Association Between Inferior Vena Cava Filter Insertion in Trauma Patients and In-Hospital and Overall Mortality.
Trauma patients admitted to the hospital are at increased risk of bleeding and thrombosis. The use of inferior vena cava (IVC) filters in this population has been increasing, despite a lack of high-quality evidence to demonstrate their efficacy. To determine if IVC filter insertion in trauma patients affects overall mortality. This retrospective cohort study used stratified 3:1 propensity matching to select a control population similar to patients who underwent IVC filter insertion at Boston Medical Center (a level I trauma center at Boston University School of Medicine) between August 1, 2003, and December 31, 2012. Among patients with an IVC filter and matched controls, age, sex, race/ethnicity, and Injury Severity Score were entered into a multivariable logistic regression model to calculate a propensity score. Matching was stratified by the date of injury. Multivariable logistic regression was used to compare hospital mortality across both groups, adjusting for age, sex, race/ethnicity, Injury Severity Score, and brain injury severity using the head and neck Abbreviated Injury Score. To determine any significant difference in mortality, patient characteristics and mortality data from the National Death Index were analyzed in all patients and in those who survived 24, 48, and 72 hours after injury, as well as at hospital discharge. Among 451 trauma patients with an IVC filter and 1343 matched controls without an IVC filter, the mean (SD) age was 47.4 (21.5) years. The median Injury Severity Score overall was 24 (range, 1-75). Based on a mean follow-up of 3.8 years (range, 0-9.4 years), there was no significant difference in overall mortality or cause of mortality in patients with vs without an IVC filter who survived more than 24 hours from the time of injury, independent of the presence or absence of deep vein thrombosis or pulmonary embolism at the time of IVC filter placement. Additional analyses at shorter intervals of 6 months and 1 year after discharge also showed no significant difference between the 2 groups of patients. Eight percent (38 of 451) of the IVC filters were removed at Boston Medical Center during the follow-up period. The research herein demonstrates no significant difference in survival in trauma patients with vs without placement of an IVC filter, whether in the presence or absence of venous thrombosis. The use of IVC filters in this population should be reexamined because filter removal rates are low and there is increased risk of morbidity in patients with filters that remain in place.


Traumatic brain injury, coronary atherosclerosis and cardiovascular mortality.
Traumatic-brain-injury (TBI) is a devastating-condition resulting in cerebral edema and ischemia. This study investigates the association of mild-TBI (mTBI) to sub-clinical atherosclerosis and cardiovascular (CV) mortality. Five hundred and forty-three veterans without known coronary artery disease or diagnosed mental disorder, who underwent coronary artery calcium (CAC) scanning for clinical indications, were followed for a median of 4-years. Veterans' medical diagnoses and neuropsychiatric health status (mTBI vs non-mTBI) were evaluated using VA electronic medical records. CAC was defined as 0, 1-100, 101-400 and 400+. CAC was higher in mTBI, compared to without-mTBI (p < 0.05). TBI was more prevalent with the-severity of CAC (p < 0.05). Regression-analyses revealed that mTBI is an independent-predictor of CAC (p < 0.01). The CV mortality rate was 25% in mTBI and 10.5% in without-mTBI (p = 0.0001). Multivariable survival regression analyses revealed a significant-association between mTBI and CAC, with increased-risk of CV mortality (p < 0.05). The hazard-ratio of CV mortality was 5.25 in mTBI & CAC > 0, compared to without-mTBI & CAC = 0 (p < 0.05). The risk of CV-mortality was 2.25 for mTBI & CAC = 1-100, 4.93 for mTBI & CAC = 101-400 and 7.06 for mTBI & CAC ≥ 400, compared to matched CAC-categories without-mTBI (p < 0.05). The area under ROC curve to predict CV mortality was 0.64 for mTBI, 0.69 for mTBI & PTSD, 0.85 for mTBI & CAC > 0 and 0.92 for the combination. The prognostication of mTBI to predict CV mortality is superior to the Framingham risk score. Also the combination of mTBI & PTSD provided incremental prognostic values to predict CV mortality (p < 0.05). mTBI is associated with the severity of sub-clinical coronary atherosclerosis and independently predicts CV mortality.


We can handle this: parents' use of religion in the first year following their child's diagnosis with cystic fibrosis.
The diagnosis of a child's life-shortening disease leads many American parents to utilize religious beliefs. Models relating religious constructs to health have been proposed. Still lacking are inductive models based on parent experience. The specific aims of this study were: 1. develop a grounded theory of parental use of religion in the year after diagnosis; 2. describe whether parents understand a relationship between their religious beliefs and their follow-through with their child's at-home treatment regimen. Fifteen parent interviews were analyzed using grounded theory method. Parents used religion to make meaning of their child's cystic fibrosis (CF) diagnosis. Parents imagined God as active, benevolent, and interventionist; found hope in their beliefs; felt supported by God; and related religion to their motivation to adhere to their child's treatment plan. Religious beliefs are clinically significant in working with many parents of children recently diagnosed with CF. Interventions that improve adherence to treatment may be enhanced by including religious aspects.


Influence of aglycone modifications on the binding of anthracycline drugs to DNA: the molecular structure of idarubicin and 4-O-demethyl-11-deoxydoxorubicin complexed to d(CGATCG).
X-ray diffraction analyses of the complexes between two anthracycline antitumor compounds, idarubicin (IDR) and 4-O-demethyl-11-deoxydoxorubicin (ddDOX), with the DNA hexamer d(CGATCG) provided the detailed three-dimensional molecular structures at 1.7 A and 1.8 A resolution, respectively. Their structures have been refined with the constrained refinement procedure to final R-factors of 0.188 (1724 reflections for IDR) and 0.179 (1247 reflections for ddDOX). The overall structures of both complexes are similar to those of the previously studied DAU- and DOX-DNA complexes. In both complexes, two IDR (and ddDOX) molecules bind to the DNA hexamer double helix with the elongated aglycone chromophore intercalated between the CpG steps at both ends of the helix. The aglycone chromophore spans the GC Watson-Crick base pairs with its amino sugar lying in the minor groove where little structural difference is seen, compared with the daunorubicin-d(CGATCG) and doxorubicin-d(CGATCG) complexes. In contrast, the missing C4 methoxy of IDR and the missing methyl group at the O4 position of ddDOX result in a different binding surface in the major groove. The O4 hydroxyl group is capable of receiving and/or donating a hydrogen bond to proteins that bind to the drug-DNA complex. The missing O11 hydroxyl group in ring B creates an empty space in the intercalation cavity between the two GC base pairs, which appears to affect the stacking interactions between the aglycone and the DNA base pairs. Those structural changes in the major groove of the drug-DNA complexes due to the modifications of the aglycone chromophore may be responsible in part for the difference in their biological activities.


Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication.
We were initially highly skeptical that differences in the concentrations of thimerosal in vaccines would have any effect on the incidence rate of neurodevelopmental disorders after childhood immunization. This study presents the first epidemiologic evidence, based upon tens of millions of doses of vaccine administered in the United States, that associates increasing thimerosal from vaccines with neurodevelopmental disorders. Specifically, an analysis of the Vaccine Adverse Events Reporting System (VAERS) database showed statistical increases in the incidence rate of autism (relative risk [RR] = 6.0), mental retardation (RR = 6.1), and speech disorders (RR = 2.2) after thimerosal-containing diphtheria, tetanus, and acellular pertussis (DTaP) vaccines in comparison with thimerosal-free DTaP vaccines. The male/female ratio indicated that autism (17) and speech disorders (2.3) were reported more in males than females after thimerosal-containing DTaP vaccines, whereas mental retardation (1.2) was more evenly reported among male and female vaccine recipients. Controls were employed to determine if biases were present in the data, but none were found. It was determined that overall adverse reactions were reported in similar-aged populations after thimerosal-containing DTaP (2.4 +/- 3.2 years old) and thimerosal-free DTaP (2.1 +/- 2.8 years old) vaccinations. Acute control adverse reactions such as deaths (RR = 1.0), vasculitis (RR = 1.2), seizures (RR = 1.6), ED visits (RR = 1.4), total adverse reactions (RR = 1.4), and gastroenteritis (RR = 1.1) were reported similarly after thimerosal-containing and thimerosal-free DTaP vaccines. An association between neurodevelopmental disorders and thimerosal-containing DTaP vaccines was found, but additional studies should be conducted to confirm and extend this study.


Quorum sensing regulates dpsA and the oxidative stress response in Burkholderia pseudomallei.
Burkholderia pseudomallei is the causative agent of melioidosis, a fatal human tropical disease. The non-specific DNA-binding protein DpsA plays a key role in protecting B. pseudomallei from oxidative stress mediated, for example, by organic hydroperoxides. The regulation of dpsA expression is poorly understood but one possibility is that it is regulated in a cell population density-dependent manner via N-acylhomoserine lactone (AHL)-dependent quorum sensing (QS) since a lux-box motif has been located within the dpsA promoter region. Using liquid chromatography and tandem mass spectrometry, it was first established that B. pseudomallei strain PP844 synthesizes AHLs. These were identified as N-octanoylhomoserine lactone (C8-HSL), N-(3-oxooctanoyl)homoserine lactone (3-oxo-C8-HSL), N-(3-hydroxyoctanoyl)-homoserine lactone (3-hydroxy-C8-HSL), N-decanoylhomoserine lactone (C10-HSL), N-(3-hydroxydecanoyl) homoserine lactone (3-hydroxy-C10-HSL) and N-(3-hydroxydodecanoyl)homoserine lactone (3-hydroxy-C12-HSL). Mutation of the genes encoding the LuxI homologue BpsI or the LuxR homologue BpsR resulted in the loss of C8-HSL and 3-oxo-C8-HSL synthesis, demonstrating that BpsI was responsible for directing the synthesis of these AHLs only and that bpsI expression and hence C8-HSL and 3-oxo-C8-HSL production depends on BpsR. In bpsI, bpsR and bpsIR mutants, dpsA expression was substantially down-regulated. Furthermore, dpsA expression in Escherichia coli required both BpsR and C8-HSL. bpsIR-deficient mutants exhibited hypersensitivity to the organic hydroperoxide tert-butyl hydroperoxide by displaying a reduction in cell viability which was restored by provision of exogenous C8-HSL (bpsI mutant only), by complementation with the bpsIR genes or by overexpression of dpsA. These data indicate that in B. pseudomallei, QS regulates the response to oxidative stress at least in part via the BpsR/C8-HSL-dependent regulation of DpsA.


Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate.
The Cdc45-MCM-GINS (CMG) helicase unwinds DNA during the elongation step of eukaryotic genome duplication and this process depends on the MCM ATPase function. Whether CMG translocation occurs on single- or double-stranded DNA and how ATP hydrolysis drives DNA unwinding remain open questions. Here we use cryo-electron microscopy to describe two subnanometre resolution structures of the CMG helicase trapped on a DNA fork. In the predominant state, the ring-shaped C-terminal ATPase of MCM is compact and contacts single-stranded DNA, via a set of pre-sensor 1 hairpins that spiral around the translocation substrate. In the second state, the ATPase module is relaxed and apparently substrate free, while DNA intimately contacts the downstream amino-terminal tier of the MCM motor ring. These results, supported by single-molecule FRET measurements, lead us to suggest a replication fork unwinding mechanism whereby the N-terminal and AAA+ tiers of the MCM work in concert to translocate on single-stranded DNA.


Cluster headache is associated with unhealthy lifestyle and lifestyle-related comorbid diseases: Results from the Danish Cluster Headache Survey.
To compare the prevalence of unhealthy lifestyle factors and comorbid disorders in cluster headache patients with headache-free controls, in order to discuss pathophysiology and possible consequences. Cluster headache patients from the Danish cluster headache survey aged 18-65 years, diagnosed according to ICHD-II, were compared to sex- and age-matched headache-free controls. Participants completed questionnaires and structured interviews. A total of 400 cluster headache patients and 200 controls participated. Patients had a more unhealthy lifestyle compared with controls in the form of current and current/former smoking (48.3% vs. 9.0%, p < 0.001 and 74.5% vs. 30.0%, p < 0.001, respectively), higher average alcohol intake per week (98.2 grams vs. 77.9 grams, p = 0.033) and BMI (26.1 vs. 24.2 kg/m2, p < 0.001), whereas coffee and energy drink consumption was equally distributed. Further, lifestyle-related, psychiatric and pain-related diseases were much more prevalent in patients compared with controls, except for diabetes. Sub-group analyses revealed that current/former smokers had a worse clinical presentation than never smokers. Unhealthy lifestyle factors and lifestyle-related diseases were more prevalent in cluster headache patients compared to controls. As lifestyle-related diseases might have serious consequences in the management of cluster headache, it is key to inform patients at an early time point about the possible risks of their lifestyle choices.


Automated exploration of the low-energy chemical space with fast quantum chemical methods.
We propose and discuss an efficient scheme for the in silico sampling for parts of the molecular chemical space by semiempirical tight-binding methods combined with a meta-dynamics driven search algorithm. The focus of this work is set on the generation of proper thermodynamic ensembles at a quantum chemical level for conformers, but similar procedures for protonation states, tautomerism and non-covalent complex geometries are also discussed. The conformational ensembles consisting of all significantly populated minimum energy structures normally form the basis of further, mostly DFT computational work, such as the calculation of spectra or macroscopic properties. By using basic quantum chemical methods, electronic effects or possible bond breaking/formation are accounted for and a very reasonable initial energetic ranking of the candidate structures is obtained. Due to the huge computational speedup gained by the fast low-cost quantum chemical methods, overall short computation times even for systems with hundreds of atoms (typically drug-sized molecules) are achieved. Furthermore, specialized applications, such as sampling with implicit solvation models or constrained conformational sampling for transition-states, metal-, surface-, or noncovalently bound complexes are discussed, opening many possible applications in modern computational chemistry and drug discovery. The procedures have been implemented in a freely available computer code called CREST, that makes use of the fast and reliable GFNn-xTB methods.


Spatial Neuronal Integration Supports a Global Representation of Visual Numerosity in Primate Association Cortices.
Our sense of number rests on the activity of neurons that are tuned to the number of items and show great invariance across display formats and modalities. Whether numerosity coding becomes abstracted from local spatial representations characteristic of visual input is not known. We mapped the visual receptive fields (RFs) of numerosity-selective neurons in the pFC and ventral intraparietal area in rhesus monkeys. We found numerosity selectivity in pFC and ventral intraparietal neurons irrespective of whether they exhibited an RF and independent of the location of their RFs. RFs were not predictive of the preference of numerosity-selective neurons. Furthermore, the presence and location of RFs had no impact on tuning width and quality of the numerosity-selective neurons. These findings show that neurons in frontal and parietal cortices integrate abstract visuospatial stimuli to give rise to global and spatially released number representations as required for number perception.


Crassulacean Acid Metabolism in the Strangler Clusia rosea Jacq.
Observations of malic acid fluctuation, leaf anatomy, and stable carbon isotopic composition showed that the epiphytic strangler Clusia rosea, growing on Saint John, U.S. Virgin Islands, has crassulacean acid metabolism. This hemiepiphyte may be the only woody dicotyledonous tree species among the many thousands of flowering species in the 30 or more plant families that shows this type of metabolism. The finding has implications with respect to water balance during the process whereby Clusia rosea establishes itself as a tree, since crassulacean acid metabolism is a photosynthetic adaptation to water-stressed environments.


Noradrenergic neuron-specific overexpression of nNOS in cardiac sympathetic nerves decreases neurotransmission.
Gene transfer of neuronal nitric oxide synthase (nNOS) with nonspecific adenoviral vectors can cause promiscuous transduction. We provide direct evidence that nNOS targeted only to cardiac sympathetic neurons inhibits sympathetic neurotransmission. An adenovirus constructed with a noradrenergic neuron-specific promoter (PRSx8), driving nNOS or enhanced green fluorescence protein (eGFP) gene expression caused exclusive expression in tyrosine hydroxylase (TH) positive rat cardiac sympathetic neurons. There was no detectable leakage of transgene expression in other cell types in the preparation nor did the transgene express in choline acetyltransferase (CHAT)-positive intracardiac cholinergic ganglia. Functionally, Ad.PRS-nNOS gene transfer increased nNOS activity and significantly reduced norephinephrine release evoked by field stimulation of isolated right atria. These effects were reversed by the NOS inhibitor N(omega)-Nitro-L-arginine. Our results demonstrate that noradrenergic cell-specific gene transfer with nNOS can inhibit cardiac sympathetic neurotransmission. This targeted technique may provide a novel method for reducing presynaptic sympathetic hyperactivity.


Biotechnological solutions to the nitrogen problem.
The availability of nitrogen is one of the major limiting factors to crop growth. In the developed world, farmers use unsustainable levels of inorganic fertilisers to promote crop production. In contrast, in the developing world inorganic fertilisers are often not available and small-holder farmers suffer the resultant poor yields. Finding alternatives to inorganic fertilisers is critical for sustainable and secure food production. Bacteria and Archaea have evolved the capability to fix atmospheric nitrogen to ammonia, a form readily usable in biological processes. This capability presents an opportunity to improve the nutrition of crop plants, through the introduction into cereal crops of either the nitrogen fixing bacteria or the nitrogenase enzyme responsible for nitrogen fixation. While both approaches are challenging, recent advances have laid the groundwork to initiate these biotechnological solutions to the nitrogen problem.


Passive hip range of motion is reduced in active subjects with chronic low back pain compared to controls.
Non-specific low back pain is a common condition often without a clear mechanism for its presentation. Recently more attention has been placed on the hip and its potential contributions to non-specific chronic low back pain (NSCLBP). Emphasis in research has mainly been placed on motor control, strength and endurance factors in relation to NSCLBP. Limited focus has been placed on hip mobility and its potential contribution in subjects with NSCLBP. The aim of this study was to compare passive ROM in hip extension, hip internal rotation, hip external rotation and total hip rotation in active subjects with NSCLBP to healthy control subjects. The hypothesis was that active subjects with NSCLBP would present with decreased total hip ROM and greater asymmetry when compared to controls. Two group case controlled. Clinical research laboratory. 30 healthy subjects without NSCLBP and 30 active subjects with NSCLBP. Subjects categorized as NSCLBP were experiencing pain in the low back area with or without radicular symptoms of greater than three months duration. Passive hip extension (EXT), hip internal rotation (IR), hip external rotation (ER) and total hip rotation ROM. A digital inclinometer was used for measurements. There was a statistically significant difference (p<0.001) in hip passive extension ROM between the control group and the NSCLBP group bilaterally. Mean hip extension for the control group was 6.88 bilaterally. For the NSCLBP group, the mean hip extension was -4.28 bilaterally. This corresponds to a difference of means between groups of 10.88. There was no statistically significant differences (p>0.05) in hip IR, ER, or total rotation ROM between groups. The results of this study indicate that a significant difference in hip extension exists in active subjects with NSCLBP compared to controls. It may be important to consider hip mobility restrictions and their potential impact on assessment of strength in NSLBP subjects. Future studies may be needed to investigate the relationship between measurements and intervention strategies. 2b.


Atorvastatin as a potential anti-malarial drug: in vitro synergy in combinational therapy with quinine against Plasmodium falciparum.
Quinine (QN) remains the first line anti-malarial drug for the treatment of complicated malaria in Europe and Africa. The emergence of QN resistance has been documented. QN resistance is not yet a significant problem, but there is an urgent need to discover partners for use in combination with QN. The aim of the study was to assess the in vitro potentiating effects of atorvastatin (AVA), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in combination with QN against Plasmodium falciparum and to evaluate whether the effects of AVA could be associated with gene copy number or mutations in genes involved in QN resistance, such as pfcrt, pfmdr1, pfmrp and pfnhe. The susceptibilities to combination of AVA with QN were assessed against 21 parasite strains using the in vitro isotopic microtest. Genotypes and gene copy number were assessed for pfcrt, pfmdr1, pfmdr2, pfmrp genes. In addition, the number of DNNND, DDNHNDNHNN repeats in pfnhe-1 ms4760 and the ms4760 profile were determined for each strains of P. falciparum. AVA demonstrated synergistic effects in combination with QN against 21 P. falciparum strains. The QN IC50 was reduced by 5% (0% to 15%; 95%CI: 1%-8%), 10% (3% to 23%; 95%CI: 7%-14%) and 22% (14% to 40%; 95%CI: 19%-25%) in presence of AVA at concentrations of 0.1, 0.5 and 1.0 microM, respectively. These reductions were all significant (p < 0.009). The reduction in the QN IC50 in presence of AVA was not significantly correlated with the QN IC50 (r = 0.22, P = 0.3288) or the AVA IC50 (r = 0.03, P = 0.8946). The synergistic effect of AVA in combination with QN was not significantly associated with polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe-1 genes that could be involved in QN resistance. The synergistic effect of AVA on QN responses was not significantly associated with pfmdr1 copy number (P = 0.0428). The synergistic effect of AVA in combination with QN was found to be unrelated to mutations occurring in transport protein genes involved in QN drug resistance. The different mechanisms of drug uptake and/or mode of action for AVA compared to the other anti-malarial drugs, as well as the AVA-mediated synergy of the anti-malarial effect of QN, suggests that AVA will be a good candidate for combinatorial malaria treatment. All of these observations support calls for both an in vivo evaluation with pharmacokinetic component and clinical trials of AVA as an anti-malarial therapy.


Explaining the unique nature of individual gait patterns with deep learning.
Machine learning (ML) techniques such as (deep) artificial neural networks (DNN) are solving very successfully a plethora of tasks and provide new predictive models for complex physical, chemical, biological and social systems. However, in most cases this comes with the disadvantage of acting as a black box, rarely providing information about what made them arrive at a particular prediction. This black box aspect of ML techniques can be problematic especially in medical diagnoses, so far hampering a clinical acceptance. The present paper studies the uniqueness of individual gait patterns in clinical biomechanics using DNNs. By attributing portions of the model predictions back to the input variables (ground reaction forces and full-body joint angles), the Layer-Wise Relevance Propagation (LRP) technique reliably demonstrates which variables at what time windows of the gait cycle are most relevant for the characterisation of gait patterns from a certain individual. By measuring the time-resolved contribution of each input variable to the prediction of ML techniques such as DNNs, our method describes the first general framework that enables to understand and interpret non-linear ML methods in (biomechanical) gait analysis and thereby supplies a powerful tool for analysis, diagnosis and treatment of human gait.


Clinical significance of psychotic-like experiences across U.S. ethnoracial groups.
Prevalence of psychotic-like experiences (PLEs) - reports of hallucinations and delusional thinking not meeting criteria for psychotic disorder - varies substantially across ethnoracial groups. What explains this range of PLE prevalence? Despite extensive research, the clinical significance of PLEs remains unclear. Are PLE prevalence and clinical severity differentially associated across ethnoracial groups? We examined the lifetime prevalence and clinical significance of PLEs across ethnoracial groups in the Collaborative Psychiatric Epidemiology Surveys (N = 11 139) using the Composite International Diagnostic Interview (CIDI) psychosis symptom screener. Outcomes included mental healthcare use (inpatient, outpatient), mental health morbidity (self-perceived poor/fair mental health, suicidal ideation or attempts), and impairment (role interference). Individuals with outcome onsets prior to PLE onset were excluded. We also examined associations of PLEs with CIDI diagnoses. Cox proportional-hazards regression and logistic regression modeling identified associations of interest. Contrary to previous reports, only Asian Americans differed significantly from other U.S. ethnoracial groups, reporting lower lifetime prevalence (6.7% v. 8.0-11.9%) and mean number (0.09 v. 0.11-0.18) of PLEs. In multivariate analyses, PLE clinical significance showed limited ethnoracial variation among Asian Americans, non-Caribbean Latinos, and Afro-Caribbeans. In other groups, mental health outcomes showed significant ethnoracial clustering by outcome (e.g. hospitalization and role interference with Caribbean-Latino origin), possibly due to underlying differences in psychiatric disorder chronicity or treatment barriers. While there is limited ethnoracial variation in U.S. PLE prevalence, PLE clinical significance varies across U.S. ethnoracial groups. Clinicians should consider this variation when assessing PLEs to avoid exaggerating their clinical significance, contributing to mental healthcare disparities.


Expression of the beta-glucan receptor, Dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions.
Dectin-1 is a pathogen-recognition receptor on macrophages (MPhis), neutrophils, and dendritic cells (DCs). On MPhis and bone marrow-derived DCs, it has been shown to mediate the nonopsonic recognition of and response to soluble and particulate yeast beta-glucans. We have optimized the immunohistochemical detection of Dectin-1 and demonstrated its expression on neutrophils, subpopulations of MPhis in splenic red and white pulp, alveolar MPhis, Kupffer cells, and MPhis and DCs in the lamina propria of gut villi. This is consistent with its role in pathogen surveillance. A significant proportion of CD11c(+) splenic DCs expressed Dectin-1, but expression was not restricted to any one subset. Dectin-1 expression was low on resident MPhis and DCs of skin and was not detected on resident MPhis or DCs in kidney, heart, brain, or eye. The proposed, additional role of Dectin-1 as a coreceptor for T cell activation is supported by its expression on DCs in the T cell areas of the spleen and lymph nodes. Strong expression of Dectin-1 on subpopulations of MPhis and DCs in the medullary and corticomedullary regions of the thymus suggests a role distinct from pathogen recognition. Tissue localization thus revealed potential roles of Dectin-1 in leukocyte interactions during innate immune responses and T cell development.


A novel approach to the statistical evaluation of media fill tests by the difference from no contamination data.
It is obvious that, in the media fill test and process simulation test, positive numbers in total fills should not have any significant difference from zero or asepsis. There are many reports concerning the definition of "sterility" or "asepsis." However, any scientific and practical methods to demonstrate "no significant difference from zero" have not been reported up to now. The existing criteria, such as "less than 0.1%," "less than 0.05%," and "less than two positives" are not appropriate to assure the integrity of processes, and sometimes lead to erroneous results. The purpose of this report is to demonstrate novel, reasonable and practical methods and criteria based on scientific and statistical consideration. According to the ISO 13408-1 Aseptic Processing of Health Care Products, Part 1 (1998), General Requirement for Aseptic Processing, the action level for the number of positive units in media fill tests is specified as 0.1%, and the alert level is 0.05%. In this paper it is shown that the existing ISO standard and other official methods are inappropriate in that zero contaminated units (sterile product) is outside the confidence range of probable distribution of contaminated units, even though the contaminated units are less than 0.1% in larger numbers of fills, and even less than 0.05%. This indicates that the limit of 0.1% or 0.05% is inappropriate in cases of larger numbers of fills. For sterile products, the number of contaminated units other than "zero" at the statistical confidence range must be judged to be contaminated units in process and as non-sterile. In order to harmonize this criteria-"no significant difference from zero"-with the existing criteria, the new criteria may be combined with only the existing criteria of 0.05% in smaller number of fills.


Microplicae: characteristic ridge-like folds of the plasmalemma.
Scanning electron microscopy reveals that the free surfaces of stratified squamous epithelial cells lining the alimentary tract, cornea, and conjunctiva exhibit characteristic ridge-like folds of plasmalemma. These microplicae are approximately 0.1-0.2 micronm in width, of variable height (0.2-0.8 micronm) and length, may followstraight or winding paths, often branch, and exhibit a wide variety of patterns over the surfaces of cells. Transmission electron microscopy reveals that microplicae often have a fine (100-150 A) electron-dense zone subjacent to their plasmalemma and an intracellular matrix characterized by a disorderly arrary of fine filaments (40-60 A in diameter). Microplicae appear to arise from plasmalemmal fold which once provided for intercellular interdigitation and desmosome abhesion between adjacent cells. Ruthenium red staining demonstrates that microplicae and interplical grooves are covered with a polyanionic glycocalyx. Although free surface microplicae may merely represent the renmants of intercellular interdigitations or a modified expression of microvillous-like extensions, it is also possible that they serve another specific function. In this regard it is speculated that microplical and interplical grooves may function to hold a layer of lubricating and cushioning mucin designed to protect the underlying plasmalemma from abrasive abuse.


Comparative functional genomics and the bovine macrophage response to strains of the mycobacterium genus.
Mycobacterial infections are major causes of morbidity and mortality in cattle and are also potential zoonotic agents with implications for human health. Despite the implementation of comprehensive animal surveillance programs, many mycobacterial diseases have remained recalcitrant to eradication in several industrialized countries. Two major mycobacterial pathogens of cattle are Mycobacterium bovis and Mycobacterium avium subspecies paratuberculosis (MAP), the causative agents of bovine tuberculosis (BTB) and Johne's disease (JD), respectively. BTB is a chronic, granulomatous disease of the respiratory tract that is spread via aerosol transmission, while JD is a chronic granulomatous disease of the intestines that is transmitted via the fecal-oral route. Although these diseases exhibit differential tissue tropism and distinct complex etiologies, both M. bovis and MAP infect, reside, and replicate in host macrophages - the key host innate immune cell that encounters mycobacterial pathogens after initial exposure and mediates the subsequent immune response. The persistence of M. bovis and MAP in macrophages relies on a diverse series of immunomodulatory mechanisms, including the inhibition of phagosome maturation and apoptosis, generation of cytokine-induced necrosis enabling dissemination of infection through the host, local pathology, and ultimately shedding of the pathogen. Here, we review the bovine macrophage response to infection with M. bovis and MAP. In particular, we describe how recent advances in functional genomics are shedding light on the host macrophage-pathogen interactions that underlie different mycobacterial diseases. To illustrate this, we present new analyses of previously published bovine macrophage transcriptomics data following in vitro infection with virulent M. bovis, the attenuated vaccine strain M. bovis BCG, and MAP, and discuss our findings with respect to the differing etiologies of BTB and JD.


Stable AuIII complexes with four N-heterocyclic carbene groups can be prepared in high yield directly from KAuCl4.
Gold(iii) N-heterocyclic carbene (NHC) complexes of form [Au(NHC)4Cl2]Cl were synthesized by reaction of KAuCl4 with bis- and tetrakis(imidazolium) salts in the presence of a mild base. Treatment of these complexes with KPF6 afforded four-coordinate AuIII complexes of form [Au(NHC)4](PF6)3. X-Ray crystallography showed the [AuIII(NHC)4]3+ cations in the hexafluorophosphate salts to have a square planar Au(NHC)4 moiety [AuCNHC 2.024(4)-2.082(7) Å]. In the [AuIII(NHC)4Cl2]+ cations in the chloride salts, coordination about Au was tetragonally-distorted octahedral, the axial Au-Cl bonds being substantially longer [AuCl 3.148(2)-3.693(1) Å] than the equatorial Au-CNHC bonds [AuC 2.024(4)-2.082(7) Å]. NMR and conductance studies suggested that the structures of the complexes seen in the solid state persisted in DMSO solution, except in one case where a chlorido ligand dissociated from [AuIII(NHC)4Cl2]+ to form [AuIII(NHC)4Cl]2+. The AuIII(NHC)4 unit was surprisingly robust. An AuIII complex was found to undergo H/D exchange reactions in D2O solution at 100 °C with no signs of decomposition detectable by 1H NMR spectroscopy. 1H NMR studies showed that various complexes containing AuIII(NHC)4 moieties underwent little or no decomposition when heated at 120 °C in DMSO-d6 for extended periods.


Detection and Classification of Measurement Errors in Bioimpedance Spectroscopy.
Bioimpedance spectroscopy (BIS) measurement errors may be caused by parasitic stray capacitance, impedance mismatch, cross-talking or their very likely combination. An accurate detection and identification is of extreme importance for further analysis because in some cases and for some applications, certain measurement artifacts can be corrected, minimized or even avoided. In this paper we present a robust method to detect the presence of measurement artifacts and identify what kind of measurement error is present in BIS measurements. The method is based on supervised machine learning and uses a novel set of generalist features for measurement characterization in different immittance planes. Experimental validation has been carried out using a database of complex spectra BIS measurements obtained from different BIS applications and containing six different types of errors, as well as error-free measurements. The method obtained a low classification error (0.33%) and has shown good generalization. Since both the features and the classification schema are relatively simple, the implementation of this pre-processing task in the current hardware of bioimpedance spectrometers is possible.


Development of an intracellular, DNA methyltransferase-specific, and gene-specific assay for studying dynamic DNA methylation.
A growing body of evidence supports that DNA methylation-mediated silencing of tumor suppressor genes plays a significant role in cancer development. DNA methylatransferase (DNMT) is the enzyme catalyzing the methylation modification of cytosines in a CpG dinucleotide context. In humans, this reaction is highly selective for certain gene promoters and/or genomic DNA domains. Elucidation of the intracellular targeting mechanism by DNMT has become the key task for understanding epigenetic regulation in cancers. Unfortunately, no suitable method is available to explore this important cell function. This study focuses on the development of an efficient technique for measuring the intracellular, DNMT isoform-specific, and methylated gene-specific, DNA methylation alterations. The technique, designated IMA for Intracellular DNA Methylation Assay, takes advantage of covalent arresting of active DNMT molecules by aza-deoxycytidine (ADC), a modified cytosine homologue readily incorporated into genomic DNA at the cytosine position. The DNMT-DNA complex was isolated by a modified ETOH precipitation procedure to remove cellular proteins including free DNMT. Chromatin immunoprecipitation using DNMT isoform-specific antibody was subsequently performed to collect DNMT-bound DNA fragments. PCR amplification was used to detect and quantify the isolated gene fragment. Validation of the IMA was performed by manipulating the DNMT activity, by treating with antisense oligonucleotides against DNMT1 and DNMT3B, and repeating the IMA experiment. One of the main discoveries with this technique was the observation of DNMT3B maintenance methylation activity. This new technique can be applied to examine the dynamic DNMT-specific action on diversified methylation-silenced genes, in a variety of cell culture conditions.


Detecting Mistakes in CPR Training with Multimodal Data and Neural Networks.
This study investigated to what extent multimodal data can be used to detect mistakes during Cardiopulmonary Resuscitation (CPR) training. We complemented the Laerdal QCPR ResusciAnne manikin with the Multimodal Tutor for CPR, a multi-sensor system consisting of a Microsoft Kinect for tracking body position and a Myo armband for collecting electromyogram information. We collected multimodal data from 11 medical students, each of them performing two sessions of two-minute chest compressions (CCs). We gathered in total 5254 CCs that were all labelled according to five performance indicators, corresponding to common CPR training mistakes. Three out of five indicators, CC rate, CC depth and CC release, were assessed automatically by the ReusciAnne manikin. The remaining two, related to arms and body position, were annotated manually by the research team. We trained five neural networks for classifying each of the five indicators. The results of the experiment show that multimodal data can provide accurate mistake detection as compared to the ResusciAnne manikin baseline. We also show that the Multimodal Tutor for CPR can detect additional CPR training mistakes such as the correct use of arms and body weight. Thus far, these mistakes were identified only by human instructors. Finally, to investigate user feedback in the future implementations of the Multimodal Tutor for CPR, we conducted a questionnaire to collect valuable feedback aspects of CPR training.


Risk reduction for HIV-positive African American and Latino men with histories of childhood sexual abuse.
While the HIV epidemic has disproportionately affected African American and Latino men who have sex with men (MSM), few HIV prevention interventions have focused on African American and Latino men who have sex with both men and women (MSMW). Even fewer interventions target HIV-positive African American and Latino MSM and MSMW with histories of childhood sexual abuse (CSA), a population that may be vulnerable to high-risk sexual behaviors, having multiple sexual partners, and depression. The Men's Health Project, a small randomized clinical trial, compared the effects of two 6-session interventions, the Sexual Health Intervention for Men (S-HIM), guided by social learning theory and aimed at decreasing high-risk sexual behaviors, number of sexual partners, and depressive symptoms, and a standard health promotion control (SHP). A community sample of 137 HIV-positive gay and non-gay identifying African American and Latino MSM and MSMW with histories of CSA was recruited. Results were based on an "intent to treat" analyses of baseline to post, 3 and 6 month follow-ups. The sample as a whole reported reductions in sexual risk behaviors and number of sexual partners from baseline to post-test, and from the 3 to 6 month follow-ups, although the decrease in sexual risk behavior from baseline to post-test was significant only for S-HIM participants. No significant differences between conditions were reported for depressive symptoms, but the total sample reported a significant decrease at 6 months. These findings highlight the importance of addressing sexual decision-making and psychological adjustment for ethnic men, while being sensitive to CSA histories and sexual minority status, and suggest the need to develop additional strategies to heighten HIV risk reduction over time.


Reactive vaccination in the presence of disease hotspots.
Reactive vaccination has recently been adopted as an outbreak response tool for cholera and other infectious diseases. Owing to the global shortage of oral cholera vaccine, health officials must quickly decide who and where to distribute limited vaccine. Targeted vaccination in transmission hotspots (i.e. areas with high transmission efficiency) may be a potential approach to efficiently allocate vaccine, however its effectiveness will likely be context-dependent. We compared strategies for allocating vaccine across multiple areas with heterogeneous transmission efficiency. We constructed metapopulation models of a cholera-like disease and compared simulated epidemics where: vaccine is targeted at areas of high or low transmission efficiency, where vaccine is distributed across the population, and where no vaccine is used. We find that connectivity between populations, transmission efficiency, vaccination timing and the amount of vaccine available all shape the performance of different allocation strategies. In highly connected settings (e.g. cities) when vaccinating early in the epidemic, targeting limited vaccine at transmission hotspots is often optimal. Once vaccination is delayed, targeting the hotspot is rarely optimal, and strategies that either spread vaccine between areas or those targeted at non-hotspots will avert more cases. Although hotspots may be an intuitive outbreak control target, we show that, in many situations, the hotspot-epidemic proceeds so fast that hotspot-targeted reactive vaccination will prevent relatively few cases, and vaccination shared across areas where transmission can be sustained is often best.


Quantization error and dynamic range considerations for compressive imaging systems design.
A natural field of application for compressive sensing theory is imaging. Indeed, numerous compressive imaging (CI) systems and applications have been developed during the last few years. This work addresses the quantization effect in CI, which is fundamental for most CI architectures. In this paper, the implications of sensor quantization on universal CI are investigated theoretically and demonstrated with numerical experiments. It is shown that employing a CI framework may set severe requirements on the quantization depth of the optical sensor used. The quantization depth overhead requirement may be prohibitive in many optical imaging scenarios employing typical CI architectures. Practical solutions that significantly alleviate this requirement are suggested.


Asymmetric quadrature split birdcage coil for hyperpolarized 3He lung MRI at 1.5T.
An asymmetric quadrature birdcage body coil for hyperpolarized (HP) (3)He lung imaging at 1.5T is presented. The coil is designed to rest on top of the patient support and be used as a temporary insert in a clinical system. A two-part construction facilitates patient access and the asymmetric design makes maximal use of available bore space to ensure comfort. Highly homogeneous, circularly polarized RF magnetic fields are produced at 48.5 MHz using a conformal mapping method for the geometrical design, combined with an algebraic method to calculate the individual capacitance values on the birdcage coil's ladder network. Efficiency and isolation from the system's proton body coil are ensured by an integrated RF screen. The design methodology is readily applicable to other field strengths or nuclei. Improvements over existing (3)He coils were found in terms of sensitivity and transmit field homogeneity, an important feature in HP MRI.


The role of actin in the temperature-dependent gelation and contraction of extracts of Acanthamoeba.
The temperature-dependent assembly and the interaction of Acanthamoeba contractile proteins have been studied in a crude extract. A cold extract of soluble proteins from Acanthamoeba castellanii is prepared by homogenizing the cells in a sucrose-ATP-ethyleneglycol-bis-(beta-aminoethyl ether) N,N'-tetraacetic acid buffer and centrifuging at 136,000 g for 1 h. When this supernate of soluble proteins is warmed to room temperature, it forms a solid gel. Upon standing at room temperature, the gel slowly contracts and squeezes out soluble components. The rates of gelation and contraction are both highly temperature dependent, with activation energies of about 20 kcal per mol. Gel formation is dependent upon the presence of ATP and Mg++. Low concentrations of Ca++ accelerate the contractile phase of this phenomenon. The major protein component of the gel is actin. It is associated with myosin, cofactor, a high molecular weight protein tentatively identfied as actin-binding protein, and several other unidentified proteins. Actin has been purified from these gels and was found to be capable of forming a solid gel when polymerized in the presence of ATP, MgCl3, and KCL. The rate of purified actin polymerication is very temperature dependent and is accelerated by the addition of fragments of muscle actin filaments. These data suggest that Acanthamoeba contractile proteins have a dual role in the cell; they may generate the forces for cellular movements and also act as cytoskeletal elements by controlling the consistency of the cytoplasm.


Neoadjuvant chemotherapy followed by surgery has no therapeutic advantages over concurrent chemoradiotherapy in International Federation of Gynecology and Obstetrics stage IB-IIB cervical cancer.
We aimed to assess the efficacy of neoadjuvant chemotherapy followed by surgery (NACT+S), and compared the clinical outcome with that of concurrent chemoradiotherapy (CCRT) in patients with International Federation of Gynecology and Obstetrics (FIGO) IB-IIB cervical cancer. We reviewed 85 patients with FIGO IB-IIB cervical cancer who received NACT+S between 1989 and 2012, and compared them to 358 control patients who received CCRT. The clinical application of NACT was classified based on the following possible therapeutic benefits: increasing resectability after NACT by reducing tumor size or negative conversion of node metastasis; downstaging adenocarcinoma regarded as relatively radioresistant; and preservation of fertility through limited surgery after NACT. Of 85 patients in the NACT+S group, the pathologic downstaging and complete response rates were 68.2% and 22.6%, respectively. Only two young patients underwent limited surgery for preservation of fertility. Patients of the NACT+S group were younger, less likely to have node metastasis, and demonstrated a higher proportion of FIGO IB cases than those of the CCRT group (p≤0.001). The 5-year locoregional control, progression-free survival, and overall survival rates in the NACT+S group were 89.7%, 75.6%, and 92.1%, respectively, which were not significantly different from the rates of 92.5%, 74%, and 84.9% observed in the CCRT group, respectively (p>0.05). NACT+S has no therapeutic advantages over CCRT, the standard treatment. Therefore, NACT+S should be considered only in selected patients through multidisciplinary discussion or clinical trial setting.


Designing a patient-centered personal health record to promote preventive care.
Evidence-based preventive services offer profound health benefits, yet Americans receive only half of indicated care. A variety of government and specialty society policy initiatives are promoting the adoption of information technologies to engage patients in their care, such as personal health records, but current systems may not utilize the technology's full potential. Using a previously described model to make information technology more patient-centered, we developed an interactive preventive health record (IPHR) designed to more deeply engage patients in preventive care and health promotion. We recruited 14 primary care practices to promote the IPHR to all adult patients and sought practice and patient input in designing the IPHR to ensure its usability, salience, and generalizability. The input involved patient usability tests, practice workflow observations, learning collaboratives, and patient feedback. Use of the IPHR was measured using practice appointment and IPHR databases. The IPHR that emerged from this process generates tailored patient recommendations based on guidelines from the U.S. Preventive Services Task Force and other organizations. It extracts clinical data from the practices' electronic medical record and obtains health risk assessment information from patients. Clinical content is translated and explained in lay language. Recommendations review the benefits and uncertainties of services and possible actions for patients and clinicians. Embedded in recommendations are self management tools, risk calculators, decision aids, and community resources--selected to match patient's clinical circumstances. Within six months, practices had encouraged 14.4% of patients to use the IPHR (ranging from 1.5% to 28.3% across the 14 practices). Practices successfully incorporated the IPHR into workflow, using it to prepare patients for visits, augment health behavior counseling, explain test results, automatically issue patient reminders for overdue services, prompt clinicians about needed services, and formulate personalized prevention plans. The IPHR demonstrates that a patient-centered personal health record that interfaces with the electronic medical record can give patients a high level of individualized guidance and be successfully adopted by busy primary care practices. Further study and refinement are necessary to make information systems even more patient-centered and to demonstrate their impact on care. Clinicaltrials.gov identifier: NCT00589173.


Venous access for hematopoietic progenitor cell collection: An international survey by the ASFA HPC donor subcommittee.
Hematopoietic Progenitor Cell (HPC) collection by apheresis is performed in patients and donors to obtain HPCs for transplantation. Although studies have shown these procedures to be safe, successful collection cannot be performed without establishment of venous access. This project's objective was to ascertain the current practices of donor vein assessment and central venous catheter (CVC) usage. The American Society for Apheresis (ASFA) HPC subcommittee created an electronic survey about precollection vein assessment and line placement, care, and removal in autologous and allogeneic donors. It was distributed to >5,000 possible participants, with one response analyzed per institution. One hundred centers performing autologous and/or allogeneic procedures provided adequate responses for analysis. Donor vein assessment is most often performed by apheresis staff more than 1 week prior to collection. For patients with questionable access, the next step performed most often is secondary assessment for autologous procedures and CVC placement for allogeneic procedures. Most centers use interventional radiology to place CVCs in jugular veins on collection day with placement verification through electronic medical records. Verbal and written postinsertion CVC care instructions are routinely provided. The apheresis team frequently provides postinsertion CVC care for autologous patients. Heparin is used most often for CVC lock. When used, tissue plasminogen activator is usually instilled for up to 60 min. These data summarize the largest single survey of donor vein assessment at institutions performing HPC collections by apheresis. The variations identified in donor venous access practice warrant further investigation and consensus to establish best practices. J. Clin. Apheresis 31:529-534, 2016. © 2015 Wiley Periodicals, Inc.


Using a cultural formulation for assessment of homicide in forensic psychiatry in the UK.
Healthcare inequalities for black and minority ethnic (BME) patients in forensic mental health services in the UK are stark. Despite the level of attention given to this over the last 15 years there has been little progress to address disparities. There is a great deal of confusion over what is understood by culture, and what aspects of culture signal specific needs of BME patients. In addition, we have a lack of empirical research demonstrating what it means for psychiatrists to be culturally competent. These are all important barriers against progress in this area. Using a homicide case study that illustrates the typical issues encountered in practice, we explore how to use a cultural formulation in order to assess the role of culture within a forensic psychiatry setting. Finally, practical advice is offered to assist expert witnesses in preparing court reports that adequately consider the significance of defendants' cultural beliefs and practices.


Evaluation of Dermatology Practice Online Reviews: Lessons From Qualitative Analysis.
Patient satisfaction is an increasingly important component of health care quality measures. Online reviews of physicians represent a promising platform for capturing patient perspectives of care. To identify qualitative themes associated with patient reviews of dermatologic care on consumer reporting websites. A qualitative analysis was conducted of patient-generated reviews of dermatology practices on 2 consumer review platforms. Yelp is an online consumer portal for users to review their experience with local businesses; ZocDoc is an online patient-scheduling portal that provides opportunity for patients to write reviews of physician practices. A total of 518 reviews from 45 dermatology practices on Yelp and 4921 reviews from 45 dermatology providers on ZocDoc were collected from 3 geographically diverse cities: Philadelphia, Pennsylvania; Houston, Texas; and Seattle, Washington. The study was conducted from January 15 to July 15, 2015. Reviews were separated into high-scoring and low-scoring groups. An inductive qualitative method was used to code and identify key themes associated with positive and negative patient experiences. Analysis was completed upon reaching thematic saturation. Reported as mean (95% CI), the overall Yelp score for the 45 selected practices was 3.46 of 5 stars (3.17-3.75) and overall ZocDoc score for the 45 selected practices was 4.72 of 5 stars (4.47-4.80). The proportion of individual reviews giving a score of 5.0 was significantly higher on ZocDoc (3986 [81.0%]) than on Yelp (229 [44.2%]) (P < .001). Qualitative themes centered on characteristics of the physician and the practice. Themes that emerged from the high-scoring and low-scoring reviews were similar in content but opposite in valence. Physician-specific themes included temperament, knowledge and competency, physical examination, communication abilities, and mindfulness of cost. Practice-specific themes included scheduling, staff temperament, office cleanliness, waiting room, and insurance. Patients appreciated physicians who are kind, respectful, and thorough with the physical examination; empathetic about the emotional difficulty of skin disease; and cognizant of cost. Negative experiences were frequently affected by considerations outside of the physician-patient interaction, such as curt interactions with staff, difficulty with scheduling, practice cleanliness, and insurance problems. Patients reported relying on consumer websites to identify dermatology providers. Online consumer review websites are designed to facilitate instantaneous and public communication among patients. These platforms provide elaborate and timely data for dermatologists to garner insight into their patients' experiences. The themes identified in this study are consistent with past satisfaction studies and may aid dermatologists in optimizing the patient care experience.


Use of combination proteomic analysis to demonstrate molecular similarity of head and neck squamous cell carcinoma arising from different subsites.
To evaluate head and neck squamous cell carcinomas (HNSCCs) for differences in protein expression between oral cavity, oropharynx, larynx, and hypopharynx subsites. Retrospective proteomic analysis using tissue microarray (TMA) and 2-dimensional difference gel electrophoresis (2D-DIGE). For the TMA, automated quantitative protein expression analysis was used to interrogate levels of 4 cell-cycle regulatory proteins chosen for their known roles in cancer (cyclin D1, p53, Rb, and p14). For the 2D-DIGE, lesional and normal adjacent tissues were enriched by laser capture microdissection. Total protein was extracted, analyzed by 2D-DIGE with saturation dye labeling, and evaluated for relative abundance levels of individual protein spots. Two tertiary-care academic medical centers. Seventy-one patients with HNSCC for TMA, and 14 patients with HNSCC with frozen tumor and normal tissue for 2D-DIGE. The automated quantitative analysis of protein expression analysis revealed no difference between subsite for cyclin D1, p53, Rb, or p14 expression. The 2D-DIGE study was based on 28 gels (14 cancer gels and 14 adjacent normal gels), and 732 spots were identified as matching across more than 90% of gels. Significance was evaluated based on false discovery rate (FDR) estimated from permuted data sets. There were no significant differences in protein expression between subsites (FDR greater than or equal to 30% in all instances). Observed differences in outcomes between HNSCCs from different subsites may not reflect differences in tumor biologic characteristics between subsites. Rather, it is possible that observed clinical heterogeneity among HNSCCs may be based on other factors, such as viral vs chemical carcinogenesis.


Spatial encoding and underlying circuitry in scene-selective cortex.
Three cortical areas (Retro-Splenial Cortex (RSC), Transverse Occipital Sulcus (TOS) and Parahippocampal Place Area (PPA)) respond selectively to scenes. However, their wider role in spatial encoding and their functional connectivity remain unclear. Using fMRI, first we tested the responses of these areas during spatial comparison tasks using dot targets on white noise. Activity increased during task performance in both RSC and TOS, but not in PPA. However, the amplitude of task-driven activity and behavioral measures of task demand were correlated only in RSC. A control experiment showed that none of these areas were activated during a comparable shape comparison task. Secondly, we analyzed functional connectivity of these areas during the resting state. Results revealed a significant connection between RSC and frontal association areas (known to be involved in perceptual decision-making). In contrast, TOS showed functional connections dorsally with the Inferior Parietal Sulcus, and ventrally with the Lateral Occipital Complex--but not with RSC and/or frontal association areas. Moreover, RSC and TOS showed differentiable functional connections with the anterior-medial and posterior-lateral parts of PPA, respectively. These results suggest two parallel pathways for spatial encoding, including RSC and TOS respectively. Only the RSC network was involved in active spatial comparisons.


Direct simulation of electron transfer in the cobalt hexammine(ii/iii) self-exchange reaction.
We present an atomistic simulation of the cobalt hexammine(ii/iii) self-exchange reaction using path integral (PI) methods. We construct a simple force field for the system in its reactant state that includes parameters for both atom-atom interactions, and interactions with an explicit transferring electron represented in the PI framework. We then calculate the outer sphere free energy barrier due to solvent reorganization from a PI molecular dynamics simulation and we obtain the dynamic transmission coefficient using ring polymer molecular dynamics. Combining these calculated values with literature values for the inner sphere reorganization energy, we obtain a reaction rate in good agreement with experimental measurements. The protocol introduced here circumvents the need for complex, system-specific force field parameterization along an assumed reaction coordinate making it sufficiently accurate, efficient, and broadly applicable to the study of both adiabatic and nonadiabatic charge transfer reactions in transition metal complexes.


Carbon isotope determination for separate components of heterogeneous materials using coupled thermogravimetric analysis/isotope ratio mass spectrometry.
A gas-tight thermal analysis system (Netzsch STA 449C Jupiter) has been connected to an isotope ratio mass spectrometer (PDZ Europa 20-20) via an interface containing an oxidizing furnace, water trap, and gas-sampling valve. Using this system, delta(13)C has been measured for CO(2) derived from the thermal decomposition of carbonate and oxalate minerals and organic materials at temperatures that correspond to different decomposition events. There is close agreement between measured and published delta(13)C values for carbonate and oxalate minerals, which have simple decarbonation reactions on heating. Cellulose and lignin-rich materials show much more complex thermal decomposition, reflecting differences in their purity and structure, and measured delta(13)C values vary with the temperature of gas sampling. Provided that measurements are made at temperatures that correspond to the decomposition of cellulose and lignin (indicated by maximum weight loss), internally consistent data can be obtained. However, measurements for cellulose and lignin are systematically enriched in delta(13)C (by up to 1.4 per thousand) with respect to those reported for reference materials, possibly due to the slower combustion kinetics (compared with EA-IRMS). Thermogravimetric analysis/isotope ratio mass spectrometry (TG-IRMS) is ideal for materials and samples for which it is not possible to use other isotopic measurement techniques, for example because of sample heterogeneity.


Chemical modification of ascorbic acid and evaluation of its lipophilic derivatives as inhibitors of secretory phospholipase A(2) with anti-inflammatory activity.
The halo 6-fatty acid esters of L-ascorbic acid 3a, 3b and 6-fatty acid esters of L-ascorbic acid 5a-g were achieved from L-ascorbic acid 1. Compounds 3a, 3b and 5a-g were evaluated for anti-oxidant, anti-lipid peroxidation, and secretory phospholipase A(2) (sPLA(2)) inhibition in vitro, and sPLA(2) induced mouse paw edema. All the derivatives retained their anti-oxidant property compared to ascorbic acid at 6 × 10(-4)M and are good inhibitors of lipid peroxidation at 1 mg ml(-1) as evaluated by 2, 2-Diphenyl-1-picrylhydrazyl radical and thio-barbituric acid methods, respectively. Compounds 5e and 5f significantly inhibited purified group I sPLA(2) from Naja naja and group II sPLA(2) from Vipera russelli, human synovial fluid and human pleural fluid with IC(50) value ranging from 64 ± 1.95 to 82 ± 1.3 and 48 ± 2.27 to 61 ± 2.23 μM, respectively. The compounds 5e and 5f also showed varying degree of potency in neutralizing indirect hemolytic activity of sPLA(2) at 50 μM concentration, and sPLA(2) induced mouse paw edema at the dose 3 mg/kg. Further docking studies also confirmed that compounds 5e and 5f have maximum interaction with increasing negative energy value. Single molecule possessing both anti-oxidant and anti-inflammatory activities is of great therapeutic significance in inflammatory disorders.


Postpartum Pain in the Community Among Migrant and Non-migrant Women in Canada.
International migrant women of childbearing age represent a large proportion of immigrants to high-income countries, yet research focusing on their postpartum health is limited. We investigated predictive factors for breast and non-breast pain 1 week post-birth in migrant and non-migrant women in Canada. Among migrant women, difficulty accessing health services; being from a middle-or high-income country; poor functionality in English and French; living with the father of their infant; and having no regular care provider were predictive of breast pain. Among non-migrant women, difficulties accessing health services, multiparity and prenatal education were predictive of breast pain, while receiving an epidural and having no regular care provider were predictive of non-breast pain. Among both groups, difficulties accessing health services and having no regular care provider were predictive of breast pain, while second degree or higher perineal tearing was predictive of non-breast pain. Migration-specific indicators should be considered in postpartum care planning.


Raman response function for silica fibers.
The commonly used Lorentzian form of the Raman response function for studying propagation of ultrashort pulses in silica fibers does not properly account for the shoulder in the Raman gain spectrum originating from the Boson peak. We propose a more accurate form of this response function and show that its predictions for the Raman-induced frequency shift should be in better agreement with experiments.


Definition of Failed Induction of Labor and Its Predictive Factors: Two Unsolved Issues of an Everyday Clinical Situation.
The objectives of this review were to identify the predictive factors of induction of labor (IOL) failure or success as well as to highlight the current heterogeneity regarding the definition and diagnosis of failed IOL. Only studies in which the main or secondary outcome was failed IOL, defined as not entering the active phase of labor after 24 h of prostaglandin administration ± 12 h of oxytocin infusion, were included in the review. The data collected were: study design, definition of failed IOL, induction method, IOL indications, failed IOL rate, cesarean section because of failed IOL and predictors of failed IOL. The database search detected 507 publications. The main reason for exclusion was that the primary or secondary outcomes were not the predetermined definition of failed IOL (not achieving active phase of labor). Finally, 7 studies were eligible. The main predictive factors identified in the review were cervical status, evaluated by the Bishop score or cervical length. Failed IOL should be defined as the inability to achieve the active phase of labor, considering that the definition of IOL is to enter the active phase of labor. A universal definition of failed IOL is an essential requisite to analyze and obtain solid results and conclusions on this issue. An important finding of this review is that only 7 of all the studies reviewed assessed achieving the active phase of labor as a primary or secondary IOL outcome. Another conclusion is that cervical status remains the most important predictor of IOL outcome, although the value of the parameters explored up to now is limited. To find or develop predictive tools to identify those women exposed to IOL who may not reach the active phase of labor is crucial to minimize the risks and costs associated with IOL failure while opening a great opportunity for investigation. Therefore, other predictive tools should be studied in order to improve IOL outcome in terms of health and economic burden.


Degradomics in Biomarker Discovery.
The upregulation of protease expression and proteolytic activity is implicated in numerous pathological conditions such as neurodegeneration, cancer, cardiovascular and autoimmune diseases, and bone degeneration. During disease progression, various proteases form characteristic patterns of cleaved proteins and peptides, which can affect disease severity and course of progression. It has been shown that qualitative and quantitative monitoring of cleaved protease substrates can provide relevant prognostic, diagnostic, and therapeutic information. As proteolytic fragments and peptides generated in the affected tissue are commonly translocated to blood, urine, and other proximal fluids, their possible application as biomarkers is the subject of ongoing research. The field of degradomics has been established to enable the global identification of proteolytic events on the organism level, utilizing proteomic approaches and sample preparation techniques that facilitate the detection of proteolytic processing of protease substrates in complex biological samples. In this review, some of the latest developments in degradomic methodologies used for the identification and validation of biologically relevant proteolytic events and their application in the search for clinically relevant biomarker candidates are presented. The current state of degradomics in clinics is discussed and the future perspectives of the field are outlined.


A qualitative study of the experience of caring for a person with bulimia nervosa. Part 1: The emotional impact of caring.
Family carers of individuals with mental disorders have been found to experience mental health difficulties of their own. There has been little research into the impact of caring for individuals with eating disorders. A preliminary study found that carers of individuals with anorexia nervosa experience more difficulties and distress than carers of people with psychoses (Treasure et al., [2001]. Social Psychiatry and Psychiatric Epidemiology, 36, 343-347). This is the first study to qualitatively investigate the experiences of carers of individuals with bulimia nervosa (BN). Twenty carers of individuals with BN were interviewed using a semistructured interview. Interviews were transcribed and the texts analyzed using content analysis to identify themes. The principal themes to emerge were the impact of the discovery of BN on the carer, the ongoing impact of care-giving, coping strategies used by the carer, and the positive impact of the illness for both the carers and the persons in their care. BN has a potent impact on carers' lives. This has implications in terms of service provision and future research in this area.


Pen size and parity effects on maternal behaviour of Small-Tail Han sheep.
The aim of this experiment was to study the effects of pen size and parity on maternal behaviour of twin-bearing Small-Tail Han ewes. A total of 24 ewes were allocated to a 2×2 design (six per pen), with parity (primiparous or multiparous) and pen size (large: 6.0×3.0 m; small: 6.0×1.5 m) as main effects at Linyi University, Shandong Province, China. Behaviour was observed from after parturition until weaning. All ewes were observed for 6 h every 5 days from 0700 to1000 h and from 1400 to 1700 h. Continuous focal animal sampling was used to quantify the duration of maternal behaviours: sucking, grooming and following as well as the frequency of udder accepting, udder refusing and low-pitched bleating. Oestradiol and cortisol concentrations in the faeces (collected in the morning every 5 days) were detected using EIA kits. All lambs were weighed 24 h after parturition and again at weaning at 35 days of age. The small pen size significantly reduced following (P<0.005), grooming (P<0.001) and suckling durations (P<0.05), as well as the frequency of udder refusals (P<0.001). However, there was a significant interaction with ewe parity, with decreased grooming and suckling in the small pen largely seen in the multiparous ewes (P<0.001). Independent of pen size, multiparous ewes accepted more sucking attempts by their lambs (P<0.05) and made more low-pitched bleats than primiparous ewes (P<0.001). Multiparous ewes had higher faecal oestradiol concentrations than primiparous ewes (P<0.001), and ewes in small pens had higher faecal cortisol levels compared with ewes in larger pens (P<0.001). As lambs increased in age, the duration of maternal grooming, following and suckling as well as frequency of udder acceptance and low-pitched bleating all declined, and the frequency of udder refusing increased (P<0.001 for all). Ewe parity, but not pen size, affected lamb weight gain during the period of observation (P<0.001). This is the first study to show that pen size, interacting with parity, can affect the expression of maternal behaviour in sheep during lactation. The study is also the first to report on the maternal behaviour of Chinese native sheep breeds (Small-Tail Han sheep), with implications for the production of sheep in China.


Reflections on inositol(s) for PCOS therapy: steps toward success.
In polycystic ovary syndrome (PCOS) pathogenesis, both the insulin resistance and the related compensatory hyperinsulinemia are involved. Despite their similarities, Myo-inositol (MI) and d-chiro-inositol (DCI) play different roles in PCOS etiology and therapy. Indeed, in tissue such as the liver both molecules are involved in the insulin signaling, i.e. MI promotes glucose uptake and DCI glycogen synthesis. In reproductive tissue such as the ovary, MI regulates glucose uptake and follicle stimulating hormone (FSH) signaling, whereas DCI is devoted to the insulin-mediated androgen production. The new hypothesis on "DCI paradox" in the ovary has provided the key for a better understanding. Unlike other tissues, ovary is not insulin resistant, indeed because the epimerase enzyme, which converts MI to DCI, is insulin dependent, the "DCI paradox" hypothesis suggests that in the ovary of PCOS women, an increased epimerase activity leads to a DCI overproduction and MI depletion. This imbalance could be the cause of the poor oocyte quality and the impairment in the FSH signaling. Owing to this situation, the focal point is the administration of both MI and DCI in a proper ratio for treating PCOS. This topic, with several other "hot" issues, was the driving thread in the discussion between the two scientists.


Rapid evolution of animal mitochondrial DNA.
Mitochondrial DNA was purified from four species of higher primates (Guinea baboon, rhesus macaque, guenon, and human) and digested with 11 restriction endonucleases. A cleavage map was constructed for the mitochondrial DNA of each species. Comparison of the maps, aligned with respect to the origin and direction of DNA replication, revealed that the species differ from one another at most of the cleavage sites. The degree of divergence in nucleotide sequence at these sites was calculated from the fraction of cleavage sites shared by each pair of species. By plotting the degree of divergence in mitochondrial DNA against time of divergence, the rate of base substitution could be calculated from the initial slope of the curve. The value obtained, 0.02 substitutions per base pair per million years, was compared with the value for single-copy nuclear DNA. The rate of evolution of the mitochondrial genome appears to exceed that of the single-copy fraction of the nuclear genome by a factor of about 10. This high rate may be due, in part, to an elevated rate of mutation in mitochondrial DNA. Because of the high rate of evolution, mitochondrial DNA is likely to be an extremely useful molecule to employ for high-resolution analysis of the evolutionary process.


Temporal validation of metabolic nodal response of esophageal cancer to neoadjuvant chemotherapy as an independent predictor of unresectable disease, survival, and recurrence.
We recently described metabolic nodal stage (mN) and response (mNR) of cancer of the esophagus and gastro-esophageal junction (GEJ) to neoadjuvant chemotherapy (NAC) using 18F-FDG PET-CT as new markers of disease progression, recurrence, and death. We aimed to validate our findings. Our validation cohort comprised all patients consecutive to our discovery cohort, staged before and after NAC using PET-CT from 2014 to 2017. Multivariate binary logistic and Cox regression were performed. Fifty-one of the 200 patients had FDG-avid nodes after NAC (25.5%; i.e., lack of complete mNR), and were more likely to progress during NAC to incurable disease on PET-CT or at surgery: odds ratio 3.84 (1.46-10.1; p = 0.006). In 176 patients undergoing successful resection, patients without complete mNR had a worse prognosis: disease-free survival hazard ratio 2.46 (1.34-4.50); p = 0.004. These associations were independent of primary tumor metabolic, pathological response, and stage. In a hybrid pathological/metabolic nodal stage, avid nodal metastases conferred a worse prognosis than non-avid metastases. Lack of complete mNR predicted recurrence or death at 1 and 2 years: positive predictive values 44.4% (31.7-57.8) and 74.1% (56.6-86.3) respectively. This study provides temporal validation for mNR as a new and independent predictive and prognostic marker of esophageal and GEJ cancer treated with NAC and surgery, although external validation is required to assess generalizability. mNR may provide surrogate information regarding the phenotype of metastatic cancer clones beyond the mere presence of nodal metastases, and might be used to better inform patients, risk stratify, and personalize management, including adjuvant therapy. • We previously described metabolic nodal response (mNR) of esophageal cancer to neoadjuvant chemotherapy using 18 F-FDG PET-CT as a predictor of unresectable disease, early recurrence, and death. • We report the first validation of these findings. In an immediately consecutive cohort, we found consistent proportions of patients with and without mNR, and associations with abandoned resection, early recurrence, and death. • This supports mNR as a new and actionable biomarker in esophageal cancer. Although external validation is required, mNR may provide surrogate information about the chemosensitivity of metastatic subclones, and the means to predict treatment success, guide personalized therapy, and follow-up.


Comparison of Bone Resorption Rates after Intraoral Block Bone and Guided Bone Regeneration Augmentation for the Reconstruction of Horizontally Deficient Maxillary Alveolar Ridges.
Purpose. Bone atrophy after tooth loss may leave insufficient bone for implant placement. We compared volumetric changes after autogenous ramus block bone grafting (RBG) or guided bone regeneration (GBR) in horizontally deficient maxilla before implant placement. Materials and Methods. In this retrospective study, volumetric changes at RBG or GBR graft sites were evaluated using cone-beam computed tomography. The primary outcome variable was the volumetric resorption rate. Secondary outcomes were bone gain, graft success, and implant insertion torque. Results. Twenty-four patients (28 grafted sites) were included (GBR, 15; RBG, 13). One patient (RBG) suffered mucosal dehiscence at the recipient site 6 weeks after surgery, which healed spontaneously. Mean volume reduction in the GBR and RBG groups was 12.48 ± 2.67% and 7.20 ± 1.40%, respectively. GBR resulted in significantly more bone resorption than RBG (P < 0.001). Mean horizontal bone gain and width after healing were significantly greater in the GBR than in the RBG group (P = 0.002 and 0.005, resp.). Implant torque was similar between groups (P > 0.05). Conclusions. Both RBG and GBR hard-tissue augmentation techniques provide adequate bone graft volume and stability for implant insertion. However, GBR causes greater resorption at maxillary augmented sites than RBG, which clinicians should consider during treatment planning.


Sources of information influencing decision-making in orthopaedic surgery - an international online survey of 1147 orthopaedic surgeons.
Manufacturers of implants and materials in the field of orthopaedics use significant amounts of funding to produce informational material to influence the decision-making process of orthopaedic surgeons with regards to choice between novel implants and techniques. It remains unclear how far orthopaedic surgeons are really influenced by the materials supplied by companies or whether other, evidence-based publications have a higher impact on their decision-making. The objective was to evaluate the subjective usefulness and usage of different sources of information upon which orthopaedic surgeons base their decisions when acquiring new implants or techniques. We undertook an online survey of 1174 orthopaedic surgeons worldwide (of whom n = 305 were head of their department). The questionnaire included 34 items. Sequences were randomized to reduce possible bias. Questions were closed or semi-open with single or multiple answers. The usage and relevance of different sources of information when learning about and selecting orthopaedic treatments were evaluated. Orthopaedic surgeons and trainees were targeted, and were only allowed to respond once over a period of two weeks. Baseline information included country of workplace, level of experience and orthopaedic subspecialisation. The results were statistically evaluated. Independent scientific proof had the highest influence on decisions for treatment while OEM (Original Equipment Manufacturer) driven activities like newsletters, white papers or workshops had the least impact. Comparison of answers from the three best-represented countries in this study (Germany, UK and USA) showed some significant differences: Scientific literature and congresses are significantly more important in the US than in the UK or Germany, although they are very important in all countries. Independent and peer-reviewed sources of information are preferred by surgeons when choosing between methods and implants. Manufacturers of medical devices in orthopaedics employ a considerable workforce to inform or influence hospital managers and leading doctors with marketing activities. Our results indicate that it might be far more effective to channel at least some of these funds into peer-reviewed research projects, thereby assuring significantly higher acceptance of the related products.


Longitudinal hearing loss in Wolfram syndrome.
Wolfram syndrome (WFS) is a rare autosomal recessive disease with clinical manifestations of diabetes mellitus (DM), diabetes insipidus (DI), optic nerve atrophy (OA) and sensorineural hearing loss (SNHL). Although SNHL is a key symptom of WFS, there is limited information on its natural history using standardized measures. Such information is important for clinical care and determining its use as an outcome measure in clinical trials. Standardized audiologic measures, including pure-tone testing, tympanometry, speech perception, and the unaided Speech Intelligibility Index (SII) were assessed in patients with confirmed WFS annually. Mixed model analyses were used to examine main effects of age, time or interactions for pure tone average (PTA), high frequency average (HFA) and SII. Forty WFS patients were evaluated between 1 and 6 times. Mean age at initial enrollment was 13.5 years (SD = 5.6). Patients were classified as having normal hearing (n = 10), mild-to-severe (n = 24) or profound SNHL (n = 6). Mean age of diagnosis for SNHL was 8.3 years (SD = 5.1) with 75% prevalence. HFA worsened over time for both ears, and SII worsened over time in the worse ear, with greater decline in both measures in younger patients. Average estimated change over 1 year for all measures was in the subclinical range and power analyses suggest that 100 patients would be needed per group (treatment vs. placebo) to detect a 60% reduction in annual change of HFA over 3 years. If trials focused on just those patients with SNHL, power estimates suggest 55 patients per group would be sufficient. Most patients had a slow progressive SNHL emerging in late childhood. Change over time with standard audiologic tests (HFA, SII) was small and would not be detectable for at least 2 years in an individual. Relatively large sample sizes would be necessary to detect significant impact on hearing progression in a clinical trial. Hearing function should be monitored clinically in WFS to provide appropriate intervention. Because SNHL can occur very early in WFS, audiologists and otolaryngologists should be aware of and refer for later emerging symptoms.


Wet degradation of keratin proteins: linking amino acid, elemental and isotopic composition.
Archaeological keratin samples are increasingly the subject of palaeodietary, provenancing and dating studies. Keratin samples from wet archaeological contexts are microbiologically and chemically degraded, causing differential diagenesis of protein structures in hair fibres. The effects of these processes on the analytical parameters of interest are currently unknown. This study examined the impact of degradation of wool fibres on isotopic (δ(13)C, δ(15)N, un-exchangeable δ(2)H and δ(18)O values) composition. It compared two models of archaeological protein degradation in wet burial environments: (1) short term (up to 8 years) experimental burial in three contrasting soil environments; and (2) laboratory wet conditions, in which elevated temperature (80 °C, 110 °C, and 140 °C) and pressure simulated longer exposure. Elemental and amino acid (AA) composition were also measured. In experimentally soil-buried samples, AA, elemental and isotopic composition changes were small, despite extensive macroscopic alteration. Isothermally heated samples showed preferential loss of hydrophilic AAs (Asx, Glx, Ser, Gly) from wool residues, with depletion in (2)H and (18)O at higher temperatures (up to -73‰ change in δ(2)H and -2.6‰ in δ(18)O values). The δ(13)C and δ(15)N values showed little change except in densely pigmented samples at low temperatures only. Samples dyed with madder/alum were better preserved than undyed samples. Diagenesis in experimentally soil-buried wool textiles was consistent with microbiological, non-protein-selective activity, in contrast to highly AA-selective hydrolytic behaviour under laboratory wet conditions. Changes in δ(2)H and δ(18)O values were correlated with degree of AA change, but the δ(13)C and δ(15)N values were not. The results contribute to a baseline for interpreting analytical data from archaeological hair samples preserved by burial in wet environments.


Internet-based cognitive behavior therapy for depression, social anxiety disorder, and panic disorder: Effectiveness and predictors of response in a teaching clinic.
Though therapist-guided Internet-based cognitive behavior therapy (ICBT) appears to be efficacious for depression, social anxiety disorder, and panic disorder, relatively little is known about real-world settings and predictors of treatment effects derived from cognitive-behavioral theory. We examined treatment effectiveness and predictors of improvement in a prospective cohort study where patients took part in 10 weeks of ICBT for depression (n = 114), social anxiety disorder (n = 150), or panic disorder (n = 106) at a teaching clinic. Patients self-reported symptoms before, during, and after treatment. Effect sizes were large for improvement in the primary symptom domain of each treatment group: depression (d = 1.48), social anxiety disorder (d = 1.01), and panic disorder (d = 1.15). In ICBT for depression, having no previous experience of psychological treatment (r = 0.21), and more frequent baseline negative automatic thoughts (r = 0.20) predicted larger improvement. In ICBT for panic disorder, having more baseline safety behaviors (r = 0.25) predicted larger improvement. Predictors remained significant when baseline symptoms were included in the statistical models. We conclude that ICBT can be effective in a real-world teaching clinic, and that patients with greater deficits at baseline benefit the most.


Typology of female sex offenders: a test of Vandiver and Kercher.
Using all 390 female sex offenders registered in New York State, this study attempted to test the analyses and findings of Vandiver and Kercher (2004). Although the current sample varied geographically from Vandiver and Kercher's sample, they were remarkably similar on key demographic variables (e.g., offender age and race, victim age), allowing for close comparison of the findings. Results of the hierarchical loglinear modeling analysis reinforced the importance of variables such as victim and offender ages to categorizing offenders. The present cluster analysis indicated the existence of six distinct types of female sex offender (with the clusters themselves differing substantially from those found by Vandiver and Kercher), supporting the view that female sex offenders are a heterogeneous group.


Behavior of primary human osteoblasts on trimmed and sandblasted Ti6Al4V surfaces functionalized with integrin αvβ3-selective cyclic RGD peptides.
It is well known that functionalization of surfaces with cell adhesive peptides mimicking the integrin binding motif of extracellular matrix proteins is a feasible approach to improve osseointegration of implant materials. Also, modification of the surface properties of the material (e.g., roughness) strongly influences cell behavior. However, these two approaches are rarely studied together. This study addressed the hypothesis that the combination of peptide functionalization and surface roughness will have an enhancing effect on the adhesion process of osteoblasts. To test this hypothesis, a series of αvβ3-selective cyclic RGD peptides were prepared and immobilized on trimmed (S(a) = 0.74 μm, smooth) and sandblasted (S(a) = 3.24 μm, rough) Ti6Al4V disks. Effects of these surface modifications were evaluated with respect to integrin αvβ3-mediated adhesive capacity, cell morphology, and spreading of primary human osteoblasts. After 3 h of incubation, osteoblasts adhered more strongly on sandblasted than on trimmed noncoated Ti6Al4V surfaces. Their attachment efficiency was further enhanced in the presence of RGD peptides. However, peptide functionalization had a relatively stronger impact on osteoblast attachment on trimmed surfaces compared with sandblasted surfaces. Cell morphology after 3 h of culture was exclusively altered by surface topography. RGD coating was critical for osteoblast spreading on both trimmed and sandblasted materials after 1 h of incubation but it showed almost negligible effects after 3 h. The results of this study provide evidence that the alliance of RGD coating and surface topography on Ti6Al4V positively influences osteoblast adhesion and spreading, especially at very early adhesion times.


Arabidopsis MSI1 connects LHP1 to PRC2 complexes.
Polycomb group (PcG) proteins form essential epigenetic memory systems for controlling gene expression during development in plants and animals. However, the mechanism of plant PcG protein functions remains poorly understood. Here, we probed the composition and function of plant Polycomb repressive complex 2 (PRC2). This work established the fact that all known plant PRC2 complexes contain MSI1, a homologue of Drosophila p55. While p55 is not essential for the in vitro enzymatic activity of PRC2, plant MSI1 was required for the functions of the EMBRYONIC FLOWER and the VERNALIZATION PRC2 complexes including trimethylation of histone H3 Lys27 (H3K27) at the target chromatin, as well as gene repression and establishment of competence to flower. We found that MSI1 serves to link PRC2 to LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), a protein that binds H3K27me3 in vitro and in vivo and is required for a functional plant PcG system. The LHP1-MSI1 interaction forms a positive feedback loop to recruit PRC2 to chromatin that carries H3K27me3. Consequently, this can provide a mechanism for the faithful inheritance of local epigenetic information through replication.


The effect of caffeine on barbiturate sleeping time and brain level.
The effect of caffeine and coffee on the sleeping time induced by barbital was tested in rats. It was found that caffeine pretreatment shortened barbital-induced sleeping time and that coffee had an effect in direct proportion to its caffeine content; decaffeinated coffee was without effect. It was hypothesized that the shortening was due to an interaction at the brain level. This hypothesis was tested using hexobarbital which is metabolized by the liver whereas barbital is only negligibly so metabolized. Pretreatment with caffeine was found to shorten the hexobarbital sleeping time even though the brain concentration of the latter was actually elevated. It was also shown that caffeine pretreatment was much less effective than phenobarbital pretreatment in stimulating the enzyme systems in the liver which metabolize hexobarbital, aminopyrine and ethylmorphine (in vitro). Consequently, it is concluded that caffeine stimulation of liver metabolism is a relatively minor factor in the shortening of barbiturate sleeping time by caffeine in comparison to the brain interaction of these two drugs.


Alpha activity in the human REM sleep EEG: topography and effect of REM sleep deprivation.
The topographical distribution of alpha activity (8.125-11.125 Hz) in the REM sleep EEG, its time course within and across REM sleep episodes, and the effects of selective REM sleep deprivation were investigated in 8 young males. Power spectra of bipolar derivations along the antero-posterior axis in the left (F3C3, C3P3, P301) and right (F4C4, C4P4, P402) hemisphere were calculated. Alpha activity increased along the antero-posterior axis in both hemispheres, and was dominant in the right hemisphere. It decreased within and across REM sleep episodes. Selective REM sleep deprivation resulted in a reduction of alpha activity in the REM sleep EEG. However, the topographical distribution and the time course were not affected. It is suggested that alpha activity in the REM sleep EEG is a marker of REM sleep homeostasis.


Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy.
5-Aza-2'-deoxycytidine (5-AZA-CdR, decitabine), an epigenetic drug that inhibits DNA methylation, is currently used to treat myelodysplastic syndrome (MDS), and is under investigation for treating acute myeloid leukemia (AML) and other malignancies. 5-AZA-CdR can reactivate tumor suppressor genes silenced by aberrant DNA methylation, a frequent event in all types of cancer. Because this epigenetic change is reversible, it is a good target for 5-AZA-CdR therapy. We have reviewed the preclinical data of 5-AZA-CdR to analyze the concentrations and exposure times required to eradicate cancer stem cells. We analyzed the dose-schedules used in animal models that show potent antineoplastic activity of 5-AZA-CdR. We attempted to correlate the preclinical data with the responses obtained in clinical trials of 5-AZA-CdR in patients with cancer. The pharmacokinetics and drug distribution of 5-AZA-CdR are key parameters because adequate therapeutic drug levels are required to eliminate cancer stem cells in all anatomic compartments. The plasma half-life of 5-AZA-CdR in humans is approximately 20 minutes due to the high levels in the liver of cytidine deaminase, the enzyme that inactivates this analogue. This provides a rationale to use an inhibitor of cytidine deaminase in combination with 5-AZA-CdR. Low-dose 5-AZA-CdR is effective for MDS and AML and can induce complete remissions (CR). However, maintenance of CR with low-dose 5-AZA-CdR is difficult. Based on analyses of preclinical and clinical data, low dose 5-AZA-CdR has the potential to be an effective form of therapy in some patients with cancer. For patients who do not respond to low dose therapy we recommend dose-intensive treatment with 5-AZA-CdR. Patients who are candidates for intensive dose 5-AZA-CdR should have a good bone marrow status so as to permit adequate recovery from myelosuppression, the major toxicity of 5-AZA-CdR. Solid tumors are also interesting targets for therapy with 5-AZA-CdR. Both low dose and intensive therapy with 5-AZA-CdR can reduce the proliferative potential of tumor stem cells in animal models. We propose novel dose schedules of 5-AZA-CdR for investigation in patients with cancer. The full chemotherapeutic potential of 5-AZA-CdR to treat cancer merits further clinical investigation and can only be realized when its optimal dose-schedule is determined.