Coronary artery disease in atrial fibrillation ablation: impact on arrhythmic outcomes.
Catheter ablation (CA) is an established treatment for atrial fibrillation (AF). A computed tomography (CT) may be performed before ablation to evaluate the anatomy of pulmonary veins. The aim of this study is to investigate the prevalence of patients with coronary artery disease (CAD) detected by cardiac CT scan pre-ablation and to evaluate the impact of CAD and revascularization on outcomes after AF ablation. All consecutive patients with AF diagnosis, hospitalized at Universitair Ziekenhuis Brussel, Belgium, between 2015 and 2019, were prospectively screened for enrolment in the study. Inclusion criteria were (i) AF diagnosis, (ii) first procedure of AF ablation with cryoballoon CA, and (iii) contrast CT scan performed pre-ablation. A total of 576 consecutive patients were prospectively included and analysed in this study. At CT scan, 122 patients (21.2%) were diagnosed with CAD, of whom 41 patients (7.1%) with critical CAD. At survival analysis, critical CAD at CT scan was a predictor of atrial tachyarrhythmia (AT) recurrence during the follow-up, only in Cox univariate analysis [hazard ratio (HR) = 1.79] but was not an independent predictor in Cox multivariate analysis. At Cox multivariate analysis, independent predictors of AT recurrence were as follows: persistent AF (HR = 2.93) and left atrium volume index (HR = 1.04). In patients undergoing CT scan before AF ablation, critical CAD was diagnosed in 7.1% of patients. Coronary artery disease and revascularization were not independent predictors of recurrence; thus, in this patient population, AF ablation should not be denied and can be performed together with CAD treatment.


Promiscuity and the evolution of cooperative breeding.
Empirical data suggest that low levels of promiscuity have played a key role in the evolution of cooperative breeding and eusociality. However, from a theoretical perspective, low levels of promiscuity can favour dispersal away from the natal patch, and have been argued to select against cooperation in a way that cannot be explained by inclusive fitness theory. Here, we use an inclusive fitness approach to model selection to stay and help in a simple patch-structured population, with strict density dependence, where helping increases the survival of the breeder on the patch. Our model predicts that the level of promiscuity has either no influence or a slightly positive influence on selection for helping. This prediction is driven by the fact that, in our model, staying to help leads to increased competition between relatives for the breeding position-when promiscuity is low (and relatedness is high), the best way to aid relatives is by dispersing to avoid competing with them. Furthermore, we found the same results with an individual-based simulation, showing that this is not an area where inclusive fitness theory 'gets it wrong'. We suggest that our predicted influence of promiscuity is sensitive to biological assumptions, and that if a possibly more biologically relevant scenario were examined, where helping provided fecundity benefits and there was not strict density dependence, then low levels of promiscuity would favour helping, as has been observed empirically.


EFNS guidelines on the molecular diagnosis of mitochondrial disorders.
These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.


Insights into the Genetic Architecture of Bran Friability and Water Retention Capacity, Two Important Traits for Whole Grain End-Use Quality in Winter Wheat.
Bran friability (particle size distribution after milling) and water retention capacity (WRC) impact wheat bran functionality in whole grain milling and baking applications. The goal of this study was to identify genomic regions and underlying genes that may be responsible for these traits. The Hard Winter Wheat Association Mapping Panel, which comprised 299 lines from breeding programs in the Great Plains region of the US, was used in a genome-wide association study. Bran friability ranged from 34.5% to 65.9% (median, 51.1%) and WRC ranged from 159% to 458% (median, 331%). Two single-nucleotide polymorphisms (SNPs) on chromosome 5D were significantly associated with bran friability, accounting for 11-12% of the phenotypic variation. One of these SNPs was located within the Puroindoline-b gene, which is known for influencing endosperm texture. Two SNPs on chromosome 4A were tentatively associated with WRC, accounting for 4.6% and 4.4% of phenotypic variation. The favorable alleles at the SNP sites were present in only 15% (friability) and 34% (WRC) of lines, indicating a need to develop new germplasm for these whole-grain end-use quality traits. Validation of these findings in independent populations will be useful for breeding winter wheat cultivars with improved functionality for whole grain food applications.


Regulation of chromatin remodeling by inositol polyphosphates.
Chromatin remodeling is required for efficient transcription of eukaryotic genes. In a genetic selection for budding yeast mutants that were defective in induction of the phosphate-responsive PHO5 gene, we identified mutations in ARG82/IPK2, which encodes a nuclear inositol polyphosphate kinase. In arg82 mutant strains, remodeling of PHO5 promoter chromatin is impaired, and the adenosine triphosphate-dependent chromatin-remodeling complexes SWI/SNF and INO80 are not efficiently recruited to phosphate-responsive promoters. These results suggest a role for the small molecule inositol polyphosphate in the regulation of chromatin remodeling and transcription.


Effects of exposure to trichloroethylene and noise on hearing in rats.
Four groups of rats (n=8 per group) were exposed to either 3000 ppm trichloroethylene (TCE) alone or to 95 dB SPL noise alone or to the combination of TCE and noise or to control conditions. Exposure was carried out 18 hours/day, 5 days/week for 3 weeks. Exposure to TCE alone resulted in hearing loss at 4, 8, 16 and 20 kHz, but not at 24 and 32 kHz. Hearing loss due to exposure to noise alone occurred at frequencies of 8, 16 and 20 kHz. In general, combined exposure to TCE and noise resulted in larger auditory threshold changes than that produced by either TCE alone or noise alone when measured 1 and 2 weeks after the completion of exposure. For frequencies of 8, 16 and 20 kHz, hearing loss due to combined TCE-noise exposure was not larger than the algebraic sum of hearing loss due to exposure to TCE or noise alone. However, at a frequency of 4 kHz, hearing loss due to combined exposure was significantly larger than that produced by TCE exposure alone or noise alone, which itself had no effect at this frequency. These results suggest evidence of an interaction of combined exposure to TCE and noise at the lower edge of the range of frequencies affected.


Management of the small renal mass.
The increasing use of cross-sectional imaging has led to an increase in the diagnosis of incidental small renal masses (SRMs). About 20% of such masses are benign, while a significant proportion of malignant SRMs demonstrate slow growth kinetics and non-aggressive histologic features. Given these characteristics, lesions that were traditionally treated surgically are increasingly managed with less aggressive approaches. Further contributing to the evolving management paradigm is accumulating evidence supporting the safety of active surveillance and the efficacy of percutaneous renal mass biopsy in guiding management decisions. This review first discusses the epidemiology and diagnostic work-up of SRMs. The available management options are then examined, with emphasis placed on the clinical factors considered in selecting an appropriate approach. The existing evidence and long-term outcomes of each strategy are discussed. Finally, an overview of the current paradigm for the management of a patient with a SRM is provided. The goal is to provide physicians with the necessary understanding to appropriately manage this increasingly common condition.


Temporal Structures in Positron Spectra and Charge-Sign Effects in Galactic Cosmic Rays.
We present the precision measurements of 11 years of daily cosmic positron fluxes in the rigidity range from 1.00 to 41.9 GV based on 3.4×10^{6} positrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The positron fluxes show distinctly different time variations from the electron fluxes at short and long timescales. A hysteresis between the electron fluxes and the positron fluxes is observed with a significance greater than 5σ at rigidities below 8.5 GV. On the contrary, the positron fluxes and the proton fluxes show similar time variation. Remarkably, we found that positron fluxes are modulated more than proton fluxes with a significance greater than 5σ for rigidities below 7 GV. These continuous daily positron fluxes, together with AMS daily electron, proton, and helium fluxes over an 11-year solar cycle, provide unique input to the understanding of both the charge-sign and mass dependencies of cosmic rays in the heliosphere.


Fidelity of bacterial source tracking: Escherichia coli vs Enterococcus spp and minimizing assignment of isolates from nonlibrary sources.
The goal of the study was to improve the fidelity of library-dependent bacterial source tracking efforts in determining sources of faecal pollution. The first objective was to compare the fidelity of source assignments using Escherichia coli vs Enterococcus spp. The second objective was to determine the efficacy of using thresholds during source assignments to reduce the rate of misassignments when nonlibrary isolates (i.e. isolates from animals not used in building the identification library) are present. E. coli and Enterococcus isolates from 784 human, cow, deer, dog, chicken, and gull faecal samples were fingerprinted using BOX-PCR. Jack-knife analysis of the fingerprints showed that the overall rate of correct assignment (ORCA) of 867 E. coli isolates was 67% compared with 82% for 1020 Enterococcus isolates. In a separate blind test using similarity value and quality factor thresholds, the ORCA of 130 E. coli and 131 Enterococcus isolates were 70% and 98%, respectively. The use of these thresholds reduced misassignment of 262 nonlibrary enterococcal isolates from horses, goats, pigs, bats, squirrels, ducks, geese, and migratory song birds. Misassignment was reduced from 100% when thresholds were not used, to 47% using similarity threshold alone, and to 12% when both thresholds were used. The use of enterococci provides higher rates of correct source assignment compared with E. coli. The use of similarity thresholds to decide whether to accept source assignments made by computer programmes reduces the rate of misassignment of nonlibrary isolates. Although both E. coli and Enterococcus spp. are still used in microbial source tracking, the use of enterococci should be preferred over the use of E. coli in DNA fingerprint-based efforts. In addition, because environmental isolates are not limited to those from animals used to build source tracking libraries, similarity thresholds should be used during source assignments to reduce the rate of misassignments.


Photosensory perception and signalling in plant cells: new paradigms?
Plants monitor informational light signals using three sensory photoreceptor families: the phototropins, cryptochromes and phytochromes. Recent advances suggest that the phytochromes act transcriptionally by targeting light signals directly to photoresponsive promoters through binding to a transcriptional regulator. By contrast, the cryptochromes appear to act post-translationally, by disrupting extant proteosome-mediated degradation of a key transcriptional activator through direct binding to a putative E3 ubiquitin ligase, thereby elevating levels of the activator and consequently of target gene expression.


Preparation and characterization of iron-copper binary oxide and its effective removal of antimony(III) from aqueous solution.
An Fe-Cu binary oxide was fabricated through a simple co-precipitation process, and was used to remove Sb(III) from aqueous solution. X-ray diffraction, scanning electron microscopy, energy dispersive X-ray and N2 adsorption-desorption measurements demonstrated that the Fe-Cu binary oxide consisted of poorly ordered ferrihydrite and CuO, and its specific surface area was higher than both iron oxide and copper oxide. A comparative test indicated that Fe/Cu molar ratio of prepared binary oxide greatly influenced Sb(III) removal and the optimum Fe/Cu molar ratio was about 3/1. Moreover, a maximum adsorption capacity of 209.23 mg Sb(III)/g Fe-Cu binary oxide at pH 5.0 was obtained. The removal of Sb(III) by Fe-Cu binary oxide followed the Freundlich adsorption isotherm and the pseudo-second-order kinetics in the batch study. The removal of Sb(III) was not sensitive to solution pH. In addition, the release of Fe and Cu ions to water was very low when the pH was greater than 6.0. X-ray photoelectron spectroscopy analysis confirmed that the Sb(III) adsorbed on the surface was not oxidized to Sb(V).


Creating adequate pulsatility with a continuous flow left ventricular assist device: just do it!
Continuous flow left ventricular assist devices (LVADs) have revolutionized the treatment of advanced heart failure; however, as experience with these devices has grown, a number of unanticipated adverse events have emerged. In this study, we review the current literature associating a lack of pulsatility with these events. It is now evident that continuous flow LVAD physiology reflects a spectrum of 'low pulsatile' rather than a truly 'nonpulsatile' state. Thus, the detrimental consequences of nonpulsatile flow noted in early experimental setups may or may not occur in humans supported with continuous flow LVADs. Such studies have demonstrated not only alterations in vascular function and structure during continuous flow LVAD support, but also a clear association of the degree of alterations in vascular, baroreceptor, and sympathetic nervous system function with the degree of actual pulsatility. In addition, a number of clinical events have been linked to continuous flow LVAD physiology, including a decreased extent of ventricular unloading possibly impairing myocardial recovery, hemolysis and device thrombosis, development of aortic insufficiency, and mucosal bleeding. Many of the adverse effects of the current continuous flow LVADs are associated with low pulsatile flow. An evolved understanding of pulsatility as a continuous rather than a binary variable may allow us to incorporate appropriate degrees of pulsatility into the next generation pumps and mitigate these effects.


Extracellular matrix in pancreatic islets: relevance to scaffold design and transplantation.
Intrahepatic islet transplantation provides a potentially more benign alternative to pancreatic transplantation. However, islet transplants are associated with limited engraftment potential. This inefficiency is likely at least partially attributable to the isolation process, which removes islets from their native environment. Isolation not only disrupts the internal vascularization and innervation of islets, but also fundamentally changes interactions between islet cells and macromolecules of the extracellular matrix (ECM). Signaling interactions between islet cells and ECM are known to regulate multiple aspects of islet physiology, including survival, proliferation, and insulin secretion. Although it is highly likely that disruptions to these interactions during isolation significantly affect transplant outcomes, the true implications of these conditions are not well understood. The following article reviews current understandings and uncertainties in islet-ECM interactions and explains their potential impact on posttransplant engraftment. Topics covered include matrix and receptor compositions in native islets, effects of isolation and culture on islet-ECM interactions, and potential for postisolation restoration of islet-ECM interactions. Greater understanding in these areas may help to reduce isolation and transplantation stresses and improve islet engraftment.


The role of the student professional association in mentoring dental hygiene students for the future.
The purpose of this study was to determine the role of the Student American Dental Hygienists' Association (SADHA) in mentoring/developing dental hygiene students for the future. This project also assessed attitudes and practices of SADHA advisors towards the utilization of SADHA as a mechanism for mentoring dental hygiene students' professional development to meet the oral health needs of the public, and the goals of the ADHA. These goals include promotion of education beyond the baccalaureate level to develop qualified faculty, encouraging dental hygiene research, and promoting leadership. The study also evaluated if geographic region and academic setting impacted the utilization of SADHA. After IRB exemption, a pilot-tested questionnaire was administered using Survey Monkey, an online survey website, to 277 individual contacts at Commission on Dental Accreditation (CODA) accredited dental hygiene programs. A response rate of 68% was achieved with 186 individual responses. Eighty percent of respondents indicated offering no mentoring opportunities outside of the curriculum, while incongruously, 58.3% felt they actively mentor through SADHA. When asked what the main focus of SADHA should be, SADHA advisors ranked community service/philanthropy as number one. SADHA chapters at institutions that offer a Bachelor of Science in Dental Hygiene (BSDH) degree completion program offer more mentoring opportunities (p= or <.001). Programs offering the BSDH offer a wider variety of topics from guest speakers (p=.038). SADHA chapters in Western states have a higher graduate membership conversion rate than other regions (p=.018). SADHA advisors do not agree on how SADHA should be utilized. The majority of SADHA chapters are not offering mentoring opportunities outside of the traditional curriculum for leadership and career development. What is clear is that both students and advisors desire more interaction with the local ADHA components and constituents. In order to address these issues, efforts should be made to provide networking support among SADHA advisors and increase faculty perception of the importance of the professional association and the role of students in its future. The ADHA should consider developing a mentoring program that builds strong partnerships among all state constituent and components and SADHA.


From E to Z and back again: reversible photoisomerisation of an isolated charge-tagged azobenzene.
Substituted azobenzenes serve as chromophores and actuators in a wide range of molecular photoswitches. Here, tandem ion mobility spectrometry coupled with laser excitation is used to investigate the photoisomerisation of selected E and Z isomers of the charge-tagged azobenzene, methyl orange. Both isomers display a weak S1(nπ*) photoisomerisation response in the blue part of the spectrum peaking at 440 nm and a more intense S2(ππ*) photoisomerisation response in the near-UV with maxima at 370 and 310 nm for the E and Z isomers, respectively. The 60 nm separation between the S2(ππ*) photo-response maxima for the two isomers allows them to be separately addressed in the gas phase and to be reversibly photoisomerised using different colours of light. This is an essential characteristic of an ideal photoswitch. The study demonstrates that a sequence of light pulses at different stages in an ion mobility spectrometer can be deployed to generate and probe isomers that cannot be electrosprayed directly from solution or produced through collisions in the ion source.


Premenstrual syndrome and alcohol consumption: a systematic review and meta-analysis.
Premenstrual syndrome (PMS) is a very common disorder worldwide which carries an important economic burden. We conducted a systematic review and a meta-analysis to assess the role of alcohol in the occurrence of PMS. We searched MEDLINE, EMBASE, the five regional bibliographic databases of the WHO, the Proceedings database and the Open Access Thesis and Dissertations (OATD) from inception to May 2017. We also reviewed the references of every article retrieved and established personal contact with researchers to trace further publications or reports. We did not include any language limitations. Studies were included if: (1) they presented original data from cohort, case-control or cross-sectional studies, (2) PMS was clearly defined as the outcome of interest, (3) one of the exposure factors was alcohol consumption, (4) they provided estimates of odds ratios, relative risks, or any other effect measure and their confidence intervals, or enough data to calculate them. We identified 39 studies of which 19 were eligible. Intake of alcohol was associated with a moderate increase in the risk of PMS (OR=1.45, 95% CI: 1.17 to 1.79). Heavy drinking yielded a larger increase in the risk than any drinking (OR=1.79, 95% CI: 1.39 to 2.32). Our results suggest that alcohol intake presents a moderate association with PMS risk. Future studies should avoid cross-sectional designs and focus on determining whether there is a threshold of alcohol intake under which the harmful effect on PMS is non-existent.


Chloride intracellular channel 4 involves in the reduced invasiveness of cancer cells treated by photodynamic therapy.
The mechanisms of photodynamic therapy (PDT) have been studied on the cellular and tissue levels. However, the cellular behaviors of cancer cells survived from PDT are still not clear. Previously, we have found that PDT-derived variants A375/3A5 and A375/6A5 have reduced invasion ability. This study attempted to further elucidate the possible molecules associated with the altered invasiveness in the PDT-derived variants and cancer cells treated with PDT. Scratch wound healing assay and invasion assay were performed to evaluate the migration and invasion ability of human A375 melanoma and MDA-MB-231 breast adenocarcinoma cells. Single colony selection and microarray analysis were performed to examine the differentially expressed transcripts in parental A375 and PDT-derived variants. RT-PCR and Western blots analysis were performed to examine the expression levels of matrix metalloproteinase 9 (MMP9) and chloride intracellular channel 4 (CLIC4). The MMP9 activity was examined by Zymography assay. CLIC4 expressing construct was used to examine the influence on MMP9 expression and invasion ability of cancer cells treated with PDT. Correlated with the reduced invasiveness, we found that A375/3A5 and A375/6A5 cells have decreased production of MMP9. Microarray analysis and RT-PCR showed CLIC4 was down-regulated in the PDT-derived variants. Furthermore, down-regulation of CLIC4 and MMP9 was found in cancer cells treated with PDT. Transfection of surviving cancer cells with a plasmid vector encoding CLIC4 increased MMP9 expression and cell invasion. Furthermore, overexpression of CLIC4 in A375 and MDA-MB-231 cancer cells constrains PDT-induced suppression of invasiveness. Our results showed that the reduced expression of CLIC4 could further down-regulate MMP9 and result in the suppression of invasion in cancer cells treated with PDT. These results provide an insight into a new mechanism by which PDT affects the metastatic potential of cancer cells through down-regulation of MMP9 by CLIC4.


Caenorhabditis elegans anti-apoptotic gene ced-9 prevents ced-3-induced cell death in Drosophila cells.
ced-9, a member of the bcl-2 gene family in Caenorhabditis elegans plays a central roles in preventing cell death in worms. Overexpression of human bcl-2 can partially prevent cell death in C. elegans. However, it remains to be elucidated whether ced-9 can regulate cell death when expressed in other organisms. We demonstrated that the CED-9 protein is co-localized with BCL-2 in COS cells and Drosophila Schneider's L2 (SL2) cells, suggesting that the site of CED-9 action is located to specific cytoplasmic compartments. Overexpression of ced-9 only poorly protected cells from the death induced by ced-3 in HeLa cells, but ced-9 significantly reduced the cell death induced by ced-3 in Drosophila SL2 cells. Furthermore, apoptosis of SL2 cells that was induced by a Drosophila cell-death gene, reaper, was shown to be partially prevented by ced-9, bcl-2 and bcl-xL. These results suggest that the signaling pathway that is required for the anti-apoptotic function of bcl-2 family members, including ced-9, is conserved in Drosophila cells. In addition, SL2 cells provide a unique systems for dissecting the main machinery of cell death.


Semi-quantitative assessment of the distribution of skin lesions in patients with psoriasis and psoriasis arthritis.
We propose that the distribution of skin lesions in psoriasis may be assessed using parametric maps on a pixel-by-pixel basis. We processed 428 patient-drawn self-descriptions of the psoriasis lesions on a supplied body template. We compared 195 patients with a confirmed diagnosis of psoriatic arthritis (PsA) with 89 who had this diagnosis rejected (Psor). Additionally, 28 Psor cases supplied drawings performed after 3 weeks of climate therapy (PsorCT) to test the treatment efficacy. The drawings were scanned, lesion areas were segmented, followed by construction of parametric maps of lesion distributions and calculation of statistical differences between groups. In PsorCT, the lesions occupied 11.2% (0-42%) [median (min.-max.)] of the body area. The area decreased to 2.4% (6-11%) after heliotherapy. The differences were statistically significant for all the areas studied and spread evenly over the body surface. PsA had a relatively low psoriasis lesion occupancy of 2.5% (0-42%) compared with Psor 9.8% (0-34%), which is attributed to the difference in recruitment. Correcting for this, we demonstrate a clear tendency for the head, palms, feet, groin and nails to be preferred lesion sites in PsA in contrast to psoriasis. Pixel-based analysis of self-reported skin lesion distributions is a powerful tool to assess systematic differences due to treatment or disease variants.


Proliferation tracing with single-cell mass cytometry optimizes generation of stem cell memory-like T cells.
Selective differentiation of naive T cells into multipotent T cells is of great interest clinically for the generation of cell-based cancer immunotherapies. Cellular differentiation depends crucially on division state and time. Here we adapt a dye dilution assay for tracking cell proliferative history through mass cytometry and uncouple division, time and regulatory protein expression in single naive human T cells during their activation and expansion in a complex ex vivo milieu. Using 23 markers, we defined groups of proteins controlled predominantly by division state or time and found that undivided cells account for the majority of phenotypic diversity. We next built a map of cell state changes during naive T-cell expansion. By examining cell signaling on this map, we rationally selected ibrutinib, a BTK and ITK inhibitor, and administered it before T cell activation to direct differentiation toward a T stem cell memory (TSCM)-like phenotype. This method for tracing cell fate across division states and time can be broadly applied for directing cellular differentiation.


The challenge of recruiting patients with anterior cruciate ligament injury of the knee into a randomized clinical trial comparing surgical and non-surgical treatment.
To determine the number of patients needed to be screened (NNS) and allocated (NNA) in order to include one participant in a randomized clinical trial (RCT), and to compare the characteristics of patients accepting or declining participation in the RCT. The recruitment process of an ongoing multicenter RCT, comparing surgical and non-surgical interventions after acute anterior cruciate ligament (ACL) injury of the knee is described. We use the known concept Number Needed to Screen (NNS) and introduce the new concept Number Needed to Allocate (NNA) as variables to support a priori sample size calculations of future investigations. 560 patients were screened to identify 162 patients (29%) eligible for inclusion in the RCT. 41 of those declined participation for various reasons, the most common being unwillingness to undergo surgery (n=23) or unwillingness to risk conservative treatment (n=8). 19 patients were excluded after MRI assessment or arthroscopy. Thus, 102 (18%) patients were allocated to one of the two treatments in the RCT. The NNS was 5.5 individuals with an acute knee injury, and the NNA was 1.6 individuals eligible for inclusion, to include 1 patient in the RCT. Patients declining to participate in the RCT were more frequently self-employed and less frequently injured in sports activities than those accepting RCT participation. We suggest that the a priori sample size calculation needs to be multiplied by at least 5.5 to provide an estimate of the number needed to screen, or 1.6 to provide an estimate of the number needed to allocate in order to include the desired number of patients in a trial comparing surgical and non-surgical treatment of the ACL injured patient.


Multiparametric Magnetic Resonance Imaging for Prediction of Parenchymal Hemorrhage in Acute Ischemic Stroke After Reperfusion Therapy.
Patients with acute ischemic stroke are at increased risk of developing parenchymal hemorrhage (PH), particularly in the setting of reperfusion therapies. We have developed a predictive model to examine the risk of PH using combined magnetic resonance perfusion and diffusion parameters, including cerebral blood volume (CBV), apparent diffusion coefficient, and microvascular permeability (K2). Voxel-based values of CBV, K2, and apparent diffusion coefficient from the ischemic core were obtained using pretreatment magnetic resonance imaging data from patients enrolled in the MR RESCUE clinical trial (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy). The associations between PH and extreme values of imaging parameters were assessed in univariate and multivariate analyses. Receiver-operating characteristic curve analysis was performed to determine the optimal parameter(s) and threshold for predicting PH. In 83 patients included in this analysis, 20 developed PH. Univariate analysis showed significantly lower 10th percentile CBV and 10th percentile apparent diffusion coefficient values and significantly higher 90th percentile K2 values within the infarction core of patients with PH. Using classification tree analysis, the 10th percentile CBV at threshold of 0.47 and 90th percentile K2 at threshold of 0.28 resulted in overall predictive accuracy of 88.7%, sensitivity of 90.0%, and specificity of 87.3%, which was superior to any individual or combination of other classifiers. Our results suggest that combined 10th percentile CBV and 90th percentile K2 is an independent predictor of PH in patients with acute ischemic stroke with diagnostic accuracy superior to individual classifiers alone. This approach may allow risk stratification for patients undergoing reperfusion therapies. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00389467.


Orofacial infection of athymic mice with defined mixtures of acyclovir-susceptible and acyclovir-resistant herpes simplex virus type 1.
Infection of athymic mice with defined populations of acyclovir-susceptible (thymidine kinase [TK]-positive) and acyclovir-resistant (TK-deficient or TK-altered) herpes simplex virus type 1 strains was used to simulate herpetic skin disease of the immunocompromised host. In vitro characterization of the defined virus mixtures revealed that the dye uptake method was quite sensitive in the detection of small amounts (3 to 9%) of acylovir-resistant virus. Mice infected with homogeneous virus populations exhibited a good correlation between clinical response and the in vitro drug susceptibility of the infecting virus. Animals infected with defined mixtures of viruses exhibited varied patterns of infection and responses to acyclovir treatment. However, disease severity was useful in predicting the TK phenotype of virus recovered from lesions. Pathogenic, TK-altered virus was responsible for progressive disease in animals receiving low-dose (0.25-mg/ml) prophylactic acyclovir or high-dose (1.25-mg/ml) delayed therapy. Although this mutant was recovered infrequently, it was responsible for clinically significant disease in the animals from which it was isolated.


Circulating levels of carboxy‐methyl‐lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study.
Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy‐methyl‐lysine (CML) are associated with risk of hip fracture.We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68–102 years; 39.8% male) for a median of 9.22 years (range, 0.01–12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD)measurement. There were 348 hip fractures during follow‐up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant‐years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95% confidence interval [CI], 1.16–1.40]; p<0.001). Sequential adjustment for age, gender, race/ethnicity,body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95% CI, 1.05–1.31; p=0.006).In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.


Reproducibility of Heart Rate Variability Is Parameter and Sleep Stage Dependent.
Objective: Measurements of heart rate variability (HRV) during sleep have become increasingly popular as sleep could provide an optimal state for HRV assessments. While sleep stages have been reported to affect HRV, the effect of sleep stages on the variance of HRV parameters were hardly investigated. We aimed to assess the variance of HRV parameters during the different sleep stages. Further, we tested the accuracy of an algorithm using HRV to identify a 5-min segment within an episode of slow wave sleep (SWS, deep sleep). Methods: Polysomnographic (PSG) sleep recordings of 3 nights of 15 healthy young males were analyzed. Sleep was scored according to conventional criteria. HRV parameters of consecutive 5-min segments were analyzed within the different sleep stages. The total variance of HRV parameters was partitioned into between-subjects variance, between-nights variance, and between-segments variance and compared between the different sleep stages. Intra-class correlation coefficients of all HRV parameters were calculated for all sleep stages. To identify an SWS segment based on HRV, Pearson correlation coefficients of consecutive R-R intervals (rRR) of moving 5-min windows (20-s steps). The linear trend was removed from the rRR time series and the first segment with rRR values 0.1 units below the mean rRR for at least 10 min was identified. A 5-min segment was placed in the middle of such an identified segment and the corresponding sleep stage was used to assess the accuracy of the algorithm. Results: Good reproducibility within and across nights was found for heart rate in all sleep stages and for high frequency (HF) power in SWS. Reproducibility of low frequency (LF) power and of LF/HF was poor in all sleep stages. Of all the 5-min segments selected based on HRV data, 87% were accurately located within SWS. Conclusions: SWS, a stable state that, in contrast to waking, is unaffected by internal and external factors, is a reproducible state that allows reliable determination of heart rate, and HF power, and can satisfactorily be detected based on R-R intervals, without the need of full PSG. Sleep may not be an optimal condition to assess LF power and LF/HF power ratio.


The anti-human leukocyte antigen-DR monoclonal antibody 1D09C3 activates the mitochondrial cell death pathway and exerts a potent antitumor activity in lymphoma-bearing nonobese diabetic/severe combined immunodeficient mice.
The fully human anti-HLA-DR antibody 1D09C3 has been shown to delay lymphoma cell growth in severe combined immunodeficient (SCID) mice. The present study was aimed at (a) investigating the mechanism(s) of 1D09C3-induced cell death and (b) further exploring the therapeutic efficacy of 1D09C3 in nonobese diabetic (NOD)/SCID mice. The chronic lymphocytic leukemia cell line JVM-2 and the mantle cell lymphoma cell line GRANTA-519 were used. Generation of reactive oxygen species (ROS) and mitochondrial membrane depolarization were measured by flow cytometry following cell incubation with dihydroethidium and TMRE, respectively. Western blot analysis was used to detect c-Jun-NH(2)-kinase (JNK) phosphorylation and apoptosis-inducing factor (AIF). NOD/SCID mice were used to investigate the activity of 1D09C3 in early- or advanced-stage tumor xenografts. In vitro, 1D09C3-induced cell death involves a cascade of events, including ROS increase, JNK activation, mitochondrial membrane depolarization, and AIF release from mitochondria. Inhibition of JNK activity significantly reduced 1D09C3-induced apoptosis, indicating that 1D09C3 activity involves activation of the kinase. In vivo, 1D09C3 induces long-term disease-free survival in a significant proportion of tumor-bearing mice treated at an early stage of disease. Treatment of mice bearing advanced-stage lymphoma results in a highly significant prolongation of survival. These data show that 1D09C3 (a) exerts a potent antitumor effect by activating ROS-dependent, JNK-driven cell death, (b) cures the great majority of mice treated at an early-stage of disease, and (c) significantly prolongs survival of mice with advanced-stage disease.


CDR3 loop flexibility contributes to the degeneracy of TCR recognition.
T cell receptor (TCR) binding degeneracy lies at the heart of several physiological and pathological phenomena, yet its structural basis is poorly understood. We determined the crystal structure of a complex involving the BM3.3 TCR and an octapeptide (VSV8) bound to the H-2K(b) major histocompatibility complex molecule at a 2.7 A resolution, and compared it with the BM3.3 TCR bound to the H-2K(b) molecule loaded with a peptide that has no primary sequence identity with VSV8. Comparison of these structures showed that the BM3.3 TCR complementarity-determining region (CDR) 3alpha could undergo rearrangements to adapt to structurally different peptide residues. Therefore, CDR3 loop flexibility helps explain TCR binding cross-reactivity.


The effect of probiotics and polysaccharides on the gut microbiota composition and function of weaned rats.
Weaning is an essential and important event for infants and rodent animals, and the dietary supplementation plays a crucial role in regulating the composition and function of gut microbiota in the initial period after weaning. In this study, we investigated the potential effects of two probiotics along with three polysaccharides (PP) in weaned rats. Male SD rats, 21 days of age, were divided into two groups: one group was administered with PP for four weeks and the other was not. Body weight, food intake, gut epithelial barrier function, digestive enzyme activities, and the composition and function of gut microbiota were analyzed. The dietary PP increased the body weight and food intake, promoted gut epithelial barrier integrity, and elevated the activities of digestive enzymes. Moreover, the microbial community structure was different between the two groups. At the genus level, Bifidobacterium, Lactobacillus, and Allobaculum were significantly increased, whereas Anaerostipes, Enterococcus, and Parabacteroides were observably reduced. Furthermore, PP significantly increased amino acid metabolism, energy metabolism, and SCFA-related metabolism. This study shows that synbiotics containing probiotics (L. acidophilus NCFM and B. lactis Bi-07) in combination with polysaccharides (LBP, PCPs, and Lentinan) can modulate the composition of gut microbiota, stimulate the maturation of gut microbiota biological function, and promote the growth performance in weaned rats.


Changes in Body Mass Index Among School-Aged Youths Following Implementation of the Healthy, Hunger-Free Kids Act of 2010.
The prevalence of obesity among youths 2 to 19 years of age in the US from 2017 to 2018 was 19.3%; previous studies suggested that school lunch consumption was associated with increased obesity. The Healthy, Hunger-Free Kids Act of 2010 (HHFKA) strengthened nutritional standards of school-based meals. To evaluate the association between the HHFKA and youth body mass index (BMI). This cohort study was conducted using data from the Environmental Influences on Child Health Outcomes program, a nationwide consortium of child cohort studies, between January 2005 and March 2020. Cohorts in the US of youths aged 5 to 18 years with reported height and weight measurements were included. Full implementation of the HHFKA. The main outcome was annual BMI z-score (BMIz) trends before (January 2005 to August 2016) and after (September 2016 to March 2020) implementation of the HHFKA, adjusted for self-reported race, ethnicity, maternal education, and cohort group. An interrupted time-series analysis design was used to fit generalized estimating equation regression models. A total of 14 121 school-aged youths (7237 [51.3%] male; mean [SD] age at first measurement, 8.8 [3.6] years) contributing 26 205 BMI measurements were included in the study. Overall, a significant decrease was observed in the annual BMIz in the period following implementation of the HHFKA compared with prior to implementation (-0.041; 95% CI, -0.066 to -0.016). In interaction models to evaluate subgroup associations, similar trends were observed among youths 12 to 18 years of age (-0.045; 95% CI, -0.071 to -0.018) and among youths living in households with a lower annual income (-0.038; 95% CI, -0.063 to -0.013). In this cohort study, HHFKA implementation was associated with a significant decrease in BMIz among school-aged youths in the US. The findings suggest that school meal programs represent a key opportunity for interventions to combat the childhood obesity epidemic given the high rates of program participation and the proportion of total calories consumed through school-based meals.


The Impact of Hospital Costing Methods on Cost-Effectiveness Analysis: A Case Study.
Several methods exist to cost hospital contacts when estimating the cost effectiveness of a new intervention. However, the implications of choosing a particular approach remain unclear. We compare the use of the three main diagnosis-related group (DRG)-based national unit costs in England to determine whether choice of approach can impact on economic evaluation results. A cost-utility model was developed to compare secondary fracture prevention models of care for hip fracture patients, using data from large primary and hospital care administrative datasets in England. A healthcare and personal social services payer perspective was adopted, and utilities were informed by a meta-regression. Hospital resource use was valued using three DRG-based unit costs, and regression-based costing models were developed using data from 13,906 patients to inform the model health states. Finished consultant episode (FCE)-level reference costs resulted in the highest costs on admission (£9075) and in the year of the fracture (£14,440). Relative to FCE-level costs, spell-level tariffs led to the lowest total hospital care costs per patient within 1 year of fracture (- £3691) compared with spell-level reference costs (- £2106). At a £20,000/quality-adjusted life-year threshold, using spell-level reference costs or spell-level tariffs, the introduction of a nurse-led fracture liaison service model of care was the cost-effective alternative. However, using FCE-level reference costs, usual care was the cost-effective option. Our results show that, conditional on the set of national unit costs adopted, the costs of hip fracture may vary considerably and different decisions may be reached regarding the introduction of new healthcare interventions.


Quantiferon-TB Gold in tube assay for the screening of tuberculosis before and during treatment with tumor necrosis factor alpha antagonists.
The usefulness of interferon-gamma (IFN-γ) release assays for tuberculosis screening before tumor necrosis factor-alpha (TNF-α) antagonists and for monitoring during treatment is a contraversial issue. The aims of this study were to determine whether TNF-α antagonists affect the results of the Quantiferon-TB Gold in-tube assay (QTF); to assess how QTF performs in comparison with the tuberculin skin test (TST) in rheumatoid arthritis (RA) patients who are about to start treatment with TNF-α antagonists, RA patients who are not candidates for treatment with TNF-α antagonists, rheumatology patients with confirmed current or past tuberculosis infection, and healthy controls, and to determine the specificity of the QTF test to differentiate leprosy patients, another group of patients infected with mycobacteria. The 38 RA patients who were prescribed TNF-α antagonists, 40 RA patients who were not considered for TNF-α antagonist use, 30 rheumatology patients with a history or new diagnosis of tuberculosis, 23 leprosy patients, and 41 healthy controls were studied. QTF and TST were done on the same day, and both were repeated after a mean of 3.6 ± 0.2 months in patients who used TNF-α antagonists. Treatment with TNF-α antagonists did not cause a significant change in the QTF or TST positivity rate (34% versus 42%; P = 0.64; and 24% versus 37%; P = 0.22). Patients with leprosy had a trend for a higher mean IFN-γ level (7.3 ± 8.0) and QTF positivity (61%) than did the other groups; however, the difference was not significant (P = 0.09 and P = 0.43). Treatment with TNF-α antagonists does not seem to affect the QTF test to an appreciable degree. The higher IFN-γ levels in leprosy patients deserves further attention.


Light-controlled versatile manipulation of liquid metal droplets: a gateway to future liquid robots.
The controlled actuation of liquid metal (LM) droplets has recently shown great potential in developing smart actuating systems for applications in robotics. However, there is a lack of a simple approach for the precise manipulation of multiple LM droplets in a 2D plane, which hinders the development of complex control over droplets for realizing useful robotic applications. To overcome this challenge, here, a versatile and powerful light-induced manipulation of LM droplets is presented. The key principle is to selectively activate phototransistors in an electrolyte using infrared laser beams to electrically control LM droplets via Marangoni forces. This approach shows the ability of inducing concurrent motion, splitting, and merging of multiple LM droplets simply using light without complex and bulky systems. Parameters affecting the manipulation of LM droplets are thoroughly investigated. Moreover, a vehicle carrier driven by wheels composed of multiple LM droplets for making a light-controlled relay is demonstrated. We believe such a light-induced control method for manipulating LM droplets has the potential for advancing the development of future field-programmable robotics and droplet-based soft collaborative robots.


Activation of cAMP-dependent protein kinase suppresses the presynaptic cannabinoid inhibition of glutamatergic transmission at corticostriatal synapses.
In a previous study, we showed that type 1 cannabinoid (CB(1)) receptor activation substantially depresses the corticostriatal glutamatergic transmission onto striatal neurons in the brain slice preparation. We now report that the adenylyl cyclase activator forskolin and cAMP analog (S)-p-8-(4-chlorophenythil) adenosine-3',5'-monophosphorothioate (Sp-8-CPT-cAMPS) strongly suppressed the synaptic depression induced by cannabimimetic aminoalkylindole, WIN 55,212-2. Application of the cAMP-dependent protein kinase (PKA) inhibitor KT5720 alone had no consistent effect on basal synaptic transmission but the synaptic enhancement elicited by forskolin was blocked. In addition, pretreatment of striatal slices with either KT5720 or another PKA inhibitor, H89, completely abolished the attenuation by forskolin on WIN 55,212-2-induced synaptic depression. The effect of forskolin on CB(1) receptor function was still observed in a low Ca(2+) bathing solution, suggesting that the forskolin's action is not attributable to its ability to saturate the presynaptic transmitter release processes. The possibility that forskolin acted by increasing CB(1) receptor phosphorylation was confirmed by demonstrating that the serine-phosphorylated component with CB(1) receptors was significantly increased after forskolin treatment. This forskolin effect was markedly attenuated in the presence of KT5720. Moreover, the activation of beta-adrenergic receptors by isoproterenol mimics forskolin to elicit a PKA-dependent inhibition of CB(1) receptor function. Together, these observations indicate that the presynaptic inhibitory action of CB(1) receptors at corticostriatal synapses could be negatively regulated by cAMP/PKA-mediated receptor phosphorylation. This effect of PKA may play a functional role in fine-tuning glutamatergic transmission at corticostriatal synapses.


Differential effects on spatial navigation of immunotoxin-induced cholinergic lesions of the medial septal area and nucleus basalis magnocellularis.
The effects on anatomy and behavior of a ribosomal inactivating protein (saporin) coupled to a monoclonal antibody against the low-affinity NGF receptor (NGFr) were examined. In adult rats, NGFr is expressed predominantly in cholinergic neurons of the medial septal area (MSA), diagonal band nuclei, and nucleus basalis magnocellularis (nBM), but also in noncholinergic cerebellar Purkinje cells. Rats with immunotoxin injections to the MSA, nBM, and lateral ventricle were compared to controls on a spatial and cued reference memory task in the Morris maze. Toxin injections to the MSA slightly impaired the initial, but not asymptotic, phase of spatial navigation. Injections to the nBM impaired all phases of spatial navigation. Cued navigation, however, was not affected in either the MSA or nBM group. The ventricular injections severely affected spatial and cued navigation. Acetylcholinesterase (AChE) histochemistry and NGFr and choline acetyltransferase immunohistochemistry revealed a loss of (1) almost all NGFr-positive cholinergic neurons in the MSA and AChE fibers in hippocampus (MSA group); (2) almost all NGFr neurons in the nBM, some in the MSA, most AChE fibers in neocortex and some in the hippocampus (nBM group), and (3) almost all NGFr neurons in the MSA and nBM and their corresponding hippocampal and cortical AChE fibers (ventricular group). Cholinergic nBM projections to the amygdala were largely preserved in all groups. The amount of cholinergic fiber loss in the cortex correlated modestly, but significantly, with the severity of impairment of the asymptotic phase of performance of the spatial task. An unambiguous interpretation of the anatomical locus of behavioral deficits was not possible because of damage to cholinergic striatal interneurons (nBM group) and to noncholinergic cerebellar Purkinje cells (ventricular group). These data suggest that the cholinergic cortical system is critical to the performance of this spatial memory task. Cholinergic denervation of the hippocampus alone, however, is not sufficient to impair markedly performance of this task.


Contrasting patterns of genetic diversity at three different genetic markers in a marine mammal metapopulation.
Many studies use genetic markers to explore population structure and variability within species. However, only a minority use more than one type of marker and, despite increasing evidence of a link between heterozygosity and individual fitness, few ask whether diversity correlates with population trajectory. To address these issues, we analysed data from the Steller's sea lion, Eumetiopias jubatus, where three stocks are distributed over a vast geographical range and where both genetic samples and detailed demographic data have been collected from many diverse breeding colonies. To previously published mitochondrial DNA (mtDNA) and microsatellite data sets, we have added new data for amplified fragment length polymorphism (AFLP) markers, comprising 238 loci scored in 285 sea lions sampled from 23 natal rookeries. Genotypic diversity was low relative to most vertebrates, with only 37 loci (15.5%) being polymorphic. Moreover, contrasting geographical patterns of genetic diversity were found at the three markers, with Nei's gene diversity tending to be higher for AFLPs and microsatellites in rookeries of the western and Asian stocks, while the highest mtDNA values were found in the eastern stock. Overall, and despite strongly contrasting demographic histories, after applying phylogenetic correction we found little correlation between genetic diversity and either colony size or demography. In contrast, we were able to show a highly significant positive relationship between AFLP diversity and current population size across a range of pinniped species, even though equivalent analyses did not reveal significant trends for either microsatellites or mtDNA.


A study of the female germ line in mosaics ofDrosophila.
Our report presents an analysis of the development and dynamics of the female germ line inDrosophila. Females were produced that were mosaic either for attached-X chromosomes[Formula: see text] and a ring-X (triplo-X-diplo-X), or for[Formula: see text] and a marked Y-chromosome[Formula: see text]. The germ-line and genitalia of these females were analysed by direct microscopic observation or by examination of the progeny.Eggs derived from triplo-X germ cells were hardly capable of supporting development, with most of the zygotes dying during embryonic development. The analysis of the germ line was therefore carried out mainly by direct observation of histochemically stained developing oocytes in the ovaries of mosaic females.The total germ cell population of both ovaries of a female was mosaic in 22-29% of the tested animals. From this frequency of mosaicism we estimated the number of functional primordial germ cells to be betwen 3 and 6 cells at the blastoderm stage. At this stage the cell lineages for the left and right ovary are not yet separated.The germ cell population of individual ovarioles was frequently mosaic which shows that the few stem cells in an ovariole are recruited as a group and are not clonal descendants of a single ancestor cell per ovariole. An analysis of the sequential pattern of oocyte-nurse cell cysts in mosaic ovarioles revealed that neighbouring cysts tend to be of the same genotype. This suggests that the stem cells of the adult ovaries preferentially divide in bursts, one of them giving rise to two, three and sometimes even more cystocytes in a row.In addition, the foci for lethality and sterility of the triplo-X condition were determined. Non-mosaic triplo-X females (metafemales) are hardly viable and invariably sterile. Using our mosaics, the focus forlethality could be mapped to a region very near the ventral prothoracic discs. The focus forsterility resides in the genitalia, since flies with triplo-X genitalia never laid any eggs, regardless of the genotype of their ovaries.


[Psychiatric past history and health care after compulsory admission. Care use as an indicator of the quality of care for patients in compulsory care in Rotterdam].
In evaluations of the Act on Special Admissions to Psychiatric Hospitals in The Netherlands (Dutch acronym BOPZ) hardly any attention has been given to the use of mental health care services before and after a compulsory admission. To investigate whether patterns of care before and after compulsory admissions can be considered as indicators of the quality of care provided by the mental health services. For 623 patients with first-time acute compulsory admissions in Rotterdam, the use of the care services was monitored over a period of 12 months before and after admission. The outcomes were compared for 3 different patient groups: 'old acquaintances', 'newcomers' and 'passers-by'. In order to identify differences before an after the introduction of the BOPZ Act of 1994, we compared the use made of care facilities by patients admitted between 1992 and 1993 and between 1996 and 1997. More than one third of the patients admitted to acute compulsory care leaves the psychiatric hospital within three weeks. The average length of stay is more than two months and in more than half of the cases the first contact with mental health services occurs within one week after discharge. Within one year after the compulsory admission more than one third of patients is re-admitted and after one year more than fifty percent of patients are still receiving mental health care. Intensive care is targeted particularly at the patient group referred to as 'old acquaintances'. Following the introduction of the BOPZ Act the percentage of suicide-threats and cases of self-neglect increased. The number ofcompulsory re-admissions increased as well. The research results provide an encouraging picture of the quality of care provided before and after compulsory admissions. However, the cases which fail to receive mental health care before emergency compulsory admission and miss out on outpatient follow-up emphasise the needfor alternative measures such as an earlier conditional compulsory admission (voorwaardelijke machtiging) and more intensive outpatient treatment.


Predictive value of some pro-oxidants in type 2 diabetes mellitus with vascular complications.
The study aims to analyze oxidative stress levels in circulation of some reactive molecules and products of biomolecular modification in type 2 diabetes mellitus (T2DM) with diabetes-specific vascular complications in order to determine their predictive value. Also, the alterations of their serum concentration with reference to disease characteristics were assessed. Reactive oxygen species (ROS), nitric oxide radicals (•NO), malondialdehyde (MDA), protein carbonyl (CO) and 8-hydroxydeoxyguanosin (8-OHdG) in serum were measured in 93 patients with T2DM with vascular complications, 94 control subjects and 16 diabetic patients who had no evidence of vascular disease. T2DM patients with clinically manifest vascular disease exhibit significantly elevated concentrations of all pro-oxidants in comparison to healthy subjects, with the highest degree of increase of •NO radicals. The levels of carbonylated proteins, ROS and 8-OHdG were significantly increased in insufficiently compensated diabetes as compared to good glycemic control state. Also, serum MDA, protein CO and 8-OHdG showed an association with glycemic control parameters. MDA, ROS and 8-OHdG correlated mostly with microvascular complications. Significant area under the curve (AUC) from plotted receiver operating characteristic (ROC) curves were obtained for all studied biomarkers, as for nitric oxide it was substantially bigger compared to those for the other pro-oxidants. Correspondingly, positive and negative predictive values related to the disease were in favor of the •NO radicals. The cutoff values of oxidative biomarkers may serve as an indicator of clinical reference for detecting T2DM with associated vascular complications, as nitric oxide radicals were the most reliable indicator.


Characterization of a multi-user indoor positioning system based on low cost depth vision (Kinect) for monitoring human activity in a smart home.
An increasing number of systems use indoor positioning for many scenarios such as asset tracking, health care, games, manufacturing, logistics, shopping, and security. Many technologies are available and the use of depth cameras is becoming more and more attractive as this kind of device becomes affordable and easy to handle. This paper contributes to the effort of creating an indoor positioning system based on low cost depth cameras (Kinect). A method is proposed to optimize the calibration of the depth cameras, to describe the multi-camera data fusion and to specify a global positioning projection to maintain the compatibility with outdoor positioning systems. The monitoring of the people trajectories at home is intended for the early detection of a shift in daily activities which highlights disabilities and loss of autonomy. This system is meant to improve homecare health management at home for a better end of life at a sustainable cost for the community.


Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women.
HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/"Phambili" vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy. To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination ("vaccination period"), corresponding to the first 7 months of follow-up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy. Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32-1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22-0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21-0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28-1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16-4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59-12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24-5.72)]. It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention. SA National Health Research Database DOH-27-0207-1539; Clinicaltrials.gov NCT00413725.


Colloquium paper: uniquely human evolution of sialic acid genetics and biology.
Darwinian evolution of humans from our common ancestors with nonhuman primates involved many gene-environment interactions at the population level, and the resulting human-specific genetic changes must contribute to the "Human Condition." Recent data indicate that the biology of sialic acids (which directly involves less than 60 genes) shows more than 10 uniquely human genetic changes in comparison with our closest evolutionary relatives. Known outcomes are tissue-specific changes in abundant cell-surface glycans, changes in specificity and/or expression of multiple proteins that recognize these glycans, and novel pathogen regimes. Specific events include Alu-mediated inactivation of the CMAH gene, resulting in loss of synthesis of the Sia N-glycolylneuraminic acid (Neu5Gc) and increase in expression of the precursor N-acetylneuraminic acid (Neu5Ac); increased expression of alpha2-6-linked Sias (likely because of changed expression of ST6GALI); and multiple changes in SIGLEC genes encoding Sia-recognizing Ig-like lectins (Siglecs). The last includes binding specificity changes (in Siglecs -5, -7, -9, -11, and -12); expression pattern changes (in Siglecs -1, -5, -6, and -11); gene conversion (SIGLEC11); and deletion or pseudogenization (SIGLEC13, SIGLEC14, and SIGLEC16). A nongenetic outcome of the CMAH mutation is human metabolic incorporation of foreign dietary Neu5Gc, in the face of circulating anti-Neu5Gc antibodies, generating a novel "xeno-auto-antigen" situation. Taken together, these data suggest that both the genes associated with Sia biology and the related impacts of the environment comprise a relative "hot spot" of genetic and physiological changes in human evolution, with implications for uniquely human features both in health and disease.


Multi-organ erythrocyte sequestration and ligand expression in rhesus monkeys infected with Plasmodium coatneyi malaria.
The pathogenesis of human cerebral malaria is suspected to be caused by blockage of cerebral microvessels by the sequestration of parasitized human red blood cells (PRBC). Examination of infected tissues indicate PRBC sequestration in microvessels is the result of PRBC knob attachment to endothelial cell surface cytoadherence receptors such as CD36, thrombospondin (TSP), and intercellular adhesion molecule-1 (ICAM-1). In lieu of fresh human tissue, several animal models for human cerebral malaria have been developed, the Plasmodium coatneyi-infected rhesus monkey model being the most versatile. To further the understanding of noncerebral malarial complications during disease, we examined noncerebral tissues of infected rhesus monkeys. Our study demonstrated similar microvessel PRBC sequestration and the presence of cytoadherence ligands in noncerebral tissues. Immunohistochemical analysis showed CD36, TSP, and ICAM-1 cytoadherence proteins in several major organs.


Ketoconazole in griseofulvin-resistant dermatophytosis.
The efficacy of ketoconazole was evaluated in twenty patients with chronic dermatophyte infections who had failed to clear with griseofulvin therapy. Trichophyton rubrum was the causative organism in nineteen of the patients, and Trichophyton mentagrophytes in one patient. Three of twelve organisms tested showed in vitro resistance to griseofulvin. Duration of infection ranged from 2 to 28 years. Patients received 200 to 400 mg of ketoconazole daily for periods up to 8 months. In addition, patients were followed for 5 months post-therapy to monitor recurrences. Clearing was seen clinically as early as 2 weeks, and by 18 weeks all patients showed marked improvement or clinical clearing, though only six achieved complete mycologic cure. Improvement followed a predictable sequence of sites, with lesions of the trunk healing first, followed by hands, feet, and finally, nails. After 8 months, though all patients showed proximal nail clearing, onychomycosis persisted in thirteen of twenty affected sites. By 5 months post-therapy, four of six patients who had achieved clearing of skin and nails showed recurrences. No significant side effects were observed during therapy, though rare, apparently idiosyncratic cases of hepatotoxicity have been reported. Ketoconazole is an affective therapeutic agent for griseofulvin-resistant dermatophytosis. Apparent cures may subsequently recur after discontinuation of therapy.


Reclassification of Haloactinobacterium glacieicola as Occultella glacieicola gen. nov., comb. nov., of Haloactinobacterium album as Ruania alba comb. nov, with an emended description of the genus Ruania, recognition that the genus names Haloactinobacterium and Ruania are heterotypic synonyms and description of Occultella aeris sp. nov., a halotolerant isolate from surface soil sampled at an ancient copper smelter.
In the course of screening the surface soils of ancient copper mines and smelters (East Harz, Germany) an aerobic, non-motile and halotolerant actinobacterium forming small rods or cocci was isolated. The strain designated F300T developed creamy to yellow colonies on tryptone soy agar and grew optimally at 28 °C, pH 7-8 and with 0.5-2 % (m/v) NaCl. Its peptidoglycan was of type A4α l-Lys-l-Glu (A11.54). The menaquinone profile was dominated by MK-8(II, III-H4) and contained minor amounts of MK-8(H2), MK-8(H6) and MK-9(H4). The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, mono and diacylated phosphatidylinositol dimannosides, and components that were not fully characterized, including two phospholipids, two glycolipids and an uncharacterized lipid. Major whole-cell sugars were rhamnose and ribose. The fatty acid profile contained mainly iso and anteiso branched fatty acids (anteiso-C15 : 0, iso-C14 : 0) and aldehydes/dimethylacetals (i.e. not fatty acids). Sequence analysis of its genomic DNA and subsequent analysis of the data placed the isolate in the group currently defined by members of the genera Ruania and Haloactinobacterium (family Ruaniaceae, order Micrococcales) as a sister taxon to the previously described species Haloactinobacterium glacieicola, sharing an average nucleotide identity and average amino acid identity values of 85.3 and 85.7 %, respectively. Genotypic and chemotaxonomic analyses support the view that strain F300T (=DSM 108350T=CIP 111667T) is the type strain of a new genus and new species for which the name Occultella aeris gen. nov., sp. nov. is proposed. Based on revised chemotaxonomic and additional genome based data, it is necessary to discuss and evaluate the results in the light of the classification and nomenclature of members of the family Ruaniaceae, i.e. the genera Haloactinobacterium and Ruania. Consequently, the reclassification of Haloactinobacterium glacieicola as Occultella glacieicola comb. nov. and Haloactinobacterium album as Ruania alba comb. nov., with an emended description of the genus Ruania are proposed.


Unprecedented layered coordination polymers of dithiolene group 10 metals: magnetic and electrical properties.
One-pot reactions between Ni(ii), Pd(ii) or Pt(ii) salts and 3,6-dichloro-1,2-benzenedithiol (HSC6H2Cl2SH) in KOH medium under argon lead to a series of bis-dithiolene coordination polymers. X-ray analysis shows the presence of a common square planar complex [M(SC6H2Cl2S)2](2-) linked to potassium cations forming either a two-dimensional coordination polymer network for {[K2(μ-H2O)2(μ-thf)(thf)2][M(SC6H2Cl2S)2]}n [M = Ni () and Pd ()] or a one-dimensional coordination polymer for {[K2(μ-H2O)2(thf)6][Pt(SC6H2Cl2S)2]}n (). In the coordination environment of the potassium ions may slightly change leading to the two-dimensional coordination polymer {[K2(μ-H2O)(μ-thf)2][Pt(SC6H2Cl2S)2]}n () that crystallizes together with . The physical characterization of compounds show similar trends, they are diamagnetic and behave as semiconductors.


The Swedish version of the multidimensional scale of perceived social support (MSPSS)--a psychometric evaluation study in women with hirsutism and nursing students.
The Multidimensional Scale of Perceived Social Support (MSPSS) is a short instrument, developed to assess perceived social support. The original English version has been widely used. The original scale has demonstrated satisfactory psychometric properties in different settings, but no validated Swedish version has been available. The aim was therefore to translate, adapt and psychometrically evaluate the Multidimensional Scale of Perceived Social Support for use in a Swedish context. In total 281 participants accepted to join the study, a main sample of 127 women with hirsutism and a reference sample of 154 nursing students. The MSPSS was translated and culturally adapted according to the rigorous official process approved by WHO. The psychometric evaluation included item analysis, evaluation of factor structure, known-group validity, internal consistency and reproducibility. The original three-factor structure was reproduced in the main sample of women with hirsutism. An equivalent factor structure was demonstrated in a cross-validation, based on the reference sample of nursing students. Known-group validity was supported and internal consistency was good for all scales (α = 0.91-0.95). The test-retest showed acceptable to very good reproducibility for the items (κw = 0.58-0.85) and the scales (ICC = 0.89-0.92; CCC = 0.89-0.92). The Swedish version of the MSPSS is a multidimensional scale with sound psychometric properties in the present study sample. The simple and short format makes it a useful tool for measuring perceived social support.


Photoactivatable Hydrogel Interfaces for Resolving the Interplay of Chemical, Mechanical, and Geometrical Regulation of Collective Cell Migration.
Collective migration is the mechanobiological interplay within migrating cell clusters and against extracellular matrixes (ECMs) underneath, mediating various physiological and pathological processes. Therefore, it is crucial to develop a robust platform on which collective migration can be studied under standardized conditions to understand how cells migrate differently between normal and disease states. We herein demonstrated phtotoactivatable hydrogel interfaces as suitable candidates for such applications. The substrate was composed of a poly(acrylamide) (PAAm) hydrogel whose surface was sequentially functionalized with poly-d-lysine (PDL) and photocleavable poly(ethylene glycol) (PEG). On the surface of the gel substrates, cell clusters with any given geometries can be prepared by controlling the irradiation patterns (geometrical cue), and their collective migration can be induced by the subsequent irradiation of the surrounding regions. Moreover, the substrate mechanical properties can be controlled by changing the composition of the PAAm hydrogel (mechanical cue), and the chemical properties were controlled by changing the amount of immobilized PDL, thereby altering the adsorbed amount of ECM proteins (chemical cue). The photoactivatable gel substrates were characterized by fluorescence microscopy, ζ-potential measurements, and the protein adsorption test. Through the study of the interplay of chemical, mechanical, and geometrical cues in the regulation of collective characteristics, we found additive effects of chemical and mechanical cues on the suppression of circular expansion by up-regulating the epithelial morphology. Also, the impact of geometrical cues became more significant by decreasing the chemical cue. We believe the present platform will be a useful research tool for the comprehensive mechanobiological analysis of collective cell migration.


Protease inhibitors broadly effective against feline, ferret and mink coronaviruses.
Ferret and mink coronaviruses typically cause catarrhal diarrhea in ferrets and minks, respectively. In recent years, however, systemic fatal coronavirus infection has emerged in ferrets, which resembles feline infectious peritonitis (FIP) in cats. FIP is a highly fatal systemic disease caused by a virulent feline coronavirus infection in cats. Despite the importance of coronavirus infections in these animals, there are no effective commercial vaccines or antiviral drugs available for these infections. We have previously reported the efficacy of a protease inhibitor in cats with FIP, demonstrating that a virally encoded 3C-like protease (3CLpro) is a valid target for antiviral drug development for coronavirus infections. In this study, we extended our previous work on coronavirus inhibitors and investigated the structure-activity relationships of a focused library of protease inhibitors for ferret and mink 3CLpro. Using the fluorescence resonance energy transfer assay, we identified potent inhibitors broadly effective against feline, ferret and mink coronavirus 3CLpro. Multiple amino acid sequence analysis and modelling of 3CLpro of ferret and mink coronaviruses were conducted to probe the structural basis for these findings. The results of this study provide support for further research to develop broad-spectrum antiviral agents for multiple coronavirus infections. To the best of our knowledge, this is the first report on small molecule inhibitors of ferret and mink coronaviruses.


Exploiting the pathway structure of metabolism to reveal high-order epistasis.
Biological robustness results from redundant pathways that achieve an essential objective, e.g. the production of biomass. As a consequence, the biological roles of many genes can only be revealed through multiple knockouts that identify a set of genes as essential for a given function. The identification of such "epistatic" essential relationships between network components is critical for the understanding and eventual manipulation of robust systems-level phenotypes. We introduce and apply a network-based approach for genome-scale metabolic knockout design. We apply this method to uncover over 11,000 minimal knockouts for biomass production in an in silico genome-scale model of E. coli. A large majority of these "essential sets" contain 5 or more reactions, and thus represent complex epistatic relationships between components of the E. coli metabolic network. The complex minimal biomass knockouts discovered with our approach illuminate robust essential systems-level roles for reactions in the E. coli metabolic network. Unlike previous approaches, our method yields results regarding high-order epistatic relationships and is applicable at the genome-scale.


The crystal structure of citrate synthase from the hyperthermophilic archaeon pyrococcus furiosus at 1.9 A resolution,.
The crystal structure of the closed form of citrate synthase, with citrate and CoA bound, from the hyperthermophilic Archaeon Pyrococcus furiosus has been determined to 1.9 A. This has allowed direct structural comparisons between the same enzyme from organisms growing optimally at 37 degrees C (pig), 55 degrees C (Thermoplasma acidophilum) and now 100 degrees C (Pyrococcus furiosus). The three enzymes are homodimers and share a similar overall fold, with the dimer interface comprising primarily an eight alpha-helical sandwich of four antiparallel pairs of helices. The active sites show similar modes of substrate binding; moreover, the structural equivalence of the amino acid residues implicated in catalysis implies that the mechanism proceeds via the same acid-base catalytic process. Given the overall structural and mechanistic similarities, it has been possible to make detailed structural comparisons between the three citrate synthases, and a number of differences can be identified in passing from the mesophilic to thermophilic to hyperthermophilic citrate synthases. The most significant of these are an increased compactness of the enzyme, a more intimate association of the subunits, an increase in intersubunit ion pairs, and a reduction in thermolabile residues. Compactness is achieved by the shortening of a number of loops, an increase in the number of atoms buried from solvent, an optimized packing of side chains in the interior, and an absence of cavities. The intimate subunit association in the dimeric P. furiosus enzyme is achieved by greater complementarity of the monomers and by the C-terminal region of each monomer folding over the surface of the other monomer, in contrast to the pig enzyme where the C-terminus has a very different fold. The increased number of intersubunit ion pairs is accompanied by an increase in the number involved in networks. Interestingly, all loop regions in the P. furiosus enzyme either are shorter or contain additional ion pairs compared with the pig enzyme. The possible relevance of these structural features to enzyme hyperthermostability is discussed.


[Evaluation of the tuberculin reaction in health occupation students] .
A cross-sectional study was done at the University of Antioquia, MedellIn, Colombia, to evaluate the response to a tuberculin skin test among students in undergraduate health programs (medicine, odontology, nursing, and bacteriology) as compared to undergraduate students in nonhealth programs. The study included students from the beginning, middle, and end of the university's academic programs. The sample of 490 students included 273 from health programs and 217 from nonhealth programs. Participants were randomly selected using lists provided by the university registrar, for the second semester of 1998. The presence of a BCG vaccination scar was determined, and all the participants were also questioned about TB-related risk factors. Tuberculin skin test reactivity was evaluated by the size of induration 72 hours after intradermal injection of two tuberculin units of purified protein derivative RT 23. There were no differences in tuberculin reactivity between students from the health programs and from the nonhealth programs, irrespective of the academic level. However, there was a significantly higher proportion of positive skin tests among students with a BCG scar. These results suggest that undergraduate health students do not have extensive contact with TB patients or with clinical samples from such patients. Nevertheless, the results do not rule out TB as an occupational risk for health personnel.


Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties.
New cytostatic compounds, tubulysins, were isolated from the culture broth of strains of the myxobacteria Archangium gephyra and Angiococcus disciformis. The compounds are peptides partly consisting of unusual amino acids and are distantly related to the dolastatins. The tubulysins were not active against bacteria and only little against fungi, but showed high cytostatic activity against mammalian cell lines with IC50 values in the picomolar range. An incubation with 50 ng/ml tubulysin A led to a complete disappearance of the microtubuli network of the cells within 24 hours. The more active tubulysin D induced multipolar spindles: At 0.5 ng/ml all mitotic cells showed more than four spindle poles.


An autopsy study of maternal mortality in Mozambique: the contribution of infectious diseases.
Maternal mortality is a major health problem concentrated in resource-poor regions. Accurate data on its causes using rigorous methods is lacking, but is essential to guide policy-makers and health professionals to reduce this intolerable burden. The aim of this study was to accurately describe the causes of maternal death in order to contribute to its reduction, in one of the regions of the world with the highest maternal mortality ratios. We conducted a prospective study between October 2002 and December 2004 on the causes of maternal death in a tertiary-level referral hospital in Maputo, Mozambique, using complete autopsies with histological examination. HIV detection was done by virologic and serologic tests, and malaria was diagnosed by histological and parasitological examination. During 26 mo there were 179 maternal deaths, of which 139 (77.6%) had a complete autopsy and formed the basis of this analysis. Of those with test results, 65 women (52.8%) were HIV-positive. Obstetric complications accounted for 38.2% of deaths; haemorrhage was the most frequent cause (16.6%). Nonobstetric conditions accounted for 56.1% of deaths; HIV/AIDS, pyogenic bronchopneumonia, severe malaria, and pyogenic meningitis were the most common causes (12.9%, 12.2%, 10.1% and 7.2% respectively). Mycobacterial infection was found in 12 (8.6%) maternal deaths. In this tertiary hospital in Mozambique, infectious diseases accounted for at least half of all maternal deaths, even though effective treatment is available for the four leading causes, HIV/AIDS, pyogenic bronchopneumonia, severe malaria, and pyogenic meningitis. These observations highlight the need to implement effective and available prevention tools, such as intermittent preventive treatment and insecticide-treated bed-nets for malaria, antiretroviral drugs for HIV/AIDS, or vaccines and effective antibiotics for pneumococcal and meningococcal diseases. Deaths due to obstetric causes represent a failure of health-care systems and require urgent improvement.


Five year prognosis in patients with angina identified in primary care: incident cohort study.
To ascertain the risk of acute myocardial infarction, invasive cardiac procedures, and mortality among patients with newly diagnosed angina over five years. Incident cohort study of patients with primary care data linked to secondary care and mortality data. 40 primary care practices in Scotland. 1785 patients with a diagnosis of angina as their first manifestation of ischaemic heart disease, 1 January 1998 to 31 December 2001. Adjusted hazard ratios for acute myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, death from ischaemic heart disease, and all cause mortality, adjusted for demographics, lifestyle risk factors, and comorbidity at cohort entry. Mean age was 62.3 (SD 11.3). Male sex was associated with an increased risk of acute myocardial infarction (hazard ratio 2.01, 95% confidence interval 1.35 to 2.97), death from ischaemic heart disease (2.80, 1.73 to 4.53), and all cause mortality (1.82, 1.33 to 2.49). Increasing age was associated with acute myocardial infarction (1.04, 1.02 to 1.06, per year of age increase), death from ischaemic heart disease (1.09, 1.06 to 1.11, per year of age increase), and all cause mortality (1.09, 1.07 to 1.11, per year of age increase). Smoking was associated with subsequent acute myocardial infarction (1.94, 1.31 to 2.89), death from ischaemic heart disease (2.12, 1.32 to 3.39), and all cause mortality (2.11, 1.52 to 2.95). Obesity was associated with death from ischaemic heart disease (2.01, 1.17 to 3.45) and all cause mortality (2.20, 1.52 to 3.19). Previous stroke was associated with all cause mortality (1.78, 1.13 to 2.80) and chronic kidney disease with death from ischaemic heart disease (5.72, 1.74 to 18.79). Men were more likely than women to have coronary artery bypass grafting or percutaneous transluminal coronary angioplasty after a diagnosis of angina; older people were less likely to receive percutaneous transluminal coronary angioplasty. Acute myocardial infarction after a diagnosis of angina was associated with an increased risk of death from ischaemic heart disease and all cause mortality (8.84 (5.31 to 14.71) and 4.23 (2.78 to 6.43), respectively). Neither of the invasive cardiac procedures significantly reduced the subsequent risk of all cause mortality. In this sample of people with incident angina from primary care, there were sex differences in survival and age and sex differences in the provision of revascularisation after a diagnosis. Acute myocardial infarction after a diagnosis of angina was strongly predictive of mortality. To minimise adverse outcomes, optimal preventive treatments should be used in patients with angina.


An examination of the incidence and nature of chemical restraint on adult acute psychiatric inpatient units in Adelaide, South Australia.
Reducing and/or eliminating the use of coercive measures in psychiatric services is a priority worldwide. Chemical restraint is one such measure, yet to date has been poorly defined and poorly investigated. The aim of this study was to examine chemical restraint use in 12 adult acute inpatient psychiatric units in Adelaide, South Australia. Methods involved the analysis of all reported chemical restraint events occurring over a 12-month period analysed using a descriptive quantitative design. There were 166 chemical restraint events involving 110 consumers. The highest prevalence rate in an individual unit was 28.78 events per 1000 occupied bed days, with the lowest being 0.12 events per 1000 occupied bed days. More males (n = 69, 57.5%) were involved in chemical restraint than females. Schizophrenia, schizotypal, and delusional disorders were the predominant diagnoses among consumers who were chemically restrained. The most events occurred during three time blocks: 14.00-14.59 pm, 16.00-16.59 pm, and 21.00-21.59 pm. The two most common medications used were olanzapine and clonazepam. The study presents a general picture of the practice of chemical restraint in Adelaide and identifies areas of concern in relation to the need for monitoring of side effects and completion of systematic processes of documentation regarding chemical restraint events. Findings highlight the need for sustained focus on reducing the need for chemical restraint and exploring less restrictive measures with those most likely to receive medication against their will.


Comparative molecular analysis of community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus isolates from children in northern Taiwan.
From August 2004 to July 2005, 210 clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates were collected prospectively from 173 children admitted to Chang Gung Children's Hospital in Taiwan. A comparative molecular analysis of the 111 community-associated (CA) isolates from 102 children and the 99 healthcare-associated (HA) isolates from 71 children was conducted. In comparison to the HA isolates (31%), the CA isolates (90%) were more likely to have been isolated from pus (p <5 x 10(-8)). For each patient with MRSA infection, only the first isolate was selected for molecular analysis. The molecular characteristics differed significantly between the CA and the HA isolates (p <5 x 10(-8)). The clone characterized as sequence type (ST)59/pulsotype D (similar to USA1000)/staphylococcal chromosomal cassette (SCC)mec V(T)/Panton-Valentine leukocidin (PVL)-positive accounted for 69% of the CA isolates, and another clone, characterized as ST239/pulsotype A (Hungary clone)/SCCmec III/PVL-negative, accounted for 45% of the 71 HA isolates. The CA clone of ST59 also accounted for 20% of the HA isolates, including 47% of the 17 community-onset isolates. It was concluded that the molecular characteristics of clinical MRSA isolates from children differed significantly between the CA and the HA isolates in northern Taiwan. However, the CA clone of ST59 was also identified in a substantial proportion of HA isolates.


Biomolecules preserved in ca. 168 million year old fossil conifer wood.
Biomarkers are widely known to occur in the fossil record, but the unaltered biomolecules are rarely reported from sediments older than Paleogene. Polar terpenoids, the natural products most resistant to degradation processes, were reported mainly from the Tertiary conifers, and the oldest known are Cretaceous in age. In this paper, we report the occurrence of relatively high concentrations of ferruginol derivatives and other polar diterpenoids, as well as their diagenetic products, in a conifer wood Protopodocarpoxylon from the Middle Jurassic of Poland. Thus, the natural product terpenoids reported in this paper are definitely the oldest polar biomolecules detected in geological samples. The extracted phenolic abietanes like ferruginol and its derivatives (6,7-dehydroferruginol, sugiol, 11,14-dioxopisiferic acid) are produced only by distinct conifer families (Cupressaceae s. l., Podocarpaceae and Araucariaceae), to which Protopodocarpoxylon could belong based on anatomical characteristics. Therefore, the natural product terpenoids are of great advantage in systematics of fossil plant remains older than Paleogene and lacking suitable anatomical preservation.


A herpes simplex virus type 1 mutant expressing a baculovirus inhibitor of apoptosis gene in place of latency-associated transcript has a wild-type reactivation phenotype in the mouse.
The latency-associated transcript (LAT) is essential for the wild-type herpes simplex virus type 1 (HSV-1) high-reactivation phenotype since LAT- mutants have a low-reactivation phenotype. We previously reported that LAT can decrease apoptosis and proposed that this activity is involved in LAT's ability to enhance the HSV-1 reactivation phenotype. The first 20% of the primary 8.3-kb LAT transcript is sufficient for enhancing the reactivation phenotype and for decreasing apoptosis, supporting this proposal. For this study, we constructed an HSV-1 LAT- mutant that expresses the baculovirus antiapoptosis gene product cpIAP under control of the LAT promoter and in place of the LAT region mentioned above. Mice were ocularly infected with this mutant, designated dLAT-cpIAP, and the reactivation phenotype was determined using the trigeminal ganglion explant model. dLAT-cpIAP had a reactivation phenotype similar to that of wild-type virus and significantly higher than that of (i) the LAT- mutant dLAT2903; (ii) dLAT1.5, a control virus containing the same LAT deletion as dLAT-cpIAP, but with no insertion of foreign DNA, thereby controlling for potential readthrough transcription past the cpIAP insert; and (iii) dLAT-EGFP, a control virus identical to dLAT-cpIAP except that it contained the enhanced green fluorescent protein open reading frame (ORF) in place of the cpIAP ORF, thereby controlling for expression of a random foreign gene instead of the cpIAP gene. These results show that an antiapoptosis gene with no sequence similarity to LAT can efficiently substitute for the LAT function involved in enhancing the in vitro-induced HSV-1 reactivation phenotype in the mouse.


Diurnal fluid expression and activity of intervertebral disc cells.
The intervertebral discs are large cartilaginous structures situated between the vertebral bodies, occupying around one third of the length of the spinal column. They act as the joints of the spine and carry mechanical load arising from body weight and muscle activity. Loads change with every alteration of posture and activity and the discs thus undergo a diurnal loading pattern with high loads on the discs during the day's activity and low loads on it at night during rest. As the disc is an osmotic system, around 25% of the disc's fluid is expressed and re-imbibed during each diurnal cycle with consequent changes in the osmotic environment of the disc cells. Here, present information on the effect of osmotic changes in disc cell metabolism is reviewed; results indicate that prevailing osmolarity is a powerful regulator of disc cell activity.


An experimentally induced duplication of retinotopic mapping within the hamster primary visual cortex.
Primary cortical areas normally have a single mapping of the receptor array arising from a 'point-to-point' projection from the thalamus. We show that, for the visual cortex, this simple mapping rule breaks down when retinal input to the thalamus is altered. We utilize the monocular enucleation paradigm, which alters subcortical mappings ipsilateral to the remaining eye. We show that this manipulation produces an altered visuotopic map in area 17 with two separated, mirror-imaged representations of the central visual field. Furthermore, thalamic point-to-point connectivity is dramatically changed. There are now two overlapping geniculocortical projections: the predominant projection maps with apparently normal topography, and a second projection maps with the opposite polarity. The plane of symmetry of the duplicated anatomical projection coincides precisely with the functional map reversal and, notably, geniculocortical magnification factors are identical in the two projections. We suggest that the duplicated, abnormal geniculocortical projection is retinotopically matched to the normal projection. We speculate that aberrant geniculocortical terminals are stabilized because they have coherent activity patterns with topographically normal terminals.


Transformations of inorganic mercury by Candida albicans and Saccharomyces cerevisiae.
Saccharomyces cerevisiae and Candida albicans were incubated with 0.25, 0.5, or 0.75 micrograms of Hg (as HgCl2) per ml of Nelson's medium in the presence of trace amounts of oxygen at 28 degrees C for 12 days. Two control media were used, one without added Hg and one without yeast inoculum. Yeast cell growth was estimated after 1, 2, 3, and 8 days of incubation. The contents of organomercury in the system and of elemental mercury released from the media and collected in traps were determined at the end of the experiments. The results were as follows. (i) C. albicans was the more mercury-resistant species, but both yeast species failed to grow in the media containing 0.75 micrograms of Hg per ml. (ii) The amounts of organomercury produced by the two species were proportional to the amount of HgCl2 added to the medium. In all cases C. albicans produced considerably larger amounts of methylmercury than S. cerevisiae. (iii) The amounts of elemental Hg produced were inversely proportional to the HgCl2 level added in the case of S. cerevisiae but were all similar in the case of C. albicans. (iv) Neither organomercury nor elemental Hg was produced in any of the control media.