Sampling procedure, participation rates and representativeness in the Swedish part of the European Youth Heart Study (EYHS).
The European Youth Heart Study (EYHS) is a cross-sectional, school-based population study on risk factors for future cardiovascular disease in children, with an overall participation rate in Sweden of about 50%. To study the representativeness of the participants in the Swedish part of EYHS, a comprehensive non-participant follow-up study was carried out. A structured multilevel analysis model was developed, addressing each level in the sampling procedure. The income, educational and occupational categories of the geographical regions of the study (level I), school catchment areas (level II) and parents (level III) were compared with official data. Participating and non-participating pupils (level IV) were compared through a questionnaire. Thirty-seven state schools in two regions of Central Sweden (Orebro and southern Stockholm) were visited during the school year 1998/1999. Boys and girls aged 9 and 15 years were randomly sampled through a multiphase sampling procedure. Data for socio-economic status for levels I and II corresponded well to national and regional official data. At level III, non-manually working parents were slightly over-represented among parents of participating children. At level IV, non-participating subjects corresponded in most respects to participants with a few exceptions--mainly more interest in physical exercise among participants. Based on the knowledge from the non-participant study, we do not foresee problems regarding interpretation of the outcomes in the EYHS, despite the low participation rate.


Lipid nanoparticles for dermal drug delivery.
Lipid based drug delivery systems have been widely studied and reported over the past decade and offer a useful alternative to other colloidal drug delivery systems. Skin is a popular route of drug delivery for locally and systemically acting drugs and nanoparticles are reported as a potential formulation strategy for dermal delivery. Although the skin acts as a natural physical barrier against penetration of foreign materials, including particulates, opportunities exist for the delivery of therapeutic nanoparticles, especially in diseased and damaged skin and via appendageal routes such as the openings of hair follicles. The extent and ability of nanoparticles to penetrate into the underlying viable tissue is still the subject of debate although recent studies have identified the follicular route as the most likely route of entry; this influences the potential applications of these dosage forms as a drug delivery strategy. This paper reviews present state of art of lipid-based nanocarriers focussing on solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsions, their production methods, potential advantages and applications in dermal drug delivery.


Development and validation of novel algorithms to identify patients with inflammatory bowel diseases in Israel: an epi-IIRN group study.
Before embarking on administrative research, validated case ascertainment algorithms must be developed. We aimed at developing algorithms for identifying inflammatory bowel disease (IBD) patients, date of disease onset, and IBD type (Crohn's disease [CD] vs ulcerative colitis [UC]) in the databases of the four Israeli Health Maintenance Organizations (HMOs) covering 98% of the population. Algorithms were developed on 5,131 IBD patients and 2,072 controls, following independent chart review (60% CD and 39% UC). We reviewed 942 different combinations of clinical parameters aided by mathematical modeling. The algorithms were validated on an independent cohort of 160,000 random subjects. The combination of the following variables achieved the highest diagnostic accuracy: IBD-related codes, alone if more than five to six codes or combined with purchases of IBD-related medications (at least three purchases or ≥3 months from the first to last purchase) (sensitivity 89%, specificity 99%, positive predictive value [PPV] 92%, negative predictive value [NPV] 99%). A look-back period of 2-5 years (depending on the HMO) without IBD-related codes or medications best determined the date of diagnosis (sensitivity 83%, specificity 68%, PPV 82%, NPV 70%). IBD type was determined by the majority of CD/UC codes of the three recent contacts or the most recent when less than three contacts were recorded (sensitivity 92%, specificity 97%, PPV 97%, NPV 92%). Applying these algorithms, a total of 38,291 IBD patients were residing in Israel, corresponding to a prevalence rate of 459/100,000 (0.46%). The application of the validated algorithms to Israel's administrative databases will now create a large and accurate ongoing population-based cohort of IBD patients for future administrative studies.


Nurses at the frontline of public health emergency preparedness and response: lessons learned from the HIV/AIDS pandemic and emerging infectious disease outbreaks.
The years 2020-21, designated by WHO as the International Year of the Nurse and Midwife, are characterised by unprecedented global efforts to contain and mitigate the COVID-19 pandemic. Lessons learned from successful pandemic response efforts in the past and present have implications for future efforts to leverage the global health-care workforce in response to outbreaks of emerging infectious diseases such as COVID-19. Given its scale, reach, and effectiveness, the response to the HIV/AIDS pandemic provides one such valuable example, particularly with respect to the pivotal, although largely overlooked, contributions of nurses and midwives. This Personal View argues that impressive achievements in the global fight against HIV/AIDS would not have been attained without the contributions of nurses. We discuss how these contributions uniquely position nurses to improve the scale, reach, and effectiveness of response efforts to emerging infectious diseases with pandemic potential; provide examples from the responses to COVID-19, Zika virus disease, and Ebola virus disease; and discuss implications for current and future efforts to strengthen pandemic preparedness and response.


Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer.
To determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease. We treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100. Four patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response. Minimal toxicity and good survival in this small population suggest clinical benefit from vaccination.


Is Partial or Total Thyroidectomy Associated with Risk of Long-Term Osteoporosis: A Nationwide Population-Based Study.
Whether thyroidectomy contributes to osteoporosis (OP) and osteoporotic fracture (OF) is a subject of debate. This study aimed to determine the effect of thyroidectomy on the risk of OP and OF. This retrospective cohort study is based on patient data between January 2000 to December 2005 from the National Health Insurance Research Database. Patients who underwent thyroidectomy were enrolled in the thyroidectomy cohort, and the control cohort was selected by propensity score matching at a ratio of 1:4. Incident OP and OF cases were identified until the end of 2013. The thyroidectomy cohort to control cohort adjusted hazard ratio (aHR) for OP/OF was assessed through multivariable Cox proportional hazard regression analysis. Totals of 1426 and 5704 patients were included in the thyroidectomy and control cohorts, respectively. The incidence density of OP was higher in the thyroidectomy cohort (7.91/1000 person-years) than in the control cohort (5.98/1000 person-years), with an aHR of 1.43 (95% CI 1.16-1.77, p < 0.05). Younger patients, women, and patients with comorbidities were at a higher risk. The risks of postoperative OP/OF were significantly increased in patients who received thyroxine treatment for more than 1 year, both in the partial thyroidectomy group and in the total and subtotal thyroidectomy group (aHR: 2.47, 95% CI: 1.42-2.31 vs. aHR: 1.84, 95% CI: 1.22-2.76). Thyroidectomy significantly increased the long-term risk of OP. Younger patients, women, patients with comorbidities, and patients receiving chronic thyroxin treatment should be monitored for changes in postoperative bone density.


Peripheral blood basophils, basophil progenitors, and nasal metachromatic cells in allergic rhinitis.
Relationships among mature blood basophils, blood basophil colony-forming units in culture (CFU-c), and nasal metachromatic cells (NMC) were investigated using hemopoietic and histochemical techniques in 29 patients with allergic rhinitis and in 7 nonatopic control subjects. Total blood granulocyte and basophil CFU-c were significantly elevated in atopy; the highest levels of basophil CFU-c were found in patients with low total NMC counts in nasal scrapings (Group I), compared with those with intermediate (Group II) or high (Group III) counts: 10 +/- 3 basophil CFU-c per 10(6) cells in 10 Group I patients, 4 +/- 2 in 10 Group II patients, 3 +/- 1 in 9 Group III patients, and 0.1 +/- 0.1 in nonatopic control subjects (p less than 0.05). Mean histamine content and frequency of histamine-positive granulocyte colonies correlated with counts of basophils in colonies (r = 0.864, p less than 0.001). Peripheral blood basophils, which stained metachromatically with toluidine blue at pH 0.5 after Mota's lead acetate but not after formalin fixation, were highest in atopic Group III and lowest in Group I; a similar relationship was observed only for NMC, which also failed to stain after formalin fixation. Metachromatic cells in colonies were similar to formalin-sensitive NMC and to peripheral blood basophils in their sensitivity to different fixatives. Nasal symptoms correlated inversely with the number of basophil CFU and directly with the number of either formalin-sensitive NMC or peripheral blood basophils. These findings confirm and extend evidence for increased nasal metachromatic cells, basophilia, and alterations in basophilopoiesis in atopy.


Reinforcing endothelial junctions prevents microvessel permeability increase and tumor cell adhesion in microvessels in vivo.
Tumor cell adhesion to the microvessel wall is a critical step during tumor metastasis. Vascular endothelial growth factor (VEGF), a secretion of tumor cells, can increase microvessel permeability and tumor cell adhesion in the microvessel. To test the hypothesis that inhibiting permeability increase can reduce tumor cell adhesion, we used in vivo fluorescence microscopy to measure both microvessel permeability and adhesion rates of human mammary carcinoma MDA-MB-231 cells in post-capillary venules of rat mesentery under the treatment of VEGF and a cAMP analog, 8-bromo-cAMP, which can decrease microvessel permeability. By immunostaining adherens junction proteins between endothelial cells forming the microvessel wall, we further investigated the structural mechanism by which cAMP abolishes VEGF-induced increase in microvessel permeability and tumor cell adhesion. Our results demonstrate that 1) Pretreatment of microvessels with cAMP can abolish VEGF-enhanced microvessel permeability and tumor cell adhesion; 2) Tumor cells prefer to adhere to the endothelial cell junctions instead of cell bodies; 3) VEGF increases microvessel permeability and tumor cell adhesion by compromising endothelial junctions while cAMP abolishes these effects of VEGF by reinforcing the junctions. These results suggest that strengthening the microvessel wall integrity can be a potential approach to inhibiting hematogenous tumor metastasis.


A comparison of implant stability quotients measured using magnetic resonance frequency analysis from two directions: a prospective clinical study during the initial healing period.
Given that the orientation of the transducer (mesiodistal or buccolingual) affects the data obtained from a piezoelectric resonance frequency analysis (RFA), this study evaluated whether it is necessary to use measurements taken in two different directions (mesiodistal and buccolingual) when using magnetic RFA to assess changes in the stiffness of dental implants. A prospective clinical trial was completed, in a total of 53 patients, on 71 non-submerged dental implants that were inserted to replace the unilateral loss of mandibular molars. All of the implants were of the same diameter (4.1 mm), length (10 mm), and collar height (2.8 mm). The implant stability quotient (ISQ) was measured during the surgical procedure, and at 4 and 10 weeks after surgery. Measurements were taken twice in each direction: in the buccolingual direction from the buccal side and in the mesiodistal direction from the mesial side. The average of two measurements in each direction was regarded as the representative ISQ of that direction. The higher and lower values of the two ISQs (buccolingual and mesiodistal) were also classified separately. In addition, the variation in ISQ was quantified by subtracting the lower value from the higher value, and the implants were classified into two groups according to this variation: one with ISQ variation of 3 or more and the other with a variation of <3. There were no differences between the two ISQs when measured from different directions, but there were significant differences between the higher and lower values of the ISQs at each measurement point. A significant difference was also observed between the two ISQ variation groups in the pattern of change of the lower value for the period from immediately after surgery to 10 weeks after surgery. Acquisition of two directional measurements and classification of the higher and lower values of the two directional ISQs may allow clinicians to detect patterns of change in ISQ that would not be identified if only one directional measurement were made.


Digital signal-processing techniques for electronically scanned optical-fiber white-light interferometry.
Several important digital processing techniques for optical-fiber sensor systems that use electronically scanned white-light interferometry are presented. These include fringe restoration, fringe-order identification, and resolution enhancement techniques. A pure low-coherence interference fringe pattern is restored by dividing, pixel by pixel, the beam intensity profile from the signal. The central (zero-order) fringe of the pattern is identified by using a centroid algorithm. A linear interpolation or a localized centroid algorithm is used to enhance further the phase resolution. Theoretical analyses, computer simulations, and experimental verifications have shown that these techniques are able to increase greatly the dynamic range of the measurement under a low signal-to-noise ratio environment.


Systematic review of the effect of pneumococcal conjugate vaccine dosing schedules on prevention of pneumonia.
Pneumonia is the leading cause of morbidity and mortality among children <5 years of age globally. Pneumococcal conjugate vaccines (PCVs) are known to provide protection against vaccine serotype pneumococcal pneumonia; uncertainty exists regarding the optimum PCV dosing schedule. We conducted a systematic review of studies published from 1994 to 2010 (supplemented post hoc with studies from 2011) documenting the effect of PCV dosing schedules on clinical and radiologically confirmed pneumonia, pneumococcal pneumonia and empyema among children of ages targeted to receive vaccine. Data on 2- and 3-dose schedules were included. Percent change of pneumonia incidence rates from baseline to most recent year post-PCV introduction was calculated. We identified 42 primary citations that evaluated PCV schedules and pneumonia. Thirty-seven (88%) were from North America, Europe or Australia; 37 (88%) evaluated PCV7 and 1 (2%) PCV10. Two studies (both observational) compared multiple schedules within the study. We found evidence of reduced clinical and radiologically confirmed pneumonia incidence for all schedules, including 2+1 (1 nonrandomized trial, 5 observational studies), 3+0 (5 randomized trials, 2 observational studies) and 3+1 (5 clinical trials, 24 observational studies) schedules. The magnitude of disease impact did not differ among schedules. Evidence for impact on pneumococcal pneumonia and empyema varied. All schedules (2+1, 3+0 and 3+1) reduced clinical and radiologically confirmed pneumonia. Quantifying differences in pneumonia disease impact between schedules was difficult due to heterogeneity among studies in design, case definition and population. These findings support World Health Organization recommendations for 3-dose schedules administered as either 3+0 or 2+1 regimens. Pneumonia impact data are still needed on expanded serotype PCV products, developing country settings and the role for a booster dose.


A genome-wide enhancer/suppressor screen for Dube3a interacting genes in Drosophila melanogaster.
The genetics underlying autism spectrum disorder (ASD) are complex. Approximately 3-5% of ASD cases arise from maternally inherited duplications of 15q11.2-q13.1, termed Duplication 15q syndrome (Dup15q). 15q11.2-q13.1 includes the gene UBE3A which is believed to underlie ASD observed in Dup15q syndrome. UBE3A is an E3 ubiquitin ligase that targets proteins for degradation and trafficking, so finding UBE3A substrates and interacting partners is critical to understanding Dup15q ASD. In this study, we take an unbiased genetics approach to identify genes that genetically interact with Dube3a, the Drosophila melanogaster homolog of UBE3A. We conducted an enhancer/suppressor screen using a rough eye phenotype produced by Dube3a overexpression with GMR-GAL4. Using the DrosDel deficiency kit, we identified 3 out of 346 deficiency lines that enhanced rough eyes when crossed to two separate Dube3a overexpression lines, and subsequently identified IA2, GABA-B-R3, and lola as single genes responsible for rough eye enhancement. Using the FlyLight GAL4 lines to express uas-Dube3a + uas-GFP in the endogenous lola pattern, we observed an increase in the GFP signal compared to uas-GFP alone, suggesting a transcriptional co-activation effect of Dube3a on the lola promoter region. These findings extend the role of Dube3a/UBE3A as a transcriptional co-activator, and reveal new Dube3a interacting genes.


The Drosophila SRF homolog is expressed in a subset of tracheal cells and maps within a genomic region required for tracheal development.
The Drosophila homolog of the vertebrate serum response factor (SRF) was isolated by low stringency hybridization. Nucleotide sequence analysis revealed that the Drosophila SRF homolog (DSRF) codes for a protein that displays 93% sequence identity with human SRF in the MADS domain, the region required for DNA binding, dimerization and interaction with accessory factors. The DSRF gene is expressed during several phases of embryonic development. In the egg, both the RNA and the protein are maternal in origin and slowly decrease in amount during gastrulation. After germ band retraction, high levels of zygotic expression are observed in a distinct subset of peripheral tracheal cells distributed throughout the embryo. Many of these cells are at the tip of tracheal branches and are in direct contact with the target tissues. The DSRF gene was mapped to position 60C on the second chromosome, and overlapping deficiencies which remove the gene were identified. Analysis of tracheal development in embryos carrying these deletions revealed a degeneration of most of the major branches of the tracheal system. Although the initial migration of tracheal cells was not affected in those deficient embryos, many tracheal cells appeared not to maintain their correct position and continued to migrate. Thus, the DSRF gene might play a role in the proper formation and maintenance of the trachea.


Nonenzymic polycyclization of analogues of oxidosqualene with a preformed C-ring.
Some nonenzymic epoxide-initiated polyolefin cyclization are reported. The presented molecules are partially constrained analogues of (3S)-oxidosqualene, the natural substrate to many important cyclase enzymes. These model compounds feature a preformed C-ring with built-in stereochemical information. The experimental results allow for an instructive comparison with the enzymic processes, particularly those of the cyclases in steroid biosynthesis (i.e. lanosterol synthase).


A gender perspective on the extent to which mothers and fathers each take responsibility for care of a child with high and intermediate imperforate anus.
Imperforate anus is a malformation of the child's anus. Parents' experiences of responsibility for care of the child may differ. The aim of this study was to evaluate a gender perspective on the extent to which mothers and fathers each take responsibility for the care of a child with high and intermediate imperforate anus. Parents of children with imperforate anus and two control groups of children and parents participated. Data collection with questionnaires focusing on responsibility was performed. In conclusion, our study revealed additional evidence of unevenly divided parental responsibility for care of a child with a chronic condition. The mothers in this study were shown to be the primary caregiver.


Occupational risk factors for radial tunnel syndrome in industrial workers.
The aim of the study was to evaluate both nonoccupational and occupational factors associated with radial tunnel syndrome (RTS) among industrial workers in 3 large plants. Twenty-one cases of RTS were compared with 21 referents matched for gender, age, and plant. RTS was associated with carpal tunnel syndrome (CTS) in 9 cases. Past medical history, household activities, and ergonomic and organizational characteristics of the job were analyzed. The study found 3 occupational risk factors for RTS. Exertion of force of over 1 kg [odds ratio (OR) 9.1, 95% confidence interval (95% CI) 1.4-56.9] more than 10 times per hour was the main biomechanical risk factor. Prolonged static load applied to the hand during work was strongly associated with RTS (OR 5.9, 95% CI 1.2-29.9). Work posture with the elbow fully extended (0-45 degrees) was associated with RTS (OR 4.9, 95% CI 1.0-25.0). Full extension of the elbow, associated with a twisted posture of the forearm, stressed the radial nerve at the elbow. However, personal activities, household chores, and sport and leisure activities were not associated with RTS. The study confirms that RTS occurs in workers performing hard manual labor that requires forceful and repetitive movements involving elbow extension and forearm prosupination.


Generation of 0.66-TW pulses at 1 kHz by a Ti:sapphire laser.
A 1-kHz, 0.66-TW Ti:sapphire laser has been developed. We obtained 21-fs, 14-mJ pulses with an extraction efficiency of 32% in the final amplifier. The dispersion through the system was successfully compensated for by insertion of a pair of prisms in a regenerative amplifier. The pulses were characterized by frequency-resolved optical gating and were in good agreement with dispersion calculated by three-dimensional ray tracing.


Dbf2-Mob1 drives relocalization of protein phosphatase Cdc14 to the cytoplasm during exit from mitosis.
Exit from mitosis is characterized by a precipitous decline in cyclin-dependent kinase (Cdk) activity, dissolution of mitotic structures, and cytokinesis. In Saccharomyces cerevisiae, mitotic exit is driven by a protein phosphatase, Cdc14, which is in part responsible for counteracting Cdk activity. Throughout interphase, Cdc14 is sequestered in the nucleolus, but successful anaphase activates the mitotic exit network (MEN), which triggers dispersal of Cdc14 throughout the cell by a mechanism that has remained unknown. In this study, we show that a MEN component, protein kinase Dbf2-Mob1, promotes transfer of Cdc14 to the cytoplasm and consequent exit from mitosis by direct phosphorylation of Cdc14 on serine and threonine residues adjacent to a nuclear localization signal (NLS), thereby abrogating its NLS activity. Our results define a mechanism by which the MEN promotes exit from mitosis.


Efforts to eliminate the latent reservoir in resting CD4+ T cells: strategies for curing HIV-1 infection.
Since the introduction of the first antiretroviral drug, zidovudine, in 1987, over 25 different antiretroviral agents from six different drug classes have been approved for the treatment of HIV-1 infection. Today, combination antiretroviral therapy (ART) is extremely effective in suppressing HIV-1 replication, providing durable control of the virus in adherent patients. However, despite the effectiveness of ART in blocking viral replication, HIV-1 infection cannot be cured by ART alone because HIV-1 establishes a state of latent infection in a small pool of resting, memory CD4+ T cells. Some new developments in the search for a cure are discussed.


Population Genomic Analysis of 1,777 Extended-Spectrum Beta-Lactamase-Producing Klebsiella pneumoniae Isolates, Houston, Texas: Unexpected Abundance of Clonal Group 307.
Klebsiella pneumoniae is a major human pathogen responsible for high morbidity and mortality rates. The emergence and spread of strains resistant to multiple antimicrobial agents and documented large nosocomial outbreaks are especially concerning. To develop new therapeutic strategies for K. pneumoniae, it is imperative to understand the population genomic structure of strains causing human infections. To address this knowledge gap, we sequenced the genomes of 1,777 extended-spectrum beta-lactamase-producing K. pneumoniae strains cultured from patients in the 2,000-bed Houston Methodist Hospital system between September 2011 and May 2015, representing a comprehensive, population-based strain sample. Strains of largely uncharacterized clonal group 307 (CG307) caused more infections than those of well-studied epidemic CG258. Strains varied markedly in gene content and had an extensive array of small and very large plasmids, often containing antimicrobial resistance genes. Some patients with multiple strains cultured over time were infected with genetically distinct clones. We identified 15 strains expressing the New Delhi metallo-beta-lactamase 1 (NDM-1) enzyme that confers broad resistance to nearly all beta-lactam antibiotics. Transcriptome sequencing analysis of 10 phylogenetically diverse strains showed that the global transcriptome of each strain was unique and highly variable. Experimental mouse infection provided new information about immunological parameters of host-pathogen interaction. We exploited the large data set to develop whole-genome sequence-based classifiers that accurately predict clinical antimicrobial resistance for 12 of the 16 antibiotics tested. We conclude that analysis of large, comprehensive, population-based strain samples can assist understanding of the molecular diversity of these organisms and contribute to enhanced translational research.IMPORTANCEKlebsiella pneumoniae causes human infections that are increasingly difficult to treat because many strains are resistant to multiple antibiotics. Clonal group 258 (CG258) organisms have caused outbreaks in health care settings worldwide. Using a comprehensive population-based sample of extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae strains, we show that a relatively uncommon clonal type, CG307, caused the plurality of ESBL-producing K. pneumoniae infections in our patients. We discovered that CG307 strains have been abundant in Houston for many years. As assessed by experimental mouse infection, CG307 strains were as virulent as pandemic CG258 strains. Our results may portend the emergence of an especially successful clonal group of antibiotic-resistant K. pneumoniae.


Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception.
Transient receptor potential (TRP) ankyrin 1 (TRPA1) is a Ca(2+)-permeant, nonselective cationic channel. It is predominantly expressed in the C afferent sensory nerve fibers of trigeminal and dorsal root ganglion neurons and is highly coexpressed with the nociceptive ion channel transient receptor potential vanilloid 1 (TRPV1). Several physical and chemical stimuli have been shown to activate the channel. In this study, we have used electrophysiological techniques and behavioral models to characterize the properties of TRPA1. Whole cell TRPA1 currents induced by brief application of lower concentrations of N-methyl maleimide (NMM) or allyl isothiocyanate (AITC) can be reversed readily by washout, whereas continuous application of higher concentrations of NMM or AITC completely desensitized the currents. The deactivation and desensitization kinetics differed between NMM and AITC. TRPA1 current amplitude increased with repeated application of lower concentrations of AITC, whereas saturating concentrations of AITC induced tachyphylaxis, which was more pronounced in the presence of extracellular Ca(2+). The outward rectification exhibited by native TRPA1-mediated whole cell and single-channel currents was minimal as compared with other TRP channels. TRPA1 currents were negatively modulated by protons and polyamines, both of which activate the heat-sensitive channel, TRPV1. Interestingly, neither protein kinase C nor protein kinase A activation sensitized AITC-induced currents, but each profoundly sensitized capsaicin-induced currents. Current-clamp experiments revealed that AITC produced a slow and sustained depolarization as compared with capsaicin. TRPA1 is also expressed at the central terminals of nociceptors at the caudal spinal trigeminal nucleus. Activation of TRPA1 in this area increases the frequency and amplitude of miniature excitatory or inhibitory postsynaptic currents. In behavioral studies, intraplantar and intrathecal administration of AITC induced more pronounced and prolonged changes in nociceptive behavior than those induced by capsaicin. In conclusion, the characteristics of TRPA1 we have delineated suggest that it might play a unique role in nociception.


Quality of Life Among Asian American Youth.
The aims of the present study were to examine whether Asian American youth experience disparities in quality of life (QL) compared with Hispanic, African American, and white youth in the general population and to what extent socioeconomic status (SES) mediates any disparities among these racial/ethnic groups. Data were obtained from the Healthy Passages study, in which 4,972 Asian American (148; 3%), Hispanic (1,813; 36%), African American (1,755; 35%), and white (1,256; 25%) fifth-graders were enrolled in a population-based, cross-sectional survey conducted in three U.S. metropolitan areas. Youth reported their own QL using the PedsQL and supplemental scales. Parents reported youth's overall health status as well as parent's education and household income level. Asian American youth experienced worse status than white youth for three of 10 QL and well-being measures, better status than Hispanic youth on six measures, and better status than African American youth on three measures. However, the observed advantages for Asian American youth over Hispanic and African American youth disappeared when the marked SES differences that are also present among these racial/ethnic groups were taken into account. In contrast, the differences between Asian American and white youth remained after adjusting for SES. These findings suggest that the disparities in QL that favor white youth over Asian American youth exist independent of SES and warrant further examination. In contrast, the QL differences that favor Asian American over Hispanic and African American youth may be partly explained by SES. Interpretations are limited by the heterogeneity existing among Asian Americans.


Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.
The KvLQT1 gene encodes a voltage-gated potassium channel. Mutations in KvLQT1 underlie the dominantly transmitted Ward-Romano long QT syndrome, which causes cardiac arrhythmia, and the recessively transmitted Jervell and Lange-Nielsen syndrome, which causes both cardiac arrhythmia and congenital deafness. KvLQT1 is also disrupted by balanced germline chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth and cancer. Because of the diverse human disorders and organ systems affected by this gene, we developed an animal model by inactivating the murine Kvlqt1. No electrocardiographic abnormalities were observed. However, homozygous mice exhibited complete deafness, as well as circular movement and repetitive falling, suggesting imbalance. Histochemical study revealed severe anatomic disruption of the cochlear and vestibular end organs, suggesting that Kvlqt1 is essential for normal development of the inner ear. Surprisingly, homozygous mice also displayed threefold enlargement by weight of the stomach resulting from mucous neck cell hyperplasia. Finally, there were no features of BWS, suggesting that Kvlqt1 is not responsible for BWS.


Timed Up-and-Go Device for Unsupervised Functional Assessment of Elderly Patients.
Functional evaluation of elderly patients is one key component in a comprehensive Geriatric Assessment. The increased workload and high costs associated to close and continuous monitoring in clinical settings may be counterbalanced by the application of ICT-supported remote follow-up. Although clinical parameters and questionnaires can be supported with smartphones and smart gadgets, physical performance trials pose a challenge for community-based approaches with difficulties arising from setting up trials, the lack of guidance and supervision. We developed an ultrasonic-based device to overcome all of these barriers and enable elderly people to perform the Timed Up-and-Go test in an autonomous and unsupervised setting. Moreover, we introduce an algorithm to verify the successful performance of the test in order to increase the reliability of the information provided.


Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder.
Newer antipsychotic drugs have shown promise in ameliorating neurocognitive deficits in patients with schizophrenia, but few studies have compared newer antipsychotic drugs with both clozapine and conventional agents, particularly in patients who have had suboptimal response to prior treatments. The authors examined the effects of clozapine, olanzapine, risperidone, and haloperidol on 16 measures of neurocognitive functioning in a double-blind, 14-week trial involving 101 patients. A global score was computed along with scores in four neurocognitive domains: memory, attention, motor function, and general executive and perceptual organization. Global neurocognitive function improved with olanzapine and risperidone treatment, and these improvements were superior to those seen with haloperidol. Patients treated with olanzapine exhibited improvement in the general and attention domains but not more than that observed with other treatments. Patients treated with risperidone exhibited improvement in memory that was superior to that of both clozapine and haloperidol. Clozapine yielded improvement in motor function but not more than in other groups. Average effect sizes for change were in the small to medium range. More than half of the patients treated with olanzapine and risperidone experienced "clinically significant" improvement (changes in score of at least one-half standard deviation relative to baseline). These findings did not appear to be mediated by changes in symptoms, side effects, or blood levels of medications. Patients with a history of suboptimal response to conventional treatments may show cognitive benefits from newer antipsychotic drugs, and there may be differences between atypical antipsychotic drugs in their patterns of cognitive effects.


Neurofeedback in ADHD: a single-blind randomized controlled trial.
Neurofeedback treatment has been demonstrated to reduce inattention, impulsivity and hyperactivity in children with attention deficit/hyperactivity disorder (ADHD). However, previous studies did not adequately control confounding variables or did not employ a randomized reinforcer-controlled design. This study addresses those methodological shortcomings by comparing the effects of the following two matched biofeedback training variants on the primary symptoms of ADHD: EEG neurofeedback (NF) aiming at theta/beta ratio reduction and EMG biofeedback (BF) aiming at forehead muscle relaxation. Thirty-five children with ADHD (26 boys, 9 girls; 6-14 years old) were randomly assigned to either the therapy group (NF; n = 18) or the control group (BF; n = 17). Treatment for both groups consisted of 30 sessions. Pre- and post-treatment assessment consisted of psychophysiological measures, behavioural rating scales completed by parents and teachers, as well as psychometric measures. Training effectively reduced theta/beta ratios and EMG levels in the NF and BF groups, respectively. Parents reported significant reductions in primary ADHD symptoms, and inattention improvements in the NF group were higher compared to the control intervention (BF, d (corr) = -.94). NF training also improved attention and reaction times on the psychometric measures. The results indicate that NF effectively reduced inattention symptoms on parent rating scales and reaction time in neuropsychological tests. However, regarding hyperactivity and impulsivity symptoms, the results imply that non-specific factors, such as behavioural contingencies, self-efficacy, structured learning environment and feed-forward processes, may also contribute to the positive behavioural effects induced by neurofeedback training.


Environmental Drivers of Differences in Microbial Community Structure in Crude Oil Reservoirs across a Methanogenic Gradient.
Stimulating in situ microbial communities in oil reservoirs to produce natural gas is a potentially viable strategy for recovering additional fossil fuel resources following traditional recovery operations. Little is known about what geochemical parameters drive microbial population dynamics in biodegraded, methanogenic oil reservoirs. We investigated if microbial community structure was significantly impacted by the extent of crude oil biodegradation, extent of biogenic methane production, and formation water chemistry. Twenty-two oil production wells from north central Louisiana, USA, were sampled for analysis of microbial community structure and fluid geochemistry. Archaea were the dominant microbial community in the majority of the wells sampled. Methanogens, including hydrogenotrophic and methylotrophic organisms, were numerically dominant in every well, accounting for, on average, over 98% of the total Archaea present. The dominant Bacteria groups were Pseudomonas, Acinetobacter, Enterobacteriaceae, and Clostridiales, which have also been identified in other microbially-altered oil reservoirs. Comparing microbial community structure to fluid (gas, water, and oil) geochemistry revealed that the relative extent of biodegradation, salinity, and spatial location were the major drivers of microbial diversity. Archaeal relative abundance was independent of the extent of methanogenesis, but closely correlated to the extent of crude oil biodegradation; therefore, microbial community structure is likely not a good sole predictor of methanogenic activity, but may predict the extent of crude oil biodegradation. However, when the shallow, highly biodegraded, low salinity wells were excluded from the statistical analysis, no environmental parameters could explain the differences in microbial community structure. This suggests that the microbial community structure of the 5 shallow, up-dip wells was different than the 17 deeper, down-dip wells. Also, the 17 down-dip wells had statistically similar microbial communities despite significant changes in environmental parameters between oil fields. Together, this implies that no single microbial population is a reliable indicator of a reservoir's ability to degrade crude oil to methane, and that geochemistry may be a more important indicator for selecting a reservoir suitable for microbial enhancement of natural gas generation.


Movement seasonality in a desert-dwelling bat revealed by miniature GPS loggers.
Bats are among the most successful desert mammals. Yet, our understanding of their spatio-temporal dynamics in habitat use associated with the seasonal oscillation of resources is still limited. In this study, we have employed state-of-the-art lightweight GPS loggers to track the yellow-winged bat Lavia frons in a desert in northern Kenya to investigate how seasonality in a desert affects the a) spatial and b) temporal dimensions of movements in a low-mobility bat. Bats were tracked during April-May 2017 (rainy season) and January-February 2018 (dry season) using 1-g GPS loggers. Spatial and temporal dimensions of movements were quantified, respectively, as the home range and nightly activity patterns. We tested for differences between seasons to assess responses to seasonal drought. In addition, we quantified home range overlap between neighbouring individuals to investigate whether tracking data will be in accordance with previous reports on territoriality and social monogamy in L. frons. We obtained data for 22 bats, 13 during the rainy and 9 during the dry season. Home ranges averaged 5.46 ± 11.04 ha and bats travelled a minimum distance of 99.69 ± 123.42 m/hour. During the dry season, home ranges were larger than in the rainy season, and bats exhibited high activity during most of the night. No apparent association with free water was identified during the dry season. The observed spatial organisation of home ranges supports previous observations that L. frons partitions the space into territories throughout the year. Our results suggest that, in low-mobility bats, a potential way to cope with seasonally harsh conditions and resource scarcity in deserts is to cover larger areas and increase time active, suggesting lower cost-efficiency of the foraging activity. Climate change may pose additional pressures on L. frons and other low-mobility species by further reducing food abundances.


Body Mass Index Is Positively Associated with Endometrial Cancer in Chinese Women, Especially Prior to Menopause.
Obesity is a well-known risk factor for developing endometrial cancer. However, the incidence and survival rate of endometrial cancer are associated with ethnicity and geographical area. In addition, whether menopausal status is associated with developing endometrial cancer in obese women and whether obesity is associated with subtypes of endometrial cancer have not been fully investigated. Here, we investigated the effect of BMI on developing endometrial cancer in Chinese women taking into account menopausal status and cancer subtypes. Data on 1,127 women with endometrial cancer including body mass index (BMI), age at diagnosis, parity, menopausal status and cancer subtype were collected from the largest obstetrics & gynaecology hospital in China and analysed. After adjusting for age and parity, the odds for developing endometrial cancer in overweight or obese perimenopausal women was significantly higher than that in women with normal weight (OR=2.6 with 95%CI:1.9-3.5, and OR=3.5 with 95%CI: 2.2-5.4, respectively). The odds of developing endometrial cancer in overweight postmenopausal women were significantly higher than that in women who were normal weight (OR=2.4 with 95%CI: 1.8-3.1), however this was not the case for obese postmenopausal women. We further found that BMI, menopausal status, age and parity were not associated with subtypes of endometrial cancer. Our data demonstrate that obesity is positively associated with the incidence of developing endometrial cancer in Chinese women, with more significant effects in perimenopausal women.


Cyclical micromovement and fracture healing.
We studied 56 patients with fractures of the tibial shaft in a multicentre prospective randomised trial of three methods of external fixation. Group I was treated with a fixator which was unlocked at 4 to 6 weeks to allow free axial compression (axial dynamisation) with weight-bearing. Group II was treated with a fixator that was similarly unlocked at 4 to 6 weeks but included a small silicone spring which on weight-bearing could be compressed by up to 2 mm. this spring returns to its original length on cessation of weight-bearing thus allowing cycles of motion of up to 2 mm. Group III had a spring fixator like group II, but it was unlocked from the start to allow cyclical micromovement as soon as weight-bearing began. Fracture healing was monitored by the measurement of fracture stiffness. We defined healing as achieving a stiffness of 15 Nm per degree. The mean time was 14.1 weeks in group I, 15.9 weeks in group II, and 19.3 weeks in group III. The difference between groups was statistically significant (p = 0.004). The 95% confidence intervals for the average delay in healing with early cyclical micromovement (group III) as compared with later axial dynamisation (group I) was 1.8 to 8.7 weeks. The healing time in patients whose cyclical micromovement was delayed for 4 to 6 weeks (group II) was between these two extremes, but the differences from either of the other groups could have been due to patient selection. In the patients who completed the full trial, there were pin-track infections in over 60% of those in the cyclical micromovement groups compared with 20% in the axial dynamisation group (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)


Community attitudes on genetic research of gender identity, sexual orientation, and mental health.
Sex is an important factor in mental health, and a non-binary view of how variation in sex and gender influence mental health represents a new research frontier that may yield new insights. The recent acceleration of research into sexual orientation, gender identity, and mental health has generally been conducted without sufficient understanding of the opinions of sexual and gender minorities (SGM) toward this research. We surveyed 768 individuals, with an enrichment of LGBTQ+ stakeholders, for their opinions regarding genetic research of SGM and mental health. We found that the key predictors of attitudes toward genetic research specifically on SGM are 1) general attitudes toward genetic and mental health research 2) tolerance of SGM and associated behaviors and 3) age of the participant. Non-heterosexual stakeholder status was significantly associated with increased willingness to participate in genetic research if a biological basis for gender identity were discovered. We also found that heterosexual, cisgender participants with a low tolerance for SGM indicated their SGM views would be positively updated if science showed a biological basis for their behaviors and identities. These findings represent an important first step in understanding and engaging the LGBTQ+ stakeholder community in the context of genetic research.


Fatty acid composition and bacterial community changes in the rumen fluid of lactating sheep fed sunflower oil plus incremental levels of marine algae.
Supplementation of ruminant diets with plant oils and marine lipids is an effective strategy for lowering saturated fatty acid (FA) content and increasing the concentration of cis-9,trans-11 conjugated linoleic acid and long-chain n-3 FA in ruminant milk. However, changes in populations of ruminal microorganisms associated with altered biohydrogenation of dietary unsaturated FA are not well characterized. Twenty-five lactating Assaf ewes were allocated at random to 1 of 5 treatments composed of dehydrated alfalfa hay and concentrates containing no additional lipid (control), or supplemented with 25 g of sunflower oil and 0 (SO), 8 (SOMA(1)), 16 (SOMA(2)), or 24 (SOMA(3)) g of marine algae/kg of diet dry matter. On d 28 on diet, samples of rumen fluid were collected for lipid analysis and microbial DNA extraction. Appearance and identification of biohydrogenation intermediates was determined based on complementary gas chromatography and Ag+-HPLC analysis of FA methyl esters. Total bacteria and the Butyrivibrio group were studied in microbial DNA by terminal RFLP analysis, and real-time PCR was used to quantify the known Butyrivibrio bacteria that produce trans-11 18:1 or 18:0. Dietary supplements of sunflower oil alone or in combination with marine algae altered the FA profile of rumen fluid, which was associated with changes in populations of specific bacteria. Inclusion of marine algae in diets containing sunflower oil resulted in the accumulation of trans 18:1 and 10-O-18:0 and a marked decrease in 18:0 concentrations in rumen fluid. At the highest levels of supplementation (SOMA(2) and SOMA(3)), marine algae also promoted a shift in ruminal biohydrogenation pathways toward the formation of trans-10 18:1 at the expense of trans-11 18:1. Changes in the concentration of biohydrogenation intermediates were not accompanied by significant variations in the abundance of known cultivated ruminal bacteria capable of hydrogenating unsaturated FA. However, certain bacterial groups detected by terminal RFLP (such as potentially uncultured Lachnospiraceae strains or Quinella-related bacteria) exhibited variations in their relative frequency consistent with a potential role in one or more metabolic pathways of biohydrogenation in the rumen.


The long-term costs for treating multiple sclerosis in a 16-year retrospective cohort study in Brazil.
Multiple Sclerosis (MS) is a disease that appreciably impacts on the quality of life of patients and is associated with high expenditure. MS is a chronic multifactorial disease, characterized by inflammation, demyelination and axonal loss. The Brazilian public health system provides pharmacological treatment as well as hospital and outpatient care for patients with relapsing-remitting and secondary progressive multiple sclerosis. However, we are not aware of any previous publications assessing total direct medical costs in patients with a long follow-up within the Brazilian healthcare system. Consequently, the objective is to analyze public spending on patients with MS to guide stakeholders in future investment and disinvestment decisions. We retrospectively analyzed public Brazilian spending on patients with MS between 2000 and 2015 using the patient-centered registry of all patients in the public health system (SUS) obtained through deterministic-probabilistic record linkage of the Outpatient Information System, Hospital Information System and Mortality Information Systems in Brazil. Descriptive data analysis and a multiple linear regression model was performed to evaluate the associations between the mean annual cost per patient and the clinical and demographic variables. The suitability of the model was verified from a residue analysis and the level of significance adopted was 5%. 28,401 patients were identified and subsequently 23,082 patients were analyzed. The majority of the patients were female (73.3%), lived in the southeast region (58.9%), had a mean age of 36.8 (± 12.2) years and started treatment using one of the interferons beta (78.9%). The total direct medical cost spending in the sixteen years of the follow-up was US $ 2,308,393,465.60, and the mean annual expenditure per patient was US $ 13,544.40 (± 4,607.05). In the best fit model (p <0.001), approximately 40% of the variability of the mean annual cost per patient was explained by the region of residence; medication used (intention to treat); if the patient was a non-exclusive user of medicines, i.e., used SUS for other procedures other than high-cost medicines; year of treatment start; and presence of events (death; Relapse; change of treatment and/or comorbidity). In the public health system of Brazil, disease modifying therapies currently represent almost all of the total direct costs of multiple sclerosis treatment. Around the world, new and emerging health technologies to treat of MS impose a challenge to health budgets, highlighting the need for cost-effectiveness studies comparing these technologies to those already available. Our regression model may help in this process, and calls attention to the need to access the real world performance of new therapies available in SUS, with the potential for disinvestment and/ or price reductions if needed.


Management Outcomes Of Extra Abdominal Fibromatosis Among Adult Patients Treated At A Tertiary Care Hospital.
Aggressive fibromatosis or desmoid fibromatosis is a soft tissue neoplasm which is non-metastatic in nature. Among all soft tissue tumours, it comprises of 3% cases and is more common in females as compared to males. Objective of our study was to evaluate the treatment outcomes of extra abdominal fibromatosis in patients who were treated in our setup and determine the recurrence patterns. It is retrospective cohort of 15 patients that were treated in section of Orthopaedics, department of surgery, Aga Khan University hospital, Karachi from January 1990 to December 2015. It included all adult patients of age >18 years with biopsy proven extra abdominal aggressive fibromatosis. Data was analysed on SPSS 22 version.. Out of 15 patients, there were 7 males (46.7%) and 8 females (53.3%). Median age was 22 years. Majority of patients [10 (66.6%)] had upper limb lesion. On initial biopsy we had 11 (73.3%) cases of primary fibromatosis while 2 (13.3%) were recurrent and 2 (13.3%) were spindle cell carcinoma. The median (IQR) follow-up time of the participants was 3 (2-3) months. Complications occurred in 8 (53.3%) patients. A significant difference was observed in the haemoglobin levels before and after surgery with a mean difference of 2.74 (p-value<0.001). Recurrence of disease occurred in 4 (26.7%) patients and all of these patients who had recurrence underwent 2nd surgery versus 1 of the participants who had second surgery without recurrence and this was a significant difference (p value <0.004). Extra abdominal fibromatosis is commonly found among younger age groups, affecting females more as compared to males. Less than half of the patients had recurrence of disease in our study and intra-operative and postoperative complications are common surgical outcomes and our study results are compatible with previously reported literature.


Direct findings of aortic injury on contrast-enhanced CT in surgically proven traumatic aortic injury: a multi-centre review.
To review the contrast-enhanced CT findings in surgically proven traumatic aortic injury (TAI). We searched the trauma registries of three academic medical centres from 1994 to 2000 and found 34 patients with surgically proven TAI that received pre-operative contrast-enhanced chest CT. Two chest radiologists recorded by consensus the size and location of direct (pseudoaneurysm, intimal flap) and indirect (mediastinal haematoma) findings of TAI. The imaging findings were correlated with surgical reports. Direct findings of aortic injury (pseudoaneurysm or intimal flap) were seen on contrast enhanced CT in all patients and confirmed at surgery. Specifically, a pseudoaneurysm was seen in 33 (97%), presenting either as a focal bulge in 22 (65%) or as more diffuse aneurysmal enlargement in 11 (32%). An intimal flap was identified in 31 cases (91%). A periaortic haematoma was seen in 31 cases (91%). In the three patients without periaortic haematoma, the only indications of aortic injury were a focal pseudoaneurysm in two (6%) and an intimal flap in one (3%). In this series of surgically proven TAI, direct findings of aortic injury were seen in all cases. Aortic tear occurred without mediastinal haematoma in 9% (3/34) of patients.


Trimethylene carbonate and epsilon-caprolactone based (co)polymer networks: mechanical properties and enzymatic degradation.
High molecular weight trimethylene carbonate (TMC) and epsilon-caprolactone (CL) (co)polymers were synthesized. Melt pressed (co)polymer films were cross-linked by gamma irradiation (25 kGy or 50 kGy) in vacuum, yielding gel fractions of up to 70%. The effects of copolymer composition and irradiation dose on the cytotoxicity, surface properties, degradation behavior, and mechanical and thermal properties of these (co)polymers and networks were investigated. Upon incubation with cell culture medium containing extracts of (co)polymers and networks, human foreskin fibroblasts remained viable. For all (co)polymers and networks, cell viabilities were determined to be higher than 94%. The formed networks were flexible, with elastic moduli ranging from 2.7 to 5.8 MPa. Moreover, these form-stable networks were creep resistant under dynamic conditions. The permanent deformation after 2 h relaxation was as low as 1% after elongating to 50% strain for 20 times. The in vitro enzymatic erosion behavior of these hydrophobic (co)polymers and networks was investigated using aqueous lipase solutions. The erosion rates in lipase solution could be tuned linearly from 0.8 to 45 mg/(cm (2) x day) by varying the TMC to CL ratio and the irradiation dose. The copolymers and networks degraded essentially by a surface erosion mechanism.


Unique inactivation properties of NAADP-sensitive Ca2+ release.
Ca2+ mobilization from intracellular stores constitutes an important mechanism for generating cytoplasmic Ca2+ signals. Inositol trisphosphate (InsP3) and ryanodine receptors are the two families of intracellular Ca2+ release channels that have been identified, which may be regulated by separate intracellular messengers, InsP3, and cyclic adenosine 5'-diphosphate ribose, respectively. A third molecule, nicotinic acid adenine dinucleotide phosphate (NAADP), has recently been recognized as a potent Ca2+ releasing agent in sea urchin eggs and microsomes. We now report that non-releasing concentrations of NAADP fully and irreversibly inactivate the NAADP-sensitive Ca2+ release mechanism. This phenomenon occurred both in intact sea urchin eggs and in homogenates and is not shared by either InsP3 or cyclic adenosine 5'-diphosphate ribose. The novel properties of this Ca2+ release mechanism, giving a one-shot Ca2+ release, may be suited to irreversible cellular events.


Targeting the EGFR pathway for cancer therapy.
Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab/Herceptin, Pertuzumab/Omnitarg/rhuMab-2C4, Cetuximab/Erbitux/IMC-C225, Panitumumab/Abenix/ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.


Curcumin influences semen quality parameters and reverses the di(2-ethylhexyl)phthalate (DEHP)-induced testicular damage in mice.
Curcumin is a phytochemical derived from rhizome of turmeric Curcuma longa, present in the curry spice. Recently, it has attracted the attention of researchers and clinicians as an anti-inflammatory and anti-oxidant agent with a potential use in therapy of many diseases with an inflammatory component. Interestingly, curcumin despite its very low bioavailability showed protective activity against many organ lesions. In the present study we investigated the effects of curcumin treatment on mice semen quality parameters in vitro and on semen and testicular damage induced by di(2-ethylhexyl)phthalate in vivo. The study demonstrated protective effects of low concentrations (1-50 μM) of curcumin on mouse sperm motility in vitro and on DEHP-induced damage of seminiferous tubules in testes and its ability to diminish the decrease in sperm motility in vivo. In contrast, curcumin used in high concentration (100 μM) decreased sperm motility and viability in vitro. The effects of curcumin were dependent on its concentration. In male germ cells in vivo the protective effect was seen despite the low bioavailability of curcumin. In contrast, high, unattainable in the organism, concentration of curcumin had a cytotoxic effect on male reproductive cells in vitro. Curcumin also had a protective effect against the harmful impact of DEHP on the male reproductive system.


YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation.
Yin Yang 1 (YY1) regulates gene transcription in a variety of biological processes. In this study, we aim to determine the role of YY1 in vascular smooth muscle cell (VSMC) phenotypic modulation both in vivo and in vitro. Here we show that vascular injury in rodent carotid arteries induces YY1 expression along with reduced expression of smooth muscle differentiation markers in the carotids. Consistent with this finding, YY1 expression is induced in differentiated VSMCs in response to serum stimulation. To determine the underlying molecular mechanisms, we found that YY1 suppresses the transcription of CArG box-dependent SMC-specific genes including SM22α, SMα-actin and SMMHC. Interestingly, YY1 suppresses the transcriptional activity of the SM22α promoter by hindering the binding of serum response factor (SRF) to the proximal CArG box. YY1 also suppresses the transcription and the transactivation of myocardin (MYOCD), a master regulator for SMC-specific gene transcription by binding to SRF to form the MYOCD/SRF/CArG box triad (known as the ternary complex). Mechanistically, YY1 directly interacts with MYOCD to competitively displace MYOCD from SRF. This is the first evidence showing that YY1 inhibits SMC differentiation by directly targeting MYOCD. These findings provide new mechanistic insights into the regulatory mechanisms that govern SMC phenotypic modulation in the pathogenesis of vascular diseases.


Differential tissular distribution of Litomosoides sigmodontis microfilariae between microfilaremic and amicrofilaremic mice following experimental infection.
Filariases are caused by onchocercid nematodes that are transmitted by arthropod vectors. More than 180 million people are infected worldwide. Mass drug administration has been set up in many endemic areas to control the parasite burden. Although very successful in limiting microfilarial load, transmission has not been completely interrupted in such areas. A proportion of infected patients with lymphatic filariasis or loiasis are known to be amicrofilaremic, as they do not present microfilariae in their bloodstream despite the presence of adult worms. A mirror status also exists in CBA/Ca mice infected with Litomosoides sigmodontis, the well-established model of filariasis. Using this model, the goal of this study was to determine if the kinetics of blood clearance of microfilariae differed between amicrofilaremic CBA/Ca mice and microfilaremic BALB/c mice. For this purpose, a qPCR approach was devised to detect microfilariae in different tissues, after a controlled inoculation of microfilariae. We showed that the rapid clearance of microfilariae from the pleural cavity or from the bloodstream of CBA/Ca mice was associated with a massive accumulation of first stage larvae in the lungs, liver and spleen.


Time trends in prostate cancer screening in Swiss primary care (2010 to 2017) - A retrospective study.
Following years of controversy regarding screening for prostate cancer using prostate-specific antigen, evidence evolves towards a more restrained and preference-based use. This study reports the impact of landmark trials and updated recommendations on the incidence rate of prostate cancer screening by Swiss general practitioners. We performed a retrospective analysis of primary care data, separated in 3 time periods based on dates of publications of important prostate-specific antigen screening recommendations. 1: 2010-mid 2012 including 2 updates; 2: mid 2012-mid 2014 including a Smarter Medicine recommendation; 3: mid-2014-mid-2017 maintenance period. Period 2 including the Smarter Medicine recommendation was defined as reference period. We further assessed the influence of patient's age and the number of prostate-specific-antigen (PSA) tests, by the patient and within each time period, on the mean PSA concentration. Uni- and multivariable analyses were used as needed. 36,800 men aged 55 to 75 years were included. 14.6% had ≥ 2 chronic conditions, 11.7% had ≥ 1 prostate-specific antigen test, (mean 2.60 ng/ml [SD 12.3]). 113,921 patient-years were covered. Data derived from 221 general practitioners, 33.5% of GP were women, mean age was 49.4 years (SD 10.0), 67.9% used prostate-specific antigen testing. Adjusted incidence rate-ratio (95%-CI) dropped significantly over time periods: Reference Period 2: incidence rate-ratio 1.00; Period 1: incidence rate-ratio 1.74 (1.59-1.90); Period 3: incidence rate-ratio 0.61 (0.56-0.67). A higher number of chronic conditions and a patient age between 60-69 years were significantly associated with higher screening rate. Increasing numbers of PSA testing per patient, as well as increasing age, were independently and significantly associated with an increase in the PSA value. Swiss general practitioners adapted screening behavior as early as evidence of a limited health benefit evolved, while using a risk-adapted approach whenever performing multiple testing. Updated recommendations might have helped to maintain this decrease. Further recommendations and campaigns should aimed at older patients with multimorbidity, to sustain a further decline in prostate-specific antigen screening practices.


Notch1-promoted TRPA1 expression in erythroleukemic cells suppresses erythroid but enhances megakaryocyte differentiation.
The Notch1 pathway plays important roles in modulating erythroid and megakaryocyte differentiation. To screen the Notch1-related genes that regulate differentiation fate of K562 and HEL cells, the expression of transient receptor potential ankyrin 1 (TRPA1) was induced by Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor. N1IC and v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1) bound to TRPA1 promoter region to regulate transcription in K562 cells. Transactivation of TRPA1 promoter by N1IC depended on the methylation status of TRPA1 promoter. N1IC and Ets-1 suppressed the DNA methyltransferase 3B (DNMT3B) level in K562 cells. Inhibition of TRPA1 expression after Notch1 knockdown could be attenuated by nanaomycin A, an inhibitor of DNMT3B, in K562 and HEL cells. Functionally, hemin-induced erythroid differentiation could be suppressed by TRPA1, and the reduction of erythroid differentiation of both cells by N1IC and Ets-1 occurred via TRPA1. However, PMA-induced megakaryocyte differentiation could be enhanced by TRPA1, and the surface markers of megakaryocytes could be elevated by nanaomycin A. Megakaryocyte differentiation could be reduced by Notch1 or Ets-1 knockdown and relieved by TRPA1 overexpression. The results suggest that Notch1 and TRPA1 might be critical modulators that control the fate of erythroid and megakaryocyte differentiation.


Tobacco and Nicotine Cessation During Pregnancy: ACOG Committee Opinion Summary, Number 807.
Pregnant women should be advised of the significant perinatal risks associated with tobacco use, including orofacial clefts, fetal growth restriction, placenta previa, abruptio placentae, preterm prelabor rupture of membranes, low birth weight, increased perinatal mortality, ectopic pregnancy, and decreased maternal thyroid function. Children born to women who smoke during pregnancy are at an increased risk of respiratory infections, asthma, infantile colic, bone fractures, and childhood obesity. Pregnancy influences many women to stop smoking, and approximately 54% of women who smoke before pregnancy quit smoking directly before or during pregnancy. Smoking cessation at any point in gestation benefits the pregnant woman and her fetus. The greatest benefit is observed with cessation before 15 weeks of gestation. Although cigarettes are the most commonly used tobacco product in pregnancy, alternative forms of tobacco use, such as e-cigarettes or vaping products, hookahs, and cigars, are increasingly common. Clinicians should advise cessation of tobacco products used in any form and provide motivational feedback. Although counseling and pregnancy-specific materials are effective cessation aids for many pregnant women, some women continue to use tobacco products. Clinicians should individualize care by offering psychosocial, behavioral, and pharmacotherapy interventions. Available cessation-aid services and resources, including digital resources, should be discussed and documented regularly at prenatal and postpartum follow-up visits.


Rebleeding and Mortality After Lower Gastrointestinal Bleeding in Patients Taking Antiplatelets or Anticoagulants.
Patients who develop lower gastrointestinal bleeding (LGIB) while receiving anticoagulants or anti-platelets have increased severity of bleeding and risk of rebleeding. We compared outcomes of patients receiving antiplatelets, anticoagulants, or direct oral anticoagulants (DOACs) who develop LGIB, as well as the effects of withholding these drugs on their course of bleeding. We performed a retrospective study of 2528 consecutive adult patients with LGIB at 143 hospitals in the United Kingdom, from September through December 2015; 917 were taking anticoagulant or antiplatelet drugs and 1218 were taking neither (unexposed). We collected data on demographic features of patients, interventions or medications, outcomes, laboratory test results, and patient readmission until patient death, discharge, or 28 days after admission (whichever came first). Rebleeding was defined as additional transfusion requirements and/or a decrease in hematocrit ≥20% after 24 hrs of clinical stability. Multivariate regression was used to examine the relationship between drug class on presentation with LGIB and rebleeding, mortality, and cardiovascular events. Rates of rebleeding and cardiovascular complications in patients who had these drugs withheld were also analyzed. Patients receiving antiplatelets, but not those receiving warfarin (n = 232) or DOACs (n = 102), had a higher risk of in-hospital rebleeding (monotherapy hazard ratio [HR], 3.57; 95% CI, 1.13-11.28; n = 504 and dual antiplatelet therapy hazard ratio, 5.3; 95% CI, 1.56-18.54; n = 79) compared with the unexposed group. This risk was not lower in patients who received antiplatelets and had the drug withheld for fewer than 5 days, compared to those who continued the drug throughout admission (HR, 0.98; 95% CI, 0.45-2.17) No differences were observed in risk-adjusted mortality or readmission with further bleeding for patients receiving antiplatelets, DOACs, or warfarin. Cardiovascular events were too few to allow meaningful comparison. In patients with LGIB, antiplatelet drugs, but not warfarin or DOACs, are associated with an increased risk of rebleeding. Withholding antiplatelets during admission does not lead to reduction in rebleeding.


An atypical proprotein convertase in Giardia lamblia differentiation.
Proteolytic activity is important in the lifecycles of parasites and their interactions with hosts. Cysteine proteases have been best studied in Giardia, but other protease classes have been implicated in growth and/or differentiation. In this study, we employed bioinformatics to reveal the complete set of putative proteases in the Giardia genome. We identified 73 peptidase homologs distributed over 5 catalytic classes in the genome. Serial analysis of gene expression of the G. lamblia lifecycle found thirteen protease genes with significant transcriptional variation over the lifecycle, with only one serine protease transcript upregulated late in encystation. The translated gene sequence of this encystation-specific transcript was most similar to eukaryotic subtilisin-like proprotein convertases (SPC), although the typical catalytic triad was not identified. Epitope-tagged gSPC protein expressed in Giardia under its own promoter was upregulated during encystation with highest expression in cysts and it localized to encystation-specific secretory vesicles (ESV). Total gSPC from encysting cells produced proteolysis in gelatin gels that co-migrated with the epitope-tagged protease in immunoblots. Immuno-purified gSPC also had gelatinase activity. To test whether endogenous gSPC activity is involved in differentiation, trophozoites and cysts were exposed to the specific serine proteinase inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride (AEBSF). After 21 h encystation, a significant decrease in ESV was observed with 1mM AEBSF and by 42 h the number of cysts was significantly reduced, but trophozoite growth was not inhibited. Concurrently, levels of cyst wall proteins 1 and 2, and AU1-tagged gSPC protein itself were decreased. Excystation of G. muris cysts was also significantly reduced in the presence of AEBSF. These results support the idea that serine protease activity is essential for Giardia encystation and excystation.


Effects of adopting the Global Lung Function Initiative 2017 reference equations on the interpretation of carbon monoxide transfer factor.
The recently published Global Lung Function Initiative (GLI) carbon monoxide transfer factor (T LCO) reference equations provide an opportunity to adopt a current, all-age, widely applicable reference set. The aim of this study was to document the effect of changing to GLI from commonly utilised reference equations on the interpretation of T LCO results.33 863 T LCO results (48% female, 88% Caucasian, n=930 aged <18 years) from clinical pulmonary function laboratories within three Australian teaching hospitals were analysed. The lower limit of normal (LLN) and proportion of patients with a T LCO below this value were calculated using GLI and other commonly used reference equations.The average T LCO LLN for GLI was similar or lower than the other equations, with the largest difference seen for Crapo equations (median: -1.25, IQR: -1.64, -0.86 mmol·min-1·kPa-1). These differences resulted in altered rates of reduced T LCO for GLI particularly for adults (+1.9% versus Miller to -27.6% versus Crapo), more so than for children (-0.8% versus Kim to -14.2% versus Cotes). For adults, the highest raw agreement for GLI was with Miller equations (94.7%), while for children it was with Kim equations (98.1%). Results were reclassified from abnormal to normal more frequently for younger adults, and for adult females, particularly when moving from Roca to GLI equations (30% of females versus 16% of males).The adoption of GLI T LCO reference equations in adults will result in altered interpretation depending on the equations previously used and to a greater extent in adult females. The effect on interpretation in children is less significant.


3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach.
The present work focuses on the study of the three-dimensional (3D) structural requirements for selective antagonist activity of arylpyrazole compounds at the cannabinoid CB1 and CB2 receptors. Initially, a combined high-resolution two-dimensional (2D) NMR and computer modeling approach was carried out to study the solution structure of the key pyrazole derivative N-(piperidin-1-yl)-5-phenyl-1-(n-pentyl)-4-methyl-1H-pyrazole-3-carboxamide (AM263). By using the NMR-determined molecular conformers as templates, the 3D quantitative structure-activity relationship (QSAR) studies were performed with the comparative molecular field analysis (CoMFA) approach on a set of arylpyrazole cannabinoid receptor antagonists. Molecular alignments suitable for deriving valuable pharmacophoric features for this series of compounds were determined. Such systematic 3D-QSAR/CoMFA analyses of 29 molecules and their receptor affinities gave guidance for understanding the binding affinities of arylpyrazoles at the CB1 and CB2 binding sites, respectively. Comparison of CoMFA steric and potential contour maps for affinity at the two cannabinoid receptor subtypes helps to differentiate structural requirements for each subtype and serves as a basis for the design of later-generation analogues.


Three-color entanglement.
Entanglement is an essential quantum resource for the acceleration of information processing as well as for sophisticated quantum communication protocols. Quantum information networks are expected to convey information from one place to another by using entangled light beams. We demonstrated the generation of entanglement among three bright beams of light, all of different wavelengths (532.251, 1062.102, and 1066.915 nanometers). We also observed disentanglement for finite channel losses, the continuous variable counterpart to entanglement sudden death.


SLiMFinder: a probabilistic method for identifying over-represented, convergently evolved, short linear motifs in proteins.
Short linear motifs (SLiMs) in proteins are functional microdomains of fundamental importance in many biological systems. SLiMs typically consist of a 3 to 10 amino acid stretch of the primary protein sequence, of which as few as two sites may be important for activity, making identification of novel SLiMs extremely difficult. In particular, it can be very difficult to distinguish a randomly recurring "motif" from a truly over-represented one. Incorporating ambiguous amino acid positions and/or variable-length wildcard spacers between defined residues further complicates the matter. In this paper we present two algorithms. SLiMBuild identifies convergently evolved, short motifs in a dataset of proteins. Motifs are built by combining dimers into longer patterns, retaining only those motifs occurring in a sufficient number of unrelated proteins. Motifs with fixed amino acid positions are identified and then combined to incorporate amino acid ambiguity and variable-length wildcard spacers. The algorithm is computationally efficient compared to alternatives, particularly when datasets include homologous proteins, and provides great flexibility in the nature of motifs returned. The SLiMChance algorithm estimates the probability of returned motifs arising by chance, correcting for the size and composition of the dataset, and assigns a significance value to each motif. These algorithms are implemented in a software package, SLiMFinder. SLiMFinder default settings identify known SLiMs with 100% specificity, and have a low false discovery rate on random test data. The efficiency of SLiMBuild and low false discovery rate of SLiMChance make SLiMFinder highly suited to high throughput motif discovery and individual high quality analyses alike. Examples of such analyses on real biological data, and how SLiMFinder results can help direct future discoveries, are provided. SLiMFinder is freely available for download under a GNU license from http://bioinformatics.ucd.ie/shields/software/slimfinder/.


European Society of Paediatric Radiology 2019 strategic research agenda: improving imaging for tomorrow's children.
The European Society of Paediatric Radiology (ESPR) research committee was established to initiate, drive forward and foster excellence in paediatric imaging, paediatric image-guided intervention and radiation protection research, by facilitating more evidence-based standards, protocols and multi-institutional collaborations. The ESPR Strategic Research Agenda outlines our current research approach, highlighting several areas of paediatric imaging where the society can help guide current and future research, and emphasizing those areas where early research ("seed") funding may need to be allocated by this and other societies as precursors to larger grant applications. The key aims are to evaluate normal variation in order to be able to confidently diagnose disease states, develop robust image-based classification systems to aid diagnosis and treatment monitoring, and help develop evidence-based clinical guidelines using current literature and experience to identify knowledge gaps. For this reason, the development of evidence-based imaging pipelines, broken down step-by-step to include diagnosis, classification and clinical effectiveness, should be the end goal for each disease entity for each affected child. Here, we outline the 2019 ESPR Strategic Research Agenda along three points in the clinical imaging pipeline: clinical referral, disease diagnosis and evolution, and clinical therapeutic evaluation and effectiveness. Through multicentre trials, using existing high-level experience and expertise, and nurturing the next generation of researchers, we will be able to achieve these aims.


Live birth rates in the first complete IVF cycle among 20 687 women using a freeze-all strategy.
What is the chance of having a child following one complete IVF cycle for patients using a freeze-all strategy? The chance of having a child after the first complete IVF cycle was 50.74% with the freeze-all strategy. Several studies have reported on live birth rates (LBRs) based on only the fresh embryo transfer cycle or fresh and frozen-thawed embryo transfer cycles. However, the LBR using a freeze-all strategy in IVF is unknown. This retrospective cohort study included 20 687 women who started their first IVF cycles using a freeze-all strategy during the period from 1 January 2007, through 31 March 2016, in China. Data on 20 687 women undergoing their first complete cycles using a freeze-all strategy from 2007 to 2016 were analyzed to estimate LBRs. The LBR in a complete cycle was defined as the chance of a live birth from an ovarian stimulation cycle including all subsequent frozen embryo transfers from this stimulation. The relationship between LBR and number of oocyte was explored. The LBR for the first complete cycle was 50.74% for patients using a freeze-all strategy. By age group, the LBR declined from 63.81% for women under 31 years old to 4.71% for women over 40 years old after the first complete cycle. The LBRs improved as the number of oocytes retrieved increased up to 25 in the freeze-all strategy. This was a retrospective study without a control group. Data on BMI and smoking status were not collected in this database. Our results showed that 50.74% of patients could achieve a live birth after the first complete cycle via a freeze-all strategy. In addition, the LBRs were positively correlated with the number of oocytes retrieved via the freeze-all strategy. These findings are critical for patients and clinicians in making an informed decision to embark on IVF treatment. This work was supported by grants from the National Natural Science Foundation of China (NSFC) (31770989 to Y.W.) and the Shanghai Ninth People's Hospital Foundation of China (JYLJ030 to Y.W.). None of the authors have any conflicts of interest to declare.


Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism.
The molecular dysfunction in X-linked dystonia-parkinsonism is not completely understood. Thus far, only noncoding alterations have been found in genetic analyses, located in or nearby the TATA-box binding protein-associated factor 1 (TAF1) gene. Given that this gene is ubiquitously expressed and is a critical component of the cellular transcription machinery, we sought to study differential gene expression in peripheral models by performing microarray-based expression profiling in blood and fibroblasts, and comparing gene expression in affected individuals vs. ethnically matched controls. Validation was performed via quantitative polymerase chain reaction in discovery and independent replication sets. We observed consistent downregulation of common TAF1 transcripts in samples from affected individuals in gene-level and high-throughput experiments. This signal was accompanied by a downstream effect in the microarray, reflected by the dysregulation of 307 genes in the disease group. Gene Ontology and network analyses revealed enrichment of genes involved in RNA polymerase II-dependent transcription, a pathway relevant to TAF1 function. Thus, the results converge on TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism, and provide evidence of altered expression of a canonical gene in this disease. Furthermore, our study illustrates a link between the previously described genetic alterations and TAF1 dysfunction at the transcriptome level.


Increased Synthesis of Liver Erythropoietin with CKD.
Anemia of CKD seems to be related to impaired production of renal erythropoietin (Epo). The glycosylation pattern of Epo depends on the synthesizing cell and thus, can indicate its origin. We hypothesized that synthesis of Epo from nonkidney cells increases to compensate for insufficient renal Epo production during CKD. We determined plasma Epo levels and Epo glycosylation patterns in 33 patients with CKD before undergoing dialysis and nine patients with CKD undergoing dialysis. We compared these values with values obtained in healthy volunteers and other controls. Although patients with CKD before undergoing dialysis had median (interquartile range) Epo levels higher than those of healthy controls (13.8 IU/L; interquartile range, 10.0-20.7 IU/L versus 8.4 IU/L; interquartile range, 7.6-9.0 IU/L; P<0.01), these patients were moderately anemic (mean±SD; hemoglobin =118±17 g/L). Detected as the percentage of migrated isoforms (PMI), Epo glycosylation in patients with CKD before undergoing dialysis (PMI=36.1±11.7%) differed from that in healthy controls (PMI=9.2±3.8%; P<0.01) but not from that in umbilical cord plasma (PMI=53.9±10.6%; P>0.05), which contains mainly liver-derived Epo. Furthermore, glycosylation modification correlated with eGFR loss. These results suggest that patients with CKD maintain persistent Epo synthesis despite declining renal function, and this maintenance may result in part from increased liver Epo synthesis.


Unraveling Mycobacterium tuberculosis genomic diversity and evolution in Lisbon, Portugal, a highly drug resistant setting.
Multidrug- (MDR) and extensively drug resistant (XDR) tuberculosis (TB) presents a challenge to disease control and elimination goals. In Lisbon, Portugal, specific and successful XDR-TB strains have been found in circulation for almost two decades. In the present study we have genotyped and sequenced the genomes of 56 Mycobacterium tuberculosis isolates recovered mostly from Lisbon. The genotyping data revealed three major clusters associated with MDR-TB, two of which are associated with XDR-TB. Whilst the genomic data contributed to elucidate the phylogenetic positioning of circulating MDR-TB strains, showing a high predominance of a single SNP cluster group 5. Furthermore, a genome-wide phylogeny analysis from these strains, together with 19 publicly available genomes of Mycobacterium tuberculosis clinical isolates, revealed two major clades responsible for M/XDR-TB in the region: Lisboa3 and Q1 (LAM).The data presented by this study yielded insights on microevolution and identification of novel compensatory mutations associated with rifampicin resistance in rpoB and rpoC. The screening for other structural variations revealed putative clade-defining variants. One deletion in PPE41, found among Lisboa3 isolates, is proposed to contribute to immune evasion and as a selective advantage. Insertion sequence (IS) mapping has also demonstrated the role of IS6110 as a major driver in mycobacterial evolution by affecting gene integrity and regulation. Globally, this study contributes with novel genome-wide phylogenetic data and has led to the identification of new genomic variants that support the notion of a growing genomic diversity facing both setting and host adaptation.


Sporozoite-induced infections of Plasmodium berghei administered by the oral route.
Administration of suspensions of Plasmodium berghei sporozoites by the oral route to groups of susceptible animals (A/J mice, young rats, hamsters, and Thamnomys) resulted in high rates of infection (66 to 100 percent). Control animals each given a suspension of 200,000 to 500,000 erythrocytes infected with P. berghei by the same oral route did not develop parasitemia. Direct intubation of sporozoite suspensions into the stomach failed to produce parasitemia. In vitro studies showed that sporozoites kept in medium M 199 acidified to pH 3.6 (the acid environment of the rat stomach) for 5 to 15 mtinutes lost their viability and infectivity. We believe that sporozoites of P. berghei find their way to the bloodstream during their brief sojourn in the esophagus.


The Impact of Mental Health Services in a Pediatric Emergency Department: The Implications of Having Trained Psychiatric Professionals.
This study assessed improvement in the emergency department (ED) length of stay and costs after implementation of an ED program which added board-certified psychiatrists and trained psychiatric social workers to the pediatric ED. A retrospective medical record and administrative data review were conducted for all pediatric psychiatric visits of children aged 5 to 18 years who were seen and discharged from the Greenville Memorial Hospital ED between January 1, 2007, and June 31, 2013. These subjects were diagnosed by the ED physician at the time of the visit using codes ranging from 290.0 to 319.0 based on the International Statistical Classification of Diseases and Related Health Problems, Ninth Revision codes. The mean (SD) age of children in the postprogram period (14.3 ± 3.1) was younger than during the preprogram period (14.9 ± 3.1) (P < 0.001) with the greatest increase in the 11- to 15-year age group (42% vs 35%, respectively). Patients in the postprogram period were significantly more likely to be discharged to a psychiatric hospital than during the pre-program period (18% vs 9%, respectively). After the initiation of the program, ED length of stay decreased significantly from 14.7 to 12.1 hours (P < 0.001) and costs per visit decreased slightly from US $602 to US $588 (this difference was not statistically significant). Although this model of care has significant costs associated with it, the efficiency of care for psychiatric pediatric patients in the ED improved after targeted training of ED staff and provision of these specialized services within the ED.


Volar ligament release and distal radial dome osteotomy for the correction of Madelung deformity: long-term follow-up.
Madelung deformity is a disorder of growth of the distal aspect of the radius that is usually recognized in late adolescence near skeletal maturity. It results in a characteristic wrist deformity, decreased wrist motion, and wrist pain. The purpose of this study was to evaluate long-term results in patients treated by volar ligament release and distal radial dome osteotomy for Madelung deformity. Patients who had undergone volar ligament release and dome osteotomy for Madelung deformity at our institution from 1990 to 2002 and who were the subjects of a previous report on this treatment were contacted for clinical and radiographic evaluation at mid-term to long-term follow-up. Forearm and wrist motion was evaluated. Posteroanterior and lateral radiographs of both forearms were assessed for radial inclination, lunate subsidence, and arthritis changes. A Disabilities of the Arm, Shoulder and Hand (DASH) survey was completed. Twenty-seven patients underwent volar ligament release and distal radial dome osteotomy. Eight patients were either lost to follow-up or were unable to return for follow-up. Nineteen patients with thirty-one operatively treated wrists were available for follow-up. After further review, eighteen patients and twenty-six wrists were included in the study. The average age at the time of follow-up was twenty-five years (range, nineteen to thirty-one years), with an average length of follow-up of eleven years (range, seven to fourteen years). There was no change in radial inclination or in wrist motion between the immediate postoperative and long-term follow-up evaluations. There was a positive correlation between the amount of deformity correction based on more severe preoperative parameters and an increased arthritic grade at the time of follow-up. There was positive correlation between an increased DASH score and arthritis grade as well as a correlation between whole bone deformity and increased arthritis grade and DASH score. Volar ligament release and distal radial dome osteotomy for Madelung deformity provides lasting correction of the deformity. Long-term follow-up shows maintenance of original radiographic correction with good to excellent functional outcome. Patients with radiographic evidence of more severe disease preoperatively and the whole bone variety of Madelung deformity have poorer radiographic outcomes and trend toward poorer functional outcomes.


Enteric Microbiota⁻Gut⁻Brain Axis from the Perspective of Nuclear Receptors.
Nuclear receptors (NRs) play a key role in regulating virtually all body functions, thus maintaining a healthy operating body with all its complex systems. Recently, gut microbiota emerged as major factor contributing to the health of the whole organism. Enteric bacteria have multiple ways to influence their host and several of them involve communication with the brain. Mounting evidence of cooperation between gut flora and NRs is already available. However, the full potential of the microbiota interconnection with NRs remains to be uncovered. Herewith, we present the current state of knowledge on the multifaceted roles of NRs in the enteric microbiota⁻gut⁻brain axis.


Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer.
Gastric cancer is one of the major cancers worldwide. Expression profiling has proven useful in delineating novel prognostic markers in various cancer types. We previously analyzed gene-expression patterns in 90 gastric adenocarcinomas by using complementary DNA microarrays and prioritized a list of genes whose expression levels predict patient outcome. We identified a specific gene of interest, chemokine (C-C motif) ligand 18 (CCL18), on the basis of a high absolute standardized log Cox hazard ratio, a high variance in expression among all tumor samples, and putative biologic function. Detailed analysis of CCL18 expression with clinicopathologic and survival data was performed (n = 89). Quantitative reverse-transcription polymerase chain reaction was used to verify the microarray expression data and was further applied to analyze an independent cohort of tumor samples (n = 59). The cellular source of CCL18 was determined with immunohistochemistry and in situ hybridization. High CCL18 expression levels were associated with prolonged overall (P = 0.001; hazard ratio, 0.586) and disease-free (P = 0.002; hazard ratio, 0.416) patient survival in the array-based data set by univariate analysis. The observations were confirmed in an independent set of 59 patients by using quantitative reverse-transcription polymerase chain reaction. In multivariate analysis, tumor stage and CCL18 levels were independent prognostic factors for predicting both overall and disease-free survival. We found that CCL18 was expressed by a subpopulation of tumor-associated macrophages that were preferentially located at the tumor invasion front. Macrophage-derived CCL18 may function as a local antitumor immunomodulator that affects patient outcome. Our study suggests CCL18 as a novel candidate for antitumor therapeutics and risk stratification in gastric cancer patients.