Is cefepime safe for clinical use? A Bayesian viewpoint.
Cefepime hydrochloride is approved for pneumonia, empirical therapy for febrile neutropenia, uncomplicated and complicated urinary tract infections, uncomplicated skin and skin structure infections and complicated intra-abdominal infections. A recent meta-analysis by Yahav et al. (Lancet Infect Dis 2007; 7: 338-48) concluded that cefepime was associated with a statistically significant increase in mortality (risk ratio 1.26, 95% confidence interval 1.08-1.49) when compared with other antibiotics. The US FDA decided to re-evaluate the meta-analysis data in collaboration with the drug sponsor. Two years later the FDA Alert summarized that 'data do not indicate a higher rate of death in cefepime-treated patients. Cefepime remains an appropriate therapy for its approved indications.' However, a thorough evaluation of the 52-page FDA report still shows that safety remains an unresolved issue. A Bayesian re-appraisal of the findings by the FDA and by Yahav et al. indicates that there is a 90.9% (by FDA trial-level meta-analysis), 80.8% (by FDA patient-level meta-analysis) and 99.2% (by Yahav et al. meta-analysis) probability that cefepime raises mortality in neutropenic fever patients, which translates into the following numbers needed to harm (NNH), i.e. to cause one extra death with the use of cefepime: FDA trial-level meta-analysis, NNH = 109; FDA patient-level meta-analysis, NNH = 76; Yahav et al. meta-analysis, NNH = 54. A similar harmful probability was observed with skin structure infections but not with pneumonias, intra-abdominal infections and urinary tract infections. In conclusion, cefepime should be avoided in patients with neutropenic fever or with skin structure infections.


Identification of a hypothetical protein from Podospora anserina as a nitroalkane oxidase.
The flavoprotein nitroalkane oxidase (NAO) from Fusarium oxysporum catalyzes the oxidation of primary and secondary nitroalkanes to their respective aldehydes and ketones. Structurally, the enzyme is a member of the acyl-CoA dehydrogenase superfamily. To date no enzymes other than that from F. oxysporum have been annotated as NAOs. To identify additional potential NAOs, the available database was searched for enzymes in which the active site residues Asp402, Arg409, and Ser276 were conserved. Of the several fungal enzymes identified in this fashion, PODANSg2158 from Podospora anserina was selected for expression and characterization. The recombinant enzyme is a flavoprotein with activity on nitroalkanes comparable to the F. oxysporum NAO, although the substrate specificity is somewhat different. Asp399, Arg406, and Ser273 in PODANSg2158 correspond to the active site triad in F. oxysporum NAO. The k(cat)/K(M)-pH profile with nitroethane shows a pK(a) of 5.9 that is assigned to Asp399 as the active site base. Mutation of Asp399 to asparagine decreases the k(cat)/K(M) value for nitroethane over 2 orders of magnitude. The R406K and S373A mutations decrease this kinetic parameter by 64- and 3-fold, respectively. The structure of PODANSg2158 has been determined at a resolution of 2.0 A, confirming its identification as an NAO.


Cardiogenic Shock in Patients with Advanced Chronic Heart Failure.
Patients with end-stage heart failure (HF) who have failed optimal medical therapy provide a unique set of challenges compared to the more prevalent population of patients with cardiogenic shock (CS) due to ST-segment elevation myocardial infarction. Progression from "preshock" into a refractory state of CS is associated with a dismal outcome due to difficulties with the patient's recognition, response to interventions, and candidacy for salvage options. Challenges include heterogeneity of CS (eg, different phenotypes, etiologies, duration, acuity of onset, hemodynamics, end-organ effects), lack of a universal definition of CS that is applicable to this patient population, and blunted hemodynamic response given the patient's prolonged compensatory state. Individuals with advanced HF in CS require a multidisciplinary team-based assessment regarding when to escalate from medical therapy into temporary mechanical circulatory support, and they need an eligibility evaluation to determine their candidacy for advanced therapy. In this review, we discuss the definition and clinical phenotypes of CS, classification of CS in advanced HF patients, the utility of temporary mechanical circulatory support, and the role of the CS team.


Orbital physics in transition-metal oxides
An electron in a solid, that is, bound to or nearly localized on the specific atomic site, has three attributes: charge, spin, and orbital. The orbital represents the shape of the electron cloud in solid. In transition-metal oxides with anisotropic-shaped d-orbital electrons, the Coulomb interaction between the electrons (strong electron correlation effect) is of importance for understanding their metal-insulator transitions and properties such as high-temperature superconductivity and colossal magnetoresistance. The orbital degree of freedom occasionally plays an important role in these phenomena, and its correlation and/or order-disorder transition causes a variety of phenomena through strong coupling with charge, spin, and lattice dynamics. An overview is given here on this "orbital physics," which will be a key concept for the science and technology of correlated electrons.


Early cell lineage specification in a marsupial: a case for diverse mechanisms among mammals.
Early cell lineage specification in eutherian mammals results in the formation of a pluripotent inner cell mass (ICM) and trophoblast. By contrast, marsupials have no ICM. Here, we present the first molecular analysis of mechanisms of early cell lineage specification in a marsupial, the tammar wallaby. There was no overt differential localisation of key lineage-specific transcription factors in cleavage and early unilaminar blastocyst stages. Pluriblast cells (equivalent to the ICM) became distinguishable from trophoblast cells by differential expression of POU5F1 and, to a greater extent, POU2, a paralogue of POU5F1. Unlike in the mouse, pluriblast-trophoblast differentiation coincided with a global nuclear-to-cytoplasmic transition of CDX2 localisation. Also unlike in the mouse, Hippo pathway factors YAP and WWTR1 showed mutually distinct localisation patterns that suggest non-redundant roles. NANOG and GATA6 were conserved as markers of epiblast and hypoblast, respectively, but some differences to the mouse were found in their mode of differentiation. Our results suggest that there is considerable evolutionary plasticity in the mechanisms regulating early lineage specification in mammals.


Lost productivity and burden of illness in cancer survivors with and without other chronic conditions.
Cancer survivors may experience long-term and late effects from treatment that adversely affect health and limit functioning. Few studies examine lost productivity and disease burden in cancer survivors compared with individuals who have other chronic conditions or by cancer type. We identified 4960 cancer survivors and 64,431 other individuals from the 2008-2010 Medical Expenditure Panel Survey and compared multiple measures of disease burden, including health status and lost productivity, between conditions and by cancer site for cancer survivors. All analyses controlled for the effects of age, sex, race/ethnicity, and number of comorbid conditions. Overall, in adjusted analyses in multiple models, cancer survivors with another chronic disease (heart disease or diabetes) experienced higher levels of burden compared with individuals with a history of cancer only, chronic disease only, and neither cancer, heart disease, nor diabetes across multiple measures (P < .05). Among cancer survivors, individuals with short survival cancers and multiple cancers consistently had the highest levels of burden across multiple measures (P < .0001). Cancer survivors who have another chronic disease experience more limitations and higher levels of burden across multiple measures. Limitations are particularly severe in cancer survivors with short survival cancer and multiple cancers.


The impact of donor source, recipient age, pre-operative immunotherapy and induction therapy on early and late acute rejections in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).
Acute rejection is a frequent event in pediatric transplantation. In addition to graft loss, acute rejection episodes stimulate the development of chronic rejection and inhibit growth in children post-transplantation. In this study, we analyzed our data from 1987 through 1996 to identify acute rejection episodes in children. In 2,520 living donor (LD) transplants there were 2,540 rejection episodes (rejection ratio: 1.1), and in 2,579 cadaver donor (CD) transplants 3,653 episodes were observed (rejection ratio: 1.32). For LD recipients the first rejection occurred sooner when there was at least one HLA-DR mismatch (RR=1.6, p<0.001) and prophylactic T-cell antibody was not used (RR=1.4, p<0.001). For CD transplants absence of prophylactic T-cell antibody (RR=1.2, p<0.001) and donor age below five years were risk factors (RR=1.5, p<0.001). Late initial acute rejections were seen in 327 of 1,471 patients (22.2%) who were rejection free at one year. At risk for the development of late rejections were children over the age of six years at transplantation (RR=1.7, p<0.001) and children of non-white origin (RR=1.5, p <0.002). For LD transplant recipients in the age range of 0-5 years, irreversible rejection was observed in 8.7% compared to 4.1% for older children (RR=1.46, p<0.001). Similar results for CD transplants were 12.6% versus 6.6% (RR=1.5, p<0.00). The high frequency of rejection episodes in children and the greater irreversibility in younger children suggest pediatric patients may have a more robust immune response. Current ongoing studies in the molecular mechanisms of the pathogenesis of rejection in surveillance biopsies of children may help determine if this hypothesis is valid.


Pulmonary lesions caused by the nematode Rhabdias fuscovenosa in a grass snake, Natrix natrix.
In June 2005, a free-ranging grass snake, Natrix natrix infected with Rhabdias fuscovenosa was collected for histologic examination of the lungs. Gross lesions were not noted; however, histologic examination revealed vacuolar degeneration of the respiratory epithelium, hemorrhage, smooth muscle degeneration, faveolae necrosis and obstruction, and intralesional nematodes. Eosinophils were the most common inflammatory cell observed in the areas of necrosis and interstitium. Herein we describe histopathologic changes due to R. fuscovenosa in a free-ranging grass snake.


Limits of exciton delocalization in molecular aggregates.
Exciton states of molecular aggregates, with a particular focus on delocalization length, are discussed. Despite the huge number of studies of molecular excitons, it is argued that there remain interesting open questions. It is hypothesized that limits for equilibrium delocalization length are generally in the range of tens of molecules, even at very low temperatures. Effects that limit delocalization include: phase disorder from wave-zone electronic coupling, polarization fluctuations, and the extreme sensitivity of perfect delocalization to disorder as the size of the molecular aggregate increases. To gain physical insight, the inverse participation ratio is compared to the order parameter for a classical system of coupled, and hence entrained, oscillators-the Kuramoto model. The main result of the paper is that the inverse participation ratio obtained from the quantum mechanical exciton model and the Kuramoto order parameter obtained from coupled classical oscillators estimate the same coherence length. Conclusions suggest discussion topics that touch on limits of delocalization, quantum-to-classical transitions in molecular exciton systems, and whether excitons are good prospects for exploring and exploiting quantum information resources from coherence.


Degradation of thiram in water, soil and plants: a study by high-performance liquid chromatography.
A comprehensive study was conducted to evaluate the persistence of thiram in water and soil under controlled conditions and on two plants, namely tomato and radish, in field conditions. In order to follow the decay of the pesticide, an HPLC procedure was developed employing an octadecyl endcapped RP-C18 column using a mixture of acetonitrile and water as the mobile phase and an ultraviolet detector. Studies conducted in water at different temperature, pH and organic content revealed that the persistence of the pesticide decreases with the increase in all the three variables. In the three different types of soils studied, the effect of pH was more or less apparent on a similar line. On average a slower decay was observed in the case of plants than in water and soil.


Spinal-flexibility-plus-aerobic versus aerobic-only training: effect of a randomized clinical trial on function in at-risk older adults.
As exercise is associated with favorable health outcomes, impaired older adults may benefit from specialized exercise interventions to achieve gains in function. The purpose of this study was to determine the added benefit of a spinal flexibility-plus-aerobic exercise intervention versus aerobic-only exercise on function among community-dwelling elders. We employed a randomized clinical trial consisting of 3 months of supervised exercise followed by 6 months of home-based exercise with telephone follow-up. A total of 210 impaired males and females over age 64 enrolled in this study. Of these, 134 were randomly assigned to either spinal flexibility-plus-aerobic exercise or aerobic-only exercise, with 116 individuals completing the study. Primary outcomes obtained at baseline, after 3 months of supervised exercise, and after 6 months of home-based exercise included: axial rotation, maximal oxygen uptake (VO2max); functional reach, timed-bed-mobility; and the Physical Function Scale (PhysFunction) of the Medical Outcomes Study SF-36. Differences between the two interventions were minimal. Overall change scores for both groups combined indicated significant improvement for: axial rotation (p=.001), VO2max (p=.0001), and PhysFunction (p=.0016). Secondary improvements were noted for overall health (p=.0025) and reduced symptoms (p=.0008). Differences between groups were significant only for VO2max (p=.0014) at 3 months with the aerobic-only group improving twice as much in aerobic capacity as the spinal flexibility-plus-aerobic group. Repeated measures indicated both groups improved during the supervised portion of the intervention but tended to return toward baseline following the home-based portion of the trial. Gains in physical functioning and perceived overall health are obtained with moderate aerobic exercise. No differential improvements were noted for the spinal flexibility-plus-aerobic intervention.


Altering Planting Date to Manage Melanaphis sacchari (Hemiptera: Aphididae) Populations in Sweet Sorghum.
Melanaphis sacchari Zehntner is a new pest of sweet sorghum in the United States, with the potential to cause complete crop failure. In Kentucky, sweet sorghum is normally planted in early May and harvested in late August or September. Planting sweet sorghum earlier in the season may avoid damaging levels of M. sacchari that develop in late summer. In a 2-yr field study, three different planting dates separated by a month (April, May, and June) were tested for their effect on M. sacchari densities and sweet sorghum yield. April (early) planted sweet sorghum was grown in greenhouses and transplanted to the field. May (mid) and June (late) planted sweet sorghum were direct seeded in the field. Melanaphis sacchari population densities were evaluated weekly starting in June. Sweet sorghum was harvested at the onset of the hard dough stage. Plots were split into two subplots, insecticide or noninsecticide, in the second year to control for planting date effect on yield. Early-planted sweet sorghum had lower aphid densities, but had lower yield relative to mid-planting date, which had the highest yield. Insecticide drenches in 2019 reduced cumulative aphid days in mid-plantings and late plantings, but did not significantly affect yield within planting dates. Seeding sweet sorghum earlier can reduce M. sacchari densities; however, this method alone may not provide the highest yields. We documented that the recommended planting date (May) for Kentucky produced the highest yield.


Cribriform Morular Thyroid Carcinoma: A Rare Case and Associated Uncommon Features.
Cribriform morular thyroid carcinoma has been added under tumors of uncertain histogenesis. Its peculiar clinical, histomorphological pattern, and immunohistochemical profile have been proved different from papillary thyroid carcinoma. A 59-year-old female patient had a lesion in the left lobe of the thyroid. Fine needle aspiration cytology was reported as medullary thyroid carcinoma. The total thyroidectomy specimen showed a predominantly solid tumor of size 9.5 cm in the left lobe. Microscopy showed a mixed growth pattern with the dominant cribriform and solid morular area. Nuclear features of papillary carcinoma were not seen. Squamoid morules had nuclear clearing. Marked stromal hyalinization and calcification were noted. Extrathyroidal extension, lymphovascular invasion, and lymph node metastasis were not identified. Immunohistochemically the tumor cells were diffuse and strong nuclear positive for β-catenin, TTF1, PAX8, estrogen receptor, focal, and weak positivity for CD5. Synaptophysin, calcitonin, thyroglobulin, and CDX2 were negative. We report this rare cribriform morular thyroid carcinoma case with its associated uncommon histological and immunohistochemical features.


Genotoxic effects of zinc oxide nanoparticles.
The potential toxicity of nanoparticles has currently provoked public and scientific discussions, and attempts to develop generally accepted handling procedures for nanoparticles are under way. The investigation of the impact of nanoparticles on human health is overdue and reliable test systems accounting for the special properties of nanomaterials must be developed. Nanoparticular zinc oxide (ZnO) may be internalised through ambient air or the topical application of cosmetics, only to name a few, with unpredictable health effects. Therefore, we analysed the determinants of ZnO nanoparticle (NP) genotoxicity. ZnO NPs (15-18 nm in diameter) were investigated at concentrations of 0.1, 10 and 100 μg mL(-1) using the cell line A549. Internalised NPs were only infrequently detectable by TEM, but strongly increased Zn(2+) levels in the cytoplasm and even more in the nuclear fraction, as measured by atom absorption spectroscopy, indicative of an internalised zinc and nuclear accumulation. We observed a time and dosage dependent reduction of cellular viability after ZnO NP exposure. ZnCl2 exposure to cells induced similar impairments of cellular viability. Complexation of Zn(2+) with diethylene triamine pentaacetic acid (DTPA) resulted in the loss of toxicity of NPs, indicating the relevant role of Zn(2+) for ZnO NP toxicity. Foci analyses showed the induction of DNA double strand breaks (DSBs) by ZnO NPs and increased intracellular reactive oxygen species (ROS) levels. Treatment of the cells with the ROS scavenger N-acetyl-l-cysteine (NAC) resulted in strongly decreased intracellular ROS levels and reduced DNA damage. However, a slow increase of ROS after ZnO NP exposure and reduced but not quashed DSBs after NAC-treatment suggest that Zn(2+) may exert genotoxic activities without the necessity of preceding ROS-induction. Our data indicate that ZnO NP toxicity is a result of cellular Zn(2+) intake. Subsequently increased ROS-levels cause DNA damage. However, we found evidence for the assumption that DNA-DSBs could be caused by Zn(2+) without the involvement of ROS.


An application of stepwise discriminant analysis to the characterization of military heroin dependents, illicit drug users, and psychiatric patients.
This application of stepwise discriminant analysis explores a way to structure skewed-sample interview data, discusses some implications of the results and the conceptual limitations of assumptions about deviancy, and suggests a focus for future studies of the complex phenomena of drug abuse. The methodology differs from previous reports in that it uses a constant probability level, letting the computational procedure determine the number of significant variables. It also provides a method of determining the "chance" level (the amount of correct classification when there are no differences between the groups) so that the observed correct classification values may be usefully interpreted.


Beyond Race/Ethnicity: Skin Color and Cardiometabolic Health Among Blacks and Hispanics in the United States.
We investigated whether darker interviewer-ascribed skin color is associated with worse cardiometabolic health among young adult Blacks and Hispanics in the United States. Our sample was comprised of 2,128 non-Hispanic Blacks and 1603 Hispanics aged 24-32, who were in high school in the United States in 1994. We used logistic and OLS regression to predict obesity, hypertension, diabetes, and cardiometabolic risk. We tested the interaction between Hispanic immigrant generation and ascribed skin color. Darker ascribed skin color predicted worse cardiometabolic health among both young adult Blacks and Hispanics. Among Hispanics, the associations were strongest among third and higher generation respondents. Our findings suggest that among US Blacks and Hispanics how individuals are perceived by others via their skin color is significantly associated with their health and well-being. Gradients in cardiometabolic health in young adulthood will likely contribute to gradients in cardiovascular disease and all-cause mortality later in life.


Healthcare resource utilization and costs associated with inflammatory bowel disease among patients with chronic inflammatory diseases: a retrospective cohort study.
Chronic inflammatory diseases (CIDs; ankylosing spondylitis [AS], psoriatic arthritis [PsA], psoriasis [PsO], or rheumatoid arthritis [RA]) and inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) are associated with substantial economic burden. The relative increased costs among patients with CIDs and concomitant IBD compared to those without IBD is an important consideration when deciding on the clinical management of patient symptoms. Given the increasing use of novel agents for the treatment of CIDs, including those that may increase the risk of IBD in patients with CIDs, the objective of the study was to describe the incidence of IBD and to quantify healthcare resource utilization (HRU) and costs associated with IBD among patients with CIDs. The IBM MarketScan® Research Databases (1/2010-7/2017) were used to identify adult patients with ≥2 claims with a diagnosis of either AS/PsA/PsO/RA (index date was a random claim for AS/PsA/PsO/RA). The one-year incidence rate of IBD was calculated following the index date. HRU and healthcare costs were compared between patients developing and not developing IBD in the year following the index date, adjusting for baseline characteristics. A total of 537,450 patients with CIDs (mean age = 54.0 years; 63.1% female) were included in the study. The 1-year incidence rate of IBD was 0.52% (range = 0.39% in patients with PsO but without PsA to 1.73% in patients with AS). Patients who developed IBD (N = 2778) had significantly higher rates of inpatient, outpatient, and emergency room visits (incidence rate ratios [IRR] = 2.91, 1.35, 1.81; all P < 0.0001), compared to patients without IBD (N = 534,672). Patients who developed IBD had $18,500 (P < 0.0001) higher total costs per year, including $15,121 (P < 0.0001) higher medical costs and $3380 higher pharmacy costs (P < 0.0001). Higher HRU and costs were observed in patients with concomitant CID and IBD compared to patients with CID alone. Consideration should be given to treatment decisions that adequately manage CID and IBD to ensure optimal clinical and economic outcomes.


Uterine perforation during 3-dimensional image-guided brachytherapy in patients with cervical cancer: Baskent University experience.
This study aimed to determine the incidence and characteristics of uterine perforation at our department using 3-dimensional computed tomography (CT)-based brachytherapy (BRT). The characteristics of the patients presenting with perforation and impact of the perforation on the treatment course were also analyzed. The clinical and radiologic data of 200 patients with biopsy-proven cervical cancer treated using CT-based BRT were retrospectively evaluated. All patients had undergone tandem-based intracavitary BRT, and 67 patients had undergone magnetic resonance imaging (MRI) before BRT. Of the 200 patients, 17 (8.5%) had uterine perforation. Of the 626 applications with CT images, 30 (4.8%) resulted in uterine perforation. The median age of patients with perforation was higher (68 years; range, 44-89 years) than that of the patients without perforation (59 years; range, 21-87 years), and the mean (SD) tumor size at diagnosis was larger in patients with perforation (7.0 [1.5] cm) than in patients without perforation (5.0 [1.5] cm). The most frequent perforation site was the posterior uterine wall (8 patients), followed by the fundus (5 patients) and anterior wall (4 patients). Of the 7 patients with a retroverted uterus, 4 had uterine perforation during BRT. In 67 patients with MRI delivered before BRT, only 3 (4%) had uterine perforation, and 2 of the 3 patients with uterine perforation had a retroverted uterus. However, of the 133 patients with no MRI evaluation before BRT, 14 (11%) had uterine perforation. No life-threatening complications or signs of intraperitoneal tumor cell seeding were observed. Older age, larger tumors, a retroverted uterus, and a stenotic cervical os were all predisposing factors for uterine perforation during BRT. Preoperative MRI is a feasible and safe method to decrease the risks of uterine perforation and could be used preoperatively in centers where intraoperative ultrasonography is not used in routine practice.


New epistemological foundations for cultural psychology: from an atomistic to a self-organizing view of living systems.
An epistemological foundation for cultural psychology is essential to neuro- and behavioural sciences for the challenge psychological sciences must currently face: searching for an explanation of how a brain can become a mind and how individuals assign a sense to the world and their life. Biological systems are very likely determined by physical and chemical laws of spontaneous self-organization and endogenous constraints but, even if the major result of the Darwinian revolution is "the discovery that living species are their story", the modern synthesis of the evolution theory adopted only continuist and gradualist hypotheses. This nourished the analogy between the theory of natural selection and the theory of operant conditioning, thereby supporting empiricist associationism and the methodological positivism of behavioural and "classical" cognitive psychologists. Current scientific contributions provide evidence to the need for psychotherapy and psychopathology of a new epistemological approach in order to connect research stemming from animal models, up to the most abstract levels of personal meaning. The complex system oriented approach, here described, called "post-rationalism", shaped by a change initiated by evolutionary epistemology. The regulation of emotions initially develops within interpersonal relationships and evolves during both phylogeny and ontogeny, according to complex self-organization processes, leading to the acquisition of Self-organizing abilities and the construction of personal meaning. Endorsing the epistemological similarities of neo-Darwinism and behaviourism, and differentiating from this, the above mentioned approach, emphasises the fact that clinical and psycho-therapeutical practice must be founded on the laws of biological organisation: the ongoing activity of neurobiological systems, including the more abstract domains of thought and language.


Cumulative burden and trajectories of body mass index and blood pressure from childhood and carotid intima-media thickness in young adulthood.
There are significant gaps in understanding of the association between levels and rate of change of body mass index (BMI) and blood pressure (BP) at different ages during childhood and carotid intima-media thickness (CIMT) in adulthood. We investigated the association between trajectories of BMI and BP from childhood to adulthood and adult CIMT among Iranian participants in the Tehran Lipid and Glucose Study (TLGS) cohort. A total of 1334 participants (692 men), from the TLGS cohort (1999-2018) with repeated measurements of BMI and BP (2-6 times) from childhood (3-18 years) to young adulthood (20-40 years) were selected. Trajectory parameters included levels and linear slopes of BMI and BP growth curve models, and cumulative burden defined as the area under those curves (AUC). After adjusting for confounders, AUC of BMI and diastolic blood pressure (DBP) were significantly associated with high CIMT in adulthood, with the standardized odds ratios (OR) and 95% confidence interval (95% CI) of 1.35 (1.12-1.62) and 1.27 (1.01-1.60), respectively. Associations between level-independent slopes of BMI and adult CIMT were significantly positive (ORs: 1.27 to 1.26) during childhood ages (3-18 years). Further, levels of BMI (ORs: 1.23 to 1.29) and DBP (ORs: 1.25 to 1.33) during the ages of 13-18 and 11-17 years, respectively, were significantly associated with CIMT in adulthood (all P < 0.05). The cumulative burden of BMI and DBP was associated with CIMT in adulthood. Adolescence is a crucial period for high CIMT, which has implications for early prevention of atherosclerosis.


The Dutch Data Warehouse, a multicenter and full-admission electronic health records database for critically ill COVID-19 patients.
The Coronavirus disease 2019 (COVID-19) pandemic has underlined the urgent need for reliable, multicenter, and full-admission intensive care data to advance our understanding of the course of the disease and investigate potential treatment strategies. In this study, we present the Dutch Data Warehouse (DDW), the first multicenter electronic health record (EHR) database with full-admission data from critically ill COVID-19 patients. A nation-wide data sharing collaboration was launched at the beginning of the pandemic in March 2020. All hospitals in the Netherlands were asked to participate and share pseudonymized EHR data from adult critically ill COVID-19 patients. Data included patient demographics, clinical observations, administered medication, laboratory determinations, and data from vital sign monitors and life support devices. Data sharing agreements were signed with participating hospitals before any data transfers took place. Data were extracted from the local EHRs with prespecified queries and combined into a staging dataset through an extract-transform-load (ETL) pipeline. In the consecutive processing pipeline, data were mapped to a common concept vocabulary and enriched with derived concepts. Data validation was a continuous process throughout the project. All participating hospitals have access to the DDW. Within legal and ethical boundaries, data are available to clinicians and researchers. Out of the 81 intensive care units in the Netherlands, 66 participated in the collaboration, 47 have signed the data sharing agreement, and 35 have shared their data. Data from 25 hospitals have passed through the ETL and processing pipeline. Currently, 3464 patients are included in the DDW, both from wave 1 and wave 2 in the Netherlands. More than 200 million clinical data points are available. Overall ICU mortality was 24.4%. Respiratory and hemodynamic parameters were most frequently measured throughout a patient's stay. For each patient, all administered medication and their daily fluid balance were available. Missing data are reported for each descriptive. In this study, we show that EHR data from critically ill COVID-19 patients may be lawfully collected and can be combined into a data warehouse. These initiatives are indispensable to advance medical data science in the field of intensive care medicine.


[High time to make choice: preventive or curative appendectomy?].
The authors advocate prophylactic appendectomy in conditions of wide application of laparoscopic surgery, refer to literature data on the absence of life-important functions in appendix and any functional disturbances after appendectomy. Taking into account high rate of development and difficulties in the diagnosis of acute appendicitis, favourable clinical and economical results of laparoscopic appendectomy, the authors suggest wider use of preventive removal of the appendix, especially in definite groups of population.


NKG2D functions as an activating receptor on natural killer cells in the common marmoset (Callithrix jacchus).
The natural killer group 2 membrane D (NKG2D) receptor is an NK-activating receptor that plays an important role in host defense against tumors and viral infections. Although the marmoset is an important and reliable animal model, especially for the study of human-specific viral infections, functional characterization of NKG2D on marmoset NK cells has not previously been conducted. In the present study, we investigated a subpopulation of marmoset NK cells that express NKG2D and exhibit cytolytic potential. On the basis of their CD16 and CD56 expression patterns, marmoset NK cells can be classified into three subpopulations: CD16(+) CD56(-), CD16(-) CD56(+) and CD16(-) CD56(-) cells. NKG2D expression on marmoset CD16(+) CD56(-) and CD16(-) CD56(+) splenocytes was confirmed using an NKG2D ligand composed of an MHC class I chain-related molecule A (MICA)-Fc fusion protein. When marmoset splenocytes were cultured with IL-2 for 4 days, NKG2D expression was retained on CD16(+) CD56(-) and CD16(-) CD56(+). In addition, CD16(+) CD56(+) cells within the marmoset NK population appeared which expressed NKG2D after IL-2 stimulation. IL-2-activated marmoset NK cells showed strong cytolytic activity against K562 target cells and target cells stably expressing MICA. Further, the cytolytic activity of marmoset splenocytes was significantly reduced after addition of MICA-Fc fusion protein. Thus, NKG2D functions as an activating receptor on marmoset NK cells that possesses cytotoxic potential, and phenotypic profiles of marmoset NK cell subpopulations are similar to those seen in humans.


Dutch Cochlear Implant Group (CI-ON) consensus protocol on postmeningitis hearing evaluation and treatment.
One of the most devastating sequelae of bacterial meningitis is profound hearing loss or even deafness. Although cochlear implantation is able to restore (some) hearing abilities, obliteration due to fibrosis and especially calcification of the cochlea in the postmeningitis period is limiting the success rate of an implantation. A national consensus assembled in a postmeningitis follow-up protocol has to increase awareness and thus the chances of an early detection and possible intervention when profound hearing loss occurs. All cochlear implant (CI) centers of The Netherlands located in the 8 academic otorhinolaryngology and audiology departments of The Netherlands, gathered in the Dutch Cochlear Implant Group (CI-ON, Cochlear Implant Overleg Nederland). A protocol proposed by 3 centers was sent to all other CI centers in The Netherlands to review and agree on. The CI centers agreed on the need for, and use of, the proposed protocol. Keystones of the protocol are treatment with dexamethasone before start of antibiotics, early magnetic resonance imaging and repeated audiological follow-up, and urgent referral to a CI center in all cases with greater than 30 dB SNHL. The Cochlear Implant Centers in The Netherlands (CI-ON) have agreed on a protocolized follow-up after bacterial meningitis to increase the chances of an early detection and possible intervention should profound hearing loss occur.


Treatment of non-atopic dermatitis with polarized UV-free polychromatic light: A case report.
Non-atopic dermatitis is a common inflammatory condition, which is potentially debilitating and can compromise life quality. Polarized ultraviolet-free polychromatic light is used as therapeutic option for the treatment of wound healing and dermatological conditions. It has not yet been tested in the management of non-atopic dermatitis. In this case report, we present a 67- year-old female patient who had suffered with moderate non-atopic dermatitis for the past 20 years, and had undergone multiple treatments during that time without significant improvement or relief from her symptoms. She was treated for six weeks only with daily light therapy applications (10 minutes/area). Our results showed that light therapy offered a significant reduction in erythema of the affected zones with a concomitant reduction in pruritus and dehydration of the skin, without side effects or discomfort.


The Intricate Relationship between Psychotic-Like Experiences and Associated Subclinical Symptoms in Healthy Individuals.
The interplay between subclinical psychotic, negative, and affective symptoms has gained increased attention regarding the etiology of psychosis spectrum and other mental disorders. Importantly, research has tended to not differentiate between different subtypes of psychotic-like experiences (PLE) although they may not have the same significance for mental health. In order to gain information on the subclinical interplay between specific PLE and other symptoms as well as the significance of PLE for mental health, we investigated their specific associations in 206 healthy individuals (20-60 years, 73 females) using correlational and linear regression analyses. PLE were assessed with the Magical Ideation Questionnaire, the revised Exceptional Experiences Questionnaire, and subscales of the Schizotypal Personality Questionnaire (SPQ). The revised Symptom Checklist 90, the SPQ, and the Physical Anhedonia Scale were used to measure subclinical negative symptoms, affective symptoms, and other symptoms such as, emotional instability. As hypothesized, we found that (1) most affective symptoms and all other subclinical symptoms correlated positively with all PLE, whereas we found only partial associations between negative symptoms and PLE. Notably, (2) magical ideation and paranormal beliefs correlated negatively with physical anhedonia. In the regression analyses we found (3) similar patterns of specific positive associations between PLE and other subclinical symptoms: Suspiciousness was a specific predictor of negative-like symptoms, whereas ideas of reference, unusual perceptual experiences, and dissociative anomalous perceptions specifically predicted anxiety symptoms. Interestingly, (4) ideas of reference negatively predicted physical anhedonia. Similarly, paranormal beliefs were negatively associated with constricted affect. Moreover, odd beliefs were a negative predictor of depression, emotional instability, and unspecific symptoms. Our findings indicated that subtypes of PLE are differentially implicated in psychological functioning and should therefore not be categorized homogeneously. Moreover, paranormal beliefs, odd beliefs, and partly ideas of reference might also contribute to subjective well being in healthy individuals. Our results might serve as a starting point for longitudinal studies investigating the interplay of subtypes of subclinical symptoms along a psychopathological trajectory leading to mental disorders. Importantly, this research might help to improve therapeutic strategies for psychosis prevention.


Effects of surfactant on biofilm formation on silicone nasal splints.
Biofilms are sessile communities of bacteria embedded in self-produced extracellular polysaccharide matrix and are considered to be responsible for bacterial infections in humans. Topical surfactant use on silicone nasal splints may have a preventive effect on biofilm formation. The objective of this study is to investigate the effect of surfactant-containing nasal solutions on biofilm formation over the surface of silicone nasal splints. Forty patients were randomized after septoplasty to receive surfactant-containing saline solution (group 1) or saline without surfactant (group 2). At the postoperative 48th, 72th and 96th hours, pieces of splint samples were taken and prepared for scanning electron microscopic evaluation. Biofilm formation was observed in 3, 6 and 14 of 20 samples in group 1 (surfactant used) and 3, 14 and 20 of 20 samples in group 2 (control) at 48th, 72th and 96th hours, respectively. Biofilm formation incidences of groups at 48th hour were similar (p > 0.05), whereas it was significantly lower at group 1 regarding 72th and 96th hours (p < 0.05). Surfactant-containing nasal solutions have an inhibitory effect on biofilm formation over the surface of silicone nasal splints especially after 48 h. Surfactant-containing nasal solutions may have an important role in nasal septal dressing in the future.


Fission yeast TOR complex 2 activates the AGC-family Gad8 kinase essential for stress resistance and cell cycle control.
Members of the mitogen-activated protein kinase (MAPK) subfamily responsive to environmental stress stimuli are known as SAPKs (stress-activated protein kinases), which are conserved from yeast to humans. In the fission yeast Schizosaccharomyces pombe, Spc1/Sty1 SAPK is activated by diverse forms of stress, such as osmostress, oxidative stress and heat shock, and induces gene expression through the Atf1 transcription factor. Sin1 (SAPK interacting protein 1) was originally isolated as a protein that interacts with Spc1, and its orthologs were also found in diverse eukaryotes. Here we report that Sin1 is not required for the stress gene expression regulated by Spc1 and Atf1, and that Sin1 is an essential component of TOR (target of rapamycin) complex 2 (TORC2). TORC2 is not essential for cell viability in S. pombe but plays important roles in cellular survival of stress conditions through phosphorylation and activation of an AGC-family protein kinase, Gad8. In addition, inactivation of Gad8 results in a synthetic growth defect with cdc25-22, a temperature-sensitive mutation of the Cdc25 phosphatase that activates Cdc2 kinase at G(2)/M. Gad8 also positively regulates expression of the CDK inhibitor gene rum1+, which is essential for cell cycle arrest in G(1) after nitrogen starvation. These results strongly suggest that the TORC2-Gad8 pathway has multiple physiological functions in cellular stress resistance and cell cycle progression at both G(1)/S and G(2)/M transitions.


The effect of pressure on the hydration structure around hydrophobic solute: a molecular dynamics simulation study.
Molecular dynamics simulations are performed to study the effects of pressure on the hydrophobic interactions between neopentane molecules immersed in water. Simulations are carried out for five different pressure values ranging from 1 atm to 8000 atm. From potential of mean force calculations, we find that with enhancement of pressure, there is decrease in the well depth of contact minimum (CM) and the relative stability of solvent separated minimum over CM increases. Lower clustering of neopentane at high pressure is also observed in association constant and cluster-structure analysis. Selected site-site radial distribution functions suggest efficient packing of water molecules around neopentane molecules at elevated pressure. The orientational profile calculations of water molecules show that the orientation of water molecules in the vicinity of solute molecule is anisotropic and this distribution becomes flatter as we move away from the solute. Increasing pressure slightly changes the water distribution. Our hydrogen bond properties and dynamics calculations reveal pressure-induced formation of more and more number of water molecules with five and four hydrogen bond at the expense of breaking of two and three hydrogen bonded water molecules. We also find lowering of water-water continuous hydrogen bond lifetime on application of pressure. Implication of these results for relative dispersion of hydrophobic molecules at high pressure are discussed.


Infants of depressed mothers exhibit atypical frontal electrical brain activity during interactions with mother and with a familiar, nondepressed adult.
Previous studies have shown that infants of depressed mothers exhibit atypical frontal brain electrical activity when they are interacting with their mothers. Whereas typically developing infants exhibit greater left versus right frontal brain activity, infants of depressed mothers have been found to exhibit reduced relative left frontal activity. The left frontal brain region has been associated with the expression of positive emotions. In the present study, the question of whether the atypical pattern of brain activity found in infants of depressed mothers generalizes to situations not involving mother was addressed. Brain electrical activity was recorded from 13- to 15-month-old infants of depressed (N = 59) versus nondepressed (N = 40) mothers during a baseline condition, and during several social conditions that included a playful social interaction with a familiar experiments. Infants of depressed mothers exhibited reduced left relative to right frontal activity during the baseline condition, and during interactions with their mothers and with the familiar experimenter. The present results suggest that the atypical pattern of electrical brain activity found in infants of depressed mothers generalizes to a variety of situations, including positive interactions with nondepressed adults.


Assessment of gestational age and neuromaturation.
Neuromaturation is the functional development of the central nervous system (CNS). It is by its very nature a dynamic process, a continuous interaction between the genome and first the intrauterine environment, then the extrauterine environment. Understanding neuromaturation and being able to measure it is fundamental to infant neurodevelopmental assessment. Fetal and preterm neuromaturation has become easier to observe with the advent of prenatal ultrasonography and neonatal intensive care units. A number of measures of degree of fetal maturation have been developed and used to estimate gestational age (GA) at birth. The most reliable measures of GA are prenatal measures, especially from the first trimester. Postnatal GA measurements tend to be least accurate at the extremes of gestation, that is, in extremely preterm and post-term infants. Observations of measures of neuromaturation in infants born to mothers with pregnancy complications, including intrauterine growth restriction, multiple gestation, and chronic hypertension, have led to the discovery that stressed pregnancies may accelerate fetal pulmonary and CNS maturation. This acceleration of neuromaturation does not occur before 30 weeks' gestation and has a cost with respect to cognitive limitations manifested in childhood. The ability to measure fetal and preterm neuromaturation provides an assessment of neurodevelopmental progress that can be used to reassure parents or identify at risk infants who would benefit from limited comprehensive follow-up and early intervention services. In addition, measures of neuromaturation have the potential to provide insight into mechanisms of CNS injury and recovery, much-needed early feedback in intervention or treatment trials and a measure of early CNS function for research into the relationships between CNS structure and function.


Radon in residences: influences of geological and housing characteristics.
222Rn is a radioactive gas emitted during the decay of 238U. 222Rn is a recognized lung carcinogen in humans and a common indoor air contaminant. This paper describes the results of research undertaken in 894 residences of the Province of Quebec (Canada), in which one of the objectives was to evaluate the influence of geological and housing characteristics on 222Rn levels. After a random selection of homes, 222Rn concentrations were measured with alpha track detectors in the basement and the main bedroom during two consecutive 6-mo periods. Geological subsoil characteristics were determined from various sources (e.g., geological maps, databanks on uranium sampling in lake and stream sediments), and housing characteristics were documented with a questionnaire. Statistical variance analysis of data indicates that geological factors only explain 5% and 4.5% of the variations in 222Rn concentrations, respectively, in the basement and on the first floor. When variables relative to housing characteristics are added, the analysis explains only 18% and 15% of the variations in 222Rn concentrations in the basement and on the first floor. These results illustrate the difficulties in predicting 222Rn concentrations in homes.


The Protective Effect of Apigenin on Myocardial Injury in Diabetic Rats mediating Activation of the PPAR-γ Pathway.
We substantiated the role of peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in the protective effect of apigenin against the myocardial infarction (MI) in diabetic rats. Diabetes was induced by intraperitoneal administration of a single dose of streptozotocin (55 mg/kg). The study groups included diabetic rats receiving vehicle, apigenin (75 mg/kg/day, orally), GW9662 (1 mg/kg/day, intraperitoneally), and a combination of apigenin and GW9662 for 14 days. The MI was induced in all the study groups except the diabetic control group by subcutaneous injection of 100 mg/kg/day of isoproterenol on the two terminal days. The diabetes and isoproterenol-induced MI was evident as a reduction in the maximal positive and negative rate of developed left ventricular pressure and an increase in the left ventricular end-diastolic pressure. The activities of creatine kinase on myocardial bundle (CK-MB) and lactate dehydrogenase (LDH) were also reduced. Apigenin treatment prevented the hemodynamic perturbations, restored the left ventricular function and reinstated a balanced redox status. It protected rats against an MI by attenuating myonecrosis, edema, cell death, and oxidative stress. GW9662, a PPAR-γ antagonist reversed the myocardial protection conferred by apigenin. Further, an increase in the PPAR-γ expression in the myocardium of the rats receiving apigenin reinforces the role of PPAR-γ pathway activation in the cardioprotective effects of apigenin.


A motion-based approach to abdominal clutter reduction.
In ultrasound images, clutter is a noise artifact most easily observed in anechoic or hypoechoic regions. It appears as diffuse echoes overlying anatomical structures of diagnostic importance, obscuring tissue borders and reducing image contrast. A novel clutter reduction method for abdominal images is proposed, wherein the abdominal wall is displaced during successive-frame image acquisitions. A region of clutter distal to the abdominal wall was observed to move with the abdominal wall, and finite impulse response (FIR) and blind source separation (BSS) motion filters were implemented to reduce this clutter. The proposed clutter reduction method was tested in simulated and phantom data and applied to fundamental and harmonic in vivo bladder and liver images from 2 volunteers. Results show clutter reductions ranging from 0 to 18 dB in FIR-filtered images and 9 to 27 dB in BSS-filtered images. The contrast-to-noise ratio was improved by 21 to 68% and 44 to 108% in FIR- and BSS-filtered images, respectively. Improvements in contrast ranged from 4 to 12 dB. The method shows promise for reducing clutter in other abdominal images.


INACTIVATION OF AIRBORNE VIRUSES BY ULTRAVIOLET IRRADIATION.
Aerosolized viruses were passed through a high-intensity ultraviolet (UV) cell. This cell consisted of a long cylindrical aluminum tube [diameter, 7 in. (17.7 cm); length, 36 in. (91.4 cm)] with a highly reflective inner surface and a longitudinally extending helical baffle system which directed airborne particles in close proximity to a centrally located UV lamp. After having been passed through the UV cell, viral aerosols were collected with an Andersen sampler, and viral concentrations were determined by plaque assay methods on tissue cultures. Inactivation rates of greater than 99.9% were obtained for Coxsackie, influenza, Sindbis, and vaccinia viruses, and slightly less for adenovirus (96.8%), when the aerosols passed through the UV cell at 100 ft(3)/min. At aerosol flow rates of 200 ft(3)/min, inactivation rates were slightly lower; 91.3 for adenovirus, 97.5 and 96.7 for Coxsackie and Sindbis, respectively, and greater than 99.9% for influenza and vaccinia viruses.


Soluble major histocompatibility complex class I chain-related antigen A level in chronic allograft dysfunction.
Soluble major histocompatibility complex class I chain-related antigen A (soluble MICA) has recently been considered as an inhibitory molecule which is shed from tumors and protects them against natural killers and some subgroups of T cells' cytolysis. In transplantation, soluble MICA is also a foreign antigenic molecule that can induce allospecific responses. This study aimed to clarify its possible role in long-term kidney allograft outcome. Thirty patients with biopsy-proven chronic allograft dysfunction (CAD) were pair-matched with kidney allograft recipients with 30 stable graft function. Fifteen healthy individuals were enrolled as controls. Soluble MICA antigen and anti-HLA antibodies were measured in their serum. There was no significant difference between CAD patients, stable recipients, and healthy volunteers in frequency or titer of soluble MICA; however, soluble MICA-positive patients were more frequent in the stable group was than the CAD group (43.4% versus 33.3%). In addition, a high level of soluble MICA was accompanied by enhanced humoral responses. No significant difference was found in anti-HLA antibodies production between the CAD and stable groups. Our data suggest that soluble MICA, at least in a defined range, can protect the allograft against natural killers and T cell cytolysis; nonetheless, its excessive amounts might stimulate immune system to exert enhanced humoral response. In order to confirm the protective or detrimental role of soluble MICA in kidney transplantation, conducting larger studies is necessary.


The primary structures of Pseudomonas AM1 amicyanin and pseudoazurin. Two new sequence classes of blue copper proteins.
The amino acid sequences of two blue copper proteins from the pink facultative methylotroph Pseudomonas AM1 (N.C.I.B. 9133) were determined. They each consist of a single polypeptide chain and bind one copper atom. Amicyanin contains 99 and pseudoazurin 123 residues. Copper-binding sites, consisting of the side chains of two histidine, one cysteine and one methionine residues, can be recognized in each protein by analogy with azurin and plastocyanin, but the spacings of the ligand residues are different, and other sequence similarity is limited. Proteins that are in the pseudoazurin sequence class can be recognized in some strains of Alcaligenes, and probably also in Paracoccus denitrificans. Detailed evidence for the amino acid sequences of the proteins has been deposited as Supplementary Publication SUP 50130 (23 pp.) at the British Library (Lending Division), Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1985) 225, 5.


Alemtuzumab and CHOP Chemotherapy for the Treatment of Aggressive Histology Peripheral T Cell Lymphomas: A Multi-Center Phase I Study.
Alemtuzumab has single-agent activity in relapsed peripheral T cell lymphoma (PTL), but the optimal dose and/or schedule in combination with chemotherapy for first-line use is unknown. The primary objectives were to establish the maximally tolerated dose and pharmacokinetics (PK) of alemtuzumab combined in this way. Adult patients with untreated CD52-positive (CD52(+)) PTL were enrolled in a phase I trial. Alemtuzumab was given subcutaneously in escalating doses and/or schedules in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) using a 3+3 design. Trough PK of alemtuzumab were measured on day 1 of each 21-day cycle and B and T cell subsets were serially measured. Twenty patients were enrolled across 4 dose levels. Dose-limiting toxicities necessitated expansion at 10 mg weekly (fatal tuberculosis reactivation) and 60 mg every 3 weeks (grade 4 thrombocytopenia) dose levels. Maximally tolerated dose was not reached. Ten patients developed asymptomatic cytomegalovirus reactivations at a median of 39 days (range, 4-99 days). Two patients developed fungal pneumonias. The overall and complete response rates were 68% and 37%, respectively. Highest day 1 alemtuzumab trough levels were achieved at 60 mg (1973 ng/mL), but with significant inter- and intradose variability. Lymphopenia at baseline was common and T cell recovery was significantly delayed. With monitoring and prophylaxis, alemtuzumab 60 mg combined with CHOP showed activity in CD52(+) PTL and achieved the highest drug levels.


Developmental and psychosocial issues in cystic fibrosis.
Cystic fibrosis (CF) is a multisystemic life-limiting genetic disorder, primarily affecting respiratory functioning. Most patients with CF are diagnosed by 2 years of age, and the current median predicted survival rate is 37.4 years old, with 95% of patients dying from complications related to pulmonary infection. Given the chronic, progressive, and disabling nature of CF, multiple treatments are prescribed, most on a daily basis. Thus, this illness requires children, with the aid of their families, to adopt multiple health-related behaviors in addition to managing more typical developmental demands. The morbidity and mortality factors pose cognitive, emotional, and behavioral challenges for many children with CF and their families. This article applies a developmental perspective to describing the psychosocial factors affecting psychological adjustment and health-related behaviors relevant to infants, preschool and school-age children, and adolescents with CF. Topics particularly pertinent to developmental periods and medical milestones are noted, with clinical implications highlighted.


Medetomidine as a premedicant for ketamine, propofol or fentanyl anaesthesia in dogs.
This study evaluated the quality of anaesthesia and the cardiorespiratory effects induced by the combination of medetomidine with either ketamine, propofol or fentanyl. Medetomidine premedication (1000 or 1500 micrograms/m2 body surface area) was followed by intravenous induction of anaesthesia with ketamine (3.0 mg/kg), propofol (2.0 mg/kg) or fentanyl (2.0 micrograms/kg) in bitches undergoing elective ovariohysterectomy. Anaesthesia was prolonged by incremental doses of the induction agents as necessary. The mean (sem) overall doses (including induction) were 0.09 (0.01) mg/kg/min for ketamine, 0.06 (0.01) mg/kg/min for propofol and 0.07 (0.005) microgram/kg/min for fentanyl during procedures which lasted 88 (6) minutes, 72 (3) minutes and 79 (7) minutes, respectively. At the end of the procedure, medetomidine was antagonised with atipamezole. The quality of anaesthesia, heart rate and arterial blood pressure were recorded continuously and arterial blood gases were measured at intervals. At the end of the procedure, the animals received 10 micrograms/kg buprenorphine intramuscularly for postoperative analgesia. From the adequacy of anaesthesia, the lack of significant adverse side effects and the reliable and rapid recovery it is concluded that, in healthy dogs anaesthetised with ketamine or propofol, medetomidine is a satisfactory sedative-analgesic premedicant. The differences in haemodynamics and the quality of recovery suggest that the combination of medetomidine with propofol provided the better quality anaesthesia. The combination of medetomidine with fentanyl was unsuitable for obtaining surgical anaesthesia in spontaneously breathing animals owing to the severity of the respiratory depression at dosages needed for general anaesthesia.


Predictors and impact of non-adherence in adults with attention-deficit/hyperactivity disorder receiving OROS methylphenidate: results from a randomized, placebo-controlled trial.
Medication non-adherence has an important impact on treatment efficacy and healthcare burden across a range of conditions and therapeutic areas. The aim of this analysis was to determine predictors of non-adherence and impact of non-adherence on treatment response in adults with attention-deficit/hyperactivity disorder (ADHD). Post-hoc analysis of a 13-week randomized, double-blind placebo-controlled study of OROS methylphenidate (MPH) 54 and 72 mg/day. Primary efficacy variable was the Conners' Adult ADHD Rating Scale - Screening Version (CAARS:O-SV). Daily adherence was calculated as average daily adherence (100 × capsules taken/2), with overall adherence calculated as the average daily adherence. Predictors of adherence were assessed using mixed-effects logistic regression. Descriptive statistics were generated for change in CAARS:O-SV score for adherent (> 95% adherence) and non-adherent subjects. Predictors of change were analyzed using a mixed model. Subjects were allocated to OROS MPH (54 mg, n = 87; 72 mg, n = 92) or placebo (n = 97). Mean adherence was 92.6% and 93.3% (OROS MPH 54 and 72 mg/day, respectively), versus 97.5% (placebo). Adherence was higher and less variable in completers. Factors significantly associated with non-adherence included female sex, shorter time since ADHD diagnosis, higher education level (completion of university) and score on the Drug Use Screening Inventory psychiatric disorders subscale. Improvements from baseline in CAARS:O-SV score were numerically greater in subjects defined as adherent than in those who were non-adherent. Significant predictors of CAARS:O-SV change in patients who completed the study included percentage adherence up to the point of assessment (p < 0.0001), baseline score (p < 0.0001) and family history of ADHD (p = 0.0003). The results of this analysis suggest that newly diagnosed patients, those with a high score on the DUSI-R psychiatric disorder scale, women, and subjects with high educational degrees may be at increased risk of non-adherence. Clinicians and policymakers should therefore pay special attention to these individuals, as non-adherence is a significant predictor of reduced response to treatment. EudraCT #: 2007-002111-82.


Diaporthe: a genus of endophytic, saprobic and plant pathogenic fungi.
Diaporthe (Phomopsis) species have often been reported as plant pathogens, non-pathogenic endophytes or saprobes, commonly isolated from a wide range of hosts. The primary aim of the present study was to resolve the taxonomy and phylogeny of a large collection of Diaporthe species occurring on diverse hosts, either as pathogens, saprobes, or as harmless endophytes. In the present study we investigated 243 isolates using multilocus DNA sequence data. Analyses of the rDNA internal transcribed spacer (ITS1, 5.8S, ITS2) region, and partial translation elongation factor 1-alpha (TEF1), beta-tubulin (TUB), histone H3 (HIS) and calmodulin (CAL) genes resolved 95 clades. Fifteen new species are described, namely Diaporthe arengae, D. brasiliensis, D. endophytica, D. hongkongensis, D. inconspicua, D. infecunda, D. mayteni, D. neoarctii, D. oxe, D. paranensis, D. pseudomangiferae, D. pseudophoenicicola, D. raonikayaporum, D. schini and D. terebinthifolii. A further 14 new combinations are introduced in Diaporthe, and D. anacardii is epitypified. Although species of Diaporthe have in the past chiefly been distinguished based on host association, results of this study confirm several taxa to have wide host ranges, suggesting that they move freely among hosts, frequently co-colonising diseased or dead tissue. In contrast, some plant pathogenic and endophytic taxa appear to be strictly host specific. Given this diverse ecological behaviour among members of Diaporthe, future species descriptions lacking molecular data (at least ITS and HIS or TUB) should be strongly discouraged.


Rapid Sequential in Situ Multiplexing with DNA Exchange Imaging in Neuronal Cells and Tissues.
To decipher the molecular mechanisms of biological function, it is critical to map the molecular composition of individual cells or even more importantly tissue samples in the context of their biological environment in situ. Immunofluorescence (IF) provides specific labeling for molecular profiling. However, conventional IF methods have finite multiplexing capabilities due to spectral overlap of the fluorophores. Various sequential imaging methods have been developed to circumvent this spectral limit but are not widely adopted due to the common limitation of requiring multirounds of slow (typically over 2 h at room temperature to overnight at 4 °C in practice) immunostaining. We present here a practical and robust method, which we call DNA Exchange Imaging (DEI), for rapid in situ spectrally unlimited multiplexing. This technique overcomes speed restrictions by allowing for single-round immunostaining with DNA-barcoded antibodies, followed by rapid (less than 10 min) buffer exchange of fluorophore-bearing DNA imager strands. The programmability of DEI allows us to apply it to diverse microscopy platforms (with Exchange Confocal, Exchange-SIM, Exchange-STED, and Exchange-PAINT demonstrated here) at multiple desired resolution scales (from ∼300 nm down to sub-20 nm). We optimized and validated the use of DEI in complex biological samples, including primary neuron cultures and tissue sections. These results collectively suggest DNA exchange as a versatile, practical platform for rapid, highly multiplexed in situ imaging, potentially enabling new applications ranging from basic science, to drug discovery, and to clinical pathology.


IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk.
The authors sought to clarify the relationship between IQ and subsequent risk for schizophrenia. IQ was assessed at ages 18-20 in 1,204,983 Swedish males born between 1951 and 1975. Schizophrenia was assessed by hospital diagnosis through 2010. Cox proportional hazards models were used to investigate future risk for schizophrenia in individuals as a function of their IQ score, and then stratified models using pairs of relatives were used to adjust for familial cluster. Finally, regression models were used to examine the interaction between IQ and genetic liability on risk for schizophrenia. IQ had a monotonic relationship with schizophrenia risk across the IQ range, with a mean increase in risk of 3.8% per 1-point decrease in IQ; this association was stronger in the lower than the higher IQ range. Co-relative control analyses showed a similar association between IQ and schizophrenia in the general population and in cousin, half-sibling, and full-sibling pairs. A robust interaction was seen between genetic liability to schizophrenia and IQ in predicting schizophrenia risk. Genetic susceptibility for schizophrenia had a much stronger impact on risk of illness for those with low than high intelligence. The IQ-genetic liability interaction arose largely from IQ differences between close relatives. IQ assessed in late adolescence is a robust risk factor for subsequent onset of schizophrenia. This association is not the result of a declining IQ associated with insidious onset. In this large, representative sample, we found no evidence for a link between genius and schizophrenia. Co-relative control analyses showed that the association between lower IQ and schizophrenia is not the result of shared familial risk factors and may be causal. The strongest effect was seen with IQ differences within families. High intelligence substantially attenuates the impact of genetic liability on the risk for schizophrenia.


Lymphocyte enzyme activities in East African blacks: decrease in 5'nucleotidase and possible relation to immunosuppression.
Microanalysis of subcellular organelle marker enzymes was applied to cryopreserved lymphocytes (obtained and processed in the field) from East African blacks with moderate to severe malnutrition and subject to locally endemic parasitic and infectious diseases. An initial study demonstrated that activities of these enzymes, with the partial exception of catalase, were stable to cryopreservation. Cryopreserved and thawed lymphocyte specimens (1 to 3 X 10(6) viable cells) from 26 Africans and 20 Caucasian controls were studied. There was a highly significant decrease in 5'nucleotidase activity in these African subjects. Activity of another plasma membrane enzyme, gamma-glutamyl transferase, and of marker enzymes for other intracellular organelles, was not significantly different between the two groups, indicating that the nucleotidase alteration is highly specific. 5'Nucleotidase activity in a group of 17 East African blacks of high socio-economic status lay between the values obtained in the other two groups and was not significantly different from either. Further studies on 5'nucleotidase showed no evidence that the enzyme is functionally different in Africans. The differences in activity of this enzyme in Africans may reflect the known immuno-suppressive effects of infectious disease and malnutrition or may have a genetic basis which may in turn be associated with the pathogenesis of secondary immunodeficiency.


Experimental Investigation of Temperature-Dependent Gilbert Damping in Permalloy Thin Films.
The Gilbert damping of ferromagnetic materials is arguably the most important but least understood phenomenological parameter that dictates real-time magnetization dynamics. Understanding the physical origin of the Gilbert damping is highly relevant to developing future fast switching spintronics devices such as magnetic sensors and magnetic random access memory. Here, we report an experimental study of temperature-dependent Gilbert damping in permalloy (Py) thin films of varying thicknesses by ferromagnetic resonance. From the thickness dependence, two independent contributions to the Gilbert damping are identified, namely bulk damping and surface damping. Of particular interest, bulk damping decreases monotonically as the temperature decreases, while surface damping shows an enhancement peak at the temperature of ~50 K. These results provide an important insight to the physical origin of the Gilbert damping in ultrathin magnetic films.


1-methylcyclopropene effects on temporal changes of aroma volatiles and phytochemicals of fresh-cut cantaloupe.
Orange-fleshed cantaloupe melons have intense aroma and flavor but are very perishable during storage life. Fresh-cut processing enhances ethylene-mediated quality losses. Post-cutting 1-methylcyclopene (1-MCP) application to fresh-cut cantaloupe was evaluated for its effects on quality attributes, phytochemical content and aroma volatiles. Fresh-cut cantaloupe (Cucumis melo var. cantalupensis 'Fiesta') cubes treated with 1.0 µL L(-1) of 1-MCP for 24 h at 5 °C, packaged in vented plastic clamshells and stored under normal atmosphere at 5 °C for 9 days, preserved their soluble solids, total phenolics, total carotenoids and β-carotene contents, but significant softening occurred. A significant increase of non-acetate esters and a decrease of aldehydes occurred during storage. Most quality attributes of fresh-cut cantaloupe were unaffected by the treatment with 1-MCP. 1-MCP-treated fresh-cut cantaloupe accumulated higher levels of propyl acetate, 2-methylbutyl acetate, methyl butanoate, methyl 2-methyl butanoate, methyl hexanoate, 2-methylbutyl alcohol and phenethyl alcohol, and lower levels of benzyl alcohol and heptanal than untreated controls. Post-cutting treatment with 1-MCP affected nine of the flavor-important volatiles, particularly those derived from the amino acids isoleucine and phenylalanine, but had no practical effect on phytochemicals or other quality attributes.


The receptor-like kinase SERK3/BAK1 is a central regulator of innate immunity in plants.
In pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI), plant cell surface receptors sense potential microbial pathogens by recognizing elicitors called PAMPs. Although diverse PAMPs trigger PTI through distinct receptors, the resulting intracellular responses overlap extensively. Despite this, a common component(s) linking signal perception with transduction remains unknown. In this study, we identify SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK)3/brassinosteroid-associated kinase (BAK)1, a receptor-like kinase previously implicated in hormone signaling, as a component of plant PTI. In Arabidopsis thaliana, AtSERK3/BAK1 rapidly enters an elicitor-dependent complex with FLAGELLIN SENSING 2 (FLS2), the receptor for the bacterial PAMP flagellin and its peptide derivative flg22. In the absence of AtSERK3/BAK1, early flg22-dependent responses are greatly reduced in both A. thaliana and Nicotiana benthamiana. Furthermore, N. benthamiana Serk3/Bak1 is required for full responses to unrelated PAMPs and, importantly, for restriction of bacterial and oomycete infections. Thus, SERK3/BAK1 appears to integrate diverse perception events into downstream PAMP responses, leading to immunity against a range of invading microbes.


A-Situ: a computational framework for affective labeling from psychological behaviors in real-life situations.
This paper presents a computational framework for providing affective labels to real-life situations, called A-Situ. We first define an affective situation, as a specific arrangement of affective entities relevant to emotion elicitation in a situation. Then, the affective situation is represented as a set of labels in the valence-arousal emotion space. Based on psychological behaviors in response to a situation, the proposed framework quantifies the expected emotion evoked by the interaction with a stimulus event. The accumulated result in a spatiotemporal situation is represented as a polynomial curve called the affective curve, which bridges the semantic gap between cognitive and affective perception in real-world situations. We show the efficacy of the curve for reliable emotion labeling in real-world experiments, respectively concerning (1) a comparison between the results from our system and existing explicit assessments for measuring emotion, (2) physiological distinctiveness in emotional states, and (3) physiological characteristics correlated to continuous labels. The efficiency of affective curves to discriminate emotional states is evaluated through subject-dependent classification performance using bicoherence features to represent discrete affective states in the valence-arousal space. Furthermore, electroencephalography-based statistical analysis revealed the physiological correlates of the affective curves.


[Therapeutic trials for Duchenne muscular dystrophy: between hopes and disappointments].
Duchenne muscular dystrophy is an X-linked progressive muscle disease. Since the discovery of the dystrophin gene responsible for the condition, various therapeutic strategies have been elaborated. In this paper we introduce three of them, which are well into clinical trials. The first is based on the ability to read through premature stop codons, the second is based on the technique of exon skipping. Both strategies are examples of "personalized medicines", tailored for specific mutation types. The third approach is a pharmacological one, potentially useful for all Duchenne patients, regardless of their mutation type. These first clinical trials raise many questions for researchers as well as for patients and their families, some of which are discussed.


The impact of prematurity and maternal socioeconomic status and education level on achievement-test scores up to 8th grade.
The relative influence of prematurity vs. maternal social factors (socioeconomic status and education level) on academic performance has rarely been examined. To examine the impact of prematurity and maternal social factors on academic performance from 3rd through 8th grade. We conducted a retrospective cohort study of infants born in 1998 at the University of Arkansas for Medical Sciences. The study sample included 58 extremely low gestational age newborns (ELGANs, 23‒<28 weeks), 171 preterm (≥28‒<34 weeks), 228 late preterm (≥34‒<37 weeks), and 967 term ((≥37‒<42 weeks) infants. Neonatal and maternal variables were collected including maternal insurance status (proxy measure for socioeconomic status) and education level. The primary outcomes were literacy and mathematics achievement-test scores from 3rd through 8th grade. Linear mixed models were used to identify significant predictors of academic performance. All two-way interactions between grade level, gestational-age (GA) groups, and social factors were tested for statistical significance. Prematurity, social factors, gender, race, gravidity, and Apgar score at one minute were critical determinants of academic performance. Favorable social factors were associated with a significant increase in both literacy and mathematic scores, while prematurity was associated with a significant decrease in mathematic scores. Examination of GA categories and social factors interaction suggested that the impact of social factors on test scores was similar for all GA groups. Furthermore, the impact of social factors varied from grade to grade for literacy, while the influence of either GA groups or social factors was constant across grades for mathematics. For example, an ELGAN with favorable social factors had a predicted literacy score 104.1 (P <.001), 98.2 (P <.001), and 76.4 (P <.01) points higher than an otherwise similar disadvantaged term infant at grades 3, 5, and 8, respectively. The difference in their predicted mathematic scores was 33.4 points for all grades (P <.05). While there were significant deficits in academic performance for ELGANs compared to PT, LPT, and term infants, the deficit could be offset by higher SES and better-educated mothers. These favorable social factors were critical to a child's academic achievement. The role of socioeconomic factors should be incorporated in discussions on outcome with families of preterm infants.


Pressor effect on blood pressure and renal nerve activity elicited by electroacupuncture in intact and acute hemorrhage rats.
The neural mechanism underlying the effect of electroacupuncture (Ea) on arterial blood pressure (BP) and renal nerve activity (RNA) in the intact state and during acute hemorrhage was investigated in anesthetized rats. Two acupoints, Hoku (Li-4, at the junction of the first and the second metacarpal bone) and Tsusanli (St-36, at the lateral upper tibia bone), were tested using Ea of two different frequencies (2 and 20 Hz). In the intact state, Ea at Hoku elicited an elevation of BP in parallel with RNA, while Ea found no response with identical parameters at Tsusanli. The pattern of the pressor response caused by a low frequency Ea (2 Hz) at Hoku was different than a high frequency one (20 Hz), i.e. a tonic effect was elicited with 2 Hz, while a phasic one was induced with 20 Hz. In mild hemorrhage conditions (10% of BP decrease), similar pressor effects, as in intact rats, were also elicited by Ea. However, in severe hemorrhage conditions (20 and 30% BP decrease), Ea induced a pressor effect on RNA and an attenuated effect on BP. BP and RNA showed a significant correlation in intact and mild hemorrhage conditions, but not in severe hemorrhage conditions. All the results suggested that Ea at Hoku with appropriate stimulation parameters can increase and maintain BP in normal and hemorrhage conditions, and such a therapeutic technique has potential in clinical practice.


How to develop and validate a questionnaire for orthodontic research.
The use of psychometric tools to assess various psychological aspects of malocclusion and treatment is increasing in orthodontics. Mere evaluation of an orthodontic patient with normative criteria is not enough; instead, the psychological status should be assessed using a questionnaire. Many generic and few condition-specific tools are available for assessing quality of life (QoL) in orthodontics. The steps involved in the development of such tools are complex and unknown to many. This article outlines the methodology involved in the development and validation of a psychometric tool for dental and orthodontic use. It also helps the clinician to translate and cross-culturally adapt an existing QoL tool to a different setting.


Metabolism of polycyclic aromatic hydrocarbon derivatives to ultimate carcinogens during lipid peroxidation.
Lipid peroxidation triggered by ascorbate or reduced nicotinamide adenine dinucleotide in rat liver microsomes can initiate the epoxidation of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene. The stereochemistry of epoxidation is indicative of a peroxide-dependent free radical process. Since the epoxides formed may be the most carcinogenic derivatives of benzo[a]pyrene yet identified, lipid peroxidation can effect the metabolic activation of proximate carcinogens to ultimate carcinogens.


The impact of early literacy guidance on language skills of 3-year-olds.
The objective of this prospective study was to determine the impact of early literacy anticipatory guidance (AG) with provision of books on language development in 3-year-olds in an early literacy program at a University-affiliated inner-city pediatric clinic. The Peabody Picture Vocabulary Test (PPVT-III) and the Expressive One Word Picture Vocabulary Test (EOWPVT-R) were administered to 33-39-month-old children exposed to an early literacy program, which included AG and provision of an age-appropriate book at each well-child visit starting at 2 months old. Children with developmental delays were excluded. Parental surveys on literacy and demographic data were obtained. Univariate and multivariate analyses were performed. Sixty-four children were evaluated; 88% African American, 89% Medicaid recipients. Fifty-eight percent of families reported family-centered literacy orientation. The PPVT-III scores directly correlated with the number of AG visits with book given x number of books purchased (r2 = 0.025, p = 0.0006). Higher scores in EOWPVT-R were predicted by race and the number of visits with books given x number of books purchased (r2 = 0.182, p = 0.0009). All families reported reading together, half reporting positive family-centered literacy. Given the same number of books purchased for each child, the outcome scores were higher the greater the number of clinic visits wherein AG included early literacy and provision of books.


Early discontinuation of empirical antibacterial therapy in febrile neutropenia: the ANTIBIOSTOP study.
Immediate empirical antibiotic therapy is mandatory in febrile chemotherapy-induced neutropenia, but its optimal duration is unclear, especially in patients with fever of unknown origin (FUO). The primary objective of this 20-month prospective observational study was to evaluate the feasibility and safety of short-term antibiotic treatment in afebrile or febrile patients exhibiting FUO, irrespective of their neutrophil count. The secondary objective was to describe the epidemiology of all episodes of febrile neutropenia. In the first phase of the study, empirical antibiotic therapy in FUO patients was stopped after 48 h of apyrexia, in accordance with European Conference on Infections in Leukaemia guidelines (n = 45). In the second phase of the study, antibiotics were stopped no later than day 5 for all FUO patients, regardless of body temperature or leukocyte count (n = 37). Two hundred and thirty-eight cases of febrile neutropenia in 123 patients were included. Neither the composite endpoint (p = .11), nor each component (in-hospital mortality (p = .80), intensive care unit admission (p = 0.48), relapse of infection ≤48 h after discontinuation of antibiotics (p = .82)) differed between the two FUO groups. Violation of protocol occurred in 17/82 episodes of FUO without any major impact on statistical results. Twenty-six (57.3%) and 22 (59.5%) FUO episodes did not relapse during hospital-stay (p = 1), and nine (20%) and five (13.5%) presented another FUO, respectively. One hundred and fifty-six episodes of febrile neutropenia (65.5%) were clinically or microbiologically documented, including 85 bacteremia. These results suggest that early discontinuation of empirical antibiotics in FUO is safe for afebrile neutropenic patients.


Fabrication and characterization of cross-linkable hydrogel particles based on hyaluronic acid: potential application in vocal fold regeneration.
There is a critical need to engineer hyaluronic acid (HA)-based hydrogels with prolonged in vivo residence time, temporal release of therapeutics and matching viscoelasticity for use in vocal fold tissue engineering. We have previously demonstrated the synthesis and characterization of HA-based soft hydrogel particles (HGP) and particle cross-linked networks as injectable materials to treat vocal fold scarring. In this paper, we report a more versatile technique for preparing cross-linkable HA HGP with reduced sizes. HA HGP were synthesized via chemical cross-linking with divinyl sulfone using a sodium bis(2-ethylhexyl) sulfosuccinate (AOT)/isooctane reverse micelle system in the presence of 1-heptanol. These HGP were rendered cross-linkable by introducing aldehyde groups via sodium periodate oxidation (oxHGP). The presence of aldehyde groups was confirmed by multi-photon confocal microscope upon fluorescence staining using cascade blue hydrazide. The aldehyde groups were used as reactive handles for covalent cross-linking with HA that has been previously modified with adipic acid dihydrazide (HADH). The resulting doubly cross-linked networks (DXN) are highly pliable and do not break until approx. 200-300% strain. The measured elastic modulus of the DXN is around 500 Pa, while the dynamic viscosity decreases linearly with frequency in log- log scale. The mechanical characteristics of DXN are similar to that of vocal fold lamina propria. In vitro cell-proliferation assays showed that the cross-linkable HA HGP did not adversely affect the proliferation of the cultured fibroblasts as assessed by MTT assay. A low-molecular-weight model drug, rhodamine 6G (R6G), was loaded into oxHGP, and its release was monitored using UV-Vis spectroscopy. R6G-loaded oxHGP maintained their ability to form DXN when mixed with the HAADH solution. Approximately 84% of entrapped R6G was liberated from oxHGP at a rate of 0.24%/min in the first 6 h. When encapsulated in the DXN, R6G was released at a steady rate of 0.03%/min for over 3 days. These novel hydrogels are promising implant materials for vocal fold tissue regeneration.


[From aviation to surgery: the challenge of safety].
Medical errors result in 44,000 to 98,000 deaths per year in the United States of America. Within the surgical specialties, half of these errors occur in the operating room. The origin of these errors is multifactorial, and is generally associated with problems in communication and teamwork. In order to improve safety in the operating room, many hospitals now propose to the medical staff "crew resource management" (CRM) training programs inspired by the aviation industry. This approach favors a better utilization of surgical checklists, improves efficiency during chirurgical interventions, and reduces patient mortality. In October 2009 we introduced a CRM course within the department of surgery at the Geneva University Hospitals. We are presenting this program as well as the first results following its application.


Osmium tetroxide: a new probe for site-specific distortions in supercoiled DNAs.
Supercoiled plasmids Col E1 and cDm 506 (a Col E1 derivative carrying the D. melanogaster histone gene repeat) were treated with OsO4 in presence of pyridine and the reaction products were analyzed using different approaches. Gel electrophoresis showed that OsO4 binding to supercoiled DNA induced its relaxation without nicking. The amount of osmium bound to DNA (as determined electrochemically) increased with the extent of DNA relaxation. As a result of osmium modification of supercoiled cDm 506, a single denaturation "bubble" was observed in the electron microscope. Mapping of the osmium binding site by S1 nuclease cleavage followed by restriction enzyme digestion has revealed one major site in the intergenic spacer between the H1 and H3 histone genes of D. melanogaster. This site differs from the site cleaved by S1 nuclease in supercoiled DNA in the absence of osmium.


Effect of OH substitution in 3-benzylchroman-4-ones: crystallographic, CSD, DFT, FTIR, Hirshfeld surface, and energy framework analysis.
3-Benzylchroman-4-ones (homoisoflavanones) are oxygen-containing heterocycles with a sixteen-carbon skeleton. They belong to the class of naturally occurring polyphenolic flavonoids with limited occurrence in nature and possess anti-inflammatory, antibacterial, antihistaminic, antimutagenic, antiviral, and angioprotective properties. Recently, we reported the synthesis and anticancer activity studies of fifteen 3-benzylchroman-4-one molecules, and most of them were proven to be effective against BT549 and HeLa cells. In this work, we report the single-crystal X-ray crystallographic studies of two molecules 3-[(2-hydroxyphenyl)methyl]-3,4-dihydro-2H-1-benzopyran-4-one and 3-[(2,4-dimethoxyphenyl)methyl]-3,4-dihydro-2H-1-benzopyran-4-one. The single crystals were grown using a novel laser-induced crystallization technique. We observed that the 3-benzylchroman-4-one derivative bearing OH substitution at the 2' position adopted different conformation due to formation of dimers through O-H⋯O, and C-H⋯O intermolecular hydrogen bondings. The role of OH substitution in the aforementioned conformational changes was evaluated using density functional theory (DFT), Hirshfeld surface, energy framework and FTIR spectroscopy analysis. In addition, we have carried out a Cambridge Structural Database (CSD) study to understand the conformational changes using five analogue structures. X-ray crystallographic, computational, and spectroscopic studies of 3-benzylchroman-4-ones provided an insight into the role of substitution at benzyl moieties in stabilizing the three-dimensional (3D) structures.


Chemical and ruminal in vitro evaluation of Canadian canola meals produced over 4 years.
To test the effects of year and processing plant on the nutritional value of canola meal (CM), 3 CM samples/yr were collected from each of 12 Canadian production plants over 4yr (total=144). Samples of CM were analyzed for differences in chemical composition and for in vitro ruminal protein degradability using the Michaelis-Menten inhibitor in vitro (MMIIV) method. In the MMIIV method, protein degradation rate (kd) was estimated by 2 methods: from net release (i.e., blank corrected) of (1) ammonia plus AA determined by o-phthaldialdehyde fluorescence (OPAF) assay or (2) ammonia, AA, plus oligopeptides determined by o-phthaldialdehyde absorbance (OPAA) assay; rumen-undegradable protein (RUP) was computed assuming passage rates of 0.16 and 0.06/h for, respectively, soluble and insoluble protein. Casein, solvent soybean meal (SSBM), and expeller soybean meal (ESBM) were included in all incubations as standard proteins. Differences among years and plants were assessed using the mixed procedures of SAS. Small but significant differences were found in CM among years for chemical composition, including N solubility; some of these differences may have been related to changes in our analytical methods over time. However, adjustment of degradation activity of individual in vitro incubations based on the mean degradation activity over all incubations yielded kd and RUP that did not differ by year using either assay. Simultaneously incubating CM samples from 2yr in the same in vitro runs confirmed that no year effects existed for kd or RUP. Differences existed in chemical composition of CM among the 12 processing plants over the 4yr of sample collection. Moreover, consistent differences in kd and RUP were observed among plants: kd ranged from 0.069 to 0.113/h (OPAA assay) and 0.075 to 0.120/h (OPAF assay), and RUP estimates ranged from 51 to 43% (OPAA assay) and 49 to 41% (OPAF assay). Regression of kd on insoluble N content of CM yielded correlation coefficients (R(2))=0.40 (OPAA assay) and 0.42 (OPAF assay), and regressions of kd on NDIN and N-fraction B3 yielded R(2)<0.02. Mean estimates from both OPAA and OPAF assays for casein, SSBM, ESBM, and CM were, respectively, kd=0.764, 0.161, 0.050, and 0.093/h and RUP=18, 33, 56, and 45%. A range of 8 percentage units from lowest to highest RUP suggests that substantial differences exist in metabolizable protein content of CM produced by different processing plants.


Calmodulin and S100A1 protein interact with N terminus of TRPM3 channel.
Transient receptor potential melastatin 3 ion channel (TRPM3) belongs to the TRP family of cation-permeable ion channels involved in many important biological functions such as pain transduction, thermosensation, and mechanoregulation. The channel was reported to play an important role in Ca(2+) homeostasis, but its gating mechanisms, functions, and regulation are still under research. Utilizing biophysical and biochemical methods, we characterized two independent domains, Ala-35-Lys-124 and His-291-Gly-382, on the TRPM3 N terminus, responsible for interactions with the Ca(2+)-binding proteins calmodulin (CaM) and S100A1. We identified several positively charged residues within these domains as having a crucial impact on CaM/S100A1 binding. The data also suggest that the interaction is calcium-dependent. We also performed competition assays, which suggested that CaM and S100A1 are able to compete for the same binding sites within the TRPM3 N terminus. This is the first time that such an interaction has been shown for TRP family members.


[Doping in animal rights law: the responsibility of the veterinary surgeon].
Unlike the situation in humans, it is illegal to administer doping drugs to animals. The Doping Commission of the European Council has defined the term doping. According to this definition, the therapeutic use of drugs is not doping. The treatment of pain is also therapeutic. However, governing bodies of sport can apply stricter regulations (doping lists). It is possible for veterinarians to infringe paragraph 3 (11) of the German animal welfare act if they act recklessly or without due care, and a prosecution may result. It is therefore obligatory for the veterinarian to advise of the possible consequences of administering a drug which has a doping effect, or is included on a doping list.


Race/ethnic disparities in the utilization of treatment for drug dependent inmates in U.S. state correctional facilities.
Research has documented racial and ethnic disparities in utilization, access, continuity, and quality of care for psychiatric disorders including treatment for substance use disorders among those with similar need in the general community. Currently, the extent of racial and ethnic disparities in treatment within U.S. correctional facilities is unknown. This study examines race/ethnic disparities in treatment for drug dependent inmates using the 2004 Survey of Inmates in State Correctional Facilities. Fixed effects logistic regression is used to analyze treatment outcomes for 5180 inmates housed within 286 prisons. The analysis accounts for differences in background characteristics (i.e., age, gender, marital status, foreign born status, veteran status), socioeconomic characteristics (i.e., education, employment prior to incarceration), mental health (i.e., diagnosis with a serious mental illness), and incarceration experiences (i.e., current conviction, previous incarceration episodes, time served, additional sentencing requirements, external social support, disciplinary violations). The findings identify a remarkable unmet need among drug dependent inmates in that less than one-half of drug dependent inmates had received any type of treatment in prison at the time of the interview with the most common treatment type being self-help groups. Compared to whites, drug dependent Latino inmates have significantly lower odds of utilizing treatment, yet there are no significant black--white disparities found. The current study suggests that treatment for drug dependent inmates needs to be expanded to include clinically or medically based treatment since the failure to address addictions in the criminal legal system has been identified as the single most significant reason for rearrest and recidivism once released.


Identification of polypeptides in neurofibrillary tangles and total homogenates of brains with Alzheimer's disease by tandem mass spectrometry.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD brains are characterized by the presence of neurofibrillary tangles (NFTs) and neuritic plaques. NFTs are constituted of paired helical filaments, which are structurally composed by assembled hyperphosphorylated and truncated tau polypeptides. To date, the integral constituents of NFTs remain unknown mainly due to the high insolubility of NFTs. The aim of this study was to identify by tandem mass spectrometry, the polypeptides contained in both isolated NFTs by laser capture microdissection and total homogenates, using tissue sections from paraformaldehyde-fixed AD brains. In the first case, we isolated 2,000 NFTs from tissue samples of hippocampus from each of the three Mexican AD brains used in our study. These were previously stained with anti-hyperphosphorylated tau AT-100 antibodies. After the removal of paraformaldehyde and delipidation with organic solvents, we tested three solubilization methods. We identified 102 polypeptides from total homogenates and 41 from isolated NFTs. We selected UCH-L1, transferrin, and GAPDH polypeptides to be studied by immunofluorescence and confocal microscopy. Only UCH-L1 and GAPDH colocalized with hyperphosphorylated tau in NFTs.