Clinical electrophysiology of infantile botulism.
Infantile botulism is a recently recognized cause of acute hypotonic paresis and respiratory failure in young infants. Electrophysiological testing has proven useful in early diagnosis in suspected cases by demonstrating abnormal neuromuscular transmission as is known to occur in botulism. Twenty-five infants with bacteriologically proven botulism were studied by uniform methods in our laboratory and characteristic electrophysiological abnormalities were found. Repetitive stimulation at 20 and 50 Hz was the most specific single test; 23 patients (92%) showed incremental responses. Stimulation at low rates was less specific. Concentric needle electromyography provided useful supplemental information. Short-duration, low-amplitude motor unit potentials were prominent in 22 patients (92%) accompanied by abnormal spontaneous activity in 13 patients (54%). Compound muscle action potential amplitudes were usually reduced, but motor and sensory conduction studies were otherwise normal. Electrodiagnostic testing demonstrated one or more characteristic abnormalities in all cases of infantile botulism. This constellation of electrophysiological abnormalities, combined with an appropriate clinical picture, was so distinctive as to allow early presumptive diagnosis of infant botulism, before the results of bacteriological testing were available.


Pharmacokinetics and Pharmacodynamics of Murepavadin in Neutropenic Mouse Models.
Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein-targeting antibiotics. It specifically interacts with LptD and inhibits lipopolysaccharide (LPS) transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa We determined the plasma protein binding and the pharmacokinetics of murepavadin in plasma and epithelial lining fluid (ELF; pulmonary) in infected animals, and we determined the exposure-response relationship. Treatment of CD-1 neutropenic mice was started 2 h after infection using murepavadin at different dosing frequencies for 24 h, and the number of CFU per lung was determined. The sigmoid maximum-effect model was used to fit the dose-response, and the pharmacodynamic index (PDI) response was used to determine the PDI values, resulting in a static effect and 1-log kill reduction. Using R2 as an indicator of the best fit, the area under the concentration-time curve for the unbound fraction of the drug (fAUC)/MIC ratio correlated best with efficacy. The mean AUC required to provide a static effect was 36.83 mg h/liter (fAUC = 8.25 mg h/liter), and that to provide a 1-log reduction was 44.0 mg h/liter (fAUC = 9.86 mg h/liter). The mean static fAUC/MIC was determined to be 27.78, and that for a 1-log reduction was 39.85. These data may serve to determine doses in humans that are likely to be efficacious.


Prospective evaluation of unmet needs of rural and aboriginal cancer survivors in Northern British Columbia.
The unmet needs of cancer survivors in rural, remote, and aboriginal communities are largely unexplored. We explored potential differences between rural survivors (rss) in 4 general population (gp) and 4 First Nations (fn) communities. We approached 4 gp and 4 fn rs communities to participate in a mixed-methods project. Participants completed the Hospital Anxiety and Depression Scale (hads) and the Survivor Unmet Needs Survey (suns) and provided demographic information. Each question on the suns can be scored from 0 to 4, with 0 representing "no unmet need" and 4 representing "very high unmet need." A directed approach to content analysis of focus group and interview data was used to triangulate the hads and suns results. We prospectively accrued 23 fn rss and 56 gp rss for this study. More fn rss had borderline or abnormal anxiety (5% vs. 21%, p = 0.02). Compared with gp rss, fn rss had higher unmet needs scores in all categories: Information (2.29 vs. 0.8, p < 0.001), Work and Financial (1.66 vs. 0.5, p < 0.001), Access and Continuity of Health Care (1.83 vs. 0.44, p < 0.001), Coping and Sharing (2.22 vs. 0.62, p < 0.001), and Emotional (2.12 vs. 0.63, p < 0.001). The qualitative findings provided examples and insight into the unmet needs experienced by rss. First Nations rss had significantly higher anxiety and unmet needs compared with their gp rs counterparts. In addition, different qualitative themes were identified in the groups. Our findings support the development of tailored approaches to survivorship for these populations.


Tungsten Bronze Barium Neodymium Titanate (Ba(6-3n)Nd(8+2n)Ti(18)O(54)): An Intrinsic Nanostructured Material and Its Defect Distribution.
We investigated the structure of the tungsten bronze barium neodymium titanates Ba(6-3n)Nd(8+2n)Ti(18)O(54), which are exploited as microwave dielectric ceramics. They form a complex nanostructure, which resembles a nanofilm with stacking layers of ∼12 Å thickness. The synthesized samples of Ba(6-3n)Nd(8+2n)Ti(18)O(54) (n = 0, 0.3, 0.4, 0.5) are characterized by pentagonal and tetragonal columns, where the A cations are distributed in three symmetrically inequivalent sites. Synchrotron X-ray diffraction and electron energy loss spectroscopy allowed for quantitative analysis of the site occupancy, which determines the defect distribution. This is corroborated by density functional theory calculations. Pentagonal columns are dominated by Ba, and tetragonal columns are dominated by Nd, although specific Nd sites exhibit significant concentrations of Ba. The data indicated significant elongation of the Ba columns in the pentagonal positions and of the Nd columns in tetragonal positions involving a zigzag arrangement of atoms along the b lattice direction. We found that the preferred Ba substitution occurs at Nd[3]/[4] followed by Nd[2] and Nd[1]/[5] sites, which is significantly different to that proposed in earlier studies. Our results on the Ba(6-3n)Nd(8+2n)Ti(18)O(54) "perovskite" superstructure and its defect distribution are particularly valuable in those applications where the optimization of material properties of oxides is imperative; these include not only microwave ceramics but also thermoelectric materials, where the nanostructure and the distribution of the dopants will reduce the thermal conductivity.


Tetracysteine-based fluorescent tags to study protein localization and trafficking in Plasmodium falciparum-infected erythrocytes.
Plasmodium falciparum (Pf) malaria parasites remodel host erythrocytes by placing membranous structures in the host cell cytoplasm and inserting proteins into the surrounding erythrocyte membranes. Dynamic imaging techniques with high spatial and temporal resolutions are required to study the trafficking pathways of proteins and the time courses of their delivery to the host erythrocyte membrane. Using a tetracysteine (TC) motif tag and TC-binding biarsenical fluorophores (BAFs) including fluorescein arsenical hairpin (FlAsH) and resorufin arsenical hairpin (ReAsH), we detected knob-associated histidine-rich protein (KAHRP) constructs in Pf-parasitized erythrocytes and compared their fluorescence signals to those of GFP (green fluorescent protein)-tagged KAHRP. Rigorous treatment with BAL (2, 3 dimercaptopropanol; British anti-Lewisite) was required to reduce high background due to nonspecific BAF interactions with endogenous cysteine-rich proteins. After this background reduction, similar patterns of fluorescence were obtained from the TC- and GFP-tagged proteins. The fluorescence from FlAsH and ReAsH-labeled protein bleached at faster rates than the fluorescence from GFP-labeled protein. While TC/BAF labeling to Pf-infected erythrocytes is presently limited by high background signals, it may offer a useful complement or alternative to GFP labeling methods. Our observations are in agreement with the currently-accepted model of KAHRP movement through the cytoplasm, including transient association of KAHRP with Maurer's clefts before its incorporation into knobs in the host erythrocyte membrane.


A study of the dental solid waste produced in a school of dentistry in Turkey.
Dental wastes are regulated under medical waste control regulations in most countries. Even though the quantity of hazardous wastes in dental solid wastes is a small proportion, there is still cross infection risk and potential danger for environment associated with mismanaged wastes. For this reason, knowledge of waste composition and development of proper management alternatives are necessary. In this study, the composition of solid wastes coming from eight clinics of the dental school of a University hospital in Turkey is examined. Although the waste has some variations between the two samplings, the general picture is such that the major components remain pretty much the same (in terms of %) for a fixed clinic. The composition of waste changes from one clinic to the other as expected. However, one can deduce from the data obtained that at about 35%, rubber gloves constitute close to the half of the total solid waste in almost all the clinics. Other major component is paper forming approximately 30% of the solid waste. In general, total waste coming from the clinics is related with the number of procedures conducted on patients at the clinics. Only a small fraction of the waste is hazardous indicating that at Hacettepe University School of Dentistry, hazardous waste collection rules are obeyed in most of the times.


[Perioperative myocardial infarct during the surgical treatment of IHD].
Perioperative myocardial infarction is one of the most frequent causes of death in patients subjected to surgery for coronary disease. Study of the pathogenesis of this complication may become an approach to decreasing the postoperative mortality. Forty-seven case histories and autopsy protocols of patients who died after surgery on the coronary arteries and 241 intraoperative biopsy specimens of autovenous shunts are analyzed. The mechanisms underlying the cardiomyocyte necrosis in surgical treatment of coronary disease are based on various pathological processes, the leading of which is thrombosis of the shunts and coronary arteries. The principal factors were intraoperative ischemia of autovein endothelium and shunting of coronary artery with a narrow distal bed.


Expectations of Processing Ease, Informativeness, and Accuracy Guide Toddlers' Processing of Novel Communicative Cues.
Discovering the meaning of novel communicative cues is challenging and amounts to navigating an unbounded hypothesis space. Several theories posit that this problem can be simplified by relying on positive expectations about the cognitive utility of communicated information. These theories imply that learners should assume that novel communicative cues tend to have low processing costs and high cognitive benefits. We tested this hypothesis in three studies in which toddlers (N = 90) searched for a reward hidden in one of several containers. In all studies, an adult communicated the reward's location with an unfamiliar and ambiguous cue. We manipulated the processing costs (operationalized as inferential chain length) and cognitive benefits (operationalized as informativeness) of the possible interpretations of the cues. Toddlers processing of novel communicative cues were guided by expectations of low processing costs (Study 1) and high cognitive benefits (Studies 2 and 3). More specifically, toddlers treated novel cues as if they were easy to process, informative, and accurate, even when provided with repeated evidence to the contrary. These results indicate that, from toddlerhood onward, expectations of cognitive utility shape the processing of novel communicative cues. These data also reveal that toddlers, who are in the process of learning the language and communicative conventions of people around them, exert a pressure favoring cognitive efficiency in communicative systems.


[Evaluation of clinical competence. The immediate future of nursing].
In this article, the authors analyze the concept of professional competence and they describe some of the methods destined to be used in the evaluation of said competence in nursing professionals. The authors describe different levels of professional performance to which an evaluation may be carried out according to the conceptual model developed by Miller. Special emphasis is placed on the third level of evaluation which is based on simulations of professional practice whose protagonists are the so called simulated or role-playing/standardized sick. One type of very novel evaluation test is the Objective Structured Clinical Examination (OSCE) which makes use of, besides the simulated or role-playing/standardized sick, other mediums such as manikins, standardized tests, open-ended short answer questions, etc. This is one of the most complete clinical competence evaluation methods currently available, although one should not forget that this evaluation is carried out in a simulated, laboratory, setting.


Cat Scratch Disease as a Mimicker of Malignancy.
Cat scratch disease (CSD) infrequently mimics malignancy. We reviewed 11 such cases at MD Anderson Cancer Center and an additional 36 reported from the literature. Breast cancer, sarcoma, and lymphoma were the most commonly suspected malignancies. Most patients were young, female, had prior cat exposure, and had no systemic symptoms. Regional lymphadenopathy was the most common finding.


Are public health professionals prepared for public health genomics? A cross-sectional survey in Italy.
Public health genomics is an emerging multidisciplinary approach, which aims to integrate genome-based knowledge in a responsible and effective way into public health. Despite several surveys performed to evaluate knowledge, attitudes and professional behaviors of physicians towards predictive genetic testing, similar surveys have not been carried out for public health practitioners. This study is the first to assess knowledge, attitudes and training needs of public health professionals in the field of predictive genetic testing for chronic diseases. A self-administered questionnaire was used to carry out a cross-sectional survey of a random sample of Italian public health professionals. A response rate of 67.4% (797 questionnaires) was achieved. Italian public health professionals have the necessary attitudinal background to contribute to the proper use of predictive genetic testing for chronic diseases, but they need additional training to increase their methodological knowledge. Knowledge significantly increases with exposure to predictive genetic testing during postgraduate training (odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.05-2.88), time dedicated to continuing medical education (OR = 1.53, 95% CI = 1.14-2.04) and level of English language knowledge (OR = 1.36, 95% CI = 1.07-1.72). Adequate knowledge is the strongest predictor of positive attitudes from a public health perspective (OR = 3.98, 95% CI = 2.44-6.50). Physicians show a lower level of knowledge and more public health attitudes than other public health professionals do. About 80% of public health professionals considered their knowledge inadequate and 86.0% believed that it should be improved through specific postgraduate training courses. Specific and targeted training initiatives are needed to develop a skilled public health workforce competent in identifying genomic technology that is ready for use in population health and in modeling public health genomic programs and primary care services that need to be developed, implemented and evaluated.


NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.
Cardiac structural genes have been implicated as causative factors for congenital heart diseases (CHDs). NEXN is an F-actin binding protein and previously identified as a disease gene causing cardiomyopathies. Whether NEXN contributes to CHDs aetiologically remains unknown. Here, we explored the function of NEXN in cardiac development. First, we determine the role of NEXN in cardiac differentiation using mouse P19cl6 in vitro model; we demonstrated that NEXN inhibited cardiac contractile markers, serving as a negative regulator. Interestingly, we found this effect was mediated by GATA4, a crucial transcription factor that controls cardiac development by knockdown, overexpression, and rescue experiment, respectively. We then generated transgenic mouse models and surprisingly, we discovered cardiac-selective expression of the NEXN gene caused atrial septal defects (ASDs). Next, to search for the mutations in NEXN gene in patients suffering from ASDs, we sequenced the exon and exon-intron joint regions of the NEXN gene in 150 probands with isolated ASDs and identified three mutations in the conserved region of NEXN (c.-52-78C>A, K199E, and L227S), which were not found in 500 healthy controls. Finally, we characterize the related mechanisms and found all mutations inhibited GATA4 expression. We identify NEXN as a novel gene for ASD and its function to inhibit GATA4 established a critical regulation of an F-actin binding protein on a transcription factor in cardiac development.


Immunocytochemical application of monoclonal antibodies to rat liver glucocorticoid receptor.
Seven per cent (10/145) of hybridomas raised against partially purified activated glucocorticoid receptor from rat liver produced monoclonal antibody to receptor. Six IgM secreting clones selected for further investigation bound equally well to activated and non-activated receptor from fresh rat liver, but significantly less well (11-25 per cent) to receptor from frozen rat liver. No interaction was found with oestrogen receptor from rat uterus but extensive cross reaction occurred with progesterone receptor. Although none of the antibodies bound to glucocorticoid receptor from human or porcine liver or lymphoid cells, several cross-reacted with mouse liver glucocorticoid receptor. Immunoelectroblotting of proteins from fresh and frozen rat liver cytosol showed the antibodies bound to 90,000 and 40,000 MW forms of receptor respectively. Immunostaining of both frozen and paraffin embedded sections of rat tissue showed that receptor is preserved during fixation and processing of tissues. Using both indirect immunoperoxidase and immunogold silver staining methods, the pattern of receptor staining observed correlates with the known glucocorticoid responsiveness of the tissues studied.


Topical Negative Pressure Wound Therapy of Burned Hands: Functional Outcomes.
Extensive partial- and full-thickness burns, especially of the hands, continue to pose a surgical challenge. With improved knowledge regarding fluid balance, burn pathophysiology, and lately also given the introduction of topical negative pressure wound (TNPW) therapy, treatment regimes have changed in many burn centers. The authors evaluated the results regarding long-term outcomes of patients with partial- and full-thickness burns of the hands treated with TNPW. Over a period of 72 months, 51 patients with 80 hand burns received TNPW treatment. Medical records of all patients were reviewed retrospectively. All patients were further invited by letter, telephone, and/or email to participate in follow-up examinations. Finally, 30 patients with 47 involved hands participated in this study. Follow-up examinations were performed at a mean of 35 (range: 14-72) months postinjury. Measurements regarding the ability to completely dorsally extend the fingers and complete active fist closure showed no restrictions in 85.1 and 78.7% of cases. Mean Disabilities of the Arm, Shoulder, and Hand score among all patients was 13.8 (range: 0-35.8). Regarding the quality of the scars of the hand, 41 hands showed good quality with no signs of hypertrophic scar formation and 6 hands showed acceptable quality of scars with partial hypertrophic scar formation. In the authors' experience, TNPW therapy is a safe and effective modality to treat burns of the hand.


Gender Differences and Mortality Trends After Transcatheter Aortic Valve Implantation: A 10-Year Analysis From a Single Tertiary Center.
To evaluate gender differences and mortality trends in a population undergoing transcatheter aortic valve implantation (TAVI) and to analyze the correlates to all-cause mortality at follow-up. The study comprises a prospective cohort of 592 TAVI patients (53.4% female) treated between 2008 and 2018. Mortality differences between genders at different timepoints were assessed according to log rank test. Predictors of all-cause mortality at follow-up were identified using a univariate model and were then analyzed through multivariate Cox proportional hazard models. Compared with female patients, males were younger (81 ± 7.5 years vs 84.3 ± 5.3 years) and presented more comorbidities. Twelve female and 8 male patients (3.5%) died in the first 30 days after TAVI. Despite a higher Society of Thoracic Surgeons (STS) score in women, all-cause mortality rates at 30 days and 1 year were comparable. At long-term follow-up, female patients demonstrated better survival rates, despite a higher number of periprocedural complications. Correlates identified in men were the presence of diabetes and previous history of coronary artery bypass grafting, New York Heart Association class III/IV, pulmonary artery systolic pressure, and non-transfemoral access. None of these variables remained significant in the multivariable analysis. In females, only peripheral artery disease was associated with mortality. Shock and need for renal replacement were predictors of mortality in both genders, as was heart failure readmission after discharge. STS score was also shown to correlate with long-term mortality in both genders. Despite a higher STS score in women, 30-day mortality was not significantly different from men, while women present better clinical outcomes at long-term follow-up.


Voltage-dependent membrane potential oscillations of rat striatal fast-spiking interneurons.
We used whole-cell recordings to investigate subthreshold membrane potential oscillations and their relationship with intermittent firing in striatal fast-spiking interneurons. During current injections (100-500 pA, 1 s), these cells displayed a highly variable pattern of spike bursts (comprising 1-30 action potentials) interspersed with membrane potential oscillations. The oscillation threshold was -42 +/- 10 mV, and coincided with that for action potentials. The oscillation frequency was voltage dependent and ranged between 20 and 100 Hz. Oscillations were unaffected by the calcium channel blockers cadmium and nickel and by blockers of ionotropic glutamate and GABA receptors. Conversely, the sodium channel blocker tetrodotoxin fully abolished the oscillations and the spike bursts. The first spike of a burst appeared to be triggered by an oscillation, since the timing and rate of rise of the membrane potential in the subthreshold voltage region was similar for the two events. Conversely, the second spike (and the subsequent ones) displayed much faster depolarisations in the subthreshold voltage range, indicating that they were generated by a different mechanism. Consistent with these notions, a small pulse of intracellular current delivered during the oscillation was effective in triggering a burst of action potentials that largely outlasted the pulse. We conclude that fast-spiking interneuron oscillations are generated by an intrinsic membrane mechanism that does not require fast synaptic transmission, and which depends on sodium conductance but not calcium conductance, and that such oscillations are responsible for triggering the intermittent spike bursts that are typical of these neurons.


Ambient air pollution and traffic exposures and congenital heart defects in the San Joaquin Valley of California.
Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n = 822 cases and n = 849 controls). Particulate matter < 10 microns (PM10 ) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile = 0.3) [95% CI 0.1, 0.8]. PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.


Large-scale finite element analysis of human cancellous bone tissue micro computer tomography data: a convergence study.
The complex geometry of cancellous bone tissue makes it difficult to generate finite element (FE) models. Only a few studies investigated the convergence behavior at the tissue scale using Cartesian meshes. However, these studies were not conducted according to an ideal patch test and the postelastic convergence behavior was not reported. In this study, the third principal strain and stress, and the displacement obtained from human micro finite element (microFE) models of lower resolutions were compared against the model of 19.5 μm as a reference, representing the original spatial resolution of microCT data. Uni-axial compression simulations using both linear-elastic and nonlinear constitutive equations were performed. The results showed a decrease in percentage difference in all three values as the element size decreased, with the displacement converging the fastest among the three. Simulations carried out using a nonlinear constitutive equation however, failed to show convergence for the third principal strains and stresses. It was concluded that at the tissue level, Cartesian meshes of human cancellous bone tissue were able to reach a converged solution in all three parameters investigated for linear simulation and only in displacement for nonlinear simulation. These parameters can be used as references in the future for studies in local biomechanical behavior of human cancellous bone tissues with linear simulation. The convergence behavior for human cancellous bone tissue using nonlinear constitutive equations needs further investigation.


ATM activation in the presence of oxidative stress.
The Ataxia-Telangiectasia mutated (ATM) kinase is regarded as the major regulator of the cellular response to DNA double strand breaks (DSBs). In response to DSBs, ATM dimers dissociate into active monomers in a process promoted by the Mre11-Rad50-Nbs1 (MRN) complex. ATM can also be activated by oxidative stress directly in the form of exposure to H2O2. The active ATM in this case is a disulfide-crosslinked dimer containing 2 or more disulfide bonds. Mutation of a critical cysteine residue in the FATC domain involved in disulfide bond formation specifically blocks ATM activation by oxidative stress. Here we show that ATM activation by DSBs is inhibited in the presence of H2O2 because oxidation blocks the ability of MRN to bind to DNA. However, ATM activation via direct oxidation by H2O2 complements the loss of MRN/DSB-dependent activation and contributes significantly to the overall level of ATM activity in the presence of both DSBs and oxidative stress.


New options for treatment of Parkinson's disease.
New medications recently developed for treating Parkinson's disease include two inhibitors of catechol-O-methyltransferase (COMT), entacapone and tolcapone, which, by decreasing the elimination of levodopa, extend the duration of its effects. Increased 'on' time and less 'wearing-off' symptomatology can be expected with the use of these COMT inhibitors. Two non-ergot dopaminergic agonists (pramipexole and ropinirole) and a long-acting ergoline (cabergoline) are also being introduced. These dopaminergic agonists, like the ergot derivatives currently available (bromocriptine, lisuride, and pergolide), are useful as adjuncts to levodopa, and are also efficacious as monotherapies.


Risk of lung cancer in workers producing stainless steel and metallic alloys.
The mortality of workers involved in the production of stainless and alloyed steel from 1968 to 1992 was studied, in order to investigate the risk of lung cancer due to exposure to metals, i.e. iron oxides, chromium and/or nickel compounds. The study design was a historical cohort mortality study and a nested case-control study concerning lung cancer. Standardized mortality ratios (SMRs) were computed using regional mortality rates as an external reference for comparing observed and expected numbers of deaths, adjusting for age, sex and calendar time. Conditional logistic regression was used to estimate odds ratios (ORs). Occupational exposure was assessed through the complete job histories of cases and controls and a specific job-exposure matrix. The cohort comprised 4,288 male and 609 female workers. The observed overall mortality was significantly lower than expected [649 deaths; SMR = 0.91; 95% confidence interval (CI) 0.84-0.98]. No significant SMR was observed for mortality from lung cancer (54 deaths; SMR = 1.19; CI 0.88-1.55). The case-control study was based on 54 cases and 162 individually matched controls. Smoking habits were available for 71%. No lung cancer excess was observed for exposure to (1) metals and/or their compounds, i.e. iron (OR = 0.94, CI 0.48-1.86), chromium and/or nickel (OR = 1.18, CI 0.62-2.25), and cobalt (OR =0.64, CI 0.33-1.25), (2) acid mists (OR = 0.43, CI 0.17-1.10), and (3) asbestos (OR = 1.00, CI 0.54-1.86). With respect to exposure to polycyclic aromatic hydrocarbons (PAHs) and silica, which are often found together in workplaces, (1) high and statistically significant lung cancer excesses were observed, the ORs being 1.95 (CI 1.03-3.72) and 2.47 (CI 1.28-4.77) respectively, (2) quantitative exposure parameters revealed upward trends reaching statistical significance (P < 0.05), and (3) adjustments for tobacco consumption did not reveal any confounding factors from smoking. This study failed to detect any relationship between lung cancer and exposure to iron, chromium, nickel and/or their compounds. High and statistically significant relative risks, along with increasing trends, were observed for simultaneous exposure to PAHs and silica.


THE EFFECT OF ELECTIVE CATARACT EXTRACTION BY PHACOEMULSIFICATION IN EYES WITH VITREOMACULAR TRACTION SYNDROME.
To evaluate the effect of cataract extraction (CE) by phacoemulsification on the vitreomacular interface (VMI) of eyes with preexisting vitreomacular traction (VMT). Retrospective, observational case series. Patients with VMT who elected to proceed with CE, before any vitreoretinal intervention, were studied. Eyes with at least a 12-month follow-up period were included. The status of the vitreomacular adhesion at different time points was assessed using spectral-domain optical coherence tomography. The best-corrected visual acuity was recorded at different time points. Other macular and systemic comorbidities were documented. Fifteen eyes from 15 phakic patients with symptomatic VMT were included. Six of them were male subjects. Seven patients had diabetes mellitus and two of them also had nonproliferative diabetic retinopathy. The preoperative macular comorbidities included macular hole in six eyes (Stage 1 in 3 eyes and Stage 2 or 3 in another 3 eyes), epiretinal membrane in five eyes, and cystoid macular edema in four eyes. After uncomplicated CE, the VMT was released in 5 eyes, whereas in 10 eyes, CE did not significantly change the status of the vitreomacular adhesion. Three of 3 eyes with preexisting full-thickness macular hole (Stage 2 or 3 macular hole) were found to have Stage 4 macular hole shortly after CE. In seven of seven patients with diabetes mellitus, the status of the vitreomacular interface did not change after CE. Eventually, 7 of 15 patients underwent additional pars plana vitrectomy. Compared with the baseline vision, and vision before other interventions, the visual acuity after CE improved in 5 patients, remained unchanged in 7 patients, and decreased in the 3 patients with Stage 2 or 3 macular hole. The mean preoperative and early postoperative visual acuity was 20/59 and 20/68, respectively (P > 0.05). The effect of CE in phakic eyes with known VMT varies significantly. In the current case series, every eye with VMT and Stage 2 or 3 macular hole ended up with Stage 4 macular hole, although the VMT did not change significantly in the eyes of diabetic patients. Studies with larger sample size are needed to further elucidate the impact of elective CE on VMT.


Comparison of fluorescent-antibody methods and enrichment serology for the detection of Salmonella.
Four rapid methods for detection of Salmonella, (i) the conventional fluorescent-antibody (FA) technique, (ii) a rapid direct FA technique, (iii) microcolony FA, and (iv) enrichment serology (ES), were compared with conventional cultural procedures. A total of 347 subsamples representing 16 different food prototypes, alleged to be naturally contaminated with Salmonella, were analyzed. From these samples, 52 were found to contain Salmonella by cultural methods. Conventional FA identified all 52 culturally positive samples, ES identified 51, microcolony FA identified 48, and the rapid FA method identified 34. The number of false-positive samples for each procedure was: ES-selenite, 7; tetrathionate, 8; rapid FA, 26; microcolony FA, 33; conventional FA-selenite, 27; tetrathionate, 26. Tetrathionate enrichment was found to be superior to selenite for Salmonella recovery from most foods, but the concurrent use of both media allowed maximum recovery.


Making the invisible visible: verbal but not visual cues enhance visual detection.
Can hearing a word change what one sees? Although visual sensitivity is known to be enhanced by attending to the location of the target, perceptual enhancements of following cues to the identity of an object have been difficult to find. Here, we show that perceptual sensitivity is enhanced by verbal, but not visual cues. Participants completed an object detection task in which they made an object-presence or -absence decision to briefly-presented letters. Hearing the letter name prior to the detection task increased perceptual sensitivity (d'). A visual cue in the form of a preview of the to-be-detected letter did not. Follow-up experiments found that the auditory cuing effect was specific to validly cued stimuli. The magnitude of the cuing effect positively correlated with an individual measure of vividness of mental imagery; introducing uncertainty into the position of the stimulus did not reduce the magnitude of the cuing effect, but eliminated the correlation with mental imagery. Hearing a word made otherwise invisible objects visible. Interestingly, seeing a preview of the target stimulus did not similarly enhance detection of the target. These results are compatible with an account in which auditory verbal labels modulate lower-level visual processing. The findings show that a verbal cue in the form of hearing a word can influence even the most elementary visual processing and inform our understanding of how language affects perception.


Differential modulation of rod and cone calcium currents in tiger salamander retina by D2 dopamine receptors and cAMP.
Synaptic transmission from vertebrate photoreceptors involves activation of L-type calcium currents (ICa). Dopamine is an important circadian neuromodulator in the retina and photoreceptors possess D2 dopamine receptors. We examined modulation of ICa by dopamine and cAMP in retinal slices and isolated cells of larval tiger salamander. Results show that dopamine and a D2 agonist, quinpirole, enhanced ICa in rods and red-, blue- and UV-sensitive small single cones but inhibited ICa in red-sensitive large single cones. A D1 agonist, SKF-38393, was without effect. Quinpirole effects were blocked by pertussis toxin (PTx) pretreatment indicating involvement of PTx-sensitive G-proteins. Like dopamine, inhibition of cAMP-dependent protein kinase (PKA) by Rp-cAMPS enhanced ICa in rods and small single cones, but inhibited ICa in large single cones. In contrast, forskolin and Sp-cAMPS, which stimulate PKA, inhibited ICa in rods and small single cones but enhanced ICa in large single cones. Sp-cAMPS also occluded effects of quinpirole. These results suggest that D2 receptors modulate ICa via inhibition of cAMP. Differences among the responses of photoreceptors to cAMP are consistent with the possibility that small single cones and rods may possess different Ca2+ channel subtypes than large single cones. The results with dopamine and quinpirole showing inhibition of ICa in large single cones and enhancement of rod ICa were unexpected because previous studies have shown that dopamine suppresses rod inputs and enhances cone inputs into second-order neurons. The present results therefore indicate that the dopaminergic enhancement of cone inputs does not arise from modulation of photoreceptor ICa.


Generation, representation and flow of phase information in structure determination: recent developments in and around SHARP 2.0.
The methods for treating experimental data in the isomorphous replacement and anomalous scattering methods of macromolecular phase determination have undergone considerable evolution since their inception 50 years ago. The successive formulations used are reviewed, from the most simplistic viewpoint to the most advanced, including the exploration of some blind alleys. A new treatment is proposed and demonstrated for the improved encoding and subsequent exploitation of phase information in the complex plane. It is concluded that there is still considerable scope for further improvements in the statistical analysis of phase information, which touch upon numerous fundamental issues related to data processing and experimental design.


[Pathogenic cells of rheumatic inflammation as the target of modern therapies].
In the 1970s and 1980s the course of rheumatoid arthritis (RA) could be defined as fateful despite the introduction of methotrexate as well as other immunosuppressive treatments. In most patients at this time RA was combined with an early disability due a progressive destruction of joints. In addition, comorbidity was known to be one of the major causes for a decreased life expectancy. These less than optimal options for treating RA patients led to intensive research in the pathogenesis with the aim to develop new treatment principles. Based on the increasing knowledge of pathogenically important mechanisms, so-called biologicals were developed targeting T and B cells and proinflammatory cytokines, such as tumor necrosis factor alpha. Over the past 10 years the repertoire of biologicals for treating RA has steadily and significantly increased, which was necessary especially for those patients classified as non-responders to available biological compounds. In the present overview cellular structures, T and B cells as well as cells of the monocyte/macrophage system are discussed as targets for immune interventions.


Adequacy of Critical Nutrients Affecting the Quality of the Spanish Diet in the ANIBES Study.
Diet is one of the key modifiable behaviors that can help to control and prevent non-communicable chronic diseases. Therefore, it is important to evaluate the overall diet composition of the population through non-invasive and independent indexes or scores as diet quality indexes (DQIs). The primary aim of the present work was to estimate the adequacy of the intake of critical nutrients in the Spanish "Anthropometry, Intake, and Energy Balance Study" (ANIBES) (n = 2285; 9-75 years), considering, as a reference, the European Food Scientific Authority (EFSA) values for nutrients for the European Union. We also assessed the quality of the diet for adults and older adults using four internationally accepted DQIs, namely the Healthy Diet Indicator (HDI), the Mediterranean Diet Score (MDS), the Mediterranean Diet Score-modified (MDS-mod), and the Mediterranean-Diet Quality Index (MED-DQI), as well as the ANIBES-DQI, stratified by education and income. The ANIBES-DQI was based on compliance with EFSA and Food and Agriculture Organization recommendations for a selected group of nutrients (i.e., total fat, saturated fatty acids (SFAs), simple sugars, fiber, calcium, vitamin C, and vitamin A), with a total range of 0-7. Misreporting was assessed according to the EFSA protocol, which allowed us to assess the DQIs for both the general population and plausible reporters. The majority of the Spanish population had high intakes of SFAs and sugars and low intakes of fiber, folate, and vitamins A and C. In addition, about half of the population had low DQI scores and exhibited low adherence to the Mediterranean diet pattern. Overall, older adults (>65-75 years) showed better DQIs than adults (18-64 years), without major differences between men and women. Moreover, primary education and low income were associated with low MDS and ANIBES-DQI scores. For the ANIBES-DQI, the percentage of the population with low scores was higher in the whole population (69.5%) compared with the plausible energy reporters (49.0%), whereas for medium and high scores the percentages were higher in plausible reporters (41.2% vs. 26.2% and 9.8% vs. 4.3%, respectively). In conclusion, the present study adds support to marked changes in the Mediterranean pattern in Spain, and low education and income levels seem to be associated with a low-quality diet. Additionally, the misreported evaluation in the ANIBES population suggests that this analysis should be routinely included in nutrition surveys to give more precise and accurate data related to nutrient intake and diet quality.


Health-related quality-of-life results from the phase 3 OPTIMISMM study: pomalidomide, bortezomib, and low-dose dexamethasone versus bortezomib and low-dose dexamethasone in relapsed or refractory multiple myeloma.
In the randomized phase-3 OPTIMISMM study, the addition of pomalidomide to bortezomib and low-dose dexamethasone (PVd) resulted in significant improvement in progression-free survival (PFS) in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM), including lenalidomide refractory patients. Here, we report health-related quality of life (HRQoL) results from this trial. Patients received PVd or Vd in 21-day cycles until disease progression or discontinuation. HRQoL was assessed using the EORTC QLQ-C30, QLQ-MY20, and EQ-5D-3L instruments on day 1 of each treatment cycle. Mean score changes for global QoL, physical functioning, fatigue, side effects of treatment domains, and EQ-5D-3L index were generally stable over time across treatment arms. The proportion of patients who experienced clinically meaningful worsening in global QoL and other domains of interest was similar. These HRQoL results with PVd along with previously demonstrated improvement in PFS vs Vd continue to support its use in patients with RRMM.


Metallic corneal foreign bodies: an occupational health hazard.
To analyze the risk factors, outcomes, demographic characteristics, and attitudes of workers with metallic corneal foreign body (FB) injury. One hundred consecutive patients who presented with a metallic corneal FB to the eye clinic at Diyarbakir Training and Research Hospital were evaluated. The patients completed a questionnaire and were examined to determine features of the injury. All patients were male. The mean age was 32.46 ± 1.03 years. Fifty-five percent of the patients were unregistered workers, 59% were working in the metal industry sector, and 65% injuries resulted from metal cutting. Protective goggles were available in the workplace of 64% patients. However, 57% patients were not wearing goggles when the accident occurred, and 43% were injured despite goggle use. Most patients (52%) attempted to remove FBs by themselves. FBs were located in the central zone of the cornea in 16% patients. Rust marks remained after FB removal in 26% patients. Corneal scars from previous FB injuries were present in 58% patients. Only 8% workplaces provided compensation for physician visits for occupation related illnesses. Workplaces with a high risk for eye injuries should increase their protective measures, and educational programs should be implemented for both workers and occupational physicians. The government should enforce laws regarding unregistered workers in a better manner.


An explanation of the differences in diffusivity of the components of the metallic glass Pd43Cu27Ni10P20.
Bartsch et al. [Phys. Rev. Lett. 104, 195901 (2010)] reported measurements of the diffusivities of different components of the multi-component bulk metallic glass Pd43Cu27Ni10P20. The diffusion of the largest Pd and the smallest P was found to be drastically different. The Stokes-Einstein relation breaks down when considering the P constituent atom, while the relation is obeyed by the Pd atom over 14 orders of magnitude of change in Pd diffusivity. This difference in behavior of Pd and P poses a problem challenging for explanation. With the assist of a recent finding in metallic glasses that the β-relaxation and the diffusion of the smallest component are closely related processes by Yu et al. [Phys. Rev. Lett. 109, 095508 (2012)], we use the Coupling Model to explain the observed difference between P and Pd quantitatively. The same model also explains the correlation between property of the β-relaxation with fragility found in the family of (CexLa1-x)68Al10Cu20Co2 with 0 ≤ x ≤ 1.


[Thermotherapy for laryngeal cancer].
An analysis of the data on the treatment of 91 cases of advanced cancer of the larynx showed that local UHF-hyperthermotherapy is more efficient than the SHF one as a component of radiotherapy. Use of the latter procedure was followed by a higher rate of late-onset radiation injuries. Moreover, combined application of hyper-fractionated irradiation and UHF-hyperthermotherapy involved practically no grave complications while 5-year survival increased.


Combined light and electron microscopy of Golgi-labelled neurons in lamina III of the feline spinal cord.
Golgi-impregnated neurons in lamina III of the cat spinal cord were examined using light microscopy and combined light and electron microscopy. Light microscopy revealed that the neurons formed a variety of dendrite configurations. The majority of neurons arborised in the rostrocaudal plane and were confined to the lamina of origin. However, some arborised dorsoventrally and had dendrites that penetrated lamina II. Electron microscopy of the neurons revealed that they were associated with many different types of bouton, thus suggesting that they received synaptic input from various sources. Some of the boutons were postsynaptic to other axon terminals indicating that they are under presynaptic control. One of the neurons participated in synaptic triads which consisted of two axo-axonically coupled boutons that were presynaptic to the cell.


[Temporal and spatial distribution characteristics of the crop root in intercropping system].
The ecological mechanism of competition and compensation between the crop root systems of two different intercropping patterns, wheat-soybean and corn-cabbage, was studied by field experiment. The results showed that the annual growth peak of wheat-soybean roots in intercropping was interlacing, the growth of root weight and length expressed synchronism, and the peak of root weight was appeared earlier than that of root length. The vertical distribution of the two crops' root system in two intercroppings was reduced gradually along with soil depths, which also showed that the multiple growth waves moved progressively. The root system distributed horizontally in intercropping system also showed a clearly unbalanced distribution. The root system distribution of out-row for corn elongated 20.4-40.8 cm to cabbage rows, but that of cabbage elongated only 8.5-12.6 cm to corn. The cross extent of root systems in corn-cabbage intercropping was decreased from 40.2 cm to 20.1 cm by fertilization, and the place of cross point for root concentrated region was changed from 20.5 cm to 12.4 cm below soil surface by fertilizer supply. The place of cross point for root concentrated region was an important index to decide the degrees of competition.


Distinct binding interactions of HIV-1 Gag to Psi and non-Psi RNAs: implications for viral genomic RNA packaging.
Despite the vast excess of cellular RNAs, precisely two copies of viral genomic RNA (gRNA) are selectively packaged into new human immunodeficiency type 1 (HIV-1) particles via specific interactions between the HIV-1 Gag and the gRNA psi (ψ) packaging signal. Gag consists of the matrix (MA), capsid, nucleocapsid (NC), and p6 domains. Binding of the Gag NC domain to ψ is necessary for gRNA packaging, but the mechanism by which Gag selectively interacts with ψ is unclear. Here, we investigate the binding of NC and Gag variants to an RNA derived from ψ (Psi RNA), as well as to a non-ψ region (TARPolyA). Binding was measured as a function of salt to obtain the effective charge (Zeff) and nonelectrostatic (i.e., specific) component of binding, Kd(1M). Gag binds to Psi RNA with a dramatically reduced Kd(1M) and lower Zeff relative to TARPolyA. NC, GagΔMA, and a dimerization mutant of Gag bind TARPolyA with reduced Zeff relative to WT Gag. Mutations involving the NC zinc finger motifs of Gag or changes to the G-rich NC-binding regions of Psi RNA significantly reduce the nonelectrostatic component of binding, leading to an increase in Zeff. These results show that Gag interacts with gRNA using different binding modes; both the NC and MA domains are bound to RNA in the case of TARPolyA, whereas binding to Psi RNA involves only the NC domain. Taken together, these results suggest a novel mechanism for selective gRNA encapsidation.


[Acute severe leukoencephalitis with posterior lesions due to Borrelia burgdorferi infection].
Central nervous system manifestations represent 0.54 to 8% of neurological complication in Lyme disease. A 78-year-old woman presented a severe meningo-encephalitis with visual disorders (agnosia, alexia) progressing towards coma. Cranial magnetic resonance imaging revealed large areas of hypersignal T2 in the white matter of the lower, parieto-occipital lobes and left temporal lobe. The cerebrospinal fluid (CSF) contained 16 then 293 white corpuscles/mm3 of lympho-monocytes, increased protein level from 2.67 to 5.83 g/l and an increase in IgG index with oligoclonal distribution of IgG. Serological Elisa analysis for Lyme disease was slightly positive in blood (confirmed by western blot) but clearly in the CSF (IgG and IgM). Treatment with ceftriaxone followed by methylprednisolone provided clinical improvement 3 months later. Acute meningo-encephalitis is often benign, protein-like and of good prognosis: the gnosic visual disorders with posterior leukoencephalopathy are unusual. A blood level of specific antibodies slightly positive on Elisa at the early stage of the infection warrants confirmation by Western blot in the blood and by Elisa in the CSF. Additional corticosteroid therapy may be required in the severe forms that evoke acute disseminated encephalomyelitis.


Preparation and Reactivity of 1,3-Bis(alkylthio)allenes and Tetrathiacyclic Bisallenes.
Reactions of Ph(2)C(3) dianion, prepared from 1,3-diphenylpropyne and n-butyllithium, with alkyl thiocyanates or alkane dithiocyanates gave 1,3-bis(alkylthio)allenes 1 or tetrathiacyclic bisallenes 2, respectively. Thermal reactions of 1 gave thiophenes 4 and 7, benzothiepin 5, 1,2-bis(benzylidene)cyclobutane 6, thiete 8, and alpha,beta-unsaturated ketone 9, and the reactions of tetrathiacyclic bisallenes 2a gave a cyclic dimer, 1,2-bis(benzylidene)cyclobutane derivative 10, quantitatively. Irradiation of 1,3-bis(alkylthio)allenes 1 and tetrathiacyclic bisallenes 2a caused rearrangement to give alkynes 18, 20, and 21. In the irradiation of the cyclic bisallenes 2a, isomerizations from dl to meso and meso to dl isomers were also found. In the reactions of allenes 1 and cyclic bisallenes 2a with diphenyl diazomethane, the diazomethane reacted selectively with the double bond rather than with the sulfur atom.


[Disseminated coronary occlusions and massive pulmonary embolism in a 40-year-old woman].
A 40-year-old woman was admitted to the emergency room because of severe angina pectoris and dyspnoe at rest. She developed ventricular fibrillation a few minutes later from which she had to be resuscitated . After intubation and controlled ventilation immediate angiocardiography was performed while she was still in cardiogenic shock. Coronary angiography ten days before had been unremarkable. The second coronary angiogram revealed severe thrombotic lesion at the origin of the left anterior descending branch (LAD) and total occlusions of the peripheral LAD and of the first marginal branch. After intracoronary application of 10 mg abciximab and coronary stent implantation in the origin of the LAD the patient had good clinical improvement. Massive pulmonary embolism two days later, despite of effective heparinization and inhibition of platelet aggregation (as measured by partial thromboplastin time), was treated successfully by regional injection of 100 mg tissue plasminogen activator (t-PA). Tests for possible hypercoagulability showed no detectable changes in the clotting and fibrinolytic system with a normal platelet count. In a standardized aggregation test of platelets hyperaggregation in response to ADP and epinephrine, also at low test doses, revealed the presence of a sticky platelet syndrome. This case history suggests that enhanced platelet aggregation associated with sticky platelet syndrome may provoke myocardial infarction even in angiographically normal coronary arteries.


Treatment of acute pelvic inflammatory disease in the ambulatory setting: trial of cefoxitin and doxycycline versus ampicillin-sulbactam.
Ampicillin-sulbactam (750 mg) given orally twice daily for 10 days was evaluated for the treatment of acute pelvic inflammatory disease (PID) in an ambulatory setting in Nairobi, Kenya. The first 26 women received ampicillin-sulbactam in an open-label fashion, and the remaining 75 women were randomly selected to receive either ampicillin-sulbactam (n = 38) or cefoxitin (2 g) intramuscularly and probenecid (1 g) orally, followed by doxycycline (100 mg) orally twice daily for 10 days (n = 37). Women were enrolled in a sexually transmitted disease clinic and were followed for clinical and microbiologic responses at 1 to 2 weeks and 4 to 6 weeks posttreatment. Women had a later follow-up visit to note interim pregnancy or underwent hysterosalpingography for fertility outcome assessment. The short-term clinical response rates were 70% for ampicillin-sulbactam and 72% for cefoxitin-doxycycline (P = 0.47). Among Chlamydia trachomatis-infected women treated with ampicillin-sulbactam, three had microbiologic relapse. The post-PID tubal obstruction rates were similar in the two groups: 18% for ampicillin-sulbactam and 33% for cefoxitin-doxycycline (P = 0.31). Neither regimen was highly effective as a therapy for acute PID. These data strongly argue that primary prevention must be the goal for a reduction of PID morbidity and show that improved therapy for the treatment of PID in the ambulatory setting is needed.


The Psychology of Nutrition with Advancing Age: Focus on Food Neophobia.
Many factors impact on eating behaviour and nutritional status in older adults. Strategies can be suggested to combat the impact of these factors, including the development of novel food products, but food neophobia ("the reluctance to eat and/or avoidance of novel foods") may be a barrier to the acceptance of these foods/products. This work aimed to investigate associations between food neophobia, physical disadvantage, and demographic characteristics in adults over 55 years old. Cross-sectional data from 377 older adults was analysed for relationships between food neophobia scores and physical disadvantage (denture wearing, help with food shopping and/or preparing, and risk of sarcopenia), controlling for age group, gender, living status, education, and employment level. Initial analyses demonstrated higher food neophobia scores in association with denture wearing (Beta = 0.186, p = 0.001). However, when demographic characteristics were also considered, food neophobia scores were no longer related to denture wearing (Beta = 0.069, p = 0.226) but instead were related to a higher age, living alone, and a shorter education (smallest Beta = -0.104, p = 0.048). Food neophobia may thus act as a barrier to the consumption of novel foods/products in those who are of higher age, are living alone, and have a shorter education.


[The experience of the use of intracardiac echocardiography during puncture of atrial septum].
We analyzed results of 175 intracardiac ultrasound studies (ICUS) in 113 men (mean age 54,6 +/- 11,0 years) and 62 women (mean age 49,7 +/- 8,9 years) with atrial fibrillation (n=146) and WPW syndrome (n=29). ICUS was used for guidance of catheters or electrodes from right to left atrium through atrial septum in 160 procedures of radiofrequency ablations for atrial fibrillation (n=146) or WPW syndrome (n=14). Complications of transseptal puncture developed in 4 patients (2,7%) with atrial fibrillation. There were no procedure related deaths. In all cases ICUS allowed to visualize interatrial septum and its thinnest part. Thus ICUS facilitates transseptal approach to the left atrium, provides lowering of risk of dangerous complications, and allows real time monitoring of possible intraprocedural complications.


Design of Experiments As a Tool for Optimization in Recombinant Protein Biotechnology: From Constructs to Crystals.
In this review, the basic concepts and applications of design of experiments (DoE) in recombinant protein biotechnology will be discussed. The production of recombinant proteins usually begins with the construction of an expression vector that is then introduced into a microbial host. The target protein is overexpressed in the host's cells and subsequently, it is isolated using a suitable purification method, its activity is assessed using a biological assay, while its crystallization is often required. Because each protein is unique and due to the complex interactions among the reagents in experiments, it is impossible that one set of reaction conditions would be optimal for all cases. Optimization of experimental conditions is usually carried out by the inefficient one-factor-at-a-time approach that does not take into account the combined effects of factors on a process. On the other hand, DoE approaches with a carefully selected small set of experiments, and therefore with a reduced cost and in a limited amount of time predict the effect of each factor and the effects of their interactions on a process. Importantly, several software packages are available that facilitate the choice of the DoE approach, design of the experiments, and analysis of the results.


The use of modelling to predict levels of estrogens in a river catchment: how does modelled data compare with chemical analysis and in vitro yeast assay results?
Effluent discharges at Rodbourne sewage treatment works (STWs) were assessed using chemical and in vitro biological analysis as well as modelling predictions. Results showed that Rodbourne STW discharged less estrone (E1) than expected, but similar 17beta-estradiol (E2) and 17alpha-ethinyl estradiol (EE2) to those predicted by a widely cited effluent prediction model. The Exposure Analysis Modelling System (EXAMS) model was set up using measured effluent concentrations as its starting point to predict estrogen concentrations along a 10 km length of the receiving water of the River Ray. The model adequately simulated estrogen concentrations along the river when compared to July 2007 measured data. The model predicted combined estrogen equivalents in reasonable agreement with estrogenicity as measured by passive sampler (POCIS) extracts using the yeast estrogen screen. Using gauged mean flow values for 2007 the model indicated that the most important determinand for estrogen exposure in the Ray was not season, but proximity to the Rodbourne effluent. Thus, fish in the first 3 km downstream of Rodbourne were typically exposed to two or even three times more estrogens than those living 7-10 km further downstream. The modelling indicated that, assuming the effluent estrogen concentrations measured in February 2008 were typical, throughout the year the whole length of the Ray downstream of Rodbourne would be estrogenic, i.e. exceeding the 1 ng/L E2 equivalent threshold for endocrine disruption.


[Unique papillary cystadenocarcinoma of the prostate with endocrine cells].
Histological examination of prostatic tumour of a man who died at the age of 71, revealed dark-cell small-acinar carcinoma with scattered papillary cystadenocarcinomatous structures. The latter, apart from two types of epithelial cells (dark granular and clear cells) contained argyrophilic endocrine cells detected by Grimelius' staining. These cells were absent in the dark-cell small-acinar areas. It is suggested that acinar and cystadenopapillary structures differ in their histogenesis.


Esophageal foreign bodies: 177 cases.
The aim of this study is to assess patients treated for esophageal foreign bodies. The charts of patients (n=177), between January 1994 and April 2009, were investigated retrospectively. Patients' age and gender, locations and types of foreign bodies (FBs) and interventions were taken into consideration. Fifty-seven percent of the patients were male. The youngest patient was 6 months, whereas the oldest was 83 years old. The median age was 9 years. Half of the patients were in their first decade. Treatment took place 11 h (ranging from 1 to 120 h) after impaction of the FB. One hundred fifty-two FBs were removed in 177 patients. Our negative esophagoscopy (n=25) rate was 14%. The FBs were radiopaque in 75% (n=114) and were commonly (71%; n=109) located in the cervical esophagus. Metallic coins (n=81-53%) were the most commonly observed inorganic FB while bones and/or meat impaction (n=54-35%) were the most frequent organic FB. A total of 182 endoscopic interventions were performed on these patients. One hundred eleven of them were esophagoscopy and the remaining 71 were direct laryngoscopy. The FB was pushed into the stomach in 11 patients. Our morbidity rate was 1.6% (n=3). Iatrogenic perforation occurred in two patients. There was no mortality. Esophageal FBs may vary in type: sharp or round objects, metallic, plastic or organic material. FBs are commonly found at pharyngoesophageal junction and usually removed by McGill forceps. Rigid esophagoscopy is used for children and adults because of its large working channel. Rigid instruments are considered reliable and safe for extracting foreign bodies.


FIH-1-Mint3 axis does not control HIF-1 transcriptional activity in nucleus pulposus cells.
The objective of this study was to determine the role of FIH-1 in regulating HIF-1 activity in the nucleus pulposus (NP) cells and the control of this regulation by binding and sequestration of FIH-1 by Mint3. FIH-1 and Mint3 were both expressed in the NP and were shown to strongly co-localize within the cell nucleus. Although both mRNA and protein expression of FIH-1 decreased in hypoxia, only Mint3 protein levels were hypoxiasensitive. Overexpression of FIH-1 was able to reduce HIF-1 function, as seen by changes in activities of hypoxia response element-luciferase reporter and HIF-1-C-TAD and HIF-2-TAD. Moreover, co-transfection of either full-length Mint3 or the N terminus of Mint3 abrogated FIH-1-dependent reduction in HIF-1 activity under both normoxia and hypoxia. Nuclear levels of FIH-1 and Mint3 decreased in hypoxia, and the use of specific nuclear import and export inhibitors clearly showed that cellular compartmentalization of overexpressed FIH-1 was critical for its regulation of HIF-1 activity in NP cells. Interestingly, microarray results after stable silencing of FIH-1 showed no significant changes in transcripts of classical HIF-1 target genes. However, expression of several other transcripts, including those of the Notch pathway, changed in FIH-1-silenced cells. Moreover, co-transfection of Notch-ICD could restore suppression of HIF-1-TAD activity by exogenous FIH-1. Taken together, these results suggest that, possibly due to low endogenous levels and/or preferential association with substrates such as Notch, FIH-1 activity does not represent a major mechanism by which NP cells control HIF-1-dependent transcription, a testament to their adaptation to a unique hypoxic niche.


Improved reproducibility of measurements with the nerve fiber analyzer.
This study was undertaken to assess and improve the repeatability and reproducibility of nerve fiber layer (NFL) measurements using the Nerve Fiber Analyzer (NFA I), a scanning laser polarimeter. The repeatability of two subsequent measurements was determined in 100 healthy eyes. Four methods of image evaluation were performed. Polarimetric measurements of retinal NFL were obtained along a peripapillary band at the superior and inferior poles of the optic disk and analyzed in a one-pixel band of absolute retardation values (method 1) and relative to the nasal segment (method 2). Method 3 used measurements obtained in a 10-pixel band along the same peripapillary band. Method 4 comprised measurements in selected areas outside the peripapillary band, which did not contain blood vessels. The repeatability (r) and relative reliability coefficient (Rel) were assessed as indices of agreement of repeated measurements. In addition, the reproducibility (R) from day to day for methods 3 and 4 was assessed by taking 10 images on 10 consecutive days from each of 10 subjects. The 95% critical value for r in the superior and inferior segments improved from about 30% for methods 1 and 2, to 23% for method 3, and to 11% for method 4. For the superior and inferior segments, the fourth method of image evaluation yielded a Rel of 98%, as compared with 54% in method 1, 80% in method 2, and 87% in method 3. The 95% critical value for R was 23% for method 3 but only 15% for method 4. The improved reproducibility of measurements has made the NFA I a promising device. An improved reproducibility (smaller limit for detecting change) does not necessarily indicate good sensitivity and specificity for any instrument. The role of the scanning laser polarimeter in clinical practice requires further study.


Recovery of postoperative swallowing in patients undergoing partial laryngectomy.
This study assessed the achievement of postoperative swallowing in patients undergoing partial laryngectomy surgery. Oropharyngeal swallow efficiency was used to predict time to achievement of outcome. Fifty-five patients were followed for up to 1 year in two hemilaryngectomy and four supraglottic laryngectomy groups. Within 10 days of healing, a videofluoroscopic evaluation enabled the measurement of swallowing efficiency. Times to achievement of oral intake, removal of feeding tube, preoperative diet, and normal swallow were analyzed using actuarial curves. Patients with hemilaryngectomies achieved swallowing rehabilitation sooner than patients with nonextended supraglottic laryngectomies (p < .05) who, in turn, achieved swallowing function sooner than did patients undergoing supraglottic laryngectomies with tongue base resection (p < .05). Median time to attainment of preoperative diet in these three groups was 28 days, 91 days, and > 335 days, respectively. Higher early postoperative oropharyngeal swallow efficiency was related to earlier achievement of oral food intake and of preoperative diet (p < .05). Results show that the time course for swallowing rehabilitation covers an extended postoperative period. In some surgical groups, functional swallowing and eating may be achieved within 3 months of surgery while for other types, significant impairment remains up to 9 months postoperatively Early radiographic assessments of swallowing function are useful in predicting the time to swallow recovery. Recovery of swallowing ability may be delayed in patients who have not achieved oral intake before radiotherapy is started.


Characteristics of effective interventions supporting quality pain management in Australian emergency departments: an exploratory study.
It is well established that pain is the most common presenting complaint in Emergency Departments. Despite great improvements in available pain management strategies, patients are left waiting for longer than 60min for pain relief on arrival to the emergency department. The aim of this study was to describe interventions that lead to successful implementation of the National Health and Medical Research Council approved guidelines Acute Pain Management: Scientific Evidence (2nd Edition) that include specific recommendations for best practice pain management. A two-phased, mixed-method, exploratory study of all 52 Australian hospital emergency departments participating in the National Emergency Care Pain Management Initiative incorporating interview and document analysis was undertaken. Interventions used by clinicians to improve pain management included nurse initiated analgesia, intranasal fentanyl for paediatric patients and lignocaine, and facio illiaca block. Education formed a major part of the intervention and the development of a working group of key stakeholders was critical in the successful implementation of change. Staff perceptions of patients' pain level and attitudes toward pain assessment and pain management were identified as barriers. This study highlighted how an effective framework to plan and implement practice change and tailored interventions, including education and training systems and products using the best available evidence, best equipped clinicians to manage pain in the ED.


A new atypical highly mouse virulent Toxoplasma gondii genotype isolated from a wild black bear in Alaska.
Most strains of Toxoplasma gondii isolated in North America and Europe are grouped into 3 (Types I, II, III) genotypes and are considered clonal. Recent evidence suggests that illness due to toxoplasmosis in immunocompetent persons may be related to infection with an atypical genotype; these strains are mouse virulent. In the present study, a new mouse-virulent atypical T. gondii genotype was isolated from an asymptomatic black bear ( Ursus americanus ) from Alaska. The bear had a titer of 1ratio1,600 using the modified agglutination test for T. gondii . Swiss Webster out-bred mice inoculated with bear heart homogenate died of acute toxoplasmosis, 12 days post-inoculation (PI). Cats fed tissues from chronically infected animals (day 30 PI) shed oocysts, but only 1 of 3 cats fed acutely infected mice (12, 16, 18 days PI) shed oocysts. The isolate (designated TgBbUS1) was mouse virulent; mice inoculated with 1 oocyst or 1 tachyzoite died of acute toxoplasmosis. The restricted fragment length polymorphism using 10 markers revealed that the strain possessed an atypical genotype: type I allele at loci SAG1, (5'-3')SAG2, SAG3, c22-8, c29-2, L358, and Apico; type II allele at locus alt.SAG2; and type III allele at loci BTUB, GRA6, and PK1. DNA sequencing at intron loci EF1, HP2, and UPRT1 revealed that the TgBbUS1 is a divergent T. gondii strain. These results indicate that mouse-virulent atypical T. gondii genotypes are also circulating in wildlife in North America.


[The immunohistochemical heterogeneity of mesangioproliferative glomerulonephritis].
Immunohistochemical examination of puncture biopsies of the kidneys taken from 172 patients with mesangioproliferative glomerulonephritis (MPGN) showed its heterogeneity. MPGN with IgA deposits, MPGN with IgG deposits, MPGN with IgM deposits, MPGN with C3 deposits and immunonegative MPGN are separated. Clinically, nephrotic syndrome prevails in IgG and IgM, MPGN, various clinical forms occur in MPGN with C3 and immunonegative variants, hematuric and latent forms occur in MPGN with IgA. MPGN with IgM deposits has its own morphological and clinical features, this permitting to consider it as an independent form of glomerulonephritis.


Mechanisms of action of inhibitors of prolactin secretion in GH3 pituitary cells. I. Ca2+-dependent inhibition of amino acid incorporation.
Post-transcriptional protein synthesis by GH3 cloned pituitary cells, which secrete prolactin and growth hormone, is dependent on Ca2+. The effects of antagonists of prolactin secretion were examined on overall protein synthesis in GH3 cells as a function of cellular Ca2+ depletion and restoration at varying concentrations of extracellular Ca2+. Leucine incorporation by Ca2+-depleted cells during short incubations was reduced by 80-90%. Trifluoperazine at micromolar concentrations inhibited leucine incorporation in a Ca2+-dependent manner. The extent of inhibition varied with extracellular Ca2+ concentration and was fully reversed at higher Ca2+ concentrations. Similar patterns of inhibition of leucine incorporation were observed with nifedipine, verapamil, calmidazolium, chlorpromazine, bromocriptine, ergotamine, and the (+)- and (-)-isomers of butaclamol, but dopamine, apomorphine, and chlorpromazine sulfoxide were not inhibitory. Muscarinic agonists decreased incorporation in a Ca2+-dependent manner, but lesser degrees of inhibition were obtained. Inhibitions were observed for a broad spectrum of polypeptide species, could not be explained by effects on Mg2+ availability or amino acid uptake, and were rapidly and fully reversed by Ca2+. Production of prolactin and growth hormone was decreased by secretory inhibitors to the same extent and with the same Ca2+ concentration dependence as was observed for inhibition of amino acid incorporation. It is proposed that these substances inhibit protein synthesis in GH3 cells through alterations in intracellular Ca2+ metabolism rather than through mechanisms mediated by calmodulin or dopamine receptors.


Lipid-based drug carriers for prodrugs to enhance drug delivery.
The combination of lipid drug delivery systems with prodrugs offers several advantages including improved pharmacokinetics, increased absorption, and facilitated targeting. Lipidization and use of lipid carriers can increase the pharmacological half-life of the drug, thus improving pharmacokinetics and allowing less frequent dosing. Lipids also offer advantages such as increased absorption through the intestines for oral drug absorption and to the CNS for brain delivery. Furthermore, the use of lipid delivery systems can enhance drug targeting. Endogenous proteins bind lipids in the blood and carry them to the liver to enable targeting of this organ. Drugs with significant side effects in the stomach can be specifically delivered to enterocytes by exploiting lipases for prodrug activation. Finally, lipids can be used to target the lymphatic system, thus bypassing the liver and avoiding first-pass metabolism. Lymphatic targeting is also important for antiviral drugs in the protection of B and T lymphocytes. In this review, both lipid-drug conjugates and lipid-based carriers will be discussed. An overview, including the chemistry and assembly of the systems, as well as examples from the clinic and in development, will be provided.


A Novel Concept is Needed for Combating Alzheimer's Disease and NeuroHIV.
Both Alzheimer's disease (AD) and HIV-associated neurocognitive disorders (HAND) could progress to dementia, a severe consequence of neurodegenerative diseases. Cumulating evidence suggests that the β-amyloid (Aβ) theory, currently thought to be the predominant mechanism underlying AD and AD-related dementia (ADRD), needs re-evaluation, considering all treatments and new drug trials based upon this theory have been unsuccessful. Similar intention for treating HAND, including HIV-associated dementia (HAD), has also failed. Thus, novel theory, hypothesis, and therapeutic strategies are desperately needed for future study and effective treatments of AD/ADRD and HAND. There are numerous potential upstream mechanisms that may cause AD and/or HAND; but it is unrealistic to identify all of them. However, it is realistic and feasible to intervene the downstream mechanism of these two devastating neurodegenerative diseases by blocking the final common path to neurotoxicity mediated by overactivation of NMDA receptors (NMDARs) and voltage-gated calcium channels (VGCCs). Such a combined pharmacological intervention will likely ameliorate neuronal Ca2+ homeostasis by diminishing overactivated NMDAR and VGCC-mediated Ca2+ dysregulation (i.e., by reducing excessive Ca2+ influx and intracellular levels, [Ca2+]in)-induced hyperactivity, injury, and death of neurons in the critical brain regions that regulate neurocognition in the context of AD/ADRD or HAND, especially during aging. Here we present a novel theoretical concept, hypothesis, and working model for switching the battlefield from searching-and-fighting the original mechanism that may cause AD or HAND, to abolishing AD- and neuroHIV-induced neurotoxicity mediated by NMDAR and VGCC over activation, which may ultimately improve the therapeutic strategies for treating AD and HAND.


Deciding which way to go: how do insects alter movements to negotiate barriers?
Animals must routinely deal with barriers as they move through their natural environment. These challenges require directed changes in leg movements and posture performed in the context of ever changing internal and external conditions. In particular, cockroaches use a combination of tactile and visual information to evaluate objects in their path in order to effectively guide their movements in complex terrain. When encountering a large block, the insect uses its antennae to evaluate the object's height then rears upward accordingly before climbing. A shelf presents a choice between climbing and tunneling that depends on how the antennae strike the shelf; tapping from above yields climbing, while tapping from below causes tunneling. However, ambient light conditions detected by the ocelli can bias that decision. Similarly, in a T-maze turning is determined by antennal contact but influenced by visual cues. These multi-sensory behaviors led us to look at the central complex as a center for sensori-motor integration within the insect brain. Visual and antennal tactile cues are processed within the central complex and, in tethered preparations, several central complex units changed firing rates in tandem with or prior to altered step frequency or turning, while stimulation through the implanted electrodes evoked these same behavioral changes. To further test for a central complex role in these decisions, we examined behavioral effects of brain lesions. Electrolytic lesions in restricted regions of the central complex generated site specific behavioral deficits. Similar changes were also found in reversible effects of procaine injections in the brain. Finally, we are examining these kinds of decisions made in a large arena that more closely matches the conditions under which cockroaches forage. Overall, our studies suggest that CC circuits may indeed influence the descending commands associated with navigational decisions, thereby making them more context dependent.


Lineage commitment in the thymus: only the most differentiated (TCRhibcl-2hi) subset of CD4+CD8+ thymocytes has selectively terminated CD4 or CD8 synthesis.
Lineage commitment is a developmental process by which individual CD4+CD8+ (double positive, DP) thymocytes make a decision to differentiate into either CD4+ or CD8+ T cells. However, the molecular event(s) that defines lineage commitment is controversial. We have previously proposed that lineage commitment in DP thymocytes can be molecularly defined as the selective termination of CD4 or CD8 coreceptor synthesis. The present study supports such a molecular definition by showing that termination of either CD4 or CD8 synthesis is a highly regulated event that is only evident within the most differentiated DP subset (CD5hiCD69hiTCRhibcl-2hi). In fact, essentially all cells within this DP subset actively synthesize only one coreceptor molecule. In addition, the present results identify three distinct sub-populations of DP thymocytes that define the developmental progression of the lineage commitment process and demonstrate that lineage commitment is coincident with upregulation of TCR and bcl-2. Thus, this study supports a molecular definition of lineage commitment and uniquely identifies TCRhibcl-2hi DP thymocytes as cells that are already committed to either the CD4 or CD8 T cell lineage.


HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA.
HIV-1 depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. The cellular protein Naf1 (HIV-1 Nef-associated factor 1) is a CRM1-dependent nucleo-cytoplasmic shuttling protein, and has been identified to regulate multiple receptor-mediated signal pathways in inflammation. The cytoplasm-located Naf1 can inhibit NF-κB activation through binding to A20, and the loss of Naf1 controlled NF-κB activation is associated with multiple autoimmune diseases. However, the effect of Naf1 on HIV-1 mRNA expression has not been characterized. In this study we found that the nucleus-located Naf1 could promote nuclear export of unspliced HIV-1 gag mRNA. We demonstrated that the association between Naf1 and CRM1 was required for this function as the inhibition or knockdown of CRM1 expression significantly impaired Naf1-promoted HIV-1 production. The mutation of Naf1 nuclear export signals (NESs) that account for CRM1 recruitment for nuclear export decreased Naf1 function. Additionally, the mutation of the nuclear localization signal (NLS) of Naf1 diminished its ability to promote HIV-1 production, demonstrating that the shuttling property of Naf1 is required for this function. Our results reveal a novel role of Naf1 in enhancing HIV-1 production, and provide a potential therapeutic target for controlling HIV-1 infection.


Presurgical targeted therapy with tyrosine kinase inhibitors for advanced renal cell carcinoma: clinical results and histopathological therapeutic effects.
We retrospectively analyzed our patients with advanced renal cell carcinoma who underwent presurgical targeted therapy with tyrosine kinase inhibitors to clarify the safety and clinical benefit. The histopathological effect of this treatment was also examined. Between July 2005 and February 2010, nine patients with advanced renal cell carcinoma who were treated with tyrosine kinase inhibitors before surgery were the subjects of this study. Consolidative surgery was considered when these tumors showed clinical response or stable disease while on targeted therapy without evidence of disease progression at other sites. The agents used were sorafenib in seven patients and sunitinib in two. The median duration of presurgical therapy was 12.2 weeks, and seven patients had less than 4 months of treatment. Tumor reduction at 10-30% was obtained in all patients but one. Perioperative complications were observed in five of nine patients. Major complications occurred in two patients, including intraoperative excessive bleeding and delayed localized intraperitoneal abscess. Minor complications were found in three. The characteristics of the histopathological effect of tyrosine kinase inhibitors consisted of marked atrophy of the capillary sinus, confirming the pharmacological mechanisms of these agents. Other findings included nuclear pyknosis and degeneration of tumor cells. Presurgical targeted therapy with tyrosine kinase inhibitors appears to be feasible in most patients with advanced renal cell carcinoma. However, the indications, the clinical benefit and the standard protocol still remain to be determined. Therapeutic effects in the histology were compatible to their pharmacological effects.


Image identification system based on an optical broadcast neural network processor.
We describe the implementation of a vision system based on a hardware neural processor. The architecture of the neural network processor has been designed to exploit the computational characteristics of electronics and the communication characteristics of optics in an optimal manner, thus it is based on an optical broadcast of input signals to a dense array of processing elements. The vision system has been built by use of a prototype implementation of a neural network processor with discrete optic and optoelectronic devices. It has been adapted to work as a Hamming classifier of the images taken with a 128 x 128 complementary metal-oxide semiconductor image sensor. Its results, performance characteristics of the image classification system, and an analysis of its scalability in size and speed, with the improvement of the optoelectronic neural processor, are presented.


Prenatal MR findings of the middle interhemispheric variant of holoprosencephaly.
We report a case of the middle interhemispheric variant of holoprosencephaly (MIH) with noncleavage of the posterior portion of the frontal lobes and the parietal regions in a fetus at 22 weeks' gestation. To our knowledge, this is the first case of the rare MIH variant to be diagnosed in utero by use of ultrafast MR imaging and one of the few such reports to document gross and microscopic pathologic findings. Neuroimaging results correlated with those of gross and microscopic pathologic specimens obtained from the stillborn child. We conclude that ultrafast MR imaging can accurately distinguish holoprosencephaly subtypes in utero, which may affect counseling of parents.


Undetectable Concentrations of a Food and Drug Administration-approved High-sensitivity Cardiac Troponin T Assay to Rule Out Acute Myocardial Infarction at Emergency Department Arrival.
The objective of this study was to quantify the sensitivity of very low concentrations of high-sensitivity cardiac troponin T (hsTnT) at ED arrival for acute myocardial infarction (AMI) in a large cohort of chest pain patients evaluated in real-world clinical practice. This retrospective study included consecutive ED patients with suspected cardiac chest pain evaluated in four urban EDs, excluding those with ST-elevation AMI, cardiac arrest or abnormal kidney function. The primary outcomes were AMI at 7, 30, and 90 days. Secondary outcomes included major adverse cardiac events (MACE; all-cause mortality, AMI, and revascularization) and the individual MACE components. Test characteristics were calculated for hsTnT values from 3 to 200 ng/L . A total of 7,130 patients met inclusion criteria. AMI incidences at 7, 30, and 90 days were 5.8, 6.0, and 6.2%. When the hsTnT assay was performed at ED arrival, the limit of blank of the assay (3 ng/L) ruled out 7-day AMI in 15.5% of patients with 100% sensitivity and negative predictive value (NPV). The limit of detection of the assay (5 ng/L) ruled out AMI in 33.6% of patients with 99.8% sensitivity and 99.95% NPV for 7-day AMI. The limit of quantification (the Food and Drug Administration [FDA]-approved cutoff for lower the reportable limit) of 6 ng/L ruled out AMI in 42.2% of patients with 99.8% sensitivity and 99.95% NPV. The sensitivities of the cutoffs of <3, <5, and <6 ng/L for 7-day MACE were 99.6, 97.4, and 96.6%, respectively. The NPVs of the cutoffs of <3, <5, and <6 ng/L for 7-day MACE were 99.8, 99.5, and 99.4%, respectively. A secondary analysis was performed in a subgroup of 3,549 higher-risk patients who underwent serial troponin testing. In this subgroup, a cutoff of 3 ng/L ruled out 7-day AMI in 9.6% of patients with 100% sensitivity and NPV, a cutoff of 5 ng/L ruled out 7-day AMI in 23.3% of patients with 99.7% sensitivity and 99.9% NPV, and a cutoff of 6 ng/L ruled out 7-day AMI in 29.8% of patients with 99.7 and 99.9% NPV. In the higher-risk subgroup, the sensitivities of cutoffs of <3, <5, and <6 ng/L for 7-day MACE were 99.8, 97.4, and 96.6%, respectively. In this higher-risk subgroup, the NPV of cutoffs of <3, <5, and <6 ng/L for 7-day MACE were 99.7, 98.5, and 98.4%, respectively. When used in real-world clinical practice conditions, hsTnT concentrations < 6 ng/L (below the lower reportable limit for an FDA-approved assay) at the time of ED arrival can rule out AMI with very high sensitivity and NPV. The sensitivity for MACE is unacceptably low, and thus a single-troponin rule-out strategy should only be used in the context of a structured risk evaluation.


The Diversity-Innovation Paradox in Science.
Prior work finds a diversity paradox: Diversity breeds innovation, yet underrepresented groups that diversify organizations have less successful careers within them. Does the diversity paradox hold for scientists as well? We study this by utilizing a near-complete population of ∼1.2 million US doctoral recipients from 1977 to 2015 and following their careers into publishing and faculty positions. We use text analysis and machine learning to answer a series of questions: How do we detect scientific innovations? Are underrepresented groups more likely to generate scientific innovations? And are the innovations of underrepresented groups adopted and rewarded? Our analyses show that underrepresented groups produce higher rates of scientific novelty. However, their novel contributions are devalued and discounted: For example, novel contributions by gender and racial minorities are taken up by other scholars at lower rates than novel contributions by gender and racial majorities, and equally impactful contributions of gender and racial minorities are less likely to result in successful scientific careers than for majority groups. These results suggest there may be unwarranted reproduction of stratification in academic careers that discounts diversity's role in innovation and partly explains the underrepresentation of some groups in academia.


Hot dogs: High ambient temperatures impact reproductive success in a tropical carnivore.
Climate change imposes an urgent need to recognise and conserve the species likely to be worst affected. However, while ecologists have mostly explored indirect effects of rising ambient temperatures on temperate and polar species, physiologists have predicted direct impacts on tropical species. The African wild dog (Lycaon pictus), a tropical species, exhibits few of the traits typically used to predict climate change vulnerability. Nevertheless, we predicted that wild dog populations might be sensitive to weather conditions, because the species shows strongly seasonal reproduction across most of its geographical range. We explored associations between weather conditions, reproductive costs, and reproductive success, drawing on long-term wild dog monitoring data from sites in Botswana (20°S, 24 years), Kenya (0°N, 12 years), and Zimbabwe (20°S, 6 years). High ambient temperatures were associated with reduced foraging time, especially during the energetically costly pup-rearing period. Across all three sites, packs which reared pups at high ambient temperatures produced fewer recruits than did those rearing pups in cooler weather; at the non-seasonal Kenya site such packs also had longer inter-birth intervals. Over time, rising ambient temperatures at the (longest-monitored) Botswana site coincided with falling wild dog recruitment. Our findings suggest a direct impact of high ambient temperatures on African wild dog demography, indicating that this species, which is already globally endangered, may be highly vulnerable to climate change. This vulnerability would have been missed by simplistic trait-based assessments, highlighting the limitations of such assessments. Seasonal reproduction, which is less common at low latitudes than at higher latitudes, might be a useful indicator of climate change vulnerability among tropical species.


Predicting species diversity in tropical forests.
A fundamental question in ecology is how many species occur within a given area. Despite the complexity and diversity of different ecosystems, there exists a surprisingly simple, approximate answer: the number of species is proportional to the size of the area raised to some exponent. The exponent often turns out to be roughly 1/4. This power law can be derived from assumptions about the relative abundances of species or from notions of self-similarity. Here we analyze the largest existing data set of location-mapped species: over one million, individually identified trees from five tropical forests on three continents. Although the power law is a reasonable, zeroth-order approximation of our data, we find consistent deviations from it on all spatial scales. Furthermore, tropical forests are not self-similar at areas </=50 hectares. We develop an extended model of the species-area relationship, which enables us to predict large-scale species diversity from small-scale data samples more accurately than any other available method.


Nursing management of patients receiving stereotactic radiosurgery.
Stereotactic radiosurgery (SRS) is a minimally invasive procedure that delivers high-dose radiation in a single fraction to a precisely targeted lesion in the brain. When SRS is provided using a modified linear accelerator that produces x-ray beams, a stereotactic head ring is used for localization of the target area and immobilization during treatment. Radiation oncology nurses have a unique role in caring for patients receiving SRS. Prior to the procedure, a radiation oncology nurse assesses the patient, educates the patient and family about the procedure, and collaborates in the details of planning. On the day of treatment, the radiation oncology nurse assists with head ring placement, provides care and monitoring throughout the day, and provides discharge instructions. This article describes the SRS procedure, reviews possible side effects, and discusses the radiation oncology nursing role.


Neurophysiological correlates of nociceptive heterosynaptic long-term potentiation in humans.
Long-term potentiation (LTP) is a cellular model of synaptic plasticity and reflects an increase of synaptic strength. LTP is also present in the nociceptive system and is believed to be one of the key mechanisms involved in the manifestations of chronic pain. LTP manifested as an increased response in pain perception can be induced in humans using high-frequency electrical stimulation (HFS). The aim of this study was to induce spinal heterosynaptic LTP using HFS and investigate its heterotopic effects on event-related potentials (ERPs) to repeated nonpainful cutaneous stimuli as a possible electrophysiological cortical correlate of sensitization. Twenty-two healthy subjects were randomly assigned to one of the two experimental conditions: HFS and control stimulation. Before and after the stimulation, both conditions received heterotopic mechanical (pinprick) and paired nonpainful electrical test stimuli to quantify and confirm the effects of HFS on the behavioral level. ERPs to paired nonpainful electrical stimulation were measured simultaneously. Conditioning HFS resulted in significant heterotopic effects after 30 min, including increased perceived intensity in response to (pinprick) mechanical and paired nonpainful electrical stimulation compared with control. The paired nonpainful electrical stimuli were accompanied by significantly enhanced responses regarding the ERP N1-P2 peak-to-peak and P300 amplitude compared with control. These findings suggest that HFS is capable of producing heterosynaptic spinal LTP that can be measured not only behaviorally but also using ERPs.


[Effects of (22S,23S)- and (22R,23R)-3beta-hydroxy-22,23-oxido-5alpha-ergost-8(14)-en-15-ones on cholesteryl esters biosynthesis and acyl-CoA:cholesterol acyl transferase activity in Hep G2 cells].
Novel synthetic oxysterols (22S,23S)-3beta-hydroxy-22,23-oxido-5alpha-ergost-8(14)-en-15-one (I) and (22R,23R)-3beta-hydroxy-22,23-oxido-5alpha-ergost-8(14)-en-15-one (II) influenced cholesteryl esters biosynthesis in human hepatoma Hep G2 cell line from [14C]acetate (85% and 180% compared to control at the concentrations of 5 microM). The level of cholesteryl esters biosynthesis in Hep G2 cells from [14C]oleate increased in the presence of ketosterol (I) in a dose dependent manner, whereas the level of cholesteryl esters biosynthesis in the presence of ketosterol (II) reached the maximal value (269+/-20% from control) at the concentration of 1 microM. In a cell free system ketosterol (I) increased the rate of ACAT-dependent cholesterol acylation like 25-hydroxycholesterol, however, ketosterol (II), efficiently stimulating initial rate of ACAT-catalyzed cholesterol esterification, caused in rapid inactivation of this enzyme.