Across-breed adjustment factors for expected progeny differences for carcass traits.
Adjustment factors to allow comparison of EPD from several breed associations for birth, weaning, and yearling weights have been available for more than 10 yr. This paper describes steps to calculate adjustment factors for EPD for 4 carcass traits: marbling score, fat thickness, ribeye area, and retail product percentage. The required information is the same as for the weight traits: 1) breed of sire solutions based on measurements on progeny at the US Meat Animal Research Center (USMARC) that have sires with breed association EPD, 2) mean EPD of sires weighted by number of progeny at USMARC (USMARC progeny not included in breed association EPD), and 3) mean EPD of nonparents from breed associations (defined as animals born 2 yr prior to calculation of EPD). Records at USM-ARC are adjusted to 100% heterozygosity because the purpose of the adjustment factors is to allow prediction of performance of progeny of sires mated to other breeds of dam. A critical step is to adjust breed of sire solutions, which are based on an earlier sample of sires, to the equivalent of a sample from a more recent nonparent group using the difference between mean EPD from information sources 2) and 3). The difference is multiplied by the coefficient of regression of USMARC progeny on EPD of their sires. With weight traits, these coefficients are not greatly different from unity. With the carcass traits, 2 sets of coefficients can be used depending on whether the EPD are based on carcass or ultrasound measurements. The regression coefficients also reflect differences in conditions for USMARC progeny (all steers) and factors associated with breed association EPD. Only for marbling score and ribeye area were any estimates of the regression coefficients near unity. For other traits, the coefficients ranged from 1.65 to 2.82. The solutions for breed of sire, differences in mean EPD, and regression coefficients are then used to calculate adjustment factors for EPD of 11 breeds including the arbitrary base breed, Angus.


Screening for germline phosphatase and tensin homolog-mutations in suspected Cowden syndrome and Cowden syndrome-like families among uterine cancer patients.
Cowden syndrome (CS) is an autosomal dominant disorder characterized by multiple hamartomas in the breast, thyroid and endometrium, with a prevalence of 1 per 250,000. Females with CS have a 21-28% lifetime risk of developing uterine cancer. Germline mutations in the phosphatase and tensin homolog (PTEN) gene, a tumor suppressor gene, are responsible for 30-80% of CS cases. PTEN is a nine-exon gene, located on chromosome 10q23.3, which encodes the 403 amino acid PTEN protein. It negatively regulates the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway, affecting various cellular processes and signaling pathways. The present study examined whether PTEN mutations are present in CS-like families with uterine cancer (UC). UC patients underwent surgery at Karolinska University Hospital, Stockholm, Sweden (2008-2012). Pedigrees were analyzed and 54 unrelated CS-like families were identified. CS-like families were defined as having at least one occurrence of uterine cancer and one of breast cancer, as well as at least one additional Cowden-associated tumor (uterine, breast, thyroid, colon or kidney cancer) in the same individual or in first-degree relatives. Genomic DNA was amplified using polymerase chain reaction, and DNA sequencing analysis of all nine exons of the PTEN gene was conducted. No germline PTEN mutations or polymorphisms were identified. Germline PTEN mutations are rare in CS-like families with uterine cancer, therefore, genetic screening must be restricted to patients that meet the strict National Comprehensive Cancer Network criteria. Gynecologists must be aware of the CS criteria and identify potential cases of CS in females where uterine cancer is the sentinel cancer.


Crystal structure of bullfrog M ferritin at 2.8 A resolution: analysis of subunit interactions and the binuclear metal center.
Ferritins concentrate and store iron as a mineral in all bacterial, plant, and animal cells. The two ferritin subunit types, H or M (fast) and L (slow), differ in rates of iron uptake and mineralization and assemble in vivo to form heteropolymeric protein shells made up of 24 subunits; H/L subunit ratios reflect cell specificity of H and L subunit gene expression. A diferric peroxo species that is the initial reaction product of Fe(II) in H-type ferritins, as well as in ribonucleotide reductase (R2) and methane monooxygenase hydroxylase (MMOH), has recently been characterized, exploiting the relatively high accumulation of the peroxo intermediate in frog H-subunit type recombinant ferritin with the M sequence. The stability of the diferric reaction centers in R2 and MMOH contrasts with the instability of diferric centers in ferritin, which are precursors of the ferric mineral. We have determined the crystal structure of the homopolymer of recombinant frog M ferritin in two crystal forms: P4(1)2(1)2, a = b = 170.0 A and c = 481.5 A; and P3(1)21, a = b = 210.8 A and c = 328.1 A. The structural model for the trigonal form was refined to a crystallographic R value of 19.0% (Rfree = 19.4%); the two structures have an r.m.s.d. of approximately 0.22 A for all C alpha atoms. Comparison with the previously determined crystal structure of frog L ferritin indicates that the subunit interface at the molecular twofold axes is most variable, which may relate to the presence of the ferroxidase site in H-type ferritin subunits. Two metal ions (Mg) from the crystallization buffer were found in the ferroxidase site of the M ferritin crystals and interact with Glu23, Glu58, His61, Glu103, Gln137 and, unique to the M subunit, Asp140. The data suggest that Gln137 and Asp140 are a vestige of the second GluxxHis site, resulting from single nucleotide mutations of Glu and His codons and giving rise to Ala140 or Ser140 present in other eukaryotic H-type ferritins, by additional single nucleotide mutations. The observation of the Gln137xxAsp140 site in the frog M ferritin accounts for both the instability of the diferric oxy complexes in ferritin compared to MMOH and R2 and the observed kinetic variability of the diferric peroxo species in different H-type ferritin sequences.


Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood.
There are well-recognized sex differences in many pituitary endocrine axes, usually thought to be generated by gonadal steroid imprinting of the neuroendocrine hypothalamus. However, the recognition that growth hormone (GH) cells are arranged in functionally organized networks raises the possibility that the responses of the network are different in males and females. We studied this by directly monitoring the calcium responses to an identical GH-releasing hormone (GHRH) stimulus in populations of individual GH cells in slices taken from male and female murine GH-eGFP pituitary glands. We found that the GH cell network responses are sexually dimorphic, with a higher proportion of responding cells in males than in females, correlated with greater GH release from male slices. Repetitive waves of calcium spiking activity were triggered by GHRH in some males, but were never observed in females. This was not due to a permanent difference in the network architecture between male and female mice; rather, the sex difference in the proportions of GH cells responding to GHRH were switched by postpubertal gonadectomy and reversed with hormone replacements, suggesting that the network responses are dynamically regulated in adulthood by gonadal steroids. Thus, the pituitary gland contributes to the sexually dimorphic patterns of GH secretion that play an important role in differences in growth and metabolism between the sexes.


Pericellular conditions regulate extent of cell-mediated compaction of collagen gels.
Cell-mediated compaction of the extracellular matrix (ECM) plays a critical role in tissue engineering, wound healing, embryonic development, and many disease states. The ECM is compacted as a result of cellular traction forces. We hypothesize that a cell mechanically remodels the nearby ECM until some target conditions are obtained, and then the cell stops compacting. A key feature of this hypothesis is that ECM compaction primarily occurs in the pericellular region and the properties of the ECM in the pericellular region govern cellular force generation. We developed a mathematical model to describe the amount of macroscopic compaction of cell-populated collagen gels in terms of the initial cell and collagen densities, as well as the final conditions of the pericellular environment (defined as the pericellular volume where the collagen is compacted (V(*)) and the mass of collagen within this volume (m(*))). This model qualitatively predicts the effects of varying initial cell and collagen concentrations on the extent of gel compaction, and by fitting V(*) and m(*), provides reasonable quantitative agreement with the extent of gel compaction observed in experiments with endothelial cells and fibroblasts. Microscopic analysis of compacted gels supports the assumption that collagen compaction occurs primarily in the pericellular environment.


Crystal structure of abrin-a at 2.14 A.
The crystal structure of abrin-a, a type II ribosome-inactivating protein from the seeds of Abrus precatorius, has been determined from a novel crystalline form by the molecular replacement method using the coordinates of ricin. The structure has been refined at 2.14 A to a R-factor of 18.9%. The root-mean-square deviations of bond lengths and angles from the standard values are 0.013 A and 1.82 degrees, respectively. The overall protein folding is similar to that of ricin, but there are differences in the secondary structure, mostly of the A-chain. Several parts of the molecular surface differ significantly; some of them are quite near the active site cleft, and probably influence ribosome recognition. The positions of invariant active site residues remain the same, except the position of Tyr74. Two water molecules of hydrogen-bonded active site residues have been located in the active site cleft. Both of them may be responsible for hydrolyzing the N-C glycosidic bond. The current abrin-a structure is lactose free; this is probably essential for abrin-a crystallization. The B-chain is a glycoprotein, and the positions of several sugar residues of two sugar chains linked to earlier predicted glycosylation sites were determined. One of the sugar chains is a bridge between two neighboring molecules, since one of its mannose residues is connected to the galactose binding site of the neighboring molecule. Another sugar chain covers the surface of the B-chain.


Kangaroo Mother Care and Neonatal Outcomes: A Meta-analysis.
Kangaroo mother care (KMC) is an intervention aimed at improving outcomes among preterm and low birth weight newborns. Conduct a systematic review and meta-analysis estimating the association between KMC and neonatal outcomes. PubMed, Embase, Web of Science, Scopus, African Index Medicus (AIM), Latin American and Caribbean Health Sciences Information System (LILACS), Index Medicus for the Eastern Mediterranean Region (IMEMR), Index Medicus for the South-East Asian Region (IMSEAR), and Western Pacific Region Index Medicus (WPRIM). We included randomized trials and observational studies through April 2014 examining the relationship between KMC and neonatal outcomes among infants of any birth weight or gestational age. Studies with <10 participants, lack of a comparison group without KMC, and those not reporting a quantitative association were excluded. Two reviewers extracted data on study design, risk of bias, KMC intervention, neonatal outcomes, relative risk (RR) or mean difference measures. 1035 studies were screened; 124 met inclusion criteria. Among LBW newborns, KMC compared to conventional care was associated with 36% lower mortality(RR 0.64; 95% [CI] 0.46, 0.89). KMC decreased risk of neonatal sepsis (RR 0.53, 95% CI 0.34, 0.83), hypothermia (RR 0.22; 95% CI 0.12, 0.41), hypoglycemia (RR 0.12; 95% CI 0.05, 0.32), and hospital readmission (RR 0.42; 95% CI 0.23, 0.76) and increased exclusive breastfeeding (RR 1.50; 95% CI 1.26, 1.78). Newborns receiving KMC had lower mean respiratory rate and pain measures, and higher oxygen saturation, temperature, and head circumference growth. Lack of data on KMC limited the ability to assess dose-response. Interventions to scale up KMC implementation are warranted.


Key constituents for integration of care for children assisted with long-term home ventilation: a European study.
The number of children requiring long-term home ventilation has consistently increased over the last 25 years. Given the growing population of children with complex care needs (CCNs), this was an important area of focus within the Models of Child Health Appraised (MOCHA) project, funded by the European Union (EU) under the Horizon 2020 programme. We examined the structures and processes of care in place for children with CCNs and identified key constituents for effective integration of care for these children at the community and acute care interface across 30 EU/ European Economic Area (EEA) countries. This was a non-experimental descriptive study with an embedded qualitative element. Data were collected by a Country Agent in each of the 30 countries, a local expert in child health services. Data were analysed using descriptive statistics and a thematic analysis was undertaken of the free text data provided. A total of 27 surveys were returned from a possible 30 countries (90.0%) countries. One respondent indicated that their country does not have children on long-term ventilation (LTV) in the home, therefore, responses of 26 countries (86.7%) were analysed. None of the responding countries reported that they had all of the core components in place in their country. Three themes emerged from the free text provided: 'family preparedness for transitioning to home', 'coordinated pathway to specialist care' and 'legal and governance structures'. While the clinical care of children on LTV in the acute sector has received considerable attention, the results identify the need for an enhanced focus on the care required following discharge to the community setting. The results highlight the need for a commitment to supporting care delivery that acknowledges the complexity of contemporary child health issues and the context of the families that become their primary care givers.


Co-infections with Plasmodium falciparum, Schistosoma mansoni and intestinal helminths among schoolchildren in endemic areas of northwestern Tanzania.
Malaria, schistosomiasis and intestinal helminth infections are causes of high morbidity in most tropical parts of the world. Even though these infections often co-exist, most studies focus on individual diseases. In the present study, we investigated the prevalence of Plasmodium falciparum-malaria, intestinal schistosomiasis, soil-transmitted helminth infections, and the respective co-infections, among schoolchildren in northwest Tanzania. A cross sectional study was conducted among schoolchildren living in villages located close to the shores of Lake Victoria. The Kato Katz technique was employed to screen faecal samples for S. mansoni and soil-transmitted helminth eggs. Giemsa stained thick and thin blood smears were analysed for the presence of malaria parasites. Of the 400 children included in the study, 218 (54.5%) were infected with a single parasite species, 116 (29%) with two or more species, and 66 (16.5%) had no infection. The prevalences of P. falciparum and S. mansoni were 13.5% (95% CI, 10.2-16.8), and 64.3% (95% CI, 59.6-68.9) respectively. Prevalence of hookworm infection was 38% (95% CI, 33.2-42.8). A. lumbricoides and T. trichiura were not detected. Of the children 26.5% (95% CI, 21.9-30.6) that harbored two parasite species, combination of S. mansoni and hookworm co-infections was the most common (69%). Prevalence of S. mansoni - P. falciparum co-infections was 22.6% (95%CI, 15.3-31.3) and that of hookworm - P. falciparum co-infections 5.7% (95%CI, 2.6-12.8). Prevalence of co-infection of P. falciparum, S. mansoni and hookworm was 2.8% (95%CI, 1.15-4.4). Multiple parasitic infections are common among schoolchildren in rural northwest Tanzania. These findings can be used for the design and implementation of sound intervention strategies to mitigate morbidity and co-morbidity.


Predictability of anthrax infection in the Serengeti, Tanzania.
Anthrax is endemic throughout Africa, causing considerable livestock and wildlife losses and severe, sometimes fatal, infection in humans. Predicting the risk of infection is therefore important for public health, wildlife conservation and livestock economies. However, because of the intermittent and variable nature of anthrax outbreaks, associated environmental and climatic conditions, and diversity of species affected, the ecology of this multihost pathogen is poorly understood.We explored records of anthrax from the Serengeti ecosystem in north-west Tanzania where the disease has been documented in humans, domestic animals and a range of wildlife. Using spatial and temporal case-detection and seroprevalence data from wild and domestic animals, we investigated spatial, environmental, climatic and species-specific associations in exposure and disease.Anthrax was detected annually in numerous species, but large outbreaks were spatially localized, mostly affecting a few focal herbivores.Soil alkalinity and cumulative weather extremes were identified as useful spatial and temporal predictors of exposure and infection risk, and for triggering the onset of large outbreaks.Interacting ecological and behavioural factors, specifically functional groups and spatiotemporal overlap, helped to explain the variable patterns of infection and exposure among species.Synthesis and applications. Our results shed light on ecological drivers of anthrax infection and suggest that soil alkalinity and prolonged droughts or rains are useful predictors of disease occurrence that could guide risk-based surveillance. These insights should inform strategies for managing anthrax including prophylactic livestock vaccination, timing of public health warnings and antibiotic provision in high-risk areas. However, this research highlights the need for greater surveillance (environmental, serological and case-detection-orientated) to determine the mechanisms underlying anthrax dynamics.


Twenty years of immunocontraceptive research: lessons learned.
The National Wildlife Research Center (NWRC) began immunocontraception vaccine research by testing porcine zona pellucida (PZP) on white-tailed deer (Odocoileus virginianus). Early PZP research demonstrated that PZP induced infertility; however, increased length of the rut was observed in PZP-treated deer. An alternative vaccine using a keyhole limpet hemocyanin-gonadotropin-releasing hormone (KLH-GnRH) conjugate formulated with modified Freund's adjuvant was developed at NWRC. Suppression of GnRH has reduced reproduction in both sexes but is most effective in females. This vaccine was effective in preventing contraception in female deer for several years after a prime and boost. Due to adverse side effects of Freund's adjuvant, NWRC developed a new adjuvant called AdjuVac, a mineral oil/surfactant adjuvant with the addition of Mycobacterium avium as an immunostimulant. The price of KLH prompted a search for a more economical hemocyanin carrier protein for the GnRH peptide. Blue protein, derived from the mollusk Concholepas concholepas, proved to be a successful option. Formulation improvements resulted in a vaccine that can be effective as a single injection for multiple years, now called GonaCon. GonaCon is registered with the Environmental Protection Agency (EPA) for use in white-tailed deer in urban/suburban areas and for wild horses (Equus caballus) and burros (Equus asinus). Future GonaCon applications may include reducing reproduction to manage populations of other wildlife species, such as prairie dogs (Cynomys ludovicianus) in urban areas and suppressing reproduction to reduce the spread of venereal diseases such as brucellosis. Research is being conducted to develop a GnRH vaccine used in combination with the rabies vaccine to control population growth in free-roaming dogs, with the secondary effect of managing the spread of rabies. The EPA would regulate all these uses. Research is also ongoing on a GnRH vaccine to delay the onset of adrenocortical disease in pet ferrets (Mustela putorius), a use regulated by the United States Department of Agriculture.


Racial and ethnic minority medical students' perceptions of and interest in careers in academic medicine.
To describe diverse medical students' perceptions of and interest in careers in academic medicine. In 2010, the authors invited students attending three national medical student conferences to respond to a survey and participate in six focus groups. The authors identified trends in data through bivariate analyses of the quantitative dataset and using a grounded theory approach in their analysis of focus group transcripts. The 601 survey respondents represented 103 U.S. medical schools. The majority (72%) were in their first or second year; 34% were black and 17% were Hispanic. Many respondents (64%) expressed interest in careers in academic medicine; teaching and research were viewed as positive influences on that interest. However, black and Hispanic respondents felt they would have a harder time succeeding in academia. The 73 focus group participants (25% black, 29% Hispanic) described individual- and institutional-level challenges to academic medicine careers and offered recommendations. They desired deliberate and coordinated exposure to academic career paths, research training, clarification of the promotion process, mentorship, protected time for faculty to provide teaching and research training, and an enhanced infrastructure to support diversity and inclusion. Medical students expressed an early interest in academic medicine but lacked clarity about the career path. Black and Hispanic students' perceptions of having greater difficulty succeeding in academia may be an obstacle to engaging them in the prospective pool of academicians. Strategic and dedicated institutional resources are needed to encourage racial and ethnic minority medical students to explore careers in academic medicine.


Who is afraid of black box algorithms? On the epistemological and ethical basis of trust in medical AI.
The use of black box algorithms in medicine has raised scholarly concerns due to their opaqueness and lack of trustworthiness. Concerns about potential bias, accountability and responsibility, patient autonomy and compromised trust transpire with black box algorithms. These worries connect epistemic concerns with normative issues. In this paper, we outline that black box algorithms are less problematic for epistemic reasons than many scholars seem to believe. By outlining that more transparency in algorithms is not always necessary, and by explaining that computational processes are indeed methodologically opaque to humans, we argue that the reliability of algorithms provides reasons for trusting the outcomes of medical artificial intelligence (AI). To this end, we explain how computational reliabilism, which does not require transparency and supports the reliability of algorithms, justifies the belief that results of medical AI are to be trusted. We also argue that several ethical concerns remain with black box algorithms, even when the results are trustworthy. Having justified knowledge from reliable indicators is, therefore, necessary but not sufficient for normatively justifying physicians to act. This means that deliberation about the results of reliable algorithms is required to find out what is a desirable action. Thus understood, we argue that such challenges should not dismiss the use of black box algorithms altogether but should inform the way in which these algorithms are designed and implemented. When physicians are trained to acquire the necessary skills and expertise, and collaborate with medical informatics and data scientists, black box algorithms can contribute to improving medical care.


Reliability of a viva assessment of clinical reasoning in an Australian pre-professional osteopathy program assessed using generalizability theory.
Clinical reasoning is situation-dependent and case-specific; therefore, assessments incorporating different patient presentations are warranted. The present study aimed to determine the reliability of a multi-station case-based viva assessment of clinical reasoning in an Australian pre-registration osteopathy program using generalizability theory. Students (from years 4 and 5) and examiners were recruited from the osteopathy program at Southern Cross University, Lismore, Australia. The study took place on a single day in the student teaching clinic. Examiners were trained before the examination. Students were allocated to 1 of 3 rounds consisting of 5 10-minute stations in an objective structured clinical examination-style. Generalizability analysis was used to explore the reliability of the examination. Fifteen students and 5 faculty members participated in the study. The examination produced a generalizability coefficient of 0.53, with 18 stations required to achieve a generalizability coefficient of 0.80. The reliability estimations were acceptable and the psychometric findings related to the marking rubric and overall scores were acceptable; however, further work is required in examiner training and ensuring consistent case difficulty to improve the reliability of the examination.


Validation of Nordic dairy cattle disease recording databases--completeness for locomotor disorders.
The Nordic countries Denmark (DK), Finland (FIN), Norway (NO) and Sweden (SE) all have unique national databases holding the disease records of dairy cows. The objective of this study was to estimate and compare completeness for locomotor disorders in the four Nordic national databases. Completeness figures for farmer-recorded disease events were calculated on two different levels: the first refers to disease events that were observed on the farm regardless of whether a veterinarian had been involved (FARMER); the second refers to farmer records of cases attended by a veterinarian, i.e. to veterinarian-treated disease events (VET). A sample of herds with 15 or more cows was obtained from a simple random sample of dairy farms in FIN, NO and SE, and from a systematic random sample in DK. There were 105, 167, 179 and 129 participating farmers in DK, FIN, NO and SE, respectively, and during two 2-month periods in 2008 these farmers recorded the disease events they observed on the farm. Data from the four national databases were extracted in May 2009. The two data sources, farmer recordings and national databases, were managed in a comparable way in all four countries, and common diagnostic codes were created and added to match recordings appearing in both datasets. In all 555 farmers completed data records in the first data-recording period, and 515 farmers did so in the second period. In DK, FIN, NO and SE, 55%, 77%, 82% and 75%, participating farmers completed the recordings during the first recording period, respectively; the corresponding figures for the second recording period were 71%, 82%, 83% and 91%. To calculate completeness, disease cases recorded in the national databases were compared with the farmer recordings using an exact match for the locomotor complex defined as same country, herd identification number (id), cow id, and event date at the levels of FARMER and VET. Completeness at FARMER level were 0.22, 0.21, 0.23 and 0.12 in DK, FIN, NO and SE, respectively. At VET level they were 0.37, 0.27, 0.34 and 0.17. To compare differences in completeness between countries exact 95% confidence intervals were calculated. There were significant differences in completeness between DK and SE at both FARMER and VET level. The completeness indicate that the ability to estimate true disease occurrences in the four national databases varies and is in general poor. Completeness should be taken into account when disease occurrences in different countries are compared.


Protecting the triplet excited state in sterically congested platinum porphyrin.
Platinum tetrakis(2,4,6-triethylphenyl)porphyrin (Pt-1) was synthesized and its structural (X-ray), electrochemical and photophysical properties were fully characterized. Comparative studies of Pt-1 and its unsubstituted analog PtTPP show the effect of sterically congesting ortho-substituents on the dynamics of the triplet excited states. Lowered quenching rates by 3-4 times were observed for Pt-1vs. PtTPP in the presence of oxygen and perylene, and in concentration (self)-quenching experiments.


[Trauma repetition and revictimization following physical and sexual abuse].
The tendency of victims of physical or sexual childhood abuse to become revictimized in later life has well been documented empirically. Moreover, there is a high stability of violent and abusive relationships. The aim of this paper was to summarize perspectives from psychodynamic theory, attachment theory, and posttraumatic stress research to explain revictimization phenomena. The term repetition compulsion has little explanatory value without additional theoretical assumptions. Within the psychodynamic framework, an ego-psychological view conceives trauma repetition as an attempt to master traumatic experience, while in the object relations perspective, revictimization is explained by the influence of traumatic introjects. Negative cognitions of being worthless, bad and guilty can endorse the conviction that abuse is justified and reduce the capacity of self-care. Negative learning experiences from traumatic helplessness and powerlessness account for low self-efficacy expectations and prevent the establishment of self-boundaries. Trauma repetition can also be understood as an enactment in the service of affect regulation. Research in the field of attachment theory identified attachment styles predisposing to revictimization. Research dealing with posttraumatic stress disorder emphasizes the importance of traumatic affects recurring in daily life and, consequently, the tendency of abuse victims to actively produce dangerous situations in order to cope with these affects, furthermore, the role of dissociation in missing warning signals of impending traumatization. For therapeutically addressing revictimization, a detailed analysis of underlying phenomena is required.


Molecular phylogenetic and dating analysis of pierid butterfly species using complete mitochondrial genomes.
Pieridae is a butterfly family whose evolutionary history is poorly understood. Due to the difficulties in identifying morphological synapomorphies within the group and the scarcity of the fossil records, only a few studies on higher phylogeny of Pieridae have been reported to date. In this study, we describe the complete mitochondrial genomes of four pierid butterfly species (Aporia martineti, Aporia hippia, Aporia bieti, and Mesapia peloria), in order to better characterize the pierid butterfly mitogenomes and perform the phylogenetic analyses using all available mitogenomic sequence data (13PCGs, rRNAs, and tRNAs) from the 18 pierid butterfly species comprising the three main subfamilies (Dismorphiinae, Coliadinae and Pierinae). Our analysis shows that the four new mitogenomes share similar features with other known pierid mitogenomes in gene order and organization. Phylogenetic analyses by maximum likelihood and Bayesian inference show that the pierid higher-level relationship is: Dismorphiinae + (Coliadinae + Pierinae), which corroborates the results of some previous molecular and morphological studies. However, we found that the Hebomoia and Anthocharis make a sister group, supporting the traditional tribe Anthocharidini; in addition, the Mesapia peloria was shown to be clustered within the Aporia group, suggesting that the genus Mesapia should be reduced to the taxonomic status of subgenus. Our molecular dating analysis indicates that the family Pieridae began to diverge during the Late Cretaceous about 92 million years ago (mya), while the subfamily Pierinae diverged from the Coliadinae at about 86 mya (Late Cretaceous).


The effects of economic conditions and access to reproductive health services on state abortion rates and birthrates.
The effects that such factors as wages, welfare policies and access to physicians, family planning clinics and abortion providers have on abortion rates and birthrates are examined in analyses based on 1978-1988 state-level data and longitudinal regression techniques. The incidence of abortion is found to be lower in states where access to providers is reduced and state policies are restrictive. Calculations indicate that decreased access may have accounted for about one-quarter of the 5% decline in abortion rates between 1988 and 1992. In addition, birthrates are elevated where the costs of contraception are higher because access to obstetrician-gynecologists and family planning services is reduced. Economic resources such as higher wages for men and women and generous welfare benefits are significantly and consistently related to increased birthrates; however, even a 10% cut in public assistance benefits would result in only one birth fewer for every 212 women on welfare. Economic factors showed no consistent relationship with abortion rates.


Bridging the gaps between research, policy and practice in low- and middle-income countries: a survey of health care providers.
Gaps continue to exist between research-based evidence and clinical practice. We surveyed health care providers in 10 low- and middle-income countries about their use of research-based evidence and examined factors that may facilitate or impede such use. We surveyed 1499 health care providers practising in one of four areas relevant to the Millennium Development Goals (prevention of malaria, care of women seeking contraception, care of children with diarrhea and care of patients with tuberculosis) in each of China, Ghana, India, Iran, Kazakhstan, Laos, Mexico, Pakistan, Senegal and Tanzania. The proportion of respondents who reported that research was likely to change their clinical practice if performed and published in their own country (84.6% and 86.0% respectively) was higher than the proportion who reported the same about research and publications from their region (66.4% and 63.1%) or from high-income countries (55.8% and 55.5%). Respondents who were most likely to report that the use of research-based evidence led to changes in their practice included those who reported using clinical practice guidelines in paper format (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.03-2.28), using scientific journals from their own country in paper format (OR 1.70, 95% CI 1.26-2.28), viewing the quality of research performed in their country as above average or excellent (OR 1.93, 95% CI 1.16-3.22); trusting systematic reviews of randomized controlled trials (OR 1.59, 95% CI 1.08-2.35); and having easy access to the Internet (OR 1.90, 95% CI 1.19-3.02). Locally conducted or published research has played an important role in changing the professional practice of health care providers surveyed in low- and middle-income countries. Increased investments in local research, or at least in locally adapted publications of research-based evidence from other settings, are therefore needed. Although access to the Internet was viewed as a significant factor in whether research-based evidence led to concrete changes in practice, few respondents reported having easy access to the Internet. Therefore, efforts to improve Internet access in clinical settings need to be accelerated.


Animal Models of Peritoneal Dialysis: Thirty Years of Our Own Experience.
Experimental animal models improve our understanding of technical problems in peritoneal dialysis PD, and such studies contribute to solving crucial clinical problems. We established an acute and chronic PD model in nonuremic and uremic rats. We observed that kinetics of PD in rats change as the animals are aging, and this effect is due not only to an increasing peritoneal surface area, but also to changes in the permeability of the peritoneum. Changes of the peritoneal permeability seen during chronic PD in rats are comparable to results obtained in humans treated with PD. Effluent dialysate can be drained repeatedly to measure concentration of various bioactive molecules and to correlate the results with the peritoneal permeability. Additionally we can study in in vitro conditions properties of the effluent dialysate on cultured peritoneal mesothelial cells or fibroblasts. We can evaluate acute and chronic effect of various additives to the dialysis fluid on function and permeability of the peritoneum. Results from such study are even more relevant to the clinical scenario when experiments are performed in uremic rats. Our experimental animal PD model not only helps to understand the pathophysiology of PD but also can be used for testing biocompatibility of new PD fluids.


Cognitive impairment in later life in patients with early-onset bipolar disorder.
Cognitive impairment may interfere with psychosocial functioning in bipolar disorder (BD). There is limited information regarding the cognitive function of elderly bipolar patients with onset at a young age. The present study aimed to investigate the frequency and the determinants of cognitive impairment in elderly early-onset bipolar patients. Using the Clock-drawing Test (CDT), the Mini Mental State Examination (MMSE), and the Cognitive Abilities Screening Instrument (CASI), we examined euthymic patients with bipolar I disorder in Taiwan, aged 60 years and older. Clinical data were obtained by reviewing medical records and personal interviews with patients and their family members. The onset of BD prior to the age of 40 years is defined as 'early-onset'. Of the 52 early-onset patients, 42.3% were determined to have cognitive impairment by exhibiting either abnormal CDT or education-adjusted MMSE scores. In a multiple regression model, years of education and the age at the last manic/hypomanic (but not depressive) episode accounted for the greatest variance in both MMSE and CASI scores. While educational level and the age at the last manic/hypomanic episode were not considered in the regression model, onset with depressive syndrome and current age explained 21.5% of the variance in MMSE scores. Age at the first depressive episode, the first manic episode before the age of 40 years, and comorbid diabetes accounted for 16.7% of the variance in CASI scores. There appeared to be a sizable proportion of elderly early-onset bipolar patients having cognitive impairment. It is suggested that clinical manifestation of first-onset affective episode and impact of medical comorbidity affect the cognition of early-onset BD in later life.


Hedgehog signaling is required for adult blood stem cell formation in zebrafish embryos.
Studies with embryonic explants and embryonic stem cells have suggested a role for Hedgehog (Hh) signaling in hematopoiesis. However, targeted deletion of Hh pathway components in the mouse has so far failed to provide in vivo evidence. Here we show that zebrafish embryos mutant in the Hh pathway or treated with the Hh signaling inhibitor cyclopamine display defects in adult hematopoietic stem cell (HSC) formation but not in primitive hematopoiesis. Hh is required in the trunk at three consecutive stages during vascular development: for the medial migration of endothelial progenitors of the dorsal aorta (DA), for arterial gene expression, and for the formation of intersomitic vessel sprouts. Interference with Hh signaling during the first two stages also interferes with HSC formation. Furthermore, HSC and DA formation also share Vegf and Notch requirements, which further distinguishes them from primitive hematopoiesis and underlines their close relationship during vertebrate development.


Wild monkeys flake stone tools.
Our understanding of the emergence of technology shapes how we view the origins of humanity. Sharp-edged stone flakes, struck from larger cores, are the primary evidence for the earliest stone technology. Here we show that wild bearded capuchin monkeys (Sapajus libidinosus) in Brazil deliberately break stones, unintentionally producing recurrent, conchoidally fractured, sharp-edged flakes and cores that have the characteristics and morphology of intentionally produced hominin tools. The production of archaeologically visible cores and flakes is therefore no longer unique to the human lineage, providing a comparative perspective on the emergence of lithic technology. This discovery adds an additional dimension to interpretations of the human Palaeolithic record, the possible function of early stone tools, and the cognitive requirements for the emergence of stone flaking.


In Situ Mapping of the Molecular Arrangement of Amphiphilic Dye Molecules at the TiO₂ Surface of Dye-Sensitized Solar Cells.
Amphiphilic sensitizers are central to the function of dye-sensitized solar cells. It is known that the cell's performance depends on the molecular arrangement and the density of the dye on the semiconductor surface, but a molecular-level picture of the cell-electrolyte interface is still lacking. Here, we present subnanometer in situ atomic force microscopy images of the Z907 dye at the surface of TiO2 in a relevant liquid. Our results reveal changes in the conformation and the lateral arrangement of the dye molecules, depending on their average packing density on the surface. Complementary quantitative measurements on the ensemble of the film are obtained by the quartz-crystal microbalance with dissipation technique. An atomistic picture of the dye coverage-dependent packing, the effectiveness of the hydrophobic alkyl chains as blocking layer, and the solvent accessibility is obtained from molecular dynamics simulations.


Association of demographic characteristics, symptomatology, retrospective and prospective memory, executive functioning and intelligence with social functioning in schizophrenia.
The objective of this study was to explore the influence of socio-demographic and clinical factors and neurocognitive variables (i.e. prospective and retrospective memory, executive functioning, and intelligence) on social functioning in Chinese schizophrenia patients. The study sample comprised 110 Chinese schizophrenia patients. Their clinical condition and social functioning were evaluated with the Brief Psychiatric Rating Scale (BPRS) and the Functional Needs Assessment (FNA), respectively. Three prospective memory (PM) tasks (time-, event-, and activity-based), three tests of executive functioning (the Design Fluency Test [DFT], Tower of London [TOL], and Wisconsin Card Sorting Test [WCST]), one test of intelligence (Raven's Progressive Matrices), and two retrospective memory (RM) tasks (the immediate and delayed recall conditions of the Logical Memory subtest of the Wechsler Memory Scales-Revised [WMS-R]) were administered to all patients. In correlation analyses higher education and better performance on the WCST (categories completed) and the Logical Memory subtests (delayed and immediate) of the WMS-R are significantly correlated with better social functioning, whereas a lower WCST score (perseverative errors) and more severe negative symptoms are associated with poorer social functioning. Multiple linear regression analysis revealed that higher education and a lower WCST score (perseverative errors) independently contribute to better social functioning. Unexpectedly, most socio-demographic and clinical factors do not seem to have a significant impact on social functioning of Chinese schizophrenia patients living in a Chinese society. Negative symptoms and certain cognitive deficits were the main predictors of social functioning and they should be the main targets for antipsychotic treatment and psychosocial interventions to improve social adjustment in Chinese schizophrenia patients.


A novel wireless brain stimulation device for long-term use in freely moving mice.
Deep brain stimulation (DBS) has been used in clinical settings for many years despite a paucity of knowledge related to the anatomical and functional substrates that lead to benefits and/or side-effects in various disease contexts. In order to maximize the potential of this approach in humans, a better understanding of its mechanisms of action is absolutely necessary. However, the existing micro-stimulators available for pre-clinical models, are limited by the lack of relevant small size devices. This absence prevents sustained chronic stimulation and real time monitoring of animals during stimulation, parameters that are critical for comparison to clinical findings. We therefore sought to develop and refine a novel small wireless micro-stimulator as a means by which to study consequent behavioural to molecular changes in experimental animals. Building on previous work from our group, we refined our implantable micro-stimulator prototype, to be easily combined with intravital 2-photon imaging. Using our prototype we were able to replicate the well described clinical benefits on motor impairment in a mouse model of Parkinson's disease in addition to capturing microglia dynamics live during stimulation. We believe this new device represents a useful tool for performing pre-clinical studies as well as dissecting brain circuitry and function.


[Three estimations of the outflow of orthodontists from the field].
The outflow of orthodontists through retirement is an important factor in the estimation of the required training capacity for this group of professionals. From 2002 through 2018, studies of the professional activity and retirement plans of orthodontists age 55 and older have been conducted fairly frequently, the most recent one dating from 2018. Based on the findings of these surveys, 3 estimations were obtained of the outflow through retirement. These were based on answers in earlier editions, the answers of their contemporaries and on the basis of the legal retirement age in the Netherlands. The number of active orthodontists in 2018 age 55 or older is estimated respectively to be 117, 116 and 102; according to all estimations, they will have retired in 2030. The estimations predict, respectively 56, 57 and 30 orthodontists will retire before 2023. According to 2 of the estimations, the outflow of orthodontists from the field will exceed the inflow from the universities in the coming years. The present training capacity in the Netherlands is not sufficient to compensate for the outflow of the first 2 estimations.


Modulation of cytokine gene expression by selected Lactobacillus isolates in the ileum, caecal tonsils and spleen of Salmonella-challenged broilers.
Probiotics have been used to control Salmonella colonization in the chicken intestine. Recently, we demonstrated that certain selected Lactobacillus isolates were able to reduce Salmonella infection in the chicken spleen and liver as well as down-regulated Salmonella pathogenicity island 1 virulence gene expression in the chicken caecum. To further understand the mechanisms through which Lactobacillus protected chickens from Salmonella infection, the present study has investigated the Lactobacillus isolate(s)-induced host immune response of chickens to Salmonella enterica serovar Typhimurium infection. A thorough examination of cytokine gene expression in the ileum, caecal tonsils, and spleen on days 1 and 3 post-Salmonella infection showed a dynamic spatial and temporal response to Salmonella infection and Lactobacillus treatments. In most instances, it was evident that treatment of chickens with Lactobacillus isolates could significantly attenuate Salmonella-induced changes in the gene expression profile. These included the genes encoding pro-inflammatory cytokines [lipopolysaccharide-induced TNF factor, interleukin (IL)-6, and IL-8], T helper 1 cytokines [IL-12 and interferon (IFN)-γ], and T helper 2 cytokines (IL-4 and IL-10). Another important observation from the present investigation was that the response induced by a combination of Lactobacillus isolates was generally more effective than that induced by a single Lactobacillus isolate. Our results show that administration of certain selected Lactobacillus isolates can effectively modulate Salmonella-induced cytokine gene expression, and thus help reduce Salmonella infection in chickens.


Effects of HIV infection and its treatment on self-reported menstrual abnormalities in women.
To describe menstrual abnormalities among women with HIV. Women in a multicenter prospective cohort study of HIV natural history reported menstrual abnormalities every 6-months between October 1994 and September 2002. Logistic regression and Cox proportional-hazards models were applied. The prevalence and incidence of menstrual abnormalities were <20%. HIV serostatus was not associated with prevalent menstrual abnormalities, but in HIV-seropositive women, higher CD4 counts were associated with fewer problems: compared with women with CD4 counts <200/mm3, in women with counts 200-500/mm3, odds ratio (OR) for amenorrhea was 0.55, p = 0.02, and for oligomenorrhea was 0.54, p = 0.0003; for women with counts >500/mm3, OR for amenorrhea was 0.67, p = 0.14, and for oligomenorrhea was 0.55, p = 0.001. HIV serostatus was not associated with incident abnormalities. Highly active anti-retroviral therapy (HAART) use was not associated with prevalent abnormalities, but both HAART use and higher CD4 counts were linked to lower rates of incident menstrual problems. Compared with seronegative women, HIV-seropositive women are at increased risk for some menstrual changes, although the absolute frequency of most abnormalities is low. Higher CD4 counts and HAART protect against incident abnormalities.


A Houttuynia cordata-based Chinese herbal formula improved symptoms of allergic rhinitis during the COVID-19 pandemic.
The symptoms of coronavirus disease 2019 (COVID-19) such as hyposmia, rhinorrhea, nasal obstruction, and cough are similar to those of chronic allergic rhinitis (AR). Such symptoms can easily lead AR patients to unnecessary anxiety, misdiagnosis, and invasive diagnostic tests in the COVID-19 pandemic. Interleukin-6 (IL-6) is an important mediator for chronic AR and plays a crucial role in the inflammation of COVID-19. Houttuynia cordata (HC) has been shown to reduce nasal congestion and swelling by suppressing the activation of IL-6 and is used to fight COVID-19. A novel HC-based Chinese herbal formula, Zheng-Yi-Fang (ZYF), was developed to test effects on nasal symptoms of patients with AR in the COVID-19 pandemic. Participants aged between 20 and 60 years with at least a 2-year history of moderate to severe perennial AR were enrolled. Eligible participants were randomly allocated to either the intervention group (taking ZYF) or the control group (using regular western medicine) for 4 weeks. The Chinese version of the Rhinosinusitis Outcome Measures was used to evaluate impacts on quality of life and nasal symptoms of participants with AR. In addition, the effect of ZYF on lipopolysaccharide (LPS)-induced IL-6 was investigated. Participants with AR taking ZYF improved their symptoms of nasal obstruction, nasal secretion, hyposmia, and postnasal drip in comparison with those of the control group. Meanwhile, ZYF exhibited inhibition of IL-6 secretion in the LPS-induced inflammatory model. ZYF has potential effects to relieve nasal symptoms for AR during the COVID-19 pandemic.


Halide adsorption on close-packed metal electrodes.
Two mechanisms have been cited as the reason for unexpected work function decrease upon adsorption of electronegative adatoms: electron spillout depletion [Michaelides et al., Phys. Rev. Lett., 2003, 90, 246103] and polarization of the adatom [Roman et al., Phys. Rev. Lett., 2013, 110, 156804]. We attempt to bridge the two pictures in this work. Work function changes due to the adsorption of halides on (111) surfaces of fcc metals (Ca, Sr, Ni, Pd, Pt, Cu, Ag, Au, Al and Pb) were studied using periodic density functional theory. The two mechanisms were found to be clearly independent of each other because of the opposite factors that lead to the work function decrease, and are therefore easy to distinguish. A more general picture of interpreting bond ionicity based on observed work function changes is discussed.


AP-1 and clathrin are essential for secretory granule biogenesis in Drosophila.
Regulated secretion of hormones, digestive enzymes, and other biologically active molecules requires the formation of secretory granules. Clathrin and the clathrin adaptor protein complex 1 (AP-1) are necessary for maturation of exocrine, endocrine, and neuroendocrine secretory granules. However, the initial steps of secretory granule biogenesis are only minimally understood. Powerful genetic approaches available in the fruit fly Drosophila melanogaster were used to investigate the molecular pathway for biogenesis of the mucin-containing "glue granules" that form within epithelial cells of the third-instar larval salivary gland. Clathrin and AP-1 colocalize at the trans-Golgi network (TGN) and clathrin recruitment requires AP-1. Furthermore, clathrin and AP-1 colocalize with secretory cargo at the TGN and on immature granules. Finally, loss of clathrin or AP-1 leads to a profound block in secretory granule formation. These findings establish a novel role for AP-1- and clathrin-dependent trafficking in the biogenesis of mucin-containing secretory granules.


Effects of capacitive and resistive electric transfer therapy in patients with knee osteoarthritis: a randomized controlled trial.
Capacitive and resistive electric transfer (CRET), an endogenous diathermy treatment, has been demonstrated to reduce pain and improve quality of life in numerous orthopedic degenerative and inflammatory problems but not in knee osteoarthritis (KOA). The aim of this prospective randomized controlled trial was to evaluate whether a 2-week program of CRET can reduce pain, stiffness and functional limitations in KOA compared with a sham treatment. Patients with KOA were randomly assigned to a study group (n = 31) or a control one (n = 22). The study group underwent six intermittent CRET applications, whereas the controls underwent a sham protocol without application of energy. The outcome measures were the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) (primary outcome) and the visual analogue scale (VAS) for pain and Medical Research Council Scale (secondary outcomes). All patients were evaluated before treatment (T0), at the end of treatment (T1), and at 1 (T2) and 3 months after treatment (T3). Results showed that CRET significantly improved strength, physical function and pain in patients with KOA. In the study group a reduction in WOMAC and VAS scores was observed at T1, T2, and T3 compared with T0. No significant changes of WOMAC and VAS scores were observed in the control group across all time points. Considering the small number of sessions, low cost and long-term benefits, CRET might be a useful therapeutic option for the conservative management of KOA to reduce pain, stiffness and functional limitation.


Benefits and costs of methadone treatment: results from a lifetime simulation model.
Several studies have examined the benefits and costs of drug treatment; however, they have typically focused on the benefits and costs of a single treatment episode. Although beneficial for certain analyses, the results are limited because they implicitly treat drug abuse as an acute problem that can be treated in one episode. We developed a Monte Carlo simulation model that incorporates the chronic nature of drug abuse. Our model represents the progression of individuals from the general population aged 18-60 with respect to their heroin use, treatment for heroin use, criminal behavior, employment, and health care use. We also present three model scenarios representing an increase in the probability of going to treatment, an increase in the treatment length of stay, and a scenario in which drug treatment is not available to evaluate how changes in treatment parameters affect model results. We find that the benefit-cost ratio of treatment from our lifetime model (37.72) exceeds the benefit-cost ratio from a static model (4.86). The model provides a rich characterization of the dynamics of heroin use and captures the notion of heroin use as a chronic recurring condition. Similar models can be developed for other chronic diseases, such as diabetes, mental illness, or cardiovascular disease.


A measure of conformational entropy change during thermal protein unfolding using neutron spectroscopy.
Thermal unfolding of proteins at high temperatures is caused by a strong increase of the entropy change which lowers Gibbs free energy change of the unfolding transition (DeltaG(unf) = DeltaH - TDeltaS). The main contributions to entropy are the conformational entropy of the polypeptide chain itself and ordering of water molecules around hydrophobic side chains of the protein. To elucidate the role of conformational entropy upon thermal unfolding in more detail, conformational dynamics in the time regime of picoseconds was investigated with neutron spectroscopy. Confined internal structural fluctuations were analyzed for alpha-amylase in the folded and the unfolded state as a function of temperature. A strong difference in structural fluctuations between the folded and the unfolded state was observed at 30 degrees C, which increased even more with rising temperatures. A simple analytical model was used to quantify the differences of the conformational space explored by the observed protein dynamics for the folded and unfolded state. Conformational entropy changes, calculated on the basis of the applied model, show a significant increase upon heating. In contrast to indirect estimates, which proposed a temperature independent conformational entropy change, the measurements presented here, demonstrated that the conformational entropy change increases with rising temperature and therefore contributes to thermal unfolding.


Association between the MVK rs2287218 SNP and the risk of coronary heart disease and ischemic stroke: A case-control study.
The association between the mevalonate kinase gene (MVK) single nucleotide polymorphism (SNP) and serum lipid levels has been detected in several previous genome-wide association studies, but the results are inconsistent. In addition, it is still unclear whether the loci indentified exert the similar effect on the susceptibility of coronary heart disease (CHD) or ischemic stroke (IS). Therefore, the present study was undertaken to detect the association between the MVK rs2287218 SNP and serum lipid levels, the susceptibility of CHD and IS in a Southern Chinese Han population. The genotypes of the SNP in 1764 unrelated subjects (CHD, 583; IS, 555; and healthy controls, 626) were determined by the Snapshot technology. The genotypic and allelic frequencies were different between CHD and control subjects (P ≤ 0.013 for each), or between IS and control groups (P < 0.01 for each). The T allele carriers had an increased risk of CHD and IS (CHD: OR = 1.674, 95%CI = 1.25-2.25, P = 0.001 for CT/TT vs. CC genotypes; OR = 1.595, 95%CI = 1.23-2.07, P < 0.001 for T vs. C alleles; IS: OR = 1.890, 95%CI = 1.36-2.47, P = 0.001 for CT/TT vs. CC genotypes; OR = 1.829, 95%CI = 1.38-2.42, P < 0.001 for T vs. C alleles). The T allele carriers in healthy controls had lower serum high-density lipoprotein cholesterol (HDL-C) levels than the T allele non-carriers (P = 0.013). These findings suggest that the MVK rs2287218 SNP is likely to increase the risk of CHD and IS by decreasing serum HDL-C levels in our study populations.


Diversity of hydrolases from hydrothermal vent sediments of the Levante Bay, Vulcano Island (Aeolian archipelago) identified by activity-based metagenomics and biochemical characterization of new esterases and an arabinopyranosidase.
A metagenomic fosmid expression library established from environmental DNA (eDNA) from the shallow hot vent sediment sample collected from the Levante Bay, Vulcano Island (Aeolian archipelago) was established in Escherichia coli. Using activity-based screening assays, we have assessed 9600 fosmid clones corresponding to approximately 350 Mbp of the cloned eDNA, for the lipases/esterases/lactamases, haloalkane and haloacid dehalogenases, and glycoside hydrolases. Thirty-four positive fosmid clones were selected from the total of 120 positive hits and sequenced to yield ca. 1360 kbp of high-quality assemblies. Fosmid inserts were attributed to the members of ten bacterial phyla, including Proteobacteria, Bacteroidetes, Acidobateria, Firmicutes, Verrucomicrobia, Chloroflexi, Spirochaetes, Thermotogae, Armatimonadetes, and Planctomycetes. Of ca. 200 proteins with high biotechnological potential identified therein, we have characterized in detail three distinct α/β-hydrolases (LIPESV12_9, LIPESV12_24, LIPESV12_26) and one new α-arabinopyranosidase (GLV12_5). All LIPESV12 enzymes revealed distinct substrate specificities tested against 43 structurally diverse esters and 4 p-nitrophenol carboxyl esters. Of 16 different glycosides tested, the GLV12_5 hydrolysed only p-nitrophenol-α-(L)-arabinopyranose with a high specific activity of about 2.7 kU/mg protein. Most of the α/β-hydrolases were thermophilic and revealed a high tolerance to, and high activities in the presence of, numerous heavy metal ions. Among them, the LIPESV12_24 was the best temperature-adapted, retaining its activity after 40 min of incubation at 90 °C. Furthermore, enzymes were active in organic solvents (e.g., >30% methanol). Both LIPESV12_24 and LIPESV12_26 had the GXSXG pentapeptides and the catalytic triads Ser-Asp-His typical to the representatives of carboxylesterases of EC 126.96.36.199.


First-order optical Freedericksz transition in a dye-doped nematic liquid crystal.
A first-order optical Freedericksz transition in a nematic liquid crystal doped by a small quantity of a dichroic dye with negative dichroism is observed. The initial homeotropic state corresponds to maximum absorption for the linearly polarized incident beam, while reorientation reduces absorption increasing the optical torque: this process produces the positive feedback leading to the observed bistable behavior.


Gestational Weight Gain per Pre-Pregnancy Body Mass Index and Birth Weight in Twin Pregnancies: A Cohort Study in Wuhan, China.
To assess the relationship between gestational weight gain (GWG) of twin-pregnancy women and twin birth weights, as well as to evaluate whether pre-pregnancy body mass index (BMI) influences this relationship. A cohort study was conducted in Wuhan, China, between 1/01/2011 and 8/31/2017. Women with twin pregnancies who delivered live and non-malformed twins were included (6,925 women and 13,850 infants), based on the Wuhan Maternal and Child Health Management Information System. Logistic regression models were employed to examine the association between GWG and paired small for gestational age (SGA, defined as birth weight <10th percentile for gestational age and sex)/SGA and linear regression models were utilized to explore the relationship between GWG and sum of birth weights. The associations of GWG based on both the IOM and Chinese recommendations and SGA/SGA pairs were obtained, as well as the stratified analyses by pre-pregnancy BMI. Additionally, the sum birth weight of one twin pair increased by 15.88 g when the GWG increased by 1 kg. GWG below the IOM and Chinese recommendations was associated with an increased risk of SGA/SGA pairs in all pre-pregnancy BMI categories. However, in underweight, overweight, and obese women, the association between GWG above the IOM and Chinese recommendations and SGA/SGA pairs changed with adjustment.


Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway.
Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes.


Analysis of Randomised Search Heuristics for Dynamic Optimisation.
Dynamic optimisation is an area of application where randomised search heuristics like evolutionary algorithms and artificial immune systems are often successful. The theoretical foundation of this important topic suffers from a lack of a generally accepted analytical framework as well as a lack of widely accepted example problems. This article tackles both problems by discussing necessary conditions for useful and practically relevant theoretical analysis as well as introducing a concrete family of dynamic example problems that draws inspiration from a well-known static example problem and exhibits a bi-stable dynamic. After the stage has been set this way, the framework is made concrete by presenting the results of thorough theoretical and statistical analysis for mutation-based evolutionary algorithms and artificial immune systems.


The nature and strength of the relationship between expenditure on alcohol and food: an analysis of adult-only households in the UK.
Unhealthy lifestyle behaviours can cluster to produce more detrimental overall health consequences than expected with a simple additive effect. This study aims to expand current knowledge of the nature and strength of the relationship between two such health behaviours, alcohol and diet, through analysis of household expenditure on food and drink from a nationally representative UK sample. Data from the Expenditure and Food Survey for 2005-2006 was used to analyse expenditure on alcohol and diet for 3146 UK households. The classification of a food as healthy or unhealthy was determined using dietary advice provided by the Food Standards Agency. Alcohol expenditure was disaggregated into spending in pubs, bars, clubs and restaurants (on-trade expenditure) and spending in off-licenses and supermarkets (off-trade expenditure). Analyses were stratified according to household disposable income quintile and household beverage preference. As household expenditure on alcohol increases, spending on both healthy and unhealthy food decreases. Higher income households spend proportionately more on on-trade alcohol and healthy food than lower income households, and less on unhealthy food. Off-trade alcohol expenditure does not differ significantly according to household income. Households that prefer to purchase wine have healthier expenditure patterns than those that prefer to buy beer or spirits, even after controlling for income. Low-income households and those that purchase more beer or spirits than wine could be targeted for health promotion interventions to reduce their risk of negative health outcomes from the clustering of alcohol consumption and unhealthy diet.


Association of the Psychological Response to the ACL-SPORTS Training Program and Self-reported Function at 2 Years After Anterior Cruciate Ligament Reconstruction.
Psychological readiness to return to sport has emerged as an important factor associated with outcomes after anterior cruciate ligament reconstruction (ACLR). Psychological factors are potentially modifiable during the course of rehabilitation, and improving them may lead to better outcomes. To determine whether athletes with a positive psychological response after participation in a neuromuscular training and second injury prevention program had better self-reported function and activity outcomes compared with athletes who did not have a meaningful change. Cohort study; Level of evidence, 3. After ACLR and the completion of formal rehabilitation, 66 level I/II athletes completed the following self-reported measures at enrollment (pretraining): the Anterior Cruciate Ligament-Return to Sport after Injury (ACL-RSI) scale, the International Knee Documentation Committee (IKDC) subjective knee form, and the 5 subscales of the Knee injury and Osteoarthritis Outcome Score (KOOS). Participants completed these measures after 10 sessions of agility, plyometric, and progressive strength training and at 1 and 2 years after ACLR. Participants who displayed an increase in the ACL-RSI score from pretraining to posttraining that exceeded the minimal clinically important difference (≥10 points) were defined as having a positive psychological response (responders) to training, and those who did not were defined as nonresponders. A mixed-model analysis of variance was used to determine if group differences in IKDC and KOOS scores existed over the 4 time points (pretraining, posttraining, and the 1- and 2-year follow-ups). The responders reported better self-reported function compared with the nonresponders, regardless of time, on the IKDC form (P = .001), KOOS-Sport and Recreation (P = .014), KOOS-Pain (P = .007), and KOOS-Symptoms (P = .002) but not on the KOOS-Quality of Life (P = .078). Overall, 77% of responders and 67% of nonresponders returned to their previous level of sport by 1 year after ACLR (P = .358), and 82% of responders and 78% of nonresponders returned to their previous level of sport by 2 years after ACLR (P = .668). Ultimately, 59% of the athletes in this study displayed a meaningful improvement in their psychological outlook over the course of the training program. Responders demonstrated persistently better self-reported function at posttraining and at 1 and 2 years after ACLR, but there were no between-group differences in return-to-sport rates.


Protein engineering: the potential of remote mutations.
Engineered proteins, especially enzymes, are now commonly used in many industries owing to their catalytic power, specific binding of ligands, and properties as materials and food additives. As the number of potential uses for engineered proteins has increased, the interest in engineering or designing proteins to have greater stability, activity and specificity has increased in turn. With any rational engineering or design pursuit, the success of these endeavours relies on our fundamental understanding of the systems themselves; in the case of proteins, their structure-dynamics-function relationships. Proteins are most commonly rationally engineered by targeting the residues that we understand to be functionally important, such as enzyme active sites or ligand-binding sites. This means that the majority of the protein, i.e. regions remote from the active- or ligand-binding site, is often ignored. However, there is a growing body of literature that reports on, and rationalises, the successful engineering of proteins at remote sites. This minireview will discuss the current state of the art in protein engineering, with a particular focus on engineering regions that are remote from active- or ligand-binding sites. As the use of protein technologies expands, exploiting the potential improvements made possible through modifying remote regions will become vital if we are to realise the full potential of protein engineering and design.


Treatment with CB2 agonist JWH-133 reduces histological features associated with erectile dysfunction in hypercholesterolemic mice.
Hypercholesterolemia is one of the most important risk factors for erectile dysfunction, mostly due to the impairment of oxidative stress and endothelial function in the penis. The cannabinoid system might regulate peripheral mechanisms of sexual function; however, its role is still poorly understood. We investigated the effects of CB2 activation on oxidative stress and fibrosis within the corpus cavernosum of hypercholesterolemic mice. Apolipoprotein-E-knockout mice were fed with a western-type diet for 11 weeks and treated with JWH-133 (selective CB2 agonist) or vehicle during the last 3 weeks. CB2 receptor expression, total collagen content, and reactive oxygen species (ROS) production within the penis were assessed. In vitro corpus cavernosum strips preparation was performed to evaluate the nitric oxide (NO) bioavailability. CB2 protein expression was shown in cavernosal endothelial and smooth muscle cells of wild type and hypercholesterolemic mice. Treatment with JWH-133 reduced ROS production and NADPH-oxidase expression in hypercholesterolemic mice penis. Furthermore, JWH-133 increased endothelial NO synthase expression in the corpus cavernosum and augmented NO bioavailability. The decrease in oxidative stress levels was accompanied with a reduction in corpus cavernosum collagen content. In summary, CB2 activation decreased histological features, which were associated with erectile dysfunction in hypercholesterolemic mice.


Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in vivo.
Pituitary adenylate cyclase-activating peptide (PACAP) is an important neuropeptide and immunomodulator in various tissues. Although this peptide and its receptors (ie, VPAC1R, VPAC2R, and PAC1R) are expressed in human skin, their biological roles are unknown. Therefore, we tested whether PACAP regulates vascular responses in human skin in vivo. When injected intravenously, PACAP induced a significant, concentration-dependent vascular response (ie, flush, erythema, edema) and mediated a significant and concentration-dependent increase in intrarectal body temperature that peaked at 2.7°C. Topical application of PACAP induced marked concentration-dependent edema. Immunohistochemistry revealed a close association of PACAP-immunoreactive nerve fibers with mast cells and dermal blood vessels. VPAC1R was expressed by dermal endothelial cells, CD4+ and CD8+ T cells, mast cells, and keratinocytes, whereas VPAC2R was expressed only in keratinocytes. VPAC1R protein and mRNA were also detected in human dermal microvascular endothelial cells. The PACAP-induced change in cAMP production in these cells demonstrated VPAC1R to be functional. PACAP treatment of organ-cultured human skin strongly increased the number of CD31+ vessel cross-sections. Taken together, these results suggest that PACAP directly induces vascular responses that may be associated with neurogenic inflammation, indicating for the first time that PACAP may be a crucial vascular regulator in human skin in vivo. Antagonists to PACAP function may be beneficial for the treatment of inflammatory skin diseases with a neurogenic component.


miR-21 regulates ischemic neuronal injury via the p53/Bcl-2/Bax signaling pathway.
Focal cerebral ischemia leads to a large number of neuronal apoptosis, and secondary neuronal death is the main cause of cerebral infarction. MicroRNA-21 (miR-21) has been shown to be a strong anti-apoptosis and pro-survival factor in ischemia. However, the precise mechanism of miR-21 in ischemic neuroprotection remains largely unknown. In this study, miR-21 was down-regulated while p53 was up-regulated following ischemia in vitro and in vivo. Overexpression of miR-21 in vitro and in vivo substantially inhibited the expression of p53 following ischemia, while inhibition of miR-21 in vitro and in vivo promoted p53 expression following ischemia. Moreover, the miR-21/p53 axis regulated the expression of Bcl-2/Bax and abolished OGD/R-induced neuronal injury in vitro. Furthermore, overexpression of miR-21 in vivo reduced neuronal death, protected against ischemic damage, and improved neurological functions by inhibiting p53/Bcl-2/Bax signaling, while inhibition of miR-21 enhanced the p53/Bcl-2/Bax signaling and aggravated the ischemic neuronal injury in vivo. Our data uncover a novel mechanism of miR-21 in regulating cerebral ischemic neuronal injury by inhibiting p53/Bcl-2/Bax signaling pathway, which suggests that miR-21/p53 may be attractive therapeutic molecules for treatment of ischemic stroke.


Molecular basis of fatty acid taste in Drosophila.
Behavioral studies have established that Drosophila appetitive taste responses towards fatty acids are mediated by sweet sensing Gustatory Receptor Neurons (GRNs). Here we show that sweet GRN activation requires the function of the Ionotropic Receptor genes IR25a, IR76b and IR56d. The former two IR genes are expressed in several neurons per sensillum, while IR56d expression is restricted to sweet GRNs. Importantly, loss of appetitive behavioral responses to fatty acids in IR25a and IR76b mutant flies can be completely rescued by expression of respective transgenes in sweet GRNs. Interestingly, appetitive behavioral responses of wild type flies to hexanoic acid reach a plateau at ~1%, but decrease with higher concentration, a property mediated through IR25a/IR76b independent activation of bitter GRNs. With our previous report on sour taste, our studies suggest that IR-based receptors mediate different taste qualities through cell-type specific IR subunits.


Complexin controls the force transfer from SNARE complexes to membranes in fusion.
Trans-SNAP receptor (SNARE, where SNAP is defined as soluble NSF attachment protein, and NSF is defined as N-ethylmaleimide-sensitive factor) complexes catalyze synaptic vesicle fusion and bind complexin, but the function of complexin binding to SNARE complexes remains unclear. Here we show that in neuronal synapses, complexin simultaneously suppressed spontaneous fusion and activated fast calcium ion-evoked fusion. The dual function of complexin required SNARE binding and also involved distinct amino-terminal sequences of complexin that localize to the point where trans-SNARE complexes insert into the fusing membranes, suggesting that complexin controls the force that trans-SNARE complexes apply onto the fusing membranes. Consistent with this hypothesis, a mutation in the membrane insertion sequence of the v-SNARE synaptobrevin/vesicle-associated membrane protein (VAMP) phenocopied the complexin loss-of-function state without impairing complexin binding to SNARE complexes. Thus, complexin probably activates and clamps the force transfer from assembled trans-SNARE complexes onto fusing membranes.


Bayesian segmentation of range images of polyhedral objects using entropy-controlled quadratic Markov measure field models.
We present a method based on Bayesian estimation with prior Markov random field models for segmentation of range images of polyhedral objects. This method includes new ways to determine the confidence associated with the information given for every pixel in the image as well as an improved method for localization of the boundaries between regions. The performance of the method compares favorably with other state-of-the-art procedures when evaluated using a standard benchmark.


An analysis of the temperature effects of fever on the intra-host population dynamics of Plasmodium falciparum.
Observations that growth of Plasmodium falciparum in vitro is inhibited by high temperatures have led to hypotheses that malaria fever may influence the parasite population dynamics, regulating parasite density and synchronizing parasite growth. In order to investigate the fever hypotheses, we have developed an age-structured coupled Markov chain model that describes the parasite erythrocyte cycle and its interaction with the host fever response. We estimated the model parameters using data collected from laboratory parasite cultures that were exposed to febrile or normal temperature. Using the experimental parameter values, quantitative predictions were made of the effect of fever in determining the parasite population dynamics. It was concluded from the model behaviour that, during the primary infection of a non-immune host, a typical episode of fever can effect density-dependent regulation of the parasite population, maintaining cycles of parasitaemia and promoting synchronous parasite growth.


Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo.
The adaptive immune system has evolved distinct responses against different pathogens, but the mechanism(s) by which a particular response is initiated is poorly understood. In this study, we investigated the type of Ag-specific CD4(+) Th and CD8(+) T cell responses elicited in vivo, in response to soluble OVA, coinjected with LPS from two different pathogens. We used Escherichia coli LPS, which signals through Toll-like receptor 4 (TLR4) and LPS from the oral pathogen Porphyromonas gingivalis, which does not appear to require TLR4 for signaling. Coinjections of E. coli LPS + OVA or P. gingivalis LPS + OVA induced similar clonal expansions of OVA-specific CD4(+) and CD8(+) T cells, but strikingly different cytokine profiles. E. coli LPS induced a Th1-like response with abundant IFN-gamma, but little or no IL-4, IL-13, and IL-5. In contrast, P. gingivalis LPS induced Th and T cell responses characterized by significant levels of IL-13, IL-5, and IL-10, but lower levels of IFN-gamma. Consistent with these results, E. coli LPS induced IL-12(p70) in the CD8alpha(+) dendritic cell (DC) subset, while P. gingivalis LPS did not. Both LPS, however, activated the two DC subsets to up-regulate costimulatory molecules and produce IL-6 and TNF-alpha. Interestingly, these LPS appeared to have differences in their ability to signal through TLR4; proliferation of splenocytes and cytokine secretion by splenocytes or DCs from TLR4-deficient C3H/HeJ mice were greatly impaired in response to E. coli LPS, but not P. gingivalis LPS. Therefore, LPS from different bacteria activate DC subsets to produce different cytokines, and induce distinct types of adaptive immunity in vivo.


Contrasting physiological responses of dwarf sea-lavender and marguerite to simulated sea aerosol deposition.
Plants of two wild native species from littoral areas, marguerite [Argyranthemum coronopifolium (Willd.) C.J. Humphries] and dwarf sea-lavender [Limonium pectinatum (Aiton) O. Kuntze], grown in an unheated plastic greenhouse, were sprayed 2 to 3 min per day over a 7-d period with different aqueous solutions containing (i) an anionic surfactant (S1); (ii) a solution simulating the composition of sea aerosol (S2); (iii) a solution simulating sea aerosol with anionic surfactant (S3), and (iv) deionized water alone (control). The plant resistance to sea aerosol and the ability to recover from treatments were studied. By the end of the spraying period, marguerite showed a significant reduction in growth compared with control. However, most of the growth parameters were significantly unaffected in dwarf sea-lavender when plants were treated with sea aerosol containing surfactant. Measurements of water relations variables in marguerite showed a slight decrease in leaf turgor potential after spraying with sea aerosol containing surfactant. The surfactant enhanced the foliar absorption of salt in marguerite plants, inducing reductions in leaf stomatal conductance and causing such damage in the photosynthetic apparatus that the level of net photosynthesis decreased and had not recovered by the end of the experiment. The treatments had no effect on leaf stomatal conductance and photosynthesis rate in dwarf sea-lavender plants. The response of the species studied to sea aerosol was related to the degree of salinity tolerance. Although both species are wild native plants from littoral areas, marguerite is not salt tolerant and was the most sensitive to the sea aerosol treatments, while dwarf sea-lavender, a halophyte species, was more efficient at decreasing the toxic salt content of the tissues as its growth and ornamental characteristics were not affected.


Effects of the 2009 Medical Cannabinoid Legalization Policy on Hospital Use for Cannabinoid Dependency and Persistent Vomiting.
In 2009, the U.S. Department of Justice issued a memo stating that it would not prosecute users and sellers who complied with the state laws allowing for medical use of marijuana. There are growing concerns about legalization of marijuana use and its related public health effects. We performed an interrupted time series analysis to evaluate these effects. We collected a representative sample of hospital discharge data from the Healthcare Cost and Utilization Project, from January 1993 to December 2014. We divided the data in to 3 groups: the prelegalization period (1993-2008), the legalization period (2009), and the postlegalization period (2010-2014). The disease variables were International Classification of Disease-Ninth Revision-Clinical Modification 304.30 cannabinoid dependency unspecified (CDU), 536.2 persistent vomiting, and an aggregate of CDU and persistent vomiting. We performed interrupted time series and Poisson-Gamma regression analysis to calculate each year's incidence rate of unspecified and persistent vomiting and CDU per 100,000 hospital discharges. CDU, persistent vomiting, and aggregate of CDU and persistent vomiting were modeled separately to estimate average incidence rate ratio and 95% confidence interval for each study phase. We observed an increasing trend of CDU or an aggregate of CDU and persistent vomiting during the prelegalization period. The legalization of marijuana significantly increased the incidence rate during the legalization period (by 17.9%) and the yearly average increase in rate by 6% after policy implementation, compared to the prelegalization period. The increase in rate of persistent vomiting after policy implementation increased significantly (by about 8%), although there were no significant trends in increase prior to or during marijuana legalization in 2009. In an interrupted time series analysis of before, during, and after medical marijuana legalization, we estimated levels and rate changes in CDU and persistent vomiting. We found persistent increases in rates of CDU and persistent vomiting during and after legalization of marijuana.


Randomized controlled trial of a facilitated online positive emotion regulation intervention for dementia caregivers.
To test the effects of Life Enhancing Activities for Family Caregivers (LEAF), a 6-week positive emotion regulation intervention, on outcomes of positive emotion, depression, anxiety, and physical health as measured by the Patient-Reported Outcomes Measurement Information System® (PROMIS®). A randomized controlled trial (N = 170) comparing LEAF (N = 86) to an emotion reporting/waitlist condition (N = 84) in dementia caregivers. LEAF was individually delivered online by trained facilitators. Participants in the control condition completed daily online emotion reports and then crossed over into the intervention condition after 6 weeks. The study was registered with Clinicaltrials.gov (NCT01825681) and funded by R01NR014435. Analyses of difference in change from baseline to 6 weeks demonstrated significantly greater decreases in PROMIS® depression (d = -.25; p = .02) and Quality of Life in Neurological Disorders (NeuroQOL) anxiety (d = -.33; p < .01), as well as improvements in PROMIS® physical health (d = .24; p = .02) in the intervention condition compared to the emotion reporting/waitlist control. The intervention also showed greater improvements in positive emotion (d = .58; p < .01) and positive aspects of caregiving (d = .36; p < .01). Increases in positive emotion significantly mediated the effect of LEAF on depression over time. This randomized controlled trial of the online-facilitated positive emotion regulation intervention in dementia caregivers demonstrated small to medium effect sizes on caregiver well-being and shows promise for remotely delivered programs to improve psychological well-being in caregivers of people with dementia and other chronic illnesses. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Fibrous Dysplasia with Massive Cartilaginous Differentiation (Fibrocartilaginous Dysplasia) in the Proximal Femur: A Case Report and Review of the Literature.
Fibrous dysplasia (FD) is a monostotic or polyostotic benign bone lesion with spindle-cell proliferation in woven bone and stroma. Rarely, cartilaginous differentiation can be seen in the lesions of FD. FD with massive cartilaginous differentiation is called fibrocartilaginous dysplasia (FCD) and is considered a rare variant of FD. Although pathological findings of FD show irregular immature bone formation without osteoblastic rimming in fibrous tissue, and rarely show very small amounts of cartilage, histological images of FCD are said to show that cartilage with a relatively high cell density is present in the majority and that FD-like findings are seen in parts of it. The most characteristic feature of FCD on images is calcification in the lesions reflecting cartilaginous tissue. On the other hand, typical radiographic findings of FD include shadows with a ground-glass appearance and thinning and bulging of the cortical bone, the observation if calcification is not usual. Therefore, in the diagnosis of FCD, differentiation from multiple enchondromatosis, Ollier disease, chondrosarcoma, and chondrosarcoma secondary to FD is necessary, and it seems important to make a careful diagnosis based not only on the pathological findings but also on imaging and clinical findings. Herein, we report on a case of FD of the proximal femur associated with intralesional extensive carti laginous differentiation in which a pathological fracture occurred during follow-up, with a review of the literature.


A comparison of natural-image-based models of simple-cell coding.
Models such as that of Olshausen and Field (O&F, 1997 Vision Research 37 3311-3325) and principal components analysis (PCA) have been used to model simple-cell receptive fields, and to try to elucidate the statistical principles underlying visual coding in area V1. They connect the statistical structure of natural images with the statistical structure of the coding used in V1. The O&F model has created particular interest because the basis functions it produces resemble the receptive fields of simple cells. We evaluate these models in terms of their sparseness and dispersal, both of which have been suggested as desirable for efficient visual coding. However, both attributes have been defined ambiguously in the literature, and we have been obliged to formulate specific definitions in order to allow any comparison between models at all. We find that both attributes are strongly affected by any preprocessing (e.g. spectral pseudo-whitening or a logarithmic transformation) which is often applied to images before they are analysed by PCA or the O&F model. We also find that measures of sparseness are affected by the size of the filters--PCA filters with small receptive fields appear sparser than PCA filters with larger spatial extent. Finally, normalisation of the means and variances of filters influences measures of dispersal. It is necessary to control for all of these factors before making any comparisons between different models. Having taken these factors into account, we find that the code produced by the O&F model is somewhat sparser than the code produced by PCA. However, the difference is rather smaller than might have been expected, and a measure of dispersal is required to distinguish clearly between the two models.


DNA Methyltransferases Inhibitors from Natural Sources.
DNA methyltransferases (DNMTs) catalyze the methylation at cytosine-C5 mainly in a CpG dinucleotide context. Although DNA methylation is essential for fundamental processes like embryonic development or differentiation, aberrant expression and/or activities of DNMTs are involved in several pathologies, from neurodegeneration to cancer. DNMTs inhibition can arrest tumor growth, cells invasiveness and induce differentiation, whereas their increased expression is shown in numerous cancer types. Moreover, hypermethylated promoters of tumor suppressor genes lead to their silencing. Hence, the use of specific inhibitors of DNMT might reactivate those genes and stop or even reverse the aberrant cell processes. To date, the only approved DNMTs inhibitors for therapy belong to the nucleoside-based family of drugs, but they display relevant side effects as well as high chemical instability. Thus, there is a keen interest actually exists to develop novel, potent and safe inhibitors possessing a nonnucleoside structure. Increasing literature evidence is highlighting that natural sources could help the researchers to achieve this goal. Indeed, several polyphenols, flavonoids, antraquinones, and others are described able to inhibit DNMTs activity and/or expression, thus decreasing the methylation/silencing of different genes involved in tumorigenesis. These events can lead to re-expression of such genes and to cell death in diverse cancer cell lines. Epigallocatechin-3-gallate (1) and laccaic acid A (11) resulted the most effective DNMT1 inhibitors with submicromolar IC50 values, acting as competitive inhibitors. Compound 1 and 11 both displayed gene demethylation and re-activation in several cancers. However, all of the natural compounds described in this review showed important results, from gene reactivation to cell growth inhibition. Moreover, some of them displayed interesting activity even in rodent cancer models and very recently entered clinical trials.


Effects of oral calcium gluconate on gastric acid secretion and serum gastrin concentration in man.
A single oral dose of 4-46 mmol calcium gluconate at pH 5-6 was administered intragastrically to 15 male volunteers without gastrointestinal disease. There was a significant rise in acid output from 30-90 minutes after the calcium was given compared with the basal hourly collection. The serum gastrin level 30 minutes after calcium administration was significantly raised, but no correlation could be demonstrated between the acid and gastrin responses. Serum calcium levels were unchanged throughout. An equimolar dose of magnesium sulphate had no such effects. This study suggests that the intragastric administration of calcium results in independent release of gastric acid and gastrin from the gastric mucosa.


Transcriptional changes underlying the secretory activation phase of mammary gland development.
The secretory activation stage of mammary gland development occurs after parturition and converts inactive lobuloalveoli to active milk secretion. This process is triggered by progestin withdrawal and depends upon augmented prolactin (Prl) signaling. Little is known about the Prl-induced transcriptional changes that occur in the mammary gland to drive this process. To examine changes in the mammary transcriptome responsible for secretory activation, we have used transcript profiling of three mouse models that exhibit failure of secretory activation: knockout of galanin (a regulator of pituitary Prl production and a mammary cell autonomous modulator of Prl action); treatment with S179D Prl (a phosphoprolactin mimic); and knockout of a single Prl receptor allele. A significant reduction in expression was observed in genes belonging to 46 gene ontologies including those representing milk proteins, metabolism, lipid, cholesterol and fatty acid biosynthetic enzymes, immune response, and key transcription factors. A set of 35 genes, commonly regulated in all three models, was identified and their role in lactogenesis was validated by examining their expression in response to Prl stimulation or signal transducer and activator of transcription 5 knockdown in the HC11 mouse mammary cell culture model. The transcript profiles provided by these experiments identify 35 key genes (many for the first time) involved in the secretory activation phase of mammary gland development, show that S179D acts as an antagonist of Prl action, and provide insight into the partial penetrance of failed lactation in Prl receptor heterozygous females.