Influence of basic residue content on fragment ion peak intensities in low-energy collision-induced dissociation spectra of peptides.
The primary utility of trypsin digestion in proteomics is that it cleaves proteins at predictable locations, but it is also notable for yielding peptides that terminate in basic arginine and lysine residues. Tryptic peptides fragment in ion trap tandem mass spectrometry to produce prominent C-terminal y series ions. Alternative proteolytic digests may produce peptides that do not follow these rules. In this study, we examine 2568 peptides generated through proteinase K digestion, a technique that produces a greater diversity of basic residue content in peptides. We show that the position of basic residues within peptides influences the peak intensities of b and y series ions; a basic residue near the N-terminus of a peptide can lead to prominent b series peaks rather than the intense y series peaks associated with tryptic peptides. The effects of presence and position for arginine, lysine, and histidine are explored separately and in combination. Arg shows the most dominant effects followed by His and then by Lys. Fragment ions containing basic residues produce more intense peaks than those without basic residues. Doubly charged precursor ions have generally been modeled as producing only singly charged fragment ions, but fragment ions that contain two basic residues may accept both protons during fragmentation. By characterizing the influence of basic residues on gas-phase fragmentation of peptides, this research makes possible more accurate fragmentation models for peptide identification algorithms.


User perspectives on long-term remote active electronic self-monitoring of mood symptoms in bipolar spectrum disorders.
User feedback is crucial in the development of electronic self-monitoring tools for bipolar spectrum disorders (BSD). Previous studies have examined user experiences in small samples self-monitoring over relatively short time periods. We aimed to explore the experiences of a large sample of individuals with BSD engaged in long-term remote active electronic self-monitoring. An online survey, containing closed and open questions, was sent to participants with BSD enrolled on the Bipolar Disorder Research Network (BDRN) True Colours mood-monitoring system. Questions related to experiences of using True Colours, including viewing mood graphs, and sharing data with healthcare professionals (HCPs) and/or family/friends. Response rate was 62.7 % (n = 362). 88.4 % reported finding using True Colours helpful. Commonly reported benefits were having a visual record of mood changes, patterns/triggers and identifying early warning signs. Limitations included questions not being comprehensive or revealing anything new. One third had shared their graphs, with 89.9 % finding it helpful to share with HCPs and 78.7 % helpful to share with family/friends. Perceived benefits included aiding communication and limitations included lack of interest/understanding from others. Responder bias may be present. Findings may not be generalisable to all research cohorts. The majority of participants valued long-term self-monitoring. Personalisation and ease of use were important. A potential challenge is continued use when mood is long-term stable, highlighting the need for measures to be sensitive to small changes. Sharing self-monitoring data with HCPs may enhance communication of the lived experience of those with BSD. Future research should examine HCPs' perspectives.


Society for Maternal-Fetal Medicine Special Statement: Maternal-fetal medicine subspecialist survey on abortion training and service provision.
Following a collaborative workshop at the 39th Annual Pregnancy Meeting, the Society for Maternal-Fetal Medicine Reproductive Health Advisory Group identified a need to assess the attitudes of maternal-fetal medicine subspecialists about abortion services and the available resources at the local and regional levels. The purpose of this study was to identify trends in attitudes, beliefs, and behaviors of practicing maternal-fetal medicine subspecialists in the United States regarding abortion. An online survey was distributed to associate and regular members of the Society for Maternal-Fetal Medicine to assess their personal training experience, abortion practice patterns, factors that influence their decision to provide abortion care, and their responses to a series of scenarios about high-risk maternal or fetal medical conditions. Frequencies were analyzed and univariable and multivariable analyses were conducted on the survey responses. Of the 2751 members contacted, 546 Society for Maternal-Fetal Medicine members completed all (448 of 546, 82.1%) or some (98 of 546, 17.9%) of the survey. More than 80% of the respondents reported availability of abortion services in their state, 70% reported availability at their primary institution, and 44% reported provision as part of their personal medical practice. Ease of referral to family planning subspecialists or other abortion providers, institutional restrictions, and the lack of training or continuing education were identified as the most significant factors contributing to the respondents' limited scope of abortion services or lack of any abortion services offered. In the univariable analysis, exposure to formal family planning training programs, fewer years since the completion of residency, current practice setting not being religiously affiliated, and current state categorized as supportive by the Guttmacher Institute's abortion policy landscape were factors associated with abortion provision (all P values <.01). After controlling for these factors in a multivariable regression, exposure to formal family planning training programs was no longer associated with current abortion provision (P=.20; adjusted odds ratio, 1.34; 95% confidence interval, 0.85-2.10), whereas a favorable state policy environment and fewer years since the completion of residency remained associated with abortion provision. The results of this survey suggest that factors at the individual, institutional, and state levels affect the provision of abortion care by maternal-fetal medicine subspecialists. The subspecialty of maternal-fetal medicine should be active in ensuring adequate training and education to create a community of maternal-fetal medicine physicians able to provide comprehensive reproductive healthcare services.


Variance in the expression of 5-Fluorouracil pathway genes in colorectal cancer.
Although colorectal cancer has the third highest cancer mortality rate, the treatment remains far from optimized with patients showing variable responses to standard treatment. Molecular differences in pharmacologically relevant genes may contribute to the variability in response. This study used Taqman PCR to investigate the expression of 24 5-fluorouracil (5-FU) pathway genes in colorectal cancer using paired nontumor and tumor sample from 52 patients with Dukes' C colon cancer. In comparing tumor versus nonmalignant tissue, 14 of the 24 genes showed significant variation in gene expression. For 11 of these same genes (FPGS, DHFR, GGH, NME1, NME2, RRM2, UMPH2, UNG, UMPS, TP53, and TK1), a significant proportion of the patients showed an over expression of the particular gene in tumor tissue with a tumor-to-nonmalignant (T/N) ratio >1.2, whereas one gene (DPYD) showed the converse with a large number of patients showing a lower expression in the tumor tissue (T/N < 0.8). Multiple gene correlations for the genes of the 5-FU pathway were found with the Spearman rank correlation of >0.6 (all P > 0.001), suggesting possible coregulation mechanisms. Hierarchical clustering analysis created at least three groups of genes, which were consistent with groupings by the other statistical methods. Additionally, the hierarchical clustering showed two distinct groups of patients based on their gene expression. These variations in gene expression could provide valuable insights for optimizing treatment selection for patients with colorectal cancer.


Multiple effects of S13 in modulating the strength of intersubunit interactions in the ribosome during translation.
The ribosomal protein S13 is found in the head region of the small subunit, where it interacts with the central protuberance of the large ribosomal subunit and with the P site-bound tRNA through its extended C terminus. The bridging interactions between the large and small subunits are dynamic, and are thought to be critical in orchestrating the molecular motions of the translation cycle. S13 provides a direct link between the tRNA-binding site and the movements in the head of the small subunit seen during translocation, thereby providing a possible pathway of signal transduction. We have created and characterized an rpsM(S13)-deficient strain of Escherichia coli and have found significant defects in subunit association, initiation and translocation through in vitro assays of S13-deficient ribosomes. Targeted mutagenesis of specific bridge and tRNA contact elements in S13 provides evidence that these two interaction domains play critical roles in maintaining the fidelity of translation. This ribosomal protein thus appears to play a non-essential, yet important role by modulating subunit interactions in multiple steps of the translation cycle.


DNA fingerprinting of Chlamydia trachomatis by use of ribosomal RNA, oligonucleotide and randomly cloned DNA probes.
DNA fingerprinting of 15 reference strains and 24 clinical isolates of Chlamydia trachomatis, 2 strains of C. psittaci and one strain of C. pneumoniae was studied by use of universal 16 + 23S RNA from Escherichia coli, 16S rDNA-directed oligonucleotide and randomly cloned chlamydial DNA probes. The rRNA-gene restriction patterns (ribotypes) enabled the differentiation of chlamydial species. Following DNA cleavage by restriction endonuclease PvuII, lymphogranuloma venereum and trachoma biovars of C. trachomatis could be differentiated. An oligonucleotide, designed to hybridize the C. trachomatis 16S rDNA, also allowed for both species-specific identification and biovar typing of C. trachomatis human strains. Molecular typing system using 3 lambda clones containing C. trachomatis serotype E random DNA inserts, combined to ribotyping, revealed 12 groups of variable banding patterns within C. trachomatis, and could provide an alternative epidemiological tool.


Prevalence of arterial hypertension in diabetic patients before and after the JNC-V.
To compare the prevalence of arterial hypertension in patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) according to blood pressure (BP) criteria from the World Health Organization (WHO) and The Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V). Two cohorts of Caucasian patients attending the outpatient clinic at Hvidöre Hospital were identified: 1) 957 patients with IDDM; 53% men, 40 (18-75) years of age (mean [range]); and 2) 549 patients with NIDDM; 53% men, 60 (20-76) years of age. BP was measured at least yearly, while patients rested in a sitting position, with a standard clinical sphygmomanometer. Patients were classified as hyper- or normotensive based on average BP during a 3-year follow-up period. Patients receiving antihypertensive treatment were classified as hypertensives. In IDDM patients, the prevalence of arterial hypertension rose from 15 to 42% in the normoalbuminuric group, from 26 to 52% in the microalbuminuric group, and from 61 to 79% in the macroalbuminuric group when WHO and JNC-V criteria were compared. The corresponding rises in NIDDM patients were from 51 to 71% (normo-), from 73 to 90% (micro-), and from 82 to 93% (macroalbuminuria). Of the untreated hypertensive patients, 78% of IDDM patients and 50% of NIDDM patients had stage 1 (140-159/90-99 mmHg) hypertension; 20% of IDDM patients and 37% of NIDDM patients had stage 2 (160-179/100-109 mmHg) hypertension. Two out of three untreated hypertensive patients had isolated systolic hypertension. The new JNC-V criteria approved by the American Diabetes Association leads to a considerable increase in the prevalence of arterial hypertension in a population of IDDM and NIDDM patients. Isolated systolic hypertension contributes importantly.


Lipidomic profiles of Drosophila melanogaster and cactophilic fly species: models of human metabolic diseases.
The metabolic syndrome (MetS) is associated with serious diseases and represents an important threat for global public health. The common fruit fly (Drosophila melanogaster) has served as a model organism to study physiological processes of the MetS, because central metabolic pathways are conserved among species, and because the flies are easy to cultivate in a laboratory. In nature, D. melanogaster is a fruit generalist, feeding on diets rich in simple carbohydrates. Other Drosophilids, however, have specialized on distinct resources. Drosophila mojavensis, for example, is endemic to the Sonoran Desert, where it feeds on necrotic cacti which are low in carbohydrates. Its close relative Drosophila arizonae is cactophilic as well, but is also found breeding in fruits containing simple sugars. Previous studies have shown that high-sugar diets negatively affect the larval development of D. mojavensis and increase their triglyceride content, compared to D. melanogaster. More general metabolic profiles, in response to these different diets, however, have yet to be produced for any of the species. In addition, because D. arizonae appears somewhat intermediate between D. melanogaster and D. mojavensis in its development times and survival under the above mentioned diets, its general metabolic profiles are also of interest. Thus, in the present study we ask to what extent the general metabolism of these three different Drosophila species is affected by diets of distinct protein-sugar ratios. To obtain an un-biased view on possibly novel phenomena, we combined untargeted metabolomics with Random Forest data mining.


Chocolate consumption in pregnancy and reduced likelihood of preeclampsia.
Preeclampsia is a major pregnancy complication with cardiovascular manifestations. Recent studies suggest that chocolate consumption may benefit cardiovascular health. We studied the association of chocolate consumption with risk of preeclampsia in a prospective cohort study of 2291 pregnant women who delivered a singleton livebirth between September 1996 and January 2000. Chocolate consumption was measured by self report in the first and third trimesters, and by umbilical cord serum concentrations of theobromine, the major methylxanthine component of chocolate. Preeclampsia was assessed by detailed medical record review for 1943 of the women. We derived adjusted odds ratios (aOR) and 95% confidence intervals (CIs) from logistic regression models controlling for potential confounders. Preeclampsia developed in 3.7% (n = 63) of 1681 women. Cord serum theobromine concentrations were negatively associated with preeclampsia (aOR = 0.31; CI = 0.11-0.87 for highest compared with lowest quartile). Self-reported chocolate consumption estimates also were inversely associated with preeclampsia. Compared with women consuming under 1 serving of chocolate weekly, women consuming 5+ servings per week had decreased risk: aOR = 0.81 with consumption in the first 3 months of pregnancy (CI = 0.37-1.79) and 0.60 in the last 3 months (0.30-1.24). Our results suggest that chocolate consumption during pregnancy may lower risk of preeclampsia. However, reverse causality may also contribute to these findings.


Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas.
Hepatocellular carcinoma (HCC) most commonly arises from chronic inflammation due to viral infection, as a result of genetic and epigenetic abnormalities. A global picture of epigenetic changes in HCC is lacking. We used methylated CpG island amplification microarrays (MCAMs) to study 6458 CpG islands in HCC and adjacent preneoplastic tissues [chronic hepatitis (CH) or liver cirrhosis (LC)] in comparison with normal liver tissues where neither viral infection nor hepatitis has existed. MCAM identified 719 (11%) prominent genes of hypermethylation in HCCs. HCCs arising from LC had significantly more methylation than those arising from CH (1249 genes or 19% versus 444 genes or 7%, P < 0.05). There were four patterns of aberrant methylation: Type I (4%, e.g. matrix metalloproteinase 14) shows a substantially high methylation level in adjacent tissue and does not increase further in cancer. Type II (55%, e.g. RASSF1A) shows progressively increasing methylation from adjacent tissue to HCC. Type III (4%, e.g. GNA14) shows decreased methylation in adjacent tissue but either similar or increased methylation in HCC. Type IV (37%, e.g. CDKN2A) shows low levels of methylation in normal tissue and adjacent tissue but high levels in HCC. These DNA methylation changes were confirmed by quantitative pyrosequencing methylation analysis in representative 24 genes and were analyzed for correlation with clinicopathological parameters in 38 patients. Intriguingly, methylation in the Type IV genes is characteristic of moderately/poorly differentiated cancer. Our global epigenome analysis reveals distinct patterns of methylation that are probably to represent different pathophysiologic processes in HCCs.


Grain boundary phases in bcc metals.
We report a computational discovery of novel grain boundary structures and multiple grain boundary phases in elemental body-centered cubic (bcc) metals represented by tungsten, tantalum and molybdenum. While grain boundary structures created by the γ-surface method as a union of two perfect half crystals have been studied extensively, it is known that the method has limitations and does not always predict the correct ground states. Herein, we use a newly developed computational tool, based on evolutionary algorithms, to perform a grand-canonical search of high-angle symmetric tilt and twist boundaries, and we find new ground states and multiple phases that cannot be described using the conventional structural unit model. We use molecular dynamics (MD) simulations to demonstrate that the new structures can coexist at finite temperature in a closed system, confirming that these are examples of different grain boundary phases. The new ground state is confirmed by first-principles calculations.


In silico analyses of metagenomes from human atherosclerotic plaque samples.
Through several observational and mechanistic studies, microbial infection is known to promote cardiovascular disease. Direct infection of the vessel wall, along with the cardiovascular risk factors, is hypothesized to play a key role in the atherogenesis by promoting an inflammatory response leading to endothelial dysfunction and generating a proatherogenic and prothrombotic environment ultimately leading to clinical manifestations of cardiovascular disease, e.g., acute myocardial infarction or stroke. There are many reports of microbial DNA isolation and even a few studies of viable microbes isolated from human atherosclerotic vessels. However, high-resolution investigation of microbial infectious agents from human vessels that may contribute to atherosclerosis is very limited. In spite of the progress in recent sequencing technologies, analyzing host-associated metagenomes remain a challenge. To investigate microbiome diversity within human atherosclerotic tissue samples, we employed high-throughput metagenomic analysis on: (1) atherosclerotic plaques obtained from a group of patients who underwent endarterectomy due to recent transient cerebral ischemia or stroke. (2) Presumed stabile atherosclerotic plaques obtained from autopsy from a control group of patients who all died from causes not related to cardiovascular disease. Our data provides evidence that suggest a wide range of microbial agents in atherosclerotic plaques, and an intriguing new observation that shows these microbiota displayed differences between symptomatic and asymptomatic plaques as judged from the taxonomic profiles in these two groups of patients. Additionally, functional annotations reveal significant differences in basic metabolic and disease pathway signatures between these groups. We demonstrate the feasibility of novel high-resolution techniques aimed at identification and characterization of microbial genomes in human atherosclerotic tissue samples. Our analysis suggests that distinct groups of microbial agents might play different roles during the development of atherosclerotic plaques. These findings may serve as a reference point for future studies in this area of research.


On the evolving portfolio of community-standards and data sharing policies: turning challenges into new opportunities.
There are thousands of biology databases with hundreds of terminologies, reporting guidelines, representations models, and exchange formats to help annotate, report, and share bioscience investigations. It is evident, however, that researchers and bioinformaticians struggle to navigate the various standards and to find the appropriate database to collect, manage, and share data. Further, policy makers, funders, and publishers lack sufficient information to formulate their guidelines. In this paper, we highlight a number of key issues that can be used to turn these challenges into new opportunities. It is time for all stakeholders to work together to reconcile cause and effect and make the data-sharing culture functional and efficient.


Reaping the Benefits and Avoiding the Risks: Unrealistic Optimism in the Health Domain.
People's perceptions of benefits and risks play a key role in their acceptance or rejection of medical interventions, yet these perceptions may be poorly calibrated. This online study with N = 373 adults aged 19-76 years focused on unrealistic optimism in the health domain. Participants indicated how likely they were to experience benefits and risks associated with medical conditions and completed objective and subjective numeracy scales. Participants exhibited optimistic views about the likelihood of experiencing the benefits and the side effects of treatment options described in the scenarios. Objective and subjective numeracy were not associated with more accurate ratings. Moreover, participants' underestimation of the risks was significantly greater than their overestimation of the benefits. From an applied perspective, these results suggest that clinicians may need to ensure that patients do not underestimate risks of medical interventions, and that they convey realistic expectations about the benefits that can be obtained with certain procedures.


Comprehensive screening of Arabidopsis mutants suggests the lysine histidine transporter 1 to be involved in plant uptake of amino acids.
Plant nitrogen (N) uptake is a key process in the global N cycle and is usually considered a "bottleneck" for biomass production in land ecosystems. Earlier, mineral N was considered the only form available to plants. Recent studies have questioned this dogma and shown that plants may access organic N sources such as amino acids. The actual mechanism enabling plants to access amino acid N is still unknown. However, a recent study suggested the Lysine Histidine Transporter 1 (LHT1) to be involved in root amino acid uptake. In this study, we isolated mutants defective in root amino acid uptake by screening Arabidopsis (Arabidopsis thaliana) seeds from ethyl methanesulfonate-treated plants and seeds from amino acid transporter T-DNA knockout mutants for resistance against the toxic D-enantiomer of alanine (Ala). Both ethyl methanesulfonate and T-DNA knockout plants identified as D-Ala resistant were found to be mutated in the LHT1 gene. LHT1 mutants displayed impaired capacity for uptake of a range of amino acids from solutions, displayed impaired growth when N was supplied in organic forms, and acquired substantially lower amounts of amino acids than wild-type plants from solid growth media. LHT1 mutants grown on mineral N did not display a phenotype until at the stage of flowering, when premature senescence of old leaf pairs occurred, suggesting that LHT1 may fulfill an important function at this developmental stage. Based on the broad and unbiased screening of mutants resistant to D-Ala, we suggest that LHT1 is an important mediator of root uptake of amino acids. This provides a molecular background for plant acquisition of organic N from the soil.


Hospital bloodborne pathogens programs: program characteristics and blood and body fluid exposure rates.
To describe hospital practices and policies relating to bloodborne pathogens and current rates of occupational exposure among healthcare workers. Hospitals in Iowa and Virginia were surveyed in 1996 and 1997 about Standard Precautions training programs and compliance. The primary outcome measures were rates of percutaneous injuries and mucocutaneous exposures. 153 (64%) of 240 hospitals responded. New employee training was offered no more than twice per year by nearly one third. Most (79%-80%) facilities monitored compliance of nurses, housekeepers, and laboratory technicians; physicians rarely were trained or monitored. Implementation of needlestick prevention devices was the most common action taken to decrease sharps injuries. Over one half of hospitals used needleless intravenous systems; larger hospitals used these significantly more often. Protected devices for phlebotomy or intravenous placement were purchased by only one third. Most (89% of large and 80% of small) hospitals met the recommended infection control personnel-to-bed ratio of 1:250. Eleven percent did not have access to postexposure care during all working hours. Percutaneous injury surveillance relied on incident reports (99% of facilities) and employee health records (61%). The annual reported percutaneous injury incidence rate from 106 hospitals was 5.3 injuries per 100 personnel. Compared to single tertiary-referral institution rates determined more than 5 years previously, current injury rates remain elevated in community hospitals. Healthcare institutions need to commit sufficient resources to Standard Precautions training and monitoring and to infection control programs to meet the needs of all workers, including physicians. Healthcare workers clearly remain at risk for injury. Further effective interventions are needed for employee training, improving adherence, and providing needlestick prevention devices.


In visible bodies: minority women, nurses, time, and the new economy of care.
Health care reform in Canadian hospitals has resulted in increased workloads and bureaucratization of patient care contributing to the development of a new economy of care. Interviews with nurses and visible (non-white) minority women who have given birth in institutions undergoing health care reform revealed that nurses felt compelled to avoid interactions with patients deemed too costly in terms of time. Overwhelmingly, these patients were members of culturally marginalized populations whose bodies were read by nurses as potentially problematic and time consuming. As their calls for assistance go unanswered, visible minority women complained of feeling invisible. Taken in context of historical and contemporary interethnic relations, these women regarded such avoidance patterns as evidence of racism. Obstetrical nurses, too, understood that the new economy of care wrought by health care restructuring has altered nursing practice and patient care to the detriment of minority women.


Peripheral B cell maturation. II. Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells.
HSAhi B cells comprise 5 to 10% of adult mouse splenic B cells and are phenotypically and functionally immature. To assess their origin and relationship to mature, heat-stable Ag (HSA)lo B cells, we determined HSA and surface IgD phenotype among splenic B cells throughout development, as well as during reconstitution of lethally irradiated adults given adult B-depleted bone marrow. In each case, HSAhi splenic B cells predominate during the earliest stages of B cell genesis. Furthermore, 5-bromo-2'-deoxyuridine labeling experiments indicate rapid turnover within both the marrow and peripheral HSAhi pools, and adoptive transfer studies show that peripheral HSAhi splenic B cells differentiate to HSAlo within 4 days. Finally, splenic HSAhi B cells reconstitute both primary and memory humoral responses. Together, these data indicate that splenic B cells in the HSAhi subset are an intermediate maturational stage in the adult periphery.


Mental health and structural harm: a qualitative study of sexual minority men's experiences of mental healthcare in Toronto, Canada.
Compared to the general population, sexual minority men report poorer mental health outcomes and higher mental healthcare utilisation. However, they also report more unmet mental health needs. To better understand this phenomenon, we conducted qualitative interviews with 24 sexual minority men to explore the structural factors shaping their encounters with mental healthcare in Toronto, Canada. Interviews were analysed using grounded theory. Many participants struggled to access mental healthcare and felt more marginalised and distressed because of two interrelated sets of barriers. The first were general barriers, hurdles to mental healthcare not exclusive to sexual minorities. These included financial and logistical obstacles, the prominence of psychiatry and the biomedical model, and unsatisfactory provider encounters. The second were sexual minority barriers, obstacles explicitly rooted in heterosexism and homophobia sometimes intersecting with other forms of marginality. These included experiencing discrimination and distrust, and limited sexual minority affirming options. Discussions of general barriers outweighed those of sexual minority barriers, demonstrating the health consequences of structural harms in the absence of overt structural stigma. Healthcare inaccessibility, income insecurity and the high cost of living are fostering poor mental health among sexual minority men. Research must consider the upstream policy changes necessary to counteract these harms.


Symmetric vs. asymmetric stem cell divisions: an adaptation against cancer?
Traditionally, it has been held that a central characteristic of stem cells is their ability to divide asymmetrically. Recent advances in inducible genetic labeling provided ample evidence that symmetric stem cell divisions play an important role in adult mammalian homeostasis. It is well understood that the two types of cell divisions differ in terms of the stem cells' flexibility to expand when needed. On the contrary, the implications of symmetric and asymmetric divisions for mutation accumulation are still poorly understood. In this paper we study a stochastic model of a renewing tissue, and address the optimization problem of tissue architecture in the context of mutant production. Specifically, we study the process of tumor suppressor gene inactivation which usually takes place as a consequence of two "hits", and which is one of the most common patterns in carcinogenesis. We compare and contrast symmetric and asymmetric (and mixed) stem cell divisions, and focus on the rate at which double-hit mutants are generated. It turns out that symmetrically-dividing cells generate such mutants at a rate which is significantly lower than that of asymmetrically-dividing cells. This result holds whether single-hit (intermediate) mutants are disadvantageous, neutral, or advantageous. It is also independent on whether the carcinogenic double-hit mutants are produced only among the stem cells or also among more specialized cells. We argue that symmetric stem cell divisions in mammals could be an adaptation which helps delay the onset of cancers. We further investigate the question of the optimal fraction of stem cells in the tissue, and quantify the contribution of non-stem cells in mutant production. Our work provides a hypothesis to explain the observation that in mammalian cells, symmetric patterns of stem cell division seem to be very common.


Spatially multiplexed X-Y lateral shear interferometer with varying shears using holographic lens and spatial Fourier transform.
Current methods in shear interferometry provide shear only along one direction at a time. We propose a method in which interferograms with shear along the x, y, and xy directions can be obtained simultaneously from a single exposure recording via the concept of spatial multiplexing. The method utilizes holographic lenses, which have been recorded on a single plate with their optical centers translated along the x and y directions. The phase information is extracted through the Fourier transform method. In addition, this technique also provides a method to obtain interferograms with shear in multiples of the original shear along the x and y axis in one single frame capture due to the nonlinearity inherent in the phase holographic lens.


Evolution of novel abdominal appendages in a sepsid fly from histoblasts, not imaginal discs.
Abdominal appendages in male sepsid flies are a complex novel structure of unknown developmental and evolutionary origin. Although these abdominal appendages superficially resemble serially homologous insect appendages, they do not develop from imaginal discs like other dipteran appendages. Cauterization of the genital disc and ventral abdominal histoblasts in Themira biloba (Sepsidae, Diptera) revealed that these abdominal appendages develop from the ventral histoblast nests of the fourth abdominal segment. Cell counts of the histoblasts in males and females revealed that the ventral histoblast nests on the fourth abdominal segment in males were significantly larger than other histoblast nests, indicating that the specification of that segment as the location of the abdominal appendages occurs before the last larval instar. The recruitment of histoblasts to produce appendages has not been documented before, and implies a developmental and evolutionary potential for histoblasts that was previously unknown.


Ice massage. Effects on exercise-induced muscle damage.
The purpose of this study was to examine the effects of ice massage on the signs and symptoms associated with exercise-induced muscle damage. Nine recreationally resistance trained males performed an exercise protocol designed to induce muscle damage on 2 separate occasions; this was performed on the dominant or non-dominant arm in a random cross over design. The protocol consisted of 3 sets of 10 repetitions of single arm biceps curls, at 70% of a pre-determined one repetition maximum (1RM), with the eccentric phase of the contraction extended to 7 seconds. Subjects were also randomly assigned to an ice massage group or control group in the cross over design and received treatments immediately post-exercise, 24 hours and 48 hours post-exercise. 1RM, plasma creatine kinase (CK), muscle soreness (DOMS), limb girth and range of motion (ROM) were measured pre, immediately post, 24 hours, 48 hours and 72 hours post-exercise. Significant time effects were observed for all dependent variables (p<0.05), though no significant group effects were observed. A group by time interaction was found for CK (p<0.05), which at 72 hours post-exercise was significantly lower in the ice massage group (p<0.05). These results indicate that although ice massage reduces the appearance of CK it has no other effect on signs and symptoms associated with exercise-induced muscle damage.


Fucaceae: A Source of Bioactive Phlorotannins.
Fucaceae is the most dominant algae family along the intertidal areas of the Northern Hemisphere shorelines, being part of human customs for centuries with applications as a food source either for humans or animals, in agriculture and as remedies in folk medicine. These macroalgae are endowed with several phytochemicals of great industrial interest from which phlorotannins, a class of marine-exclusive polyphenols, have gathered much attention during the last few years due to their numerous possible therapeutic properties. These compounds are very abundant in brown seaweeds such as Fucaceae and have been demonstrated to possess numerous health-promoting properties, including antioxidant effects through scavenging of reactive oxygen species (ROS) or enhancement of intracellular antioxidant defenses, antidiabetic properties through their acarbose-like activity, stimulation of adipocytes glucose uptake and protection of β-pancreatic cells against high-glucose oxidative stress; anti-inflammatory effects through inhibition of several pro-inflammatory mediators; antitumor properties by activation of apoptosis on cancerous cells and metastasis inhibition, among others. These multiple health properties render phlorotannins great potential for application in numerous therapeutical approaches. This review addresses the major contribution of phlototannins for the biological effects that have been described for seaweeds from Fucaceae. In addition, the bioavailability of this group of phenolic compounds is discussed.


Tooth structure removal associated with various preparation designs for posterior teeth.
The amount of tooth structure removed for various innovative and conventional preparation designs for fixed prosthodontics was quantified. Four Typodont resin teeth representing maxillary and mandibular premolars and molars were prepared in various abutment designs: adhesive, box (A2); adhesive, wing and groove (A3); mesioocclusal or distoocclusal inlay; mesio-occlusodistal inlay (13); mesio-occlusodistal onlay; partial crown; half crown (only molars); complete crown, 0.8-mm circumferential tapered chamfer (F1); complete crown, 1.0-mm circumferential rounded shoulder; and complete crown, 1.4-mm axial reduction facial shoulder, 0.7-mm lingual chamfer (F3). After tooth preparation (10 per group), the root was separated from the anatomic crown at the cementoenamel junction. Removal of tooth structure was measured by gravimetric analysis in a high-precision balance. Preparations A3 and F3 were assigned as abutments for metal-supported restorations, whereas all other preparations were used for all-ceramic restorations. When the mean structure removal of all teeth tested was compared, the adhesive and inlay abutments were the least invasive preparation designs, ranging from approximately 5.5% (A2) to 27.2% (13) tooth structure removal. Complete crowns required the most invasive preparations, ranging from 67.5% (F1) to 75.6% (F3) tooth structure removal. The tooth structure removal required for F3 retainers was almost 14 times greater than for an A2 preparation. Tooth structure removal was also influenced by the morphology of the tooth. The first comprehensive tooth preparation design classification system was introduced. The measurement system used in this study provides an accurate method of quantifying tooth structure removal for fixed prosthodontic preparations. The innovative preparation designs studied conserved significant amounts of tooth structure, yielding a better prognosis for the restored tooth.


The heart of the matter: an essay about the effects of managed care on family therapy with children.
This essay is based on a pilot study that examined the effects of managed care on the treatment of children and families, with special attention to community mental health. We embarked on the pilot study to test the accuracy and generalizability of our impression that family therapy and other systemic practices have been marginalized in ordinary clinics and agencies, and to understand the reasons why. We interviewed managed care providers, researchers, family therapy trainers, and clinicians in the Northeast. Our findings led to seven themes that support our impression that, even though there is a consensus about the need for coordinated family-based services, there is a disconnection between state policies, contractual requirements and what is actually occurring at the implementation level. This study suggests that our knowledge of human systems may be in danger of being disqualified and lost, with damaging consequences for the care of children. Yet, as systemic thinkers and practitioners, it is our belief that ethical and effective treatment need not be at odds with care that is cost-efficient. The direction of our future research will be to study whether the involvement of all stakeholders at all levels of planning and training leads to systemic family-based practices that consistently save costs and provide high-quality care.


Correlated immunohistochemical and cytological assays for the prediction of hematogenous dissemination of breast cancer.
Although metastasis is a major cause of death from breast cancer, our ability to predict which tumors will metastasize is limited (American Cancer Society 2010). Proper assessment of metastatic risk and elucidating the underlying mechanisms of metastasis will help personalize therapy and may provide insight into potential therapeutic targets. Traditionally, histologic grading, staging, hormone receptors, HER2/Neu, and proliferation assays have been the gold standard on which oncologists based their treatment decisions. However, all of these are indirect measures of metastatic risk. Recent insights from intravital imaging directly address questions of mechanism and have led to a new way of using histologic and cytologic material to assess metastatic risk. This review describes the tumor microenvironment model of invasion and intravasation, as well as an emerging histopathologic application based on this model. In particular, the authors describe a new immunohistochemical approach to the assessment of metastatic risk based on the density of intravasation microenvironment sites called the tumor microenvironment of metastasis. In addition, they describe an isoform assay for the actin regulatory protein Mena using fine needle aspiration samples and the details about how these 2 assays may be applied in clinical practice in a synergistic way to assess the risk of metastasis.


Cardiovascular malformations in Smith-Lemli-Opitz syndrome.
We reviewed 215 patients (59 new, 156 from the literature) with Smith-Lemli-Opitz syndrome (SLOS), and found that 95 (44%) had a cardiovascular malformation (CVM). Classifying CVMs by disordered embryonic mechanisms, there were 5 (5.3%) class 1 (ectomesenchymal tissue migration abnormalities), 56 (58.9%) class II (abnormal intracardiac blood flow), 25 (26.3%) class IV (abnormal extracellular matrix), and 5 (5.3%) class V (abnormal targeted growth). Comparing the frequencies of individual CVMs in this series with a control group (the Baltimore-Washington Infant Study), there were 6 individual CVMs which showed a significant difference from expected values. When frequencies of CVMs in SLOS were analyzed by mechanistic class, classes IV and V were significantly more frequent, and class I significantly less frequent, than the control group. Although CVMs in SLOS display mechanistic heterogeneity, with an overall predominance of class II CVMs, the developmental error appears to favor alteration of the cardiovascular developmental mechanisms underlying atrioventricular canal and anomalous pulmonary venous return. This information should assist the clinical geneticist evaluating a patient with possible SLOS, and should suggest research direction for the mechanisms responsible for the SLOS phenotype.


Microfluidic cell electroporation using a mechanical valve.
A microfluidic electroporation technique is demonstrated based on the operation of an elastomeric valve in a poly(dimethylsiloxane) (PDMS) fabricated microchip and a common dc power supply. The pulse needed for permeabilization of the cell membrane is generated by temporarily interrupting the circuit using the valve. The electropermeabilization of suspended and adherent Chinese hamster ovary cells with green DNA dye SYTOX is demonstrated. The technique eliminates the cost and complexity associated with a pulse generator and microfabricated electrodes that are often involved in microscale electroporation devices. It also offers the potential of integrating electroporation as a unit operation in large-scale microfluidic systems with the increasing application of elastomeric valves in these systems.


Neutrophils undergo apoptosis following ingestion of Escherichia coli.
Apoptosis is a distinct mechanism by which eukaryotic cells die. Neutrophils (PMN) play a fundamental role in the systemic inflammatory response syndrome. Clearance of PMN during resolution of the acute inflammatory process occurs by apoptosis, but factors inducing this process are unknown. The aims of this study were to determine whether PMN ingestion of Escherichia coli would result in PMN apoptosis and whether the mechanism was related to the respiratory burst. PMN from 10 healthy volunteers were cultured with different ratios of PMN:E. coli (1:0 to 1:25) for 12 h. Apoptosis was then assessed by propidium iodide DNA staining, morphology, gel electrophoresis, and Fc gamma RIII expression. There was a significant induction of PMN apoptosis on incubation with E. coli at a ratio of 1:10 and 1:25 PMN:E. coli as well as decreases in Fc gamma RIII. This correlated with increased ingestion of FITC-labeled E. coli and intracellular reactive oxygen intermediates after a 2-h coculture. To clarify the role of reactive oxygen intermediates in E. coli-induced PMN apoptosis, we assessed the effects of the antioxidants catalase, DMSO, glutathione, and N-acetylcysteine. There was a significant decrease in E. coli-induced PMN apoptosis on incubation with DMSO (1.0%), glutathione (25 mM), and N-acetylcysteine (25 mM) compared with control PMN:E. coli. This study demonstrates for the first time that E. coli induces PMN apoptosis through an oxygen-dependent mechanism. The removal of effete PMN by the process of apoptosis rather than necrosis may be teleologically beneficial during Gram-negative septicemia.


Sedaxicenes: potential new antifungal ferrocene-based agents?
Fungal infections are a group of diseases spread all over the world with an extremely high morbidity. Worryingly, although several pathogenic fungi were found to develop resistance towards traditional therapy, research towards the discovery of novel antimycotic agents is very limited. Considering the promising results obtained with the ferrocene-based drug candidates Ferroquine and Ferrocifen as antimalarial and anticancer drug candidates, respectively, we envisaged derivatizing the organic scaffold of a new broad-spectrum fungicide, namely sedaxane, with a ferrocenyl moiety in order to obtain new metal-based antifungal agents. The new ferrocenyl sedaxane derivatives called herein Sedaxicenes (, and ) were characterized using different analytical techniques and the structures were confirmed by X-ray crystallography. As expected for antimycotic agents, , and were found to have a low or even no toxicity towards human cells (IC50 > 100 μM). Interestingly, while the parent drug did not display any mycotoxicity (EC50 > 100 μM), complex was found to have some antifungal activity with an IC50 value of 43 μM under the same experimental conditions. In order to investigate the possible redox-mediated mode of action of , we synthesized the ruthenocene analogue of , namely . Ruthenocene is known to have a completely different electrochemical behaviour from ferrocene although both the compounds are isostructural. As anticipated, complex was found to induce an increase of the reactive oxygen species level in S. cerevisiae, contrary to its analogue and to the parent compound sedaxane.


Insulin lispro in CSII: results of a double-blind crossover study.
Insulin lispro is a human insulin analog that dissociates more rapidly than human regular insulin after subcutaneous injection, resulting in higher insulin levels at an earlier point in time and a shorter duration of action. The aim of the study was to evaluate if this pharmacokinetic difference would translate into better postprandial and overall control in 30 IDDM patients (age, 35.1 +/- 1.5 years; male-female ratio, 17:13; BMI, 24.8 +/- 0.5 kg/m2; HbA1c, 8.03 +/- 0.13% at baseline) treated with continuous subcutaneous insulin infusion (CSII; Disetronic H-TRON V100) in a double-blind crossover clinical study. Patients were randomized to insulin lispro or human regular insulin for 3 months before crossing over to the other insulin for another 3 months. All meal boluses were given immediately before breakfast, lunch, and supper. An eight-point blood glucose profile was measured once weekly, and HbA1c levels were measured monthly. At the end of the 3-month treatment period, HbA1c levels were significantly lower with insulin lispro, compared with human regular insulin: 7.66 +/- 0.13 vs. 8.00 +/- 0.16% (P = 0.0041). While preprandial, bedtime, and 2:00 A.M. values for blood glucose were not significantly different, 1-h postprandial blood glucose was significantly improved after breakfast, lunch, and dinner with insulin lispro, compared with human regular insulin: 8.35 vs. 9.79 mmol/l (P = 0.006), 7.58 vs. 8.74 mmol/l (P = 0.049), and 7.85 vs. 9.01 mmol/l (P = 0.03). The incidence of hypoglycemia per 30 days (blood glucose levels, <3.0 mmol/l) was 8.4 +/- 1.3 before randomization, decreasing to 6.0 +/- 0.9 for insulin lispro and to 7.6 +/- 1.3 for regular insulin during the last month of the study. Two patients in each group reported insulin precipitation. We conclude that insulin lispro improves glycemic control in CSII without increasing the risk of hypoglycemia.


Single molecule electron transport junctions: charging and geometric effects on conductance.
A p-benzenedithiolate (BDT) molecule covalently bonded between two gold electrodes has become one of the model systems utilized for investigating molecular transport junctions. The plethora of papers published on the BDT system has led to varying conclusions with respect to both the mechanism and the magnitude of transport. Conductance variations have been attributed to difficulty in calculating charge transfer to the molecule, inability to locate the Fermi energy accurately, geometric dispersion, and stochastic switching. Here we compare results obtained using two transport codes, TRANSIESTA-C and HUCKEL-IV, to show that upon Au-S bond lengthening, the calculated low bias conductance initially increases by up to a factor of 30. This increase in highest occupied molecular orbital (HOMO) mediated conductance is attributed to charging of the terminal sulfur atom and a corresponding decrease in the energy gap between the Fermi level and the HOMO. Addition of a single Au atom to each terminal of the extended BDT molecule is shown to add four molecular states near the Fermi energy, which may explain the varying results reported in the literature.


Aid alignment: a longer term lens on trends in development assistance for health in Uganda.
Over the past decade, development assistance for health (DAH) in Uganda has increased dramatically, surpassing the government's own expenditures on health. Yet primary health care and other priorities identified in Uganda's health sector strategic plan remain underfunded. Using data available from the Creditor Reporting System (CRS), National Health Accounts (NHA), and government financial reports, we examined trends in how donors channel DAH and the extent to which DAH is aligned with sector priorities. The study follows the flow of DAH from the donor to the implementing organization, specifying the modality used for disbursing funds and categorizing funds based on program area or support function. Despite efforts to improve alignment through the formation of a sector-wide approach (SWAp) for health in 1999 and the creation of a fund to pool resources for identified priorities, increasingly DAH is provided as short-term, project-based support for disease-specific initiatives, in particular HIV/AIDS. These findings highlight the need to better align external resources with country priorities and refocus attention on longer-term sector-wide objectives.


The Hinge Region Strengthens the Nonspecific Interaction between Lac-Repressor and DNA: A Computer Simulation Study.
LacI is commonly used as a model to study the protein-DNA interaction and gene regulation. The headpiece of the lac-repressor (LacI) protein is an ideal system for investigation of nonspecific binding of the whole LacI protein to DNA. The hinge region of the headpiece has been known to play a key role in the specific binding of LacI to DNA, whereas its role in nonspecific binding process has not been elucidated. Here, we report the results of explicit solvent molecular dynamics simulation and continuum electrostatic calculations suggesting that the hinge region strengthens the nonspecific interaction, accounting for up to 50% of the micro-dissociation free energy of LacI from DNA. Consequently, the rate of microscopic dissociation of LacI from DNA is reduced by 2~3 orders of magnitude in the absence of the hinge region. We find the hinge region makes an important contribution to the electrostatic energy, the salt dependence of electrostatic energy, and the number of salt ions excluded from binding of the LacI-DNA complex.


Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection.
Human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4(+) T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing.


Quantitative bioluminescence tomography using spectral derivative data.
Bioluminescence imaging (BLI) is a non-contact, optical imaging technique based on measurement of emitted light due to an internal source, which is then often directly related to cellular activity. It is widely used in pre-clinical small animal imaging studies to assess the progression of diseases such as cancer, aiding in the development of new treatments and therapies. For many applications, the quantitative assessment of accurate cellular activity and spatial distribution is desirable as it would enable direct monitoring for prognostic evaluation. This requires quantitative spatially-resolved measurements of bioluminescence source strength inside the animal to be obtained from BLI images. This is the goal of bioluminescence tomography (BLT) in which a model of light propagation through tissue is combined with an optimization algorithm to reconstruct a map of the underlying source distribution. As most models consider only the propagation of light from internal sources to the animal skin surface, an additional challenge is accounting for the light propagation from the skin to the optical detector (e.g. camera). Existing approaches typically use a model of the imaging system optics (e.g. ray-tracing, analytical optical models) or approximate corrections derived from calibration measurements. However, these approaches are typically computationally intensive or of limited accuracy. In this work, a new approach is presented in which, rather than directly using BLI images acquired at several wavelengths, the spectral derivative of that data (difference of BLI images at adjacent wavelengths) is used in BLT. As light at similar wavelengths encounters a near-identical system response (path through the optics etc.) this eliminates the need for additional corrections or system models. This approach is applied to BLT with simulated and experimental phantom data and shown that the error in reconstructed source intensity is reduced from 49% to 4%. Qualitatively, the accuracy of source localization is improved in both simulated and experimental data, as compared to reconstruction using the standard approach. The outlined algorithm can widely be adapted to all commercial systems without any further technological modifications.


A cautionary note on the use of chromosome conformation capture in plants.
The chromosome conformation capture (3C) technique is a method to study chromatin interactions at specific genomic loci. Initially established for yeast the 3C technique has been adapted to plants in recent years in order to study chromatin interactions and their role in transcriptional gene regulation. As the plant scientific community continues to implement this technology, a discussion on critical controls, validations steps and interpretation of 3C data is essential to fully benefit from 3C in plants. Here we assess the reliability and robustness of the 3C technique for the detection of chromatin interactions in Arabidopsis. As a case study, we applied this methodology to the genomic locus of a floral integrator gene SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1), and demonstrate the need of several controls and standard validation steps to allow a meaningful interpretation of 3C data. The intricacies of this promising but challenging technique are discussed in depth. The 3C technique offers an interesting opportunity to study chromatin interactions at a resolution infeasible by microscopy. However, for interpretation of 3C interaction data and identification of true interactions, 3C technology demands a stringent experimental setup and extreme caution.


Optical biopsy of fixed human skin with backward-collected optical harmonics signals.
Harmonics-based optical microscopy has been widely applied in biomedical researches due to its noninvasiveness to the studied biomaterials. Due to momentum conservation consideration, most previous studies collect harmonics generation signals in a forward geometry, especially for third harmonic generation signals. However, the adopted forward transmission type geometry is not feasible for future clinical diagnosis. In this paper, first virtual biopsy based on backward propagating optical higher harmonics, combining second harmonic and third harmonic, is demonstrated in the fixed human skin specimens. In our study, third harmonic generation can provide morphologic information including the distribution of basal cells while second harmonic generation can provide distribution of collagen fibers in dermis. Therefore, this technique is ideal for future noninvasive in vivo skin disease examination without dye.


The Effect of Mirror Visual Feedback Therapy on the Hand Mental Rotation in Stroke Patients: An ERP study.
Mirror visual feedback (MVF) intervention is an adjunctive approach for motor recovery after stroke. It has been hypothesized that MVF can increase visual perception, motor imagery, and attention of/to the hands. However, neuroimaging evidence for this hypothesis is still lacking. In this study, we used a hand mental rotation task and event-related potential (ERP) analysis to explore the effect of MVF intervention on visual perception, motor preparation, and motor imagery of hands. We recruited 46 patients and randomly divided them into a mirror visual feedback group (MG) and a conventional intervention group (CG). By comparing ERP amplitude between the two groups and between before and after the intervention, we found that the N200 component, which was considered to be related to motor preparation, was significantly less negative in the affected hemisphere than that in the unaffected counterpart. After intervention, the N200 amplitude became more negative, reflecting a recovery of motor preparation. Specifically, MG showed a significant effect on the N200 for the hand pictures at large orientations, while the CG showed an effect mainly for the upright hand stimuli. The results suggested an improvement of preparation for motor imagery of complex and precise hand movements after MVF intervention.Clinical Relevance- This study might be helpful for understanding the neural mechanisms of MVF which can help stroke patients regain upper extremity function.


The structure and opto-thermo electronic properties of a new (Bi(Bi2S3)9I3)2/3 hexagonal nano-/micro-rod.
The semiconductor optoelectronic properties of an inorganic (Bi(Bi2S3)9I3)2/3 hexagonal nano-/micro-rod are firstly explored herein. Transmittance and thermoreflectance measurements show that (Bi(Bi2S3)9I3)2/3 hexagonal rods possess an indirect gap of 0.73 eV and a direct gap of 1.08 eV, respectively. Hot-probe measurements of (Bi(Bi2S3)9I3)2/3 reveal the p-type semiconductor behavior and high thermoelectric voltage. Polarized Raman measurements of the m-plane (Bi(Bi2S3)9I3)2/3 (along c and perpendicular to the c axis) identify the structural anisotropy of the hexagonal nano-/micro-rod.


Modeling of Direct Detection Doppler Wind Lidar. II. The Fringe Imaging Technique.
A simple analytic model is developed for the shot-noise-limited measurement precision of Doppler wind lidars based on the fringe imaging technique by use of either molecular or aerosol atmospheric backscatter. The model leads to etalon design parameters for an instrument optimized for precision. The ultimate measurement precision possible is two to four times the limit for a perfect, lossless receiver. The corresponding result for the double-edge Doppler analyzer was a ratio of 2.5, showing that the two methods are little different in this respect. For aerosol backscatter instruments, the wind speed dynamic range of the fringe imager is substantially greater than that for the edge detector. The etalon aperture needed to meet system etendue requirements is derived and shown to be approximately half that of each of the two etalons required by the double-edge technique. A comparison with more detailed modeling of fringe imaging Doppler-shift analyzers shows good agreement for the Rayleigh model and fair for the aerosol version, confirming the validity of this simpler technique for analyzer design and performance prediction.


Persistence of T-cell immune response induced by two acellular pertussis vaccines in children five years after primary vaccination.
The resurgence of pertussis suggests the need for greater efforts to understand the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of T memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac® vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa® (Infanrix) (Glaxo-SmithKline Biologicals). We evaluated magnitude and duration of T-cell responses to pertussis toxin (PT) by measuring T-cell proliferation, cytokines (IL-2 and IFNγ) production and memory subsets in two groups of children 5 years after primary vaccination. Some of the enrolled children received only primary vaccination, while others had the pre-school boost dose. Positive T-cell responses to PT were detected in 36% of children. Percentage of responsive children, T-cell proliferation and CD4IL-2+ cells were significantly higher in the children primed with Hexavac than in those who received Infanrix vaccine. No major effects of the boost on PT-specific proliferation were observed. Overall, our data documented a persistence of T-cell memory against PT in a minor fraction of children 5 years after primary vaccination. The different responses induced by Hexavac and Infanrix vaccine could rely on differences in PT inactivation process or excipients/adjuvants formulations.


2.1-watts intracavity-frequency-doubled all-solid-state light source at 671 nm for laser cooling of lithium.
We present an all-solid-state laser source emitting up to 2.1 W of single-frequency light at 671 nm developed for laser cooling of lithium atoms. It is based on a diode-pumped, neodymium-doped orthovanadate (Nd:YVO(4)) ring laser operating at 1342 nm. Optimization of the thermal management in the gain medium results in a maximum multi-frequency output power of 2.5 W at the fundamental wavelength. We develop a simple theory for the efficient implementation of intracavity second harmonic generation, and its application to our system allows us to obtain nonlinear conversion efficiencies of up to 88%. Single-mode operation and tuning is established by adding an etalon to the resonator. The second-harmonic wavelength can be tuned over 0.5 nm, and mode-hop-free scanning over more than 6 GHz is demonstrated, corresponding to around ten times the laser cavity free spectral range. The output frequency can be locked with respect to the lithium D-line transitions for atomic physics applications. Furthermore, we observe parametric Kerr-lens mode-locking when detuning the phase-matching temperature sufficiently far from the optimum value.


Eleven-year trend in acetanilide pesticide degradates in the Iowa River, Iowa.
Trends in concentration and loads of acetochlor, alachlor, and metolachlor and their ethanasulfonic (ESA) and oxanilic (OXA) acid degradates were studied from 1996 through 2006 in the main stem of the Iowa River, Iowa and in the South Fork Iowa River, a small tributary near the headwaters of the Iowa River. Concentration trends were determined using the parametric regression model SEAWAVE-Q, which accounts for seasonal and flow-related variability. Daily estimated concentrations generated from the model were used with daily streamflow to calculate daily and yearly loads. Acetochlor, alachlor, metolachlor, and their ESA and OXA degradates were generally present in >50% of the samples collected from both sites throughout the study. Their concentrations generally decreased from 1996 through 2006, although the rate of decrease was slower after 2001. Concentrations of the ESA and OXA degradates decreased from 3 to about 23% yr. The concentration trend was related to the decreasing use of these compounds during the study period. Decreasing concentrations and constant runoff resulted in an average reduction of 10 to >3000 kg per year of alachlor and metolachlor ESA and OXA degradates being transported out of the Iowa River watershed. Transport of acetochlor and metolachlor parent compounds and their degradates from the Iowa River watershed ranged from <1% to about 6% of the annual application. These trends were related to the decreasing use of these compounds during the study period, but the year-to-year variability cannot explain changes in loads based on herbicide use alone. The trends were also affected by the timing and amount of precipitation. As expected, increased amounts of water moving through the watershed moved a greater percentage of the applied herbicides, especially the relatively soluble degradates, from the soils into the rivers through surface runoff, shallow groundwater inflow, and subsurface drainage.


WiiPD--objective home assessment of Parkinson's disease using the Nintendo Wii remote.
Current clinical methods for the assessment of Parkinson's disease suffer from inconvenience, infrequency and subjectivity. WiiPD is an approach for the objective home based assessment of Parkinson's disease which utilizes the intuitive and sensor rich Nintendo Wii Remote. Combined with an electronic patient diary, a suite of mini-games, a metric analyzer, and a visualization engine, we propose that this system can complement existing clinical practice by providing objective metrics gathered frequently over extended periods of time. In this paper we detail the approach and introduce a series of metrics deemed capable of quantifying the severity of tremor and bradykinesia in those with Parkinson's disease. The system has been tested on a 71 year old participant with Parkinson's disease over a period of 15 days, a 72 year old control user without Parkinson's disease, and a group of 8 young adults. Results indicate a clear correlation between patient self rating scores of tremor severity and metric values obtained, in addition to clear differences in metrics obtained from each user group. These results suggest that this approach is capable of indicating the presence and severity of the motor symptoms of Parkinson's disease that affect arm motor control.


The Medical Student Summer Research Program at the University of Texas Medical Branch at Galveston: building research foundations.
Interest in incorporating research into the medical school curriculum has grown over the years. One of the challenges involved with providing research to medical students is developing programs that allow a large number of students to perform research. This involves securing faculty to mentor students in the design of research projects. In order to accommodate students with research interests, well-established research programs must be implemented. This article describes the design and implementation of a curriculum-based research program for medical students at the University of Texas Medical Branch (UTMB) at Galveston. The main objective of this article is to describe the program for the purpose of assisting other medical schools to develop a similar student research program. At UTMB we established a Medical Student Summer Research Program (MSSRP) that occurred between the first year and the second year of medical school. Between the years 2000-2017, MSSRP accommodated a minimum of 39 and a maximum of 90 students during an 8 week period. Two surveys were conducted to collect students' views on how MSSRP affected their interest in research. We performed a proportion statistical analysis on the data from both surveys in order to determine the significance of the responses. The benefit of MSSRP is that it provided medical students with an exposure to research. According to the proportions test, the responses were statistically significant with 85% of 26 third and fourth year students stating they would continue to incorporate research into their medical careers; 75% stating that MSSRP increased their interest in research; and 85% responding that MSSRP helped them to understand research methodology. MSSRP is a curriculum-based program that provides a framework to other medical institutions interested in the development of similar student research programs and provides students the exposure and option to continue with research as a component of their medical profession.


How to support patients who are crying in palliative home care: an interview study from the nurses' perspective.
Aim The aim of this study was to explore how nurses can support patients who are crying in a palliative home care context. In palliative care the nurse has a central role in the team whose duty it is to create a sense of security and trust, as well as to give comfort and support the patients. The nurse's responsibility is to identify different needs of the patients for support and develop a relationship with them. Patients may express their pain, anxiety, fear and suffering by crying. No studies have been found which focus on how nurses can support patients who are crying in different ways and crying for different reasons. A qualitative explorative study was performed. Semi-structured interviews were held with eight nurses aged 32-63 years (Median 40) working in Swedish palliative home care. The data were analysed using Qualitative Content analysis. Findings It was reported that the nurse should meet and confirm the patient during different types of crying episodes and should also be able to alternate between being close and physically touching the in such close contact with the patients, the nurse can provide emotional support by showing empathy, merely being present and letting the patients cry as much as they want. When the crying finally stops, the nurse can support the person by speaking with them, showing sensitivity, humility and respect for the patient's wishes. A few examples of the patients' need for information or practical support emerged. The nurse can emotionally support the person who is crying by just being present, confirming, showing empathy, offering a chance to talk and showing respect for their individual needs and the different ways they may cry.


Dynamics of wound healing in periodontal regenerative therapy.
Experimental animal and clinical studies have increased understanding of the biology of healing following periodontal regenerative therapy and factors that may influence the outcome. Formation of a new connective tissue attachment rather than a long junctional epithelium at the tooth-gingival flap interface is dependent upon the completion of a series of interactions among the root surface, plasma and tissue factors, and the connective tissue of the gingival flap. First, plasma proteins must adsorb to and remain in undisturbed contact with a generally noncompromised root surface. Next, adhesion of the established fibrin clot to the root surface must remain intact. Within days, a cellular and fibrous attachment will form; however, the tooth-gingival flap interface will still be vulnerable to wound-rupturing forces. Within two weeks the interface may have gained sufficient mechanical strength to offset such forces, at least in limited periodontal defects. Eventually, maturation of the fibrous attachment, including bone and cementum formation, will occur, particularly following adequate space provision by barrier membranes (guided tissue regeneration). A novel research focus involves how advances in molecular biology can translate to periodontal regenerative therapy. Bone morphogenetic proteins (BMPs) have been shown to support healing in a variety of skeletal sites. Recent research has demonstrated clinically significant alveolar bone and cementum regeneration with the use of a recombinant human BMP-2 implant. Such data suggest that growth-promoting substances, such as rhBMP-2, may significantly enhance periodontal regeneration and that use of such substances may radically recast current periodontal regenerative therapy.


Intra-abdominal hypertension and abdominal compartment syndrome in pancreatitis, paediatrics, and trauma.
Intra-abdominal hypertension (IAH) is an important contributor to early organ dysfunction among patients with trauma and sepsis. However, the impact of increased intra-abdominal pressure (IAP) among pediatric, pregnant, non-septic medical patients, and those with severe acute pancreatitis (SAP), obesity, and burns has been studied less extensively. The aim of this review is to outline the pathophysiologic implications and treatment options for IAH and abdominal compartment syndrome (ACS) for the above patient populations. We searched MEDLINE and PubMed to identify relevant studies. There is an increasing awareness of IAH in general medicine. The incidence of IAH and, to a lesser extent, ACS is high among patients with SAP. IAH should always be suspected and IAP measured routinely. In children, normal IAP in mechanically ventilated patients is approximately 7 ± 3 mm Hg. As an IAP of 10-15 mm Hg has been associated with organ damage in children, an IAP greater than 10 mm Hg should be considered IAH in these patients. Moreover, as ACS may occur in children at an IAP lower than 20 mm Hg, any elevation in IAP higher than 10 mm Hg associated with new organ dysfunction should be considered ACS in children until proven otherwise. Monitor IAP trends and be aware that specific interventions may need to be instituted at lower IAP than the current ACS definitions accommodate. Finally, IAH and ACS can occur both in abdominal trauma and extra-abdominal trauma patients. Early mechanical hemorrhage control and the avoidance of excessive fluid resuscitation are key elements in preventing IAH in trauma patients. IAH and ACS have been associated with many conditions beyond the general ICU patient. In adults and in children, the focus should be on the early recognition of IAH and the prevention of ACS. Patients at risk for IAH should be identified early during their treatment (with a low threshold to initiate IAP monitoring). Appropriate actions should be taken when IAP increases above 20 mm Hg, especially in patients developing difficulty with ventilation. Although on-operative measures should be instituted first, one should not hesitate to resort to surgical decompression if they fail.


Granulocyte-colony stimulating factor induced intranuclear endonuclease in murine leukemia cell line.
We have reported that murine leukemia cell line (C2M-A5) induced apoptosis by G-CSF. To clarify the mechanism, mRNA expression of apoptosis-related genes was studied. It revealed transient over-expression of c-myc, H-ras and p53 and down-expression of bcl-2. These changes were known as triggers of endonuclease induction. After 96 h culture with G-CSF, apoptosis was occurred simultaneously with endonuclease (37 kd) activation. This endonuclease induced the digestion of double-strand DNA and might be associated with caspase3. Although G-CSF accelerates cell growth and prevents apoptosis in general, it is a contradictory effect. We concluded that G-CSF induced endogenous endonuclease activity in C2M-A5.


The Anopheles gambiae adult midgut peritrophic matrix proteome.
Malaria is a devastating disease. For transmission to occur, Plasmodium, the causative agent of malaria, must complete a complex developmental cycle in its mosquito vector. Thus, the mosquito is a potential target for disease control. Plasmodium ookinetes, which develop within the mosquito midgut, must first cross the midgut's peritrophic matrix (PM), a thick extracellular sheath that completely surrounds the blood meal. The PM poses a partial, natural barrier against parasite invasion of the midgut and it is speculated that modifications to the PM may lead to a complete barrier to infection. However, such strategies require thorough characterization of the structure of the PM. Here, we describe for the first time, the complete PM proteome of the main malaria vector, Anopheles gambiae. Altogether, 209 proteins were identified by mass spectrometry. Among them were nine new chitin-binding peritrophic matrix proteins, expanding the list from three to twelve peritrophins. Lastly, we provide a model for the putative interactions among the proteins identified in this study.


Effect of CpG methylation at different sequence context on acrolein- and BPDE-DNA binding and mutagenesis.
Acrolein (Acr), an α,β-unsaturated aldehyde, is abundant in tobacco smoke and cooking and exhaust fumes. Acr induces mutagenic α- and γ- hydroxy-1,N(2)-cyclic propano-deoxyguanosine adducts in normal human bronchial epithelial cells. Our earlier work has found that Acr-induced DNA damage preferentially occurs at lung cancer p53 mutational hotspots that contain CpG sites and that methylation at CpG sites enhances Acr-DNA binding at these sites. Based on these results, we hypothesized that this enhancement of Acr-DNA binding leads to p53 mutational hotspots in lung cancer. In this study, using a shuttle vector supF system, we tested this hypothesis by determining the effect of CpG methylation on Acr-DNA binding and the mutations in human lung fibroblasts. We found that CpG methylation enhances Acr-induced mutations significantly. Although CpG methylation enhances Acr-DNA binging at all CpG sites, it enhances mutations at selective--TCGA--sites. Similarly, we found that CpG methylation enhances benzo(a)pyrene diol epoxide binding at all -CpG- sites. However, the methylated CpG sequences in which benzo(a)pyrene diol epoxide-induced mutations are enhanced are different from the CpG sequences in which Acr-induced mutations are enhanced. CpG methylation greatly increases Acr-induced G to T and G to A mutation frequency to levels similar to these types of mutations found in the CpG sites in the p53 gene in tobacco smoke-related lung cancer. These results indicate that both CpG sequence context and the chemical nature of the carcinogens are crucial factors for determining the effect of CpG methylation on mutagenesis.


Low temperature solution synthesis of silicon, germanium and Si-Ge axial heterostructures in nanorod and nanowire form.
Herein, we report the formation of silicon, germanium and more complex Si-SixGe1-x and Si-Ge axial 1D heterostructures, at low temperatures in solution. These nanorods/nanowires are grown using phenylated compounds of silicon and germanium as reagents, with precursor decomposition achieved at substantially reduced temperatures (200 °C for single crystal nanostructures and 300 °C for heterostructures), through the addition of a reducing agent. This low energy route for the production of these functional nanostructures as a wet chemical in high yield is attractive to meet the processing needs for next generation photovoltaics, batteries and electronics.


Identification of rtl1, a retrotransposon-derived imprinted gene, as a novel driver of hepatocarcinogenesis.
We previously utilized a Sleeping Beauty (SB) transposon mutagenesis screen to discover novel drivers of HCC. This approach identified recurrent mutations within the Dlk1-Dio3 imprinted domain, indicating that alteration of one or more elements within the domain provides a selective advantage to cells during the process of hepatocarcinogenesis. For the current study, we performed transcriptome and small RNA sequencing to profile gene expression in SB-induced HCCs in an attempt to clarify the genetic element(s) contributing to tumorigenesis. We identified strong induction of Retrotransposon-like 1 (Rtl1) expression as the only consistent alteration detected in all SB-induced tumors with Dlk1-Dio3 integrations, suggesting that Rtl1 activation serves as a driver of HCC. While previous studies have identified correlations between disrupted expression of multiple Dlk1-Dio3 domain members and HCC, we show here that direct modulation of a single domain member, Rtl1, can promote hepatocarcinogenesis in vivo. Overexpression of Rtl1 in the livers of adult mice using a hydrodynamic gene delivery technique resulted in highly penetrant (86%) tumor formation. Additionally, we detected overexpression of RTL1 in 30% of analyzed human HCC samples, indicating the potential relevance of this locus as a therapeutic target for patients. The Rtl1 locus is evolutionarily derived from the domestication of a retrotransposon. In addition to identifying Rtl1 as a novel driver of HCC, our study represents one of the first direct in vivo demonstrations of a role for such a co-opted genetic element in promoting carcinogenesis.


Late recurrence in pediatric cancer: a report from the Childhood Cancer Survivor Study.
An increasing percentage of childhood cancer patients are surviving their disease, but there is limited research on late recurrence. We sought to estimate late recurrence rates for the most common pediatric cancers and to determine risk factors for late recurrence. The incidence of late recurrences, or first recurrences that occurred more than 5 years after diagnosis, was analyzed for the most common pediatric cancers using data from the Childhood Cancer Survivor Study, a retrospective cohort of 5-year survivors of childhood and adolescent cancers who were diagnosed between 1970 and 1986. A total of 12,795 survivors with no history of recurrence within 5 years after their original cancer diagnosis were included in the analysis, with a total of 217,127 person-years of follow-up. Cumulative incidence of late recurrence at 5, 10, 15, and 20 years after diagnosis was calculated using death as a competing risk. Adjusted relative rates of late recurrence were obtained using multivariable Poisson regression. All statistical tests were two-sided. Overall, 5-year survivors of pediatric cancers experienced a cumulative incidence of recurrent disease of 4.4%, 5.6%, and 6.2% at 10, 15, and 20 years, respectively. Cumulative incidence varied by diagnosis: Survivors of Ewing sarcoma and astrocytoma had the highest 20-year cumulative incidences at 13.0% (95% confidence interval [CI] = 9.4 to 16.5) and 14.4% (95% CI = 12.3 to 16.6), respectively. In multivariable analysis, the greatest risk factors for late recurrence included diagnosis, combination treatment with chemotherapy and radiation, earlier treatment era, and fewer years since diagnosis (P < .001 for all). Late recurrence is a risk for some pediatric cancers. By understanding diagnosis-specific risks, patients, families, and their medical providers can be better informed of the probability of cure.


Surround modulation of perceived contrast and the role of brightness induction.
We studied iso- and cross-orientation surround modulation of perceived contrast (contrast-contrast phenomenon) with a contrast-matching method. Our results indicate (1) iso-oriented surrounds at all contrasts suppress perceived contrast of the test pattern. Cross-orientation surrounds, however, tend to enhance the perceived contrast of the test, particularly for high-contrast test patterns. Iso-orientation modulation acts over larger distances than does cross-orientation modulation. Surround modulation of perceived contrast is not accompanied by a simultaneous change of discrimination threshold. (2) Iso-orientation surround suppression is phase insensitive when brightness induction due to local luminance contrast is eliminated by a small center-surround gap. (3) Perceived contrast is similarly affected when the surround spatial frequency is equal to or higher than the center spatial frequency, but lower spatial frequency surrounds markedly enhance perceived contrast as a result of brightness induction. These data indicate that the contrast-contrast phenomenon is often mixed with brightness induction when it is measured with sinusoidal grating stimuli, and we suggest that this may account for some of the individual differences. After excluding the role of brightness induction, surround modulation of perceived contrast appears to be a second-order process that is phase independent and not tuned or very broadly tuned to spatial frequency.


Membrane-Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity.
The SLC45A2 gene encodes a Membrane-Associated Transporter Protein (MATP). Mutations of this gene cause oculocutaneous albinism type 4 (OCA4). However, the molecular mechanism of its action in melanogenesis has not been elucidated. Here, we discuss the role of MATP in melanin production. The SLC45A2 gene is highly enriched in human melanocytes and melanoma cell lines, and its protein, MATP, is located in melanosomes. The knockdown of MATP using siRNAs reduced melanin content and tyrosinase activity without any morphological change in melanosomes or the expression of melanogenesis-related proteins. Interestingly, the knockdown of MATP significantly lowered the melanosomal pH, as verified through DAMP analysis, suggesting that MATP regulates melanosomal pH and therefore affects tyrosinase activity. Finally, we found that the reduction of tyrosinase activity associated with the knockdown of MATP was readily recovered by copper treatment in the in vitro L-DOPA oxidase activity assay of tyrosinase. Considering that copper is an important element for tyrosinase activity and that its binding to tyrosinase depends on melanosomal pH, MATP may play an important role in regulating tyrosinase activity via controlling melanosomal pH.


Feasibility of remote digital monitoring using wireless Bluetooth monitors, the Smart Angel™ app and an original web platform for patients following outpatient surgery: a prospective observational pilot study.
Remote monitoring of mean arterial blood pressure (MAP), heart rate (HR) or oxygen saturation (SpO2) remains a challenge in outpatient surgery. This study evaluates a new digital technology (Smart Angel™) for remotely monitoring hemodynamic data in real time: data transmitted from the patient's home to a central server, using a dedicated web-based software package. Adults scheduled for elective outpatient surgery were prospectively enrolled. In the first 5 postoperative days, patients completed a self-report questionnaire (pain, comfort, nausea, vomiting) and recorded SpO2, HR and MAP via two wireless Bluetooth monitors connected to a 4G tablet to transmit the data to a website, in real time, using Smart Angel™ software. Before transmission to the website, these data were also self-reported by the patient on a paper form. The primary outcome was the proportion of variables (self-monitored physiological data + questionnaire scores) correctly transmitted to the hospital via the system compared with the paper version. On Day 5, a system usability scale survey (SUS score 1-100) was also attributed. From May 2018 to September 2018, data were available for 29 out of 30 patients enrolled (1 patient was not discharged from hospital after surgery). The remote monitoring technology recorded 2038 data items (62%) compared with 2656 (82%) items recorded on the paper form (p = 0.001). The most common errors with the remote technology were software malfunctioning when starting the MAP monitor and malfunctioning between the tablet and the Bluetooth monitor. No serious adverse events were noted. The SUS score for the system was 85 (68-93) for 26 patients. This work evaluates the ability of a pilot system for monitoring remote physiological data using digital technology after ambulatory surgery and highlights the digital limitations of this technology. Technological improvements are required to reduce malfunctioning (4G access, transmission between apps). ClinicalTrials.gov ( NCT03464721 ) (March 8, 2018).


Ultrasonography-guided 14-gauge core biopsy of the breast: results of 7 years of experience.
This study assessed the outcomes of ultrasound (US)-guided core needle biopsies (CNBs) of breast lesions with at least 2 years of follow-up to determine the false-negative rate and to evaluate the diagnostic accuracy of CNB. We retrospectively analyzed 13,254 consecutive US-guided 14-gauge CNBs for breast lesions. We excluded biopsies if non-malignant biopsy result was not confirmed by surgical excision or US-guided vacuum-assisted biopsy, or fewer than 2 years of follow-up data were available. A total of 4,186 biopsies were excluded, and 9,068 breast masses from 7,039 women were included. The pathologic findings from each CNB were assessed using the standard diagnostic reference, defined based on the results of surgical excision, vacuum-assisted biopsy, or at least 2 years of long-term imaging follow-up. The false-negative rate and underestimation rate were calculated. Of the 9,068 CNBs, benign pathology was found in 64.2%, high-risk results in 3.5%, and malignant results in 32.3%. Of the 5,821 benign CNBs, an additional malignancy was found at excision in 63 lesions, leading to a false-negative rate of 2.0% (63 of 3,067). The underestimation rate was 33.6% (111 of 330) for ductal carcinoma in situ and 24.5% (79 of 322) for high-risk results at surgical excision. Most false-negative diagnoses (84.1%, 53 of 63) were recognized through imaging-histology correlations, and immediate rebiopsies were performed. Ten malignancies (15.9%, 10 of 63) had delayed diagnoses and showed progression in follow-up US imaging. US-guided 14-gauge CNB provided optimal diagnostic information. Imaging-histology correlations and appropriate imaging follow-up should be performed to avoid delayed diagnoses.


Polygenic Risk Score Analysis of Alzheimer's Disease in Cases without APOE4 or APOE2 Alleles.
The We and others have previously shown that polygenic risk score analysis (PRS) has considerable predictive utility for identifying those at high risk of developing Alzheimer's disease (AD) with an area under the curve (AUC) of >0.8. However, by far the greatest determinant of this risk is the apolipoprotein E locus with the E4 allele alone giving an AUC of ~0.68 and the inclusion of the protective E2 allele increasing this to ~0.69 in a clinical cohort. An important question is to determine how good PRS is at predicting risk in those who do not carry the E4 allele (E3 homozygotes, E3E2 and E2E2) and in those who carry neither the E4 or E2 allele (i.e. E3 homozygotes). Previous studies have shown that PRS remains a significant predictor of AD risk in clinical cohorts after controlling for APOE ε4 carrier status. In this study we assess the accuracy of PRS prediction in a cohort of pathologically confirmed AD cases and controls. The exclusion of APOE4 carriers has surprisingly little effect on the PRS prediction accuracy (AUC ~0.83 [95% CI: 0.80-0.86]), and the accuracy remained higher than that in clinical cohorts with APOE included as a predictor. From a practical perspective this suggests that PRS analysis will have predictive utility even in E4 negative individuals and may be useful in clinical trial design.


B-cell precursors specific to sheep erythrocytes. Estimation of frequency in a specific helper assay.
A sensitive, specific, and reproducible in vitro helper assay is described which is suited to limiting dilution analysis of murine B cells. 1 in about 3,000 syngeneic splenic B cells can be induced to form plaque-forming cells (PFC) to sheep erythrocytes in this system. The induction of PFC is absolutely dependent on antigen and specific helper T cells.


Effects of arsenate (AS5+) on growth and production of glutathione (GSH) and phytochelatins (PCS) in Chlorella vulgaris.
The effect of arsenate (As5+) on growth and chlorophyll a production in Chlorella vulgaris, its removal by C. vulgaris and the role of glutathione (GSH) and phytochelatins (PCs) were investigated. C. vulgaris was tolerant to As5+ at up to 200 mg/L and was capable of consistently removing around 70% of the As5+ present in growth media over a wide range of exposure concentrations. Spectral analysis revealed that PCs and their arsenic-combined complexes were absent, indicating that the high bioaccumulation and tolerance to arsenic observed was not due to intracellular chelation. In contrast, GSH was found in all samples ranging from 0.8 mg/L in the control to 6.5 mg/L in media containing 200 mg/L As5+ suggesting that GSH plays a more prominent role in the detoxification of As5+ in C. vulgaris than PC. At concentrations below 100 mg/L cell surface binding and other mechanisms may play the primary role in As5+ detoxification, whereas above this concentration As5+ begins to accumulate inside the algal cells and activates a number of intracellular cell defense mechanisms, such as increased production of GSH. The overall findings complement field studies which suggest C. vulgaris as an increasingly promising low cost As phytoremediation method for developing countries.


Effect of inflammatory activity and glucocorticoid [corrected] use on nutritional variables in patients with juvenile idiopathic arthritis.
To assess nutritional status in patients with juvenile idiopathic arthritis (JIA) and the influence of inflammatory activity and glucocorticoid use. One hundred sixteen patients were evaluated. Disease subtype and disease activity were defined by the attending physician, and the cumulative glucocorticoid dose was recorded from chart review. Percentiles of body mass index (BMI) and triceps skinfold (TSF) and the Z score for height were determined: low weight and low adiposity were diagnosed when BMI and TSF were below the 5th percentile. Short stature was defined by a Z score of height for age < -2. Serum concentration of insulin-like growth factor-I (IGF-I) was measured by radioimmunoassay. The prevalences of low weight, low adiposity, and short stature were 16.4%, 20.7%, and 10.4%, respectively. Low IGF-I serum level was found in 14 patients (12.1%). The factors negatively associated with the Z score of height in multivariable regression analysis were disease duration (partial correlation coefficient -0.370, 95% confidence interval: -0.527 to -0.188; p < 0.001), erythrocyte sedimentation rate (ESR) (-0.357, -0.516 to -0.174; p < 0.001), and polyarticular or systemic disease subtype (-0.290, -0.459 to -0.100; p = 0.003), while there was no significant correlation with the cumulative dose of glucocorticoids (0.086, -0.111 to 0.277; p = 0.391). None of these variables was significantly correlated with the percentiles of BMI and TSF, albeit confidence intervals for these correlation coefficients were relatively large. Patients with a systemic or polyarticular disease subtype tended to present lower percentiles of BMI (p = 0.051). Nutritional status is frequently compromised in patients with JIA. Duration and disease subtype and the ESR are factors independently associated with short stature. The cumulative dose of glucocorticoids was not independently associated with short stature or with other nutritional variables, although a relevant negative effect of glucocorticoid dose on BMI and TSF cannot be entirely excluded.