry, Calvet-drop calorimetry, and computational chemistry (B3LYP/6-311+G(d,p)). The MSEs of these thioethers were -0.6 +/- 1.1 (NH(2)), -0.4 +/- 1.1 (CH(3)O), 0 (H), -0.3 +/- 1.3 (CN), and -0.8 +/- 1.5 (COCH(3)) kcal mol(-1). Although all the enthalpic data are rather small, it is concluded that the TSEs in 4-YC(6)H(4)SH are largely governed by the RSEs, a somewhat surprising conclusion in view of the experimental fact that the unpaired electron in C(6)H(5)S(*) is mainly localized on the S. The TSEs, RSEs, and MSEs have also been computed for a much larger series of 4-YC(6)H(4)SH and 4-YC(6)H(4)SCH(3) compounds by using a B3P86 methology and have further confirmed that the S-H/S-CH(3) TSEs are dominated by the RSEs. Good linear correlations were obtained for TSE = rho(+)sigma(p)(+)(Y), with rho(+) (kcal mol(-1)) = 3.5 (S-H) and 3.9 (S-CH(3)). It is also concluded that the SH substituent is a rather strong electron donor with a sigma(p)(+)(SH) of -0.60, and that the literature value of -0.03 is in error. In addition, the SH rotational barriers in 4-YC(6)H(4)SH have been computed and it has been found that for strong electron donating (ED) Ys, such as NH(2), the lowest energy conformer has the S-H bond oriented perpendicular to the aromatic ring plane. In this orientation the SH becomes an electron withdrawing (EW) group. Thus, although the OH group in phenols is always in-plane and ED irrespective of the nature of the 4-Y substituent, in thiophenols the SH switches from being an ED group with EW and weak ED 4-Ys, to being an EW group for strong ED 4-Ys.


A phase space spline smoother for fitting trajectories.
This paper presents a phase space spline smoother, which is especially useful for finding a best-fit trajectory from multiple examples of a given physical motion. Unlike conventional spline smoothers, the phase space spline smoother can simultaneously fit position and velocity information. The use of velocity information is important for modeling the dynamic motion of physical systems because the state space of these systems typically includes both position and velocity variables. A detailed description of the computational procedure is presented, along with a discussion of computational expense and practical guidelines for variance estimation, preprocessing of the target dataset, smoothing of multidimensional datasets, and cross-validation for selection of smoothing weights. The smoother is demonstrated on a dataset of handwriting motions.


Factors affecting growth after pediatric liver transplantation.
Poor linear growth after pediatric orthotopic liver transplantation (OLT) is a well-described phenomenon. We have undertaken a bivariate and multivariate analysis of multiple factors that might effect postOLT growth in all children who underwent transplantation at a single center, with survival > 1 year and adequate follow-up. Standardized height score (Z score) and height deficit (centimeters below the 50th percentile) were computed for each patient over time. The variables assessed were (i) age at OLT, (ii) gender, (iii) pretransplantation diagnosis, (iv) Z score and height deficit at OLT, (v) tacrolimus versus cyclosporine as primary immunosuppressive therapy, (vi) retransplantation, (vii) graft disease, (viii) chronic illness, (ix) posttransplant lymphoproliferative disease, (x) intractable rejection, and (xi) prednisone withdrawal. A total of 236 children met the inclusion criteria, with a mean follow-up of 3.8+/-1.9 years. For the population as a whole, the baseline Z score was -1.72 (fourth percentile) with a significant improvement to - 1.37 (ninth percentile) at 2 years, but with no additional gain at 5 years (Z score -1.4). The baseline height deficit was -6.4 cm, with no improvement at 2 years (-6.52 cm), and was significantly worse at 5 years (-7.87 cm). In the bivariate analysis, the most important variables affecting growth were age at OLT, Z score at OLT, and diagnosis. In general, children <2 years with biliary atresia and those with the most growth delay at OLT showed the best posttransplantation growth. In the multivariate analysis, 18 factors were considered, of which 9 were significant. These were (i) Z score at baseline, (ii) follow-up time, (iii) age at OLT, (iv) diagnosis of tumor, (v) diagnosis of fulminant hepatic failure, (vi) retransplantation, (vii) graft disease, (viii) posttransplant lymphoproliferative disease, and (ix) stoppage of prednisone. Multivariate models using these nine variables accounted for 84% of the variation in standardized height. In general, children after OLT show some potential for catch-up growth but do not achieve normal height compared with their age and sex-matched peers. A multivariate analysis was necessary to investigate the interdependent effects of the many variables that can affect growth after OLT. The most important detrimental affects were older age at time of OLT, Z scores greater than -2.0 at OLT, fulminant hepatic failure, tumor, and postOLT complications causing graft dysfunction.


The effect of a collagen membrane in regenerative therapy of two-wall intrabony defects in dogs.
Guided tissue regeneration that supports the periodontal ligament and bone cells in achieving healthy attachment between teeth and alveolar bone following periodontal therapy has been repeatedly described in the literature. The aim of the present study was to assess the effect of an absorbable collagen membrane used in guided tissue regeneration procedures in two-wall intrabony defects. For this purpose, periodontal defects were surgically created around mandibular teeth in nine dogs. In a randomly chosen quadrant in each dog, a collagen membrane was shaped to cover the interproximal bone defect and adjacent root surface. No collagen membrane was placed over the control defects. Block biopsies of test and control sites were obtained from three dogs at 30 days, three dogs at 60 days, and three dogs at 90 days after the procedures. Histomorphologic and histometric evaluations were performed. We observed that both collagen membrane treated and control defects demonstrated similar amounts of new attachment and bone. However, gingival recession and postoperative keratinized tissue loss were observed in most of the sites. Although there was a tendency towards new attachment in both groups, the gingival tissue loss due to recession led to limited regeneration.


A Meta-Analysis of Cardiovascular Events in Systemic Lupus Erythematosus.
Objective: To identify accurate occurrence and risk of cardiovascular (CV) events (stroke and myocardial infarction [MI]) in patients with systemic lupus erythematosus (SLE). Methods: Systemic literature search in PubMed and additional manual search were performed to obtain interested studies until March 31, 2018. The pooled incidences and risk of stroke and MI were calculated. Results: A total of 24 studies were included in this meta-analysis. For MI, a total of 1,516 SLE patients were reported to had MI (n = 96,154) over a mean follow-up of 9.98 years: incidence 2.0% (95% CI: 1.7-2.4%), i.e. 0.20/100 pyrs; in the five studies, 360 SLE patients (n = 18,943) and 817 controls had MI (n = 111,525), revealing that the risk of MI in SLE population was 3.04 times higher than in the general population (RR = 3.04, 95% CI: 1.81-5.11). For stroke, the incidence of 17 studies during the 10.09 follow-up period using random model was 4.4% (95% CI: 3.6-5.1%), i.e. 0.44/100 pyrs; in the 7 studies, 694 SLE patients (n = 22,594) and 4,034 controls had stroke (n = 255,023), indicating that the risk of MI in SLE population was 1.95 times higher than that in the general population (RR = 1.95, 95% CI: 1.52-2.53). Conclusion: Based on the findings from previous reports, our meta-analysis showed that patients with SLE have been at higher risk of CV events.


[Modification of precocious evoked auditory potential amplitudes observed in tinnitus].
Brainstem evoked response audiometry has been performed in 139 patients complaining of tinnitus, unilateral or bilateral. Amplitudes of I, III, V waves and the amplitude relations I/III, I/V, III/V have been compared with those obtained in a normal population (n = 20). Amplitudes of waves I and III decreased according to their localization: decrease of left I and III for left tinnitus, decrease of left I and right III for right tinnitus, and for I and III both left and right for bilateral tinnitus. Recording of brainstem evoked response before any therapeutical treatment, especially study of amplitudes, could therefore provide information an localization of tinnitus.


Strong Increase in Moxifloxacin Resistance Rate among Multidrug-Resistant Mycobacterium tuberculosis Isolates in China, 2007 to 2013.
We designed this study to determine the trend of moxifloxacin resistance among multidrug-resistant tuberculosis (MDR-TB) patients from 2007 to 2013 in China to inform the composition of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment regimens. We assessed moxifloxacin resistance among MDR-TB isolates collected in national drug resistance surveys in 2007 and 2013 that included 3,634 smear-positive and 7,206 culture-positive pulmonary tuberculosis patients, respectively. Moxifloxacin susceptibility was examined by a Mycobacterium growth indicator tube (MGIT) 960 for the 2007 isolates, and by the minimum inhibitory concentration (MIC) method for the 2013 isolates, at both breakpoints 0.5 and 2.0 μg/mL. Risk factors were explored through multivariable log-binominal regression analysis. Mutations in gyrA and gyrB for part of the isolates were also studied through sequencing. Of 401 MDR strains isolated in 2007, moxifiloxacin resistance could be determined for 319 (79.6%): 41 (12.9%) and 10 (3.1%) were resistant at 0.5 and 2.0 μg/mL, respectively. Of 365 MDR strains isolated in 2013, 338 (92.6%) could be analyzed: 140 (41.4%) and 79 (23.4%) were resistant at 0.5 and 2.0 μg/mL. For patients in 2007, no characteristics were significantly associated with moxifloxacin resistance. For patients in 2013, patients aged ≥60 years (adjusted prevalence ratio [aPR], 1.46; 95% confidence interval [CI], 1.10 to 1.93) were more likely to have resistance at 0.5 μg/mL, whereas those residing in eastern China compared to those in central China had an increased risk of resistance at both 0.5 (aPR, 1.85; 95% CI, 1.38 to 2.48) and 2.0 μg/mL (aPR, 2.14; 95% CI, 1.35 to 3.40). Sequencing results were obtained for 245 and 266 MDR-TB isolates in 2007 and 2013, respectively. In total, 34 of 38 (89.5%) and 89 of 104 (85.6%) of 2007 and 2013 moxifloxacin-resistant (0.5 μg/mL) MDR-TB strains had mutations in the gyrA and gyrB gene, respectively. Asp94Gly was the most common mutation among 2007 (11 of 38, 28.9%) and 2013 isolates (24 of 104, 23.1%) and conferred high-level moxifloxacin resistance. Moxifloxacin resistance among MDR-TB patients in China increased from modest to high from 2007 to 2013. Moxifloxacin should be used carefully as a potentially effective drug for composing MDR/RR-TB regimens especially for elderly patients in China. Individual susceptibility testing especially rapid molecular-based assays should be conducted to confirm the susceptibility to moxifloxacin. IMPORTANCE China is one of the high-burden countries for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Moxifloxacin is one of the critical antituberculosis drugs for MDR/RR-TB treatment. Susceptibility to moxifloxacin is therefore very important to compose effective regimens and to provide protection against development of resistance of companion drugs such as bedaquiline and linezolid. There are, however, no nationally representative data on moxifloxacin resistance among MDR/RR-TB cases in China. Therefore, we assessed the resistance prevalence for moxifloxacin among MDR-TB strains isolated in national drug resistance surveys in 2007 and 2013 that covered 72 sites around the country. We demonstrate that the prevalence of moxifloxacin resistance in MDR-TB isolates increased from modest to high, which should prompt the national tuberculosis program to use moxifloxacin cautiously in second-line regimens to treat MDR/RR-TB unless susceptibility can be laboratory-confirmed.


Translating recent results from the Cardiovascular Outcomes Trials into clinical practice: recommendations from the Central and Eastern European Diabetes Expert Group (CEEDEG).
These recommendations aim to improve care for patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk in Central and Eastern Europe. Cardiovascular disease (CVD) and/or chronic kidney disease (CKD) are major interdependent comorbidities in patients with T2D, accounting for 50% of mortality. Following recent CV outcomes trial (CVOT) results, including those from EMPA-REG OUTCOME®, LEADER®, SUSTAIN™-6 and, most recently, the CANVAS study, it is essential to develop regional expert consensus recommendations to aid physicians in interpreting these newest data to clinical practice. The Central and Eastern European Diabetes Expert Group (CEEDEG) followed a Delphi method to develop treatment algorithms to aid physicians in the clinical management of patients with T2D at high CV risk. In light of the latest CVOT results, and in particular the EMPA-REG OUTCOME® and LEADER® trials, the diagnosis, assessment, treatment choice and monitoring of patients with T2D and established CVD and/or CKD have been considered together with existing guidelines and presented in two reference algorithms. In addition, adherence, special prescribing considerations and a proposed multidisciplinary management approach have been discussed and are presented with the proposed algorithms. The latest available high-level evidence on glucose-lowering drugs has enabled CEEDEG to develop practical consensus recommendations for patients with established CVD and/or CKD. These recommendations represent an update to international and country-level guidelines used for these patients, with the aim of providing a resource not only to endocrinologists, but to cardiologists, nephrologists and primary care physicians in the region.


Vestibulo-ocular reflexes of adventitiously and congenitally blind adults.
The vestibulo-ocular reflex (VOR) was measured in congenitally blind, adventitiously blind, and normally sighted adults to determine how it was affected by loss of vision. VOR gain and phase were measured in subjects rotated sinusoidally in total darkness, while concentrating on an imaginary earth-fixed target. Gain was lower in adventitiously blind subjects than in sighted subjects. The gain reduction in blind subjects was accompanied by an increase in the amount of phase lead at low frequencies. The dominant time constant was typically 3 sec for adventitiously blind subjects and 16 sec for sighted subjects. No convincing vestibulo-ocular responses were measured in congenitally blind subjects except at the highest test frequencies. These findings demonstrate that vision is necessary early in life for development of the VOR, and that vision is also necessary throughout life for ongoing maintenance of the VOR.


Cardiac Progenitor Cells and the Interplay with Their Microenvironment.
The microenvironment plays a crucial role in the behavior of stem and progenitor cells. In the heart, cardiac progenitor cells (CPCs) reside in specific niches, characterized by key components that are altered in response to a myocardial infarction. To date, there is a lack of knowledge on these niches and on the CPC interplay with the niche components. Insight into these complex interactions and into the influence of microenvironmental factors on CPCs can be used to promote the regenerative potential of these cells. In this review, we discuss cardiac resident progenitor cells and their regenerative potential and provide an overview of the interactions of CPCs with the key elements of their niche. We focus on the interaction between CPCs and supporting cells, extracellular matrix, mechanical stimuli, and soluble factors. Finally, we describe novel approaches to modulate the CPC niche that can represent the next step in recreating an optimal CPC microenvironment and thereby improve their regeneration capacity.


Reorientation of health services: enablers and barriers faced by organisations when increasing health promotion capacity.
Issue addressed Primary healthcare settings are important providers of health promotion approaches. However, organisational challenges can affect their capacity to deliver these approaches. This review identified the common enablers and barriers health organisations faced and it aimed to explore the experiences health organisations, in particular Aboriginal organisations, had when increasing their health promotion capacity. Methods A systematic search of peer-reviewed literature was conducted. Articles published between 1990-2014 that focused on a health care-settings approach and discussed factors that facilitated or hindered an organisation's ability to increase health promotion capacity were included. Results Twenty-five articles met the inclusion criteria. Qualitative (n=18) and quantitative (n=7) study designs were included. Only one article described the experiences of an Aboriginal health organisation. Enablers included: management support, skilled staff, provision of external support to the organisation, committed staffing and financial resources, leadership and the availability of external partners to work with. Barriers included: lack of management support, lack of dedicated health promotion staff, staff lacking skills or confidence, competing priorities and a lack of time and resources allocated to health promotion activities. Conclusions While the literature highlighted the importance of health promotion work, barriers can limit the delivery of health promotion approaches within primary healthcare organisations. A gap in the literature exists about how Aboriginal health organisations face these challenges. So what? Primary healthcare organisations wanting to increase their health promotion capacity can pre-empt the common barriers and strengthen identified enablers through the shared learnings outlined in this review.


A transposon insertion in the Arabidopsis SSR16 gene causes an embryo-defective lethal mutation.
The SSR16 gene of Arabidopsis has been identified as a gene encoding a ribosomal protein S16 homolog through analysis of a transposon insertion mutation. The insertion mutation is lethal, arresting embryonic development at approximately the transition from the globular to the heart stage of embryonic development. Co-segregation of the mutant phenotype with the transposon-borne drug-resistance marker and loss of the inserted transposon concomitant with phenotypic reversion provided evidence that the transposon had caused the mutation. Sequences flanking the insertion site were amplified from DNA of viable heterozygotes by thermal asymmetric interlaced (TAIL) PCR. The amplified fragment flanking the 3' end of the inserted element was sequenced and found to be identical to an Arabidopsis expressed sequence tag (EST). The EST, in turn, contained a coding sequence homologous to the ribosomal protein S16 (RPS16) of bacteria such as Escherichia coli, Bacillus subtilis and Salmonella typhimurium, as well as Neurospora crassa mitochondria and higher plant plastids. Thus the gene identified by the embryo-defective lethal insertion mutation encodes an RPS16 homolog and has been designated the SSR16 gene.


Statin-induced myopathy: the two faces of Janus.
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have been shown to be effective at lowering low-density lipoprotein cholesterol and decreasing the risk of coronary heart disease. Although safe and well tolerated by most patients, statins have also been associated with muscle-related adverse events. This article reviews statin-associated myotoxicity to clarify the definitions of muscle-related adverse events and discusses their incidences in major statin trials, case reports, and review articles through January 2006. Milder complaints (ie, myalgia) are reported by approximately 5% to 7% of patients who take statins. More severe myotoxicity, namely rhabdomyolysis, is extremely rare for all statins save cerivastatin, and most recent estimates of its incidence are between 0.44 and 0.54 cases per 10 000 person-years. The mechanism of statin-associated myotoxicity has not been satisfactorily defined and is likely due to multiple factors, including membrane instability, mitochondrial dysfunction, and defects in myocyte duplication.


Archaeometric studies on rock art at four sites in the northeastern Great Basin of North America.
Rock art originated some 46,000 years ago and can provide unique insights into the minds of our human ancestors. However, dating of these ancient images, especially of petroglyphs, remains a challenge. In this study, we explore the potential of deriving age estimates from measurements of the areal densities of manganese (DMn) and iron (DFe) in the rock varnish on petroglyphs, based on the concept that the amount of varnish that has regrown on a petroglyph since its creation, relative to the surrounding intact varnish, is a measure of its age. We measured DMn and DFe by portable X-ray fluorescence (pXRF) on dated Late Pleistocene and Holocene rock surfaces, from which we derived accumulation rates of Mn and Fe in the rock varnish. The observed rates were comparable to our previous findings on basalt surfaces in North America. We derived age estimates for the rock art at four sites in the northern Great Basin region of North America based on DMn measurements on the petroglyphs and intact varnish. They suggest that rock art creation in this region began around the Pleistocene/Holocene transition and continued into the Historic Period, encompassing a wide range of styles and motifs. Evidence of reworking of the rock art at various times by Indigenous people speaks of the continued agency of these images through the millennia. Our results are in good agreement with chronologies based on archeological and other archaeometric techniques. While our method remains subject to significant uncertainty with regard to the absolute ages of individual images, it provides the unique opportunity to obtain age estimates for large ensembles of images without the need for destructive sampling.


Visual impairment in elderly patients receiving long-term hemodialysis.
Visual impairments are associated with low quality of life, impairment of daily activities, and accidental falls. As dialysis patients are increasingly older and more disabled, we sought to assess visual impairments within an elderly dialysis population. Based on data from the general population, we hypothesized that more than 30% of dialysis patients 65 years or older would have visual impairment manifested by loss of visual acuity, depth perception, or contrast sensitivity. Single-center cross-sectional study. Patients established on hemodialysis therapy, age older than 65 years. The proportion of elderly hemodialysis patients with impairments in visual acuity, contrast sensitivity, and depth perception. Lighthouse Near Visual Acuity Test, Lea Screener contrast sensitivity test (Goodlite, MA, USA), Titmus Stereotest, Folstein Mini-Mental Status Examination. 152 of 159 patients (95.6%) had visual acuity levels less than age-expected values. Under North American (American Medical Association, edition 4) guidelines for disability compensation, 62 patients (39.0%) fulfilled criteria for legal blindness. Sixty patients (37.0%) had poor contrast sensitivity and 48 (30.6%) failed the Housefly component of the Titmus Stereotest. Failing the Housefly component was associated with a lower Folstein Mini-Mental Status Examination score (23.4 +/- 4.2 v 25.1 +/- 3.5; P = 0.01). This study is limited by the cross-sectional study design and abbreviated test protocol used for vision assessment. Results of this study suggest that elderly hemodialysis patients have a high frequency of visual impairment. Formal low vision assessment and low vision rehabilitation may be useful in elderly dialysis patients. Additional study is required to determine whether the absence of depth perception in this patient group is associated with deteriorating cognitive function.


Ceramic-Based Multisite Platinum Microelectrode Arrays: Morphological Characteristics and Electrochemical Performance for Extracellular Oxygen Measurements in Brain Tissue.
Ceramic-based multisite Pt microelectrode arrays (MEAs) were characterized for their basic electrochemical characteristics and used for in vivo measurements of oxygen with high resolution in the brain extracellular space. The microelectrode array sites showed a very smooth surface mainly composed of thin-film polycrystalline Pt, with some apparent nanoscale roughness that was not translated into an increased electrochemical active surface area. The electrochemical cyclic voltammetric behavior was characteristic of bulk Pt in both acidic and neutral media. In addition, complex plane impedance spectra showed the required low impedance (0.22 MΩ; 10.8 Ω cm2) at 1 kHz and very smooth electrode surfaces. The oxygen reduction reaction on the Pt surface proceeds as a single 4-electron reduction pathway at -0.6 V vs Ag/AgCl reference electrode. Cyclic voltammetry and amperometry demonstrate excellent electrocatalytic activity toward oxygen reduction in addition to a high sensitivity (-0.16 ± 0.02 nA μM-1) and a low limit of detection (0.33 ± 0.20 μM). Thus, these Pt MEAs provide an excellent microelectrode platform for multisite O2 recording in vivo in the extracellular space of the brain, demonstrated in anaesthetized rats, and hold promise for future in vivo studies in animal models of CNS disease and dysfunction.


Estrogen induces distinct patterns of microRNA expression within the mouse uterus.
Control of estrogenic activity within the uterus is evident as unopposed estrogen action is associated with endometrial pathologies such as endometriosis and endometrial carcinoma. MicroRNAs (miRNAs) have emerged as important posttranscriptional regulators, which are postulated to fine-tune the actions of steroids in many systems including the uterus. The objective of the current study was to examine uterine expression of miRNAs in response to estrogen treatment within the mouse uterus using an ovariectomized, steroid-reconstituted mouse model. MicroRNA microarray analysis and subsequent quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) verification revealed that expression of mirn155, mirn429, and mirn451 was significantly increased by estrogen administration whereas mirn181b and mirn204 expression was significantly reduced. Pretreatment with the estrogen receptor (ER) antagonist ICI 182,780 confirmed that estrogen regulation was mediated via the classical ER pathway. This study demonstrates that estrogen regulates specific miRNAs within the murine uterus, which may participate in posttranscriptional regulation of estrogen-regulated genes.


Profile differences between overdose and non-overdose suicide attempts in a multi-ethnic Asian society.
This study explores differences in characteristics of overdose (OD) and non-overdose (NOD) suicide attempts in Singapore. Four hundred eighty-five medical records of people who attempted suicide were extracted from a local general hospital patient database and classified into OD and NOD groups. Differences in socio-demographic factors, suicide characteristics and hospital admission types between both groups were examined. Indians were more likely than the Chinese and Malays to employ OD method in their attempts. More suicide attempts in the OD group than NOD group were self-reported. The most likely place for suicide attempts for both groups was at home, though more NOD suicide attempts were in public areas as compared to the OD group. Analgesics were the most used substance in the OD group. Those who attempted suicide using OD had a higher number of psychiatric ward admissions than the NOD group. Risk and protective factors varied between both groups. Differences in socio-demographics, suicide characteristics and admission characteristics between OD and NOD groups were observed. Recommendations for suicide prevention in the community are discussed. Further studies on the mediators and moderators of these trends and characteristics of suicide attempts are necessary to ensure maximal efficacy of prevention and management.


Non-thermal effects of terahertz radiation on gene expression in mouse stem cells.
In recent years, terahertz radiation sources are increasingly being exploited in military and civil applications. However, only a few studies have so far been conducted to examine the biological effects associated with terahertz radiation. In this study, we evaluated the cellular response of mesenchymal mouse stem cells exposed to THz radiation. We apply low-power radiation from both a pulsed broad-band (centered at 10 THz) source and from a CW laser (2.52 THz) source. Modeling, empirical characterization, and monitoring techniques were applied to minimize the impact of radiation-induced increases in temperature. qRT-PCR was used to evaluate changes in the transcriptional activity of selected hyperthermic genes. We found that temperature increases were minimal, and that the differential expression of the investigated heat shock proteins (HSP105, HSP90, and CPR) was unaffected, while the expression of certain other genes (Adiponectin, GLUT4, and PPARG) showed clear effects of the THz irradiation after prolonged, broad-band exposure.


A photographic diary of travels with David Kupfer.
The present article focuses on David Kupfer as a colleague and fellow traveler who participated in numerous meetings on cytochrome P450 held at exotic venues. It was always a pleasure to renew a long-standing friendship with David by meeting him at these meetings. His inscrutable smile combined with residues of an accent derived from his earlier background in Poland and Israel characterized this warm and delightful man. A number of photos of David in various locales are presented with this article in an attempt to fully capture the outstanding qualities of this man.


Vertical Localization of the Malar Prominence.
During reconstruction or augmentation, it is important to localize the malar complex in a symmetrical and aesthetically pleasing position. Few studies have determined the location of this feature and none related the location to gender, age, or ethnicity. Some of these have attempted to relate the position to the aesthetically pleasing Golden Ratio φ. We assessed the vertical location of the malar prominence relative to other facial landmarks, determined consistency among individuals, and compared this with values used in artistry. Study population consisted of a convenience sample of 67 patients taken from an otolaryngology practice at a large urban medical center. Coordinates of the malar prominence were referenced to distinct facial landmarks from which the ratio of chin-to-malar prominence to chin-to-eye canthus was determined. Average chin-to-malar prominence distance was 0.793 ± 0.023 (SD) of the chin-to-eye canthus distance. Variability due to the specific image chosen [coefficient of variation (CV) = 1.19%] and combined inter/intrareader variability (CV = 1.71%) validate the methodology. Variability among individuals (CV = 2.84%) indicates population consistency. No difference was found between gender and age groups or between whites and Hispanics. Individuals of other/unknown ethnicities were within the range common to whites and Hispanics. Our population's value is not different from the value of 0.809 used in artistry, which is based on the Golden Ratio φ. The vertical position of the malar prominence is consistent among individuals, is clinically well-approximated by the value based on the Golden Ratio, and may be useful as a reference for surgical reconstruction or augmentation.


Application of the Prunus spp. Cyanide Seed Defense System onto Wheat: Reduced Insect Feeding and Field Growth Tests.
Many crops are ill-protected against insect pests during storage. To protect cereal grains from herbivores during storage, pesticides are often applied. While pesticides have an undoubtable functionality, increasing concerns are arising about their application. In the present study, we investigated a bioinspired cyanogenic grain coating with amygdalin as cyanogenic precursor mimicking the feeding-triggered release of hydrogen cyanide (HCN) found for example in bitter almonds. The multilayer coating consisted of biodegradable polylactic acid with individual layers containing amygdalin or β-glucosidase which is capable of degrading amygdalin to HCN. This reaction occurred only when the layers were ruptured, e.g., by a herbivore attack. Upon feeding coated cyanogenic wheat grains to Tenebrio molitor (mealworm beetle), Rhizopertha dominica (lesser grain borer), and Plodia interpunctella (Indianmeal moth), their reproduction as well as consumption rate were significantly reduced, whereas germination ability increased compared to noncoated grains. In field experiments, we observed an initial growth delay compared to uncoated grains which became negligible at later growth stages. The here shown strategy to artificially apply a naturally occurring defense mechanisms could be expanded to other crops than wheat and has the potential to replace certain pesticides with the benefit of complete biodegradability and increased safety during storage.


Conductive conjugated polyelectrolyte as hole-transporting layer for organic bulk heterojunction solar cells.
Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been extensively used as the hole-transporting layer (HTL) in bulk heterojunction (BHJ) solar cells, however, its anisotropic electrical conduction and intrinsic acidic nature generally limit the device performance. Here we demonstrate the application of a water/alcohol soluble CPE (CPE-K) as HTLs in BHJ solar cells, achieving a PCE up to 8.2%. The more superior and uniform vertical electrical conductivity found in CPE-K reduces the series resistance and provides efficient hole extraction.


Preoperative assesment of the immunocompromised patient.
In some surgical patients immunosuppression is easily apparent and directly caused by known underlying disease or treatment. In others, although induced by the underlying disease, immunosuppression may be less obvious. Perioperative management of immunocompromised patient is mostly directed by the fact that immunosuppression itself does not cause pathology, but does leave the patient prone to infection. Immunodeficiency can be broadly characterized as congenital (primary) or acquired (secondary). The majority of immune deficiencies that are of interest to the anaesthetist are acquired. They can be present both in children and adults, in a huge variety of patients that are presented preoperatively. Most of them do not require different than usual perioperative anaesthetic management. However, in some of them specific aspects of treatment should be considered, such as HIV infected, cancer, transplant patients, and those scheduled for organ transplantation.


Genomic and supragenomic structure of the nucleotide-like G-protein-coupled receptor GPR34.
Directed cloning approaches and large-scale sequencing of several vertebrate genomes unveiled many new members of the G-protein-coupled receptor (GPCR) superfamily, among them GPR34. Initial studies showed that GPR34 is an evolutionarily old GPCR structurally related to a group of ADP-like receptors. To gain insight into the genomic organization, regulation of expression, and supragenomic diversification of GPR34 several vertebrate species were analyzed. In contrast to the obviously intronless coding region GPR34 displays an evolutionary preserved 5' noncoding intron-exon structure. Further, an alternatively used cryptic intron was identified within the coding region, which shortens the N terminus by 47 amino acids. Ubiquitous expression of GPR34 is driven by genomic sequences upstream of at least two transcriptional start regions in mouse and rat but only one region in human. In rodents, both promoters are active in all tissues investigated, but the level of activity is tissue-specific. At the translational level, several conserved in-frame AUGs within the first 150 bp of the coding region may serve as start points for translation in human and other mammals. Combinatory mutagenesis and expression of reporter constructs confirmed these multiple translational start points and revealed a preference for the second in-frame AUG in human GPR34. Our data show that multiple translation initiation starts and alternative splicing contribute to the supragenomic diversification of GPR34.


Translocation breakpoint disrupting the host SNHG14 gene but not coding genes or snoRNAs in typical Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a well-known imprinting disorder arising from a loss of paternally imprinted gene(s) at 15q11.2-q13. We report a typical PWS patient with a balanced reciprocal translocation, 46, XY, t(15;19)(q11.2;q13.3). After Illumina whole-genome sequencing, we used BreakDancer-1.45 software to predict candidate breakpoints and manually investigated via the Integrated Genome Viewer. Breakpoint PCR followed by Sanger sequencing determined the t(15;19) breakpoints. We investigated the expression of upstream/centromeric and downstream/telomeric genes of the 15q11.2 breakpoint by reverse transcriptase PCR, using total RNA extracted from the patient's lymphoblasts. Of note, the expression of paternally expressed genes PWAR6, SNORD109A/B, SNORD116, IPW, and PWAR1, downstream of the breakpoint, was abolished. Interestingly, the breakpoint did not destroy protein coding genes or individual snoRNAs. These results indicate that these genes may play a major role in the PWS phenotype.


Epidemiology of adult acute hand infections at an urban medical center.
To define the current epidemiology of adult acute hand infections in an urban setting, with the aim of helping to improve empiric treatment, as hand infections represent a major source of morbidity and can result in stiffness and, possibly, amputation. We performed an electronic medical record search to identify all patients admitted to our urban academic medical center with diagnoses related to open wounds and infections in the hand and fingers over a 6-year period (2005-2010). We recorded demographic data, location of infection, medical comorbidities, and culture data. Of the 2,287 patients admitted with diagnoses related to open wounds and infections in the hand and fingers, 1,507 incision and drainage procedures were performed, which resulted in 458 patients (30%) with culture-positive infections. Wound cultures identified 39 different species of bacteria. Most of these were methicillin-resistant Staphylococcus aureus, which compromised 53% of positive cultures, followed by methicillin-sensitive S aureus in 23% of positive cultures. The cultures were polymicrobial in 19%. History of intravenous drug use or diabetes mellitus was a strong predictor of polymicrobial infection. Methicillin-resistant Staphylococcus aureus was the most common bacteria cultured from these infections. Empiric antibiotic coverage should routinely cover methicillin-resistant S aureus. We noted a higher incidence of polymicrobial infections than previously reported, particularly with intravenous drug use, diabetes, and human bites. Volar hand infections had the highest percentage of positive cultures, whereas paronychia had the lowest percentage. Prognostic IV.


[Hypertensive intracerebral hemorrhage in isolated islands in Nagasaki Prefecture: a remote teleradiology and helicopter transportation system].
Hypertensive intracerebral hemorrhage (HICH) causes significant morbidity and mortality. The time required to transport the patients to a specialized hospital can influence the prognosis. In the isolated islands in Nagasaki prefecture, there is no medical institution which can offer emergent neurosurgical intervention. We reviewed the cases of HICH in this region from January 2006 to September 2010, who were transferred to Nagasaki Medical Center by a helicopter after consultation via teleradiology. Eighty four cases (23%) were transferred via helicopter to our institution from isolated islands. In three of them (4%), re-hemorrhage was demonstrated on computed tomography after helicopter transportation, and one of three had been administered an anti-coagulant agent. Only one case (1%) has deteriorated during helicopter transportation because of acute obstructive hydrocephalus. The outcome at discharge was as follows: modified Rankin Scale (mRS) I: 3 cases (4%), II: 5 cases (6%), III: 3 cases (4%), IV: 30 cases (36%), V: 31 cases (37%), VI: 12 cases (14%), 43 cases (51%) showed poor outcome (mRS V, VI). For medical management in isolated islands, a remote teleradiology system is indispensable to decide a strategy of treatment rapidly, and a helicopter transportation system is very useful in cases requiring emergent neurosurgical intervention, particular in cases of impending cerebral herniation or acute hydrocephalus. However, we may need to expand logistical supporting hospitals or secure other transportation facilities because many of the patients with poor outcome can not return to their home islands.


Involvement of l(-)-rhamnose in sea urchin gastrulation. Part II: α-l-Rhamnosidase.
The sea urchin embryo is recognized as a model system to reveal developmental mechanisms involved in human health and disease. In Part I of this series, six carbohydrates were tested for their effects on gastrulation in embryos of the sea urchin Lytechinus pictus. Only l-rhamnose caused dramatic increases in the numbers of unattached archenterons and exogastrulated archenterons in living, swimming embryos. It was found that at 30 h post-fertilization the l-rhamnose had an unusual inverse dose-dependent effect, with low concentrations (1-3 mM) interfering with development and higher concentrations (30 mM) having little to no effect on normal development. In this study, embryos were examined for inhibition of archenteron development after treatment with α-l-rhamnosidase, an endoglycosidase that removes terminal l-rhamnose sugars from glycans. It was observed that the enzyme had profound effects on gastrulation, an effect that could be suppressed by addition of l-rhamnose as a competitive inhibitor. The involvement of l-rhamnose-containing glycans in sea urchin gastrulation was unexpected, since there are no characterized biosynthetic pathways for rhamnose utilization in animals. It is possible there exists a novel l-rhamnose-containing glycan in sea urchins, or that the enzyme and sugar interfere with the function of rhamnose-binding lectins, which are components of the innate immune system in many vertebrate and invertebrate species.


Wegener's granulomatosis presenting as otomastoiditis. A case report.
A 55-year-old male presented with left-sided otorrhoea, hearing loss and tinnitus of 3 months duration. On clinical examination polypoid tissue was seen prolapsing in the external ear canal. A CT scan of the mastoid cells and middle ear showed otomastoiditis with osteolysis. Oral antibiotic therapy and eardrops were started. When a facial nerve paresis appeared one month later, a mastoidectomy was performed. The mastoid cells and middle ear were filled with a connective tissue-like substance. Postoperative corticosteroids were administered. Despite the therapy the facial nerve problem aggravated and the patient developed severe parietotemporal headache, meningeal irritation and somnolence. The diagnosis of neurosarcoidosis was hypothesised. Blood analysis, including c-ANCA's, culture of the otorrhoea and biopsies of the connective tissue were inconclusive. A CT scan of the brain showed thickening of the left tentorium. A biopsy of the dura indicated a diagnosis of Wegener's granulomatosis. The patient was treated with immunosuppressive medication with satisfactory results.


AACR-NCI-EORTC--21st International Symposium. Molecular targets and cancer therapeutics--Part 1.
The 21st international symposium of the American Association for Cancer Research (AACR), the NCI and the European Organization for Research and Treatment of Cancer (EORTC), held in Boston, included topics covering the development of therapeutics and molecular targets in the field of cancer research. This conference report highlights selected presentations on the development of novel drugs for cancer. Investigational drugs discussed include XL-139 (Bristol-Myers Squibb Co/Exelixis Inc), SPC-3042 (Enzon Pharmaceuticals Inc/ Santaris Pharma A/S), CH-5137291 (Chugai Pharmaceutical Co Ltd), SN-29966/SN-29926/SN-3000 (Proacta Inc), withaferin-A (University of Kansas), Reolysin (Oncolytics Biotech Inc), EZN-3889 and EZN-3892 (Enzon Pharmaceuticals/Santaris Pharma), and CBP-501 (CanBas Co Ltd/Takeda Pharmaceutical Co Ltd).


Genetic and Ecogeographic Controls on Species Cohesion in Australia's Most Diverse Lizard Radiation.
AbstractSpecies vary extensively in geographic range size and climatic niche breadth. If range limits are primarily determined by climatic factors, species with broad climatic tolerances and those that track geographically widespread climates should have large ranges. However, large ranges might increase the probability of population fragmentation and adaptive divergence, potentially decoupling climatic niche breadth and range size. Conversely, ecological generalism in large-ranged species might lead to higher gene flow across climatic transitions, increasing species' cohesion and thus decreasing genetic isolation by distance (IBD). Focusing on Australia's iconic Ctenotus lizard radiation, we ask whether species range size scales with climatic niche breadth and the degree of population isolation. To this end, we infer independently evolving operational taxonomic units (OTUs), their geographic and climatic ranges, and the strength of IBD within OTUs based on genome-wide loci from 722 individuals spanning 75 taxa. Large-ranged OTUs were common and had broader climatic niches than small-ranged OTUs; thus, large ranges do not appear to simply result from passive tracking of widespread climatic zones. OTUs with larger ranges and broader climatic niches showed relatively weaker IBD, suggesting that large-ranged species might possess intrinsic attributes that facilitate genetic cohesion across large distances and varied climates. By influencing population divergence and persistence, traits that affect species cohesion may play a central role in large-scale patterns of diversification and species richness.