Reduction of arsenic uptake by lettuce with ferrous sulfate applied to contaminated soil.
Soil contamination by arsenic (As) presents a hazard in many countries and there is a need for techniques to minimize As uptake by plants. A proposed in situ remediation method was tested by growing lettuce (Lactuca sativa L. cv. Kermit) in a greenhouse pot experiment on soil that contained 577 mg As kg(-1), taken from a former As smelter site. All combinations of iron (Fe) oxides, at concentrations of 0.00, 0.22, 0.54, and 1.09% (w/w), and lime, at concentrations of 0.00, 0.27, 0.68, and 1.36% (w/w), were tested in a factorial design. To create the treatments, field-moist soil, commercial-grade FeSO4, and ground agricultural lime were mixed and stored for one week, allowing Fe oxides to precipitate. Iron oxides gave highly significant (P < 0.001) reductions in lettuce As concentrations, down to 11% of the lettuce As concentration for untreated soil. For the Fe oxides and lime treatment combinations where soil pH was maintained nearly constant, the lettuce As concentration declined in an exponential relationship with increasing FeSO4 application rate and lettuce yield was almost unchanged. Iron oxides applied at a concentration of 1.09% did not give significantly lower lettuce As concentrations than the 0.54% treatment. Simultaneous addition of lime with FeSO4, was essential. Ferrous sulfate with insufficient lime lowered soil pH and caused mobilization of Al, Ba, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, Sr, and Zn. At the highest Fe oxide to lime ratios, Mn toxicity caused severe yield loss.


PEGylated enhanced cell penetrating peptide nanoparticles for lung gene therapy.
The lung remains an attractive target for the gene therapy of monogenetic diseases such as cystic fibrosis (CF). Despite over 27 clinical trials, there are still very few gene therapy vectors that have shown any improvement in lung function; highlighting the need to develop formulations with improved gene transfer potency and the desirable physiochemical characteristics for efficacious therapy. Herein, we introduce a novel cell penetrating peptide (CPP)-based non-viral vector that utilises glycosaminoglycan (GAG)-binding enhanced transduction (GET) for highly efficient gene transfer. GET peptides couple directly with DNA through electrostatic interactions to form nanoparticles (NPs). In order to adapt the GET peptide for efficient in vivo delivery, we engineered PEGylated versions of the peptide and employed a strategy to form DNA NPs with different densities of PEG coatings. We were able to identify candidate formulations (PEGylation rates ≥40%) that shielded the positively charged surface of particles, maintained colloidal stability in bronchoalveolar lavage fluid (BALF) and retained gene transfer activity in human bronchial epithelial cell lines and precision cut lung slices (PCLS) in vitro. Using multiple particle tracking (MPT) technology, we demonstrated that PEG-GET complexes were able to navigate the mucus mesh and diffuse rapidly through patient CF sputum samples ex vivo. When tested in mouse lung models in vivo, PEGylated particles demonstrated superior biodistribution, improved safety profiles and efficient gene transfer of a reporter luciferase plasmid compared to non-PEGylated complexes. Furthermore, gene expression was significantly enhanced in comparison to polyethylenimine (PEI), a non-viral gene carrier that has been widely tested in pre-clinical settings. This work describes an innovative approach that combines novel GET peptides for enhanced transfection with a tuneable PEG coating for efficacious lung gene therapy.


BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters.
BRCA mutation-associated (BRCAmut) breast cancer represents a heterogeneous group displaying certain molecular features. Claudin-low breast cancers (CLBC) overlap with characteristics of BRCAmut tumors; therefore, we have investigated whether these are identical subtypes. Using public gene expression data, CLDN, CDH1, 9-cell line claudin-low predictor (9CLCLP) and PAM50 expression was evaluated in BRCAmut and BRCA wild-type (BRCAwt) breast cancer cases focusing on their possible overlap with the CLBC subtype. A separate formalin-fixed, paraffin-embedded (FFPE) cohort of 22 BRCAmut and 19 BRCAwt tumor tissues was used for immunohistochemical examination of AR, CD24, CD44, CK5/6, claudin-1, -3, -4 and -7, E-cadherin, EGFR, estrogen receptor (ER), EZH2, HER2, Ki67, p53, progesterone receptor (PgR) and vimentin expression. In the data sets, CLDN1 (ROC = 0.785, p < 0.001), CDH1 (ROC = 0.785, p < 0.001), CLDN7 (ROC = 0.723, p < 0.001), CLDN3 (ROC = 0.696, p = 0.020) and CLDN4 (ROC = 0.685, p = 0.027) were expressed at higher level in BRCAmut than BRCAwt tumor tissue. The PAM50 subtype differed from the assigned immunohistochemistry (IHC)-based subtype in 30%. Based on accessible 9CLCLP predictor genes, BRCAmut breast cancer does not display the claudin-low phenotype. Utilizing FFPE samples, claudins were evidently expressed in both BRCAmut and BRCAwt cases. However, at the protein level, only claudin-3 expression was higher in BRCAmut tumors, while claudin-1, -4 and -7 and E-cadherin expression was lower compared to BRCAwt cases. A CD24low/CD44high phenotype was found in BRCAmut tumors upon comparison with BRCAwt cases (p < 0.001 and p = 0.001, respectively). There is a prominent correlation between the genes under focus herein and BRCA mutation status. BRCAmut tumors bear stem cell characteristics displaying a distinct cell adhesion molecule profile characterized by high expression of CDH1 and CLDN4 according to public gene expression data set analysis, and higher claudin-3 expression as detected by IHC; thus, BRCAmut breast carcinomas are not identical with the previously identified claudin-low subtype of breast cancer.


Is the Relationship Between Religiosity and Filial Elder-Care Norms Declining? A Comparison Between Two Middle-Aged Generations.
We investigated whether religiosity among middle-aged adults in the Baby Boom generation and Generation-X was associated with filial elder-care norms. The sample consisted of 720 Baby Boom and 520 Gen-X respondents participating in the Longitudinal Study of Generations. A cohort-comparative model was devised using data from Baby Boomers in 1994 and Gen-Xers in 2016, when they were 42 and 40 years old, respectively. A three-step latent class modeling technique identified three religious classes in both generations: strongly religious, weakly religious, and doctrinally religious. Weakly religious Baby Boomers and Gen-Xers reported weaker filial elder-care norms than the strongly religious in each generation. No difference in these effects were detected by generation. However, only among Baby Boomers did the doctrinally religious express stronger filial norms, suggesting cross-cohort weakening in how beliefs translate into filial responsibility in the absence of congregational practice. This research opens lines of inquiry that examine long-term effects of adult children's religiosity on the actual provision of assistance to older parents when they face health difficulties.


Physical activity recommendations: an alternative approach using energy expenditure.
Most adults do not meet the American College of Sports Medicine and Centers for Disease Control and Prevention (ACSM/CDC) physical activity recommendations. Even fewer meet the more extreme Institute of Medicine (IOM) physical activity recommendations. Compliance with either recommendation has been conventionally assessed by combining frequencies and durations of self-reported activities. Leisure-time energy expenditure is a cumulative measure of activity that offers an alternative method of defining compliance. To calculate the leisure-time energy expenditure of adults complying with the ACSM/CDC or the IOM physical activity recommendations determined by conventional measures and to reexamine compliance with the IOM recommendation using energy expenditure criteria. National, cross-sectional data from the 2000 Behavioral Risk Factor Surveillance System determined the mode, frequency, and duration of up to two leisure-time activities performed by adults. Four mutually exclusive activity groups (Non-, Low-, ACSM/CDC-, and IOM-Active) were defined on the basis of frequencies and durations of reported activities. Leisure-time energy expenditure (kcal x kg(-1) x wk(-1)) was calculated per respondent. The energy expenditure threshold for meeting the IOM recommendation was calculated as 21 kcal x kg(-1) x wk(-1). Of the 162,669 respondents included in the analyses, 29.9% were Nonactive, whereas 42.3%, 23.3%, and 4.5% were Low-, ACSM/CDC-, and IOM-Active, respectively. Median leisure-time energy expenditure values were 9.0, 27.4, and 63.0 kcal x kg(-1) x wk(-1) for Low-, ACSM/CDC-, and IOM-Active groups, respectively. When using energy expenditure criteria, compliance with the IOM recommendation rose to 27.7% of respondents. Compliance with the IOM physical activity recommendation dramatically increased when assessed by energy expenditure compared with conventional criteria, thereby highlighting the potential bias of conventional methods. A significant proportion of adults meet the intent but not the letter of the IOM activity recommendation.


Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13).
SARS-CoV-2 has caused COVID-19 outbreak with nearly 2 M infected people and over 100K death worldwide, until middle of April 2020. There is no confirmed drug for the treatment of COVID-19 yet. As the disease spread fast and threaten human life, repositioning of FDA approved drugs may provide fast options for treatment. In this aspect, structure-based drug design could be applied as a powerful approach in distinguishing the viral drug target regions from the host. Evaluation of variations in SARS-CoV-2 genome may ease finding specific drug targets in the viral genome. In this study, 3458 SARS-CoV-2 genome sequences isolated from all around the world were analyzed. Incidence of C17747T and A17858G mutations were observed to be much higher than others and they were on Nsp13, a vital enzyme of SARS-CoV-2. Effect of these mutations was evaluated on protein-drug interactions using in silico methods. The most potent drugs were found to interact with the key and neighbor residues of the active site responsible from ATP hydrolysis. As result, cangrelor, fludarabine, folic acid and polydatin were determined to be the most potent drugs which have potency to inhibit both the wild type and mutant SARS-CoV-2 helicase. Clinical data supporting these findings would be important towards overcoming COVID-19.


Immunisation of children by a nurse without a doctor present.
Over 16 months 148 children were referred by health visitors and general practitioners to a specially trained nurse for failing to complete courses of immunisation. A further 91 children of travellers' families were identified as needing immunisation. The nurse carried out 810 immunisations on 237 of these children in their homes without a doctor being present. There were only two refusals, and one child suffered a mild anaphylactic shock. The cost per immunisation, in nurse's salary and travel expenses, was pounds 8. This is an effective and fairly inexpensive way of achieving uptake of immunisation in such groups of children, and there seems no reason why trained nurses should not give immunisations either in a child health clinic or at home, without a doctor present.


Sex Hormones and Incident Heart Failure in Men and Postmenopausal Women: The Atherosclerosis Risk in Communities Study.
Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. General community. 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. Plasma sex hormone levels were measured at visit 4 (1996-1998). Incident HF events were identified through hospital discharge codes and death certificates. The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.


Effect of Short-Term Desiccation, Recovery Time, and CAPA-PVK Neuropeptide on the Immune System of the Burying Beetle Nicrophorus vespilloides.
Environmental conditions, especially related to winter, are crucial for shaping activity of insect immune system. However, our previous research clearly indicates differences in the immune system functioning when the cold stress was induced in the laboratory conditions and when the beetles were collected from natural environment during winter. This is probably related to the multiplication of observed effects by simultaneous presence of different stress factors characteristic of winter, including desiccation. For these reasons, our next step was analysis of the effects of short-term desiccation and recovery time on the functioning of immune system of burying beetle Nicrophorus vespilloides. Also, the effect of Tenmo-PVK-2 (tenebrionid periviscerokinin), member of the CAPA-PVK neuropeptide family, was investigated to better understand observed changes. Short-term desiccation decreases the phagocytic activity of burying beetle haemocytes, which is correlated with a reduction in their adhesive ability. On the other hand, there was a significant increase in phenoloxidase (PO) activity and the level of proPO expression, which may suggest sealing the cuticula by melanin deposition and prevention of water loss. Additionally, the elevated level of defensin expression may be associated with the cross-talk between mechanisms, which participate in insect response to environmental stress, including pathogen infection. After 1 h of recovery time, the activity of tested cellular and humoral mechanisms was mostly back to the control level. However, inhibition of the activity of PO and down-regulation of proPO were noted. These results also indicate importance of melanin deposition during water loss. Moreover, it suggests that some changes in immune system functioning during stress conditions do not have an immune function. Interestingly, part of the effects characteristic of recovery time were also observed after the application of Tenmo-PVK-2, mainly related to haemocyte morphology. These results indicate that CAPA-PVK neuropeptides may also influence on activity of burying beetle immune system. It should be also highlighted that, because of the study of the effects of CAPA-PVK neuropeptides, homologs of vertebrate neuromedin U, the results may be interesting for search evolutionary similarities in the functioning of the neuroendocrine system of insects and vertebrates.


The orientation of HIV-1 gp120 binding to the CD4 receptor differentially modulates CD4+ T cell activation.
Progressive quantitative and qualitative decline of CD4(+) T cell responses is one hallmark of HIV-1 infection and likely depends on several factors, including a possible contribution by the HIV-1 envelope glycoprotein gp120, which binds with high affinity to the CD4 receptor. Besides virion-associated and cell-expressed gp120, considerable amounts of soluble gp120 are found in plasma or lymphoid tissue, predominantly in the form of gp120-anti-gp120 immune complexes (ICs). Because the functional consequences of gp120 binding to CD4(+) T cells are controversially discussed, we investigated how gp120 affects TCR-mediated activation of human CD4(+) T cells by agonistic anti-CD3 mAb or by HLA class II-presented peptide Ags. We show that the spatial orientation of gp120-CD4 receptor binding relative to the site of TCR engagement differentially affects TCR signaling efficiency and hence CD4(+) T cell activation. Whereas spatially and temporally linked CD4 and TCR triggering at a defined site promotes CD4(+) T cell activation by exceeding local thresholds for signaling propagation, CD4 receptor engagement by gp120-containing ICs all around the CD4(+) T cell undermine its capacity in supporting proximal TCR signaling. In vitro, gp120 ICs are efficiently captured by CD4(+) T cells and thereby render them hyporesponsive to TCR stimulation. Consistent with these in vitro results we show that CD4(+) T cells isolated from HIV(+) individuals are covered with ICs, which at least partially contain gp120, and suggest that IC binding to CD4 receptors might contribute to the progressive decline of CD4(+) T cell function during HIV-1 infection.


Assisted delivery of anti-tumour platinum drugs using DNA-coiling gold nanoparticles bearing lumophores and intercalators: towards a new generation of multimodal nanocarriers with enhanced action.
New gold and lipoic based nanocarriers for the delivery of platinum(ii) and platinum(iv) drugs are developed, which allow enhanced loading of the drug on the surface of the nanocarriers and release in a pH-dependent fashion, with superior release at lower pHs which are associated with many tumours. The conjugate nanoparticles and their conjugates enter cells rapidly (within 3 hours). They tend to cluster in vesicles and are also observed by light and electron microscopies in the cytoplasm, endoplasmic reticulum and nucleus. We further incorporate aminoanthraquinone units that are both fluorophores and DNA intercalators. This results in nanocarriers that after drug release will remain surface decorated with DNA-binders challenging the conventional design of the nanocarrier as an inert component. The outcome is nanocarriers that themselves have distinctive, remarkable and unusual DNA binding properties being able to bind and wrap DNA (despite their anionic charge) and provide enhanced cytotoxic activity beyond that conferred by the platinum agents they release. DNA coiling is usually associated with polycations which can disrupt cell membranes; anionic nanoparticles that can cause novel and dramatic effects on DNA may have fascinating potential for new approaches to in-cell nucleic acid recognition. Our findings have implications for the understanding and interpretation of the biological activities of nanoparticles used to deliver other DNA-binding drugs including clinical drug doxorubicin and its formulations.


The reliability of diagnostic techniques in the diagnosis and management of malaria in the absence of a gold standard.
The accuracy of techniques for the diagnosis of malaria are usually compared with optical microscopy, which is considered to be a gold standard. However, microscopy is prone to error and therefore makes it difficult to assess the reliability of other diagnostic techniques. We did a systematic review to assess the specificity and sensitivity of diagnostic techniques in different settings, using a statistical method that avoided defining a gold standard. Performance varied depending on species of the malaria parasite, level of parasitaemia, and immunity. Overall, histidine-rich protein 2 (HRP2)-based dipsticks showed a high sensitivity (92.7%) and specificity (99.2%) for Plasmodium falciparum in endemic areas. The acridine orange test was more sensitive (97.1%) in detecting P falciparum in epidemiological studies, with a specificity of 97.9%. In the absence of a gold standard, HRP2 dipsticks and acridine orange could provide an alternative for detecting falciparum infections in endemic areas and epidemiological studies, respectively. Microscopy still remains more reliable in detecting non-falciparum infections.


Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy.
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.


A modular hip system for simplification of revision hip arthroplasty.
Revision femoral arthroplasty can be a daunting task. Historical success with a host of different reconstructive options has previously been reported. The Zimmer Modular Revision (ZMR®) system provides a complete armamentarium for the revision setting. For lesser femoral defects, the modular ZMR system can be used to create a custom preassembled implant. For more difficult situations, the implant can be sequentially assembled in vivo. The ZMR system can thus separate the tasks of revision femoral surgery so that the surgeon does not have to manage all issues at once. Fixation, length, offset, and implant version can all be handled independently to allow a safe, easy, and reproducible reconstruction in all settings.


Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors.
Hepatocyte growth factor (HGF) is a mesenchymal derived growth factor known to induce proliferation and "scattering" of epithelial and endothelial cells. Its receptor is the tyrosine kinase encoded by the c-MET protooncogene. Here we show that highly purified recombinant HGF stimulates hemopoietic progenitors to form colonies in vitro. In the presence of erythropoietin, picomolar concentrations of HGF induced the formation of erythroid burst-forming unit colonies from CD34-positive cells purified from human bone marrow, peripheral blood, or umbilical cord blood. The growth stimulatory activity was restricted to the erythroid lineage. HGF also stimulated the formation of multipotent CFU-GEMM colonies. This effect is synergized by stem cell factor, the ligand of the tyrosine kinase receptor encoded by the c-KIT protooncogene, which is active on early hemopoietic progenitors. By flow cytometry analysis, the receptor for HGF was found to be expressed on the cell surface in a fraction of CD34+ progenitors. Moreover, in situ hybridization experiments showed that HGF receptor mRNA is highly expressed in embryonic erythroid cells (megaloblasts). HGF mRNA was also found to be produced in the embryonal liver. These data show that HGF plays a direct role in the control of proliferation and differentiation of erythroid progenitors, and they suggest that it may be one of the long-sought mediators of paracrine interactions between stromal and hemopoietic cells within the hemopoietic microenvironment.


Effects of Physical Therapy on Pain, Functional Status, Sagittal Spinal Alignment, and Spinal Mobility in Chronic Non-specific Low Back Pain.
To investigate the effects of physical therapy (PT) on pain, functional status, sagittal spinal alignment, and spinal mobility in chronic non-specific low back pain (NSLBP). The study population consisted of 100 patients with chronic NSLBP. The study group comprised 60 patients to whom a PT program including superficial heat, transcutaneous electrical nerve stimulation, and ultrasound for 10 sessions was assigned. The control group was composed of 40 patients who received no PT. Home exercise programs were applied to both groups. Pain severity was determined using a Visual Analog Scale (VAS), and functional status was evaluated using the Oswestry Disability Index (ODI). Spinal sagittal alignment in regard to lumbosacral, lumbar lordosis, and thoracic kyphosis angles and spinal mobility regarding lumbar and thoracic flexion and extension degrees were assessed using a digital inclinometer. Lumbar flexion was also assessed using the modified lumbar Schober test (mLST). Evaluations were performed at baseline and after completing the therapy sessions. There were significant decreases in VAS scores in each group upon therapy completion. However, significant improvements in ODI, mLST, and all inclinometric evaluations in terms of sagittal spinal alignment and spinal mobility were noted only in the study group compared with baseline values (p<0.05). Despite the short course of treatment, PT was found to have significant positive effects on pain severity, functional status, sagittal spinal alignment, and spinal mobility. PT was determined to be an effective treatment option for chronic NSLBP.


Serum Free Light Chains in Neoplastic Monoclonal Gammopathies: Relative Under-Detection of Lambda Dominant Kappa/Lambda Ratio, and Underproduction of Free Lambda Light Chains, as Compared to Kappa Light Chains, in Patients With Neoplastic Monoclonal Gammopathies.
Quantitative evaluation of serum free light chains is recommended for the work up of monoclonal gammopathies. Immunoglobulin light chains are generally produced in excess of heavy chains. In patients with monoclonal gammopathy, κ/λ ratio is abnormal less frequently with lambda chain lesions. This study was undertaken to ascertain if the levels of overproduction of the two light chain types and their detection rates are different in patients with neoplastic monoclonal gammopathies. Results of serum protein electrophoresis (SPEP), serum protein immunofixation electrophoresis (SIFE), urine protein electrophoresis (UPEP), urine protein immunofixation electrophoresis (UIFE), and serum free light chain assay (SFLCA) in patients with monoclonal gammopathies were examined retrospectively. The κ/λ ratios were appropriately abnormal more often in kappa chain lesions. Ratios of κ/λ were normal in about 25% of patients with lambda chain lesions in whom free homogenous lambda light chains were detectable in urine. An illustrative case suggests underproduction of free lambda light chains, in some instances. The lower prevalence of lambda dominant κ/λ ratio in lesions with lambda light chains is estimated to be due to relative under-detection of lambda dominant κ/λ ratio in about 25% of the patients and because lambda chains are not produced in as much excess of heavy chains as are kappa chains, in about 5% of the patients. The results question the medical necessity and clinical usefulness of the serum free light chain assay. UPEP/UIFE is under-utilized.


Prosthetic-joint Infections: Mortality Over The Last 10 Years.
Background: There is a constant increase of joint arthroplasties to improve the quality of life of an ever-aging population. Although prosthetic-joint infections are rare, with an incidence of 1-2%, they represent a serious complication in terms of morbidity and mortality. Infection related mortality is known to be approaching 8% at one year. The aim of this retrospective study is to reassess the one and two-year mortality over the last ten years. Methods: Patients treated for prosthetic joint infection at the University Hospital of Lausanne (Switzerland) between 2006 and 2016 were included. The one and two-year cumulative mortality depending on sex, age, type of prosthesis, infecting organism and type of surgical treatment were computed. Results: 363 patients (60% hips, 40% knees) were identified with a median age of 70 years. The one-year cumulative mortality was 5.5% and it was 7.3% after two years. No difference was seen between hip and knee prostheses, but the mortality was higher in men than in women and increased with age. Furthermore, there was a significant difference depending of the germ with enterococci infections associated with a higher risk of death. Finally, patients treated with a one-stage or two-stage exchange had a lower mortality than those treated with debridement and retention. Conclusion: The mortality is still high and differs according to sex, age, infecting organism and type of surgical treatment. There is a need of studies to improve the management of patients at risk of increased mortality.


Effects of gestational hyperglycemia on glucose metabolism and its hormonal control in the fasted, newborn rat during the early postnatal period.
To evaluate the effects of gestational hyperglycemia on glucose metabolism and its regulation in the fasted rat during the early postnatal period, unrestrained rats were continuously infused with glucose during the last week of pregnancy. Control rats were infused with distilled water. Newborns were studied during the first six postnatal hours. At birth, newborns from glucose-infused rats, compared with controls, showed higher plasma glucose levels, increased plasma insulin, and lower plasma glucagon and catecholamine concentrations. Between birth and 2 h postpartum, newborn rats from both groups exhibited a marked hypoglycemia, which was, however, more severe in newborns from glucose-infused rats (15 mg/dl) than in controls (26 mg/dl). During the first four postnatal hours, plasma insulin concentration remained higher, while plasma glucagon and catecholamine concentrations remained lower in newborns from hyperglycemic rats. At 6 h, the glycemia reached normal values and the concentrations of the different hormones were similar in controls and newborns from glucose-infused mothers. Concurrently, in the newborns from glucose-infused rats, hepatic glucose production was altered, as they were unable to mobilize liver glycogen stores during the six postnatal hours. Despite slightly delayed phosphoenolpyruvate carboxykinase induction, the rate of gluconeogenesis from 10 mmol/L lactate estimated on isolated hepatocytes was higher in newborns from hyperglycemic mothers than in controls. These results show that gestational hyperglycemia compromises the metabolic and hormonal adaptation of the newborn rat to early extrauterine life; the striking feature of these neonates is the absence of mobilization of liver glycogen stores, which can probably be explained by fetal and neonatal hyperinsulinism associated with the defect of counterregulatory hormones.


Modeling and measurements of atomic surface roughness.
We present a geometrical model of atomic topography with which to obtain a quantitative assessment of surface roughness. A series of two- and three-dimensional atomic surface roughness equations with sufficiently realistic parameters is developed to permit quantitative comparison with scanning-tunneling microscope and atomic-force microscope (AFM) experimental results. The model is sufficiently simple that one can easily use it to interpret experimental data. Tables are provided with estimated values for two- and three-dimensional rms atomic surface roughness in pure metal crystals and ionic crystals based on the atomic surface roughness equations. We use these roughness equations to determine the roughness of cleaved muscovite mica [essentially, KAl(2)(OH)(2)Si(3)AlO(10)]; the calculated values for both two- and three-dimensional roughness are consistent with those obtained in our AFM measurements. In addition, we demonstrate both theoretically and experimentally that atomic surface roughness is never zero.


A rapid 'one-plate' in vitro test for pyrogens.
A rapid, 'one-plate' monocyte-activation test is described for detecting endotoxin and non-endotoxin pyrogens in parenteral medicinal products. The one-plate test offers useful gains over conventional 'two-plate' (cell culture plate+ELISA plate) tests in terms of its limit of detection, robustness, speed and cost. The 'one-plate' test is likely to be applicable to a wide range of products because it allows less time for product interference in the test. The 'one-plate' test utilises pyrogen-free anti-cytokine (interleukin (IL)-6 or tumour necrosis factor alpha (TNFalpha)) antibodies (Ab), coated and stabilised onto (pyrogen-free) 96-well plates. Monocytes/monocytic cells, endotoxin (lipopolysaccharides, LPS) standard or sample and (pyrogen-free) second (labelled) Ab are cultured together (usually for 2-4 h) on the Ab-coated plate and then the plate is washed and the ELISA completed. There is no transfer from one plate to another and no (further) incubations of (released) cytokine with, first, coating Ab and, then, developing Ab since these steps have already taken place during the initial cell culture. The rapid, 'one-plate' test is readily automated. The preferred readout is IL-6, which gives a limit of detection of 0.015 endotoxin units (EU)/ml with peripheral blood mononuclear cell (PBMNC), 0.03 EU/ml with diluted whole blood and 0.05 EU/ml with a monocytic cell line (MONO MAC 6).


APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling.
5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets. Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified. APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013]. A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.


Cultured human cells can acquire resistance to the antiproliferative effect of sodium aurothiomalate.
Cultured human epithelial cells (HE), grown as monolayers, acquired resistance to otherwise lethal concentrations (300 mumol/l, culture medium) of sodium aurothiomalate during five months' exposure to stepwise increased concentrations of the drug. The resistance acquired was shown by exposure to drug concentrations ranging from 25 to 300 mumol/, resulting in 100% of the resistant cells (HeMyo) surviving compared with controls. Only 13% of the sensitive parent cells survived when exposed to 300 mumol/l for four days. The HeMyo cells were also resistant to the antiproliferative effects of equimolar concentrations of thiomalic acid without gold. The cytosolic gold concentration and the association of 199Au with cytosolic proteins after gel filtration were similar in both cell lines after sodium aurothiomalate exposure to the exponentially growing cells. No synthesis of gold binding proteins of metallothionein character was observed in the HEMyo cells. The concentration of free thiomalate in the sonicates and cytosols of the HeMyo cells was decreased to 25-30% of the concentration found in the HE cells. Comparison with previous data for the cytosolic concentration of total thiomalate in the HE cells suggests that most of the cytosolic thiomalate present was free thiomalate. We conclude that the cells can develop resistance to the antiproliferative effect of sodium aurothiomalate, and that the resistance may be due to their capacity to maintain low concentrations of free thiomalate in the sonicates and cytosols. The results support previous findings that sodium aurothiomalate appears to dissociate within cells.


Membrane structure formation induced by two types of banana-shaped proteins.
The assembly of banana-shaped rodlike proteins on membranes and the associated membrane shape transformations are investigated by analytical theory and coarse-grained simulations. The membrane-mediated interactions between two banana-shaped inclusions are derived theoretically using a point-like formalism based on fixed anisotropic curvatures, both for zero surface tension and for finite surface tension. On a larger scale, the interactions between the assemblies of such rodlike inclusions are determined analytically. Meshless membrane simulations are performed in the presence of a large number of inclusions of two types, corresponding to the curved rods of opposite curvatures, both for flat membranes and vesicles. Rods of the same type aggregate into linear assemblies perpendicular to the rod axis, leading to membrane tubulation. However, rods of the other type, those of opposite curvature, are attracted to the lateral sides of these assemblies, and stabilize a straight bump structure that prevents tubulation. When the two types of rods have almost opposite curvatures, the bumps attract one another, forming a striped structure. Positive surface tension is found to stabilize stripe formation. The simulation results agree well with the theoretical predictions provided the point-like curvatures of the model are scaled-down to account for the effective flexibility of the simulated rods.


Collagen-induced arthritis as a model for rheumatoid arthritis.
Collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA) that is widely used to address questions of disease pathogenesis and to validate therapeutic targets. Arthritis is normally induced in mice or rats by immunization with autologous or heterologous type II collagen in adjuvant. Susceptibility to collagen-induced arthritis is strongly associated with major histocompatibility complex class II genes, and the development of arthritis is accompanied by a robust T- and B-cell response to type II collagen. The chief pathological features of CIA include a proliferative synovitis with infiltration of polymorphonuclear and mononuclear cells, pannus formation, cartilage degradation, erosion of bone, and fibrosis. As in RA, pro-inflammatory cytokines, such as tumor necrosis factor alpha(TNFalpha) and interleukin (IL)-1beta, are abundantly expressed in the arthritic joints of mice with CIA, and blockade of these molecules results in a reduction of disease severity.


The impact of disappointment in decision making: inter-individual differences and electrical neuroimaging.
Disappointment, the emotion experienced when faced to reward prediction errors (RPEs), considerably impacts decision making (DM). Individuals tend to modify their behavior in an often unpredictable way just to avoid experiencing negative emotions. Despite its importance, disappointment remains much less studied than regret and its impact on upcoming decisions largely unexplored. Here, we adapted the Trust Game to effectively elicit, quantify, and isolate disappointment by relying on the formal definition provided by Bell's in economics. We evaluated the effects of experienced disappointment and elation on future cooperation and trust as well as the rationality and utility of the different behavioral and neural mechanisms used to cope with disappointment. All participants in our game trusted less and particularly expected less from unknown opponents as a result of disappointing outcomes in the previous trial but not necessarily after elation indicating that behavioral consequences of positive and negative RPEs are not the same. A large variance in the tolerance to disappointment was observed across subjects, with some participants needing only a small disappointment to impulsively bias their subsequent decisions. As revealed by high-density EEG recordings the most tolerant individuals - who thought twice before making a decision and earned more money - relied on different neural generators to contend with neutral and unexpected outcomes. This study thus provides some support to the idea that different neural systems underlie reflexive and reflective decisions within the same individuals as predicted by the dual-system theory of social judgment and DM.


Variation in medication use in cancer patients at the end of life: a cross-sectional analysis.
Despite advances in cancer treatment, patients still die with unnecessary suffering. Therefore, high-quality end-of-life care is needed. Variations in medication use at the end of life may suggest areas for improvement. This study aims to describe the use of medications during the last days of life of cancer patients and to explore the possibility of using it as a quality measure. We conducted an international survey on experts' opinions regarding potentially inappropriate medications for dying patients. Subsequently, a chart review of deceased cancer patients was conducted, which assessed the current medication use in different settings. The mean number of medications used in the last 3 days of life was 4.8 (SD 2.1). Hospital patients were less likely than hospice patients to receive opioids, midazolam, haloperidol, and drugs for pulmonary secretions or nausea/vomiting. Over 90 % of experts rated 12 medications as unlikely to be appropriate. Hospital patients were more likely than hospice patients to receive these potentially inappropriate medications. Before the implementation of an end-of-life care pathway, hospital patients had a higher probability, than after, to receive potentially inappropriate medication. Moreover, after implementation of such pathway, patients for whom a pathway was not used were more likely to receive potentially inappropriate medications than patients for whom it was used. Medication use at the end of life varies widely by setting, both for potentially appropriate and inappropriate medications. Combining experts' opinion and current medication use resulted in the identification of 16 medications that might be used to assess the quality of cancer care at the end of life.


GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease.
DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI -1.1-12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6-16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG.


Efficacy of a tart cherry juice blend in preventing the symptoms of muscle damage.
Numerous antioxidant and anti-inflammatory agents have been identified in tart cherries. To test the efficacy of a tart cherry juice blend in preventing the symptoms of exercise induced muscle damage. This was a randomised, placebo controlled, crossover design. Fourteen male college students drank 12 fl oz of a cherry juice blend or a placebo twice a day for eight consecutive days. A bout of eccentric elbow flexion contractions (2 x 20 maximum contractions) was performed on the fourth day of supplementation. Isometric elbow flexion strength, pain, muscle tenderness, and relaxed elbow angle were recorded before and for four days after the eccentric exercise. The protocol was repeated two weeks later with subjects who took the placebo initially, now taking the cherry juice (and vice versa). The opposite arm performed the eccentric exercise for the second bout to avoid the repeated bout protective effect. Strength loss and pain were significantly less in the cherry juice trial versus placebo (time by treatment: strength p<0.0001, pain p = 0.017). Relaxed elbow angle (time by treatment p = 0.85) and muscle tenderness (time by treatment p = 0.81) were not different between trials. These data show efficacy for this cherry juice in decreasing some of the symptoms of exercise induced muscle damage. Most notably, strength loss averaged over the four days after eccentric exercise was 22% with the placebo but only 4% with the cherry juice.


Autoregulation of rhodopsin synthesis in Chlamydomonas reinhardtii.
A sensitive assay for the induction of carotenoid and rhodopsin synthesis, based on the phototactic response, has been developed in a mutant of the unicellular alga Chlamydomonas reinhardtii. In the dark, the mutant fails to synthesize carotene and retinal, but it contains the apoprotein opsin. When retinal synthesis is induced by light treatment, the retinal combines with opsin to form rhodopsin, and the cells swim away from a source of light. Since the amount of light required to trigger a phototactic response is inversely proportional to the concentration of rhodopsin, the decrease in amount of light necessary to generate that response can serve as a measure of the amount of retinal synthesized in cells after induction. Using this assay, we found that (i) light induction of retinal depends linearly on light exposure and rhodopsin concentration during the exposure; (ii) the action spectrum of light induction is identical with that for phototaxis for which the receptor pigment is rhodopsin; and (iii) incubation with all-trans-7,8-dihydroretinal before light exposure shifts the action-spectrum peak for light induction 0.41 eV (-71 nm). We conclude that the photopigment for induction of retinal synthesis is a rhodopsin. The time lag required for induction of retinal synthesis and preliminary experiments with transcription or translation inhibitors suggest that alterations in gene expression could be involved in the induction process. Its control could be similar to other processes in which membrane receptors for hormones, neurotransmitters, or growth factors regulate gene expression.


Alendronate and naproxen are synergistic for development of gastric ulcers.
Both alendronate sodium use and nonsteroidal anti-inflammatory drug use are associated with gastric ulcers. The aim of this study was to investigate whether alendronate and naproxen are synergistic as causes of gastric ulcers. We performed an endoscopist-blind, randomized, crossover, single-center comparison of 10 mg/d of alendronate sodium, 500 mg of naproxen sodium twice daily, or the combination taken orally for 10 days in volunteers aged 30 years or older. Videoendoscopy was used to evaluate the presence and degree of mucosal damage to the esophagus, stomach, or duodenal bulb before and after each treatment. There was a 1- to 4-week washout between evaluations. Twenty-six healthy volunteers participated (18 women and 8 men), aged 30 to 50 years. Gastric ulcers were present in 2 subjects receiving alendronate (8%), in 3 receiving naproxen (12%), and in 10 receiving both (38%) (P<.05 for the combination vs either drug alone). Both alendronate and naproxen can cause gastric ulcers. The combination appears synergistic. Alendronate should be used with caution in those who simultaneously require nonsteroidal anti-inflammatory drugs.


Transverse characterization of high air-fill fraction tapered photonic crystal fiber.
We demonstrate tapering of a high air-fill fraction photonic crystal fiber by using the flame-brushing technique. Transverse probing along the taper allows us to ascertain how the microstructure is preserved during tapering. Experimental results are compared with numerical simulations performed with the finite-difference time-domain and plane-wave expansion methods. Through this investigation we find that the fiber geometry is well preserved throughout the tapering process and we resolve the apparent discrepancies between simulation and experiment that arise through the finite extent of the fiber microstructure.


The receptor RAGE: Bridging inflammation and cancer.
The receptor for advanced glycation end products (RAGE) is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer.


Estimating recombination rates from population genetic data.
We introduce a new method for estimating recombination rates from population genetic data. The method uses a computationally intensive statistical procedure (importance sampling) to calculate the likelihood under a coalescent-based model. Detailed comparisons of the new algorithm with two existing methods (the importance sampling method of Griffiths and Marjoram and the MCMC method of Kuhner and colleagues) show it to be substantially more efficient. (The improvement over the existing importance sampling scheme is typically by four orders of magnitude.) The existing approaches not infrequently led to misleading results on the problems we investigated. We also performed a simulation study to look at the properties of the maximum-likelihood estimator of the recombination rate and its robustness to misspecification of the demographic model.


Constructive genetic algorithm for clustering problems.
Genetic algorithms (GAs) have recently been accepted as powerful approaches to solving optimization problems. It is also well-accepted that building block construction (schemata formation and conservation) has a positive influence on GA behavior. Schemata are usually indirectly evaluated through a derived structure. We introduce a new approach called the Constructive Genetic Algorithm (CGA), which allows for schemata evaluation and the provision of other new features to the GA. Problems are modeled as bi-objective optimization problems that consider the evaluation of two fitness functions. This double fitness process, called fg-fitness, evaluates schemata and structures in a common basis. Evolution is conducted considering an adaptive rejection threshold that contemplates both objectives and attributes a rank to each individual in population. The population is dynamic in size and composed of schemata and structures. Recombination preserves good schemata, and mutation is applied to structures to get population diversification. The CGA is applied to two clustering problems in graphs. Representation of schemata and structures use a binary digit alphabet and are based on assignment (greedy) heuristics that provide a clearly distinguished representation for the problems. The clustering problems studied are the classical p-median and the capacitated p-median. Good results are shown for problem instances taken from the literature.


Current state of the art in rapid diagnostics for antimicrobial resistance.
Antimicrobial resistance (AMR) is a fundamental global concern analogous to climate change threatening both public health and global development progress. Infections caused by antimicrobial-resistant pathogens pose serious threats to healthcare and human capital. If the increasing rate of AMR is left uncontrolled, it is estimated that it will lead to 10 million deaths annually by 2050. This global epidemic of AMR necessitates radical interdisciplinary solutions to better detect antimicrobial susceptibility and manage infections. Rapid diagnostics that can identify antimicrobial-resistant pathogens to assist clinicians and health workers in initiating appropriate treatment are critical for antimicrobial stewardship. In this review, we summarize different technologies applied for the development of rapid diagnostics for AMR and antimicrobial susceptibility testing (AST). We briefly describe the single-cell technologies that were developed to hasten the AST of infectious pathogens. Then, the different types of genotypic and phenotypic techniques and the commercially available rapid diagnostics for AMR are discussed in detail. We conclude by addressing the potential of current rapid diagnostic systems being developed as point-of-care (POC) diagnostic tools and the challenges to adapt them at the POC level. Overall, this review provides an insight into the current status of rapid and POC diagnostic systems for AMR.


Integration of hormonal signaling networks and mobile microRNAs is required for vascular patterning in Arabidopsis roots.
As multicellular organisms grow, positional information is continually needed to regulate the pattern in which cells are arranged. In the Arabidopsis root, most cell types are organized in a radially symmetric pattern; however, a symmetry-breaking event generates bisymmetric auxin and cytokinin signaling domains in the stele. Bidirectional cross-talk between the stele and the surrounding tissues involving a mobile transcription factor, SHORT ROOT (SHR), and mobile microRNA species also determines vascular pattern, but it is currently unclear how these signals integrate. We use a multicellular model to determine a minimal set of components necessary for maintaining a stable vascular pattern. Simulations perturbing the signaling network show that, in addition to the mutually inhibitory interaction between auxin and cytokinin, signaling through SHR, microRNA165/6, and PHABULOSA is required to maintain a stable bisymmetric pattern. We have verified this prediction by observing loss of bisymmetry in shr mutants. The model reveals the importance of several features of the network, namely the mutual degradation of microRNA165/6 and PHABULOSA and the existence of an additional negative regulator of cytokinin signaling. These components form a plausible mechanism capable of patterning vascular tissues in the absence of positional inputs provided by the transport of hormones from the shoot.


Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity.
Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or differentiated in vitro under either pathogenic or non-pathogenic polarization conditions. Computational analysis relates a spectrum of cellular states in vivo to in-vitro-differentiated Th17 cells and unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four new genes: Gpr65, Plzp, Toso, and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity and can identify targets for selective suppression of pathogenic Th17 cells while potentially sparing non-pathogenic tissue-protective ones.


Prm1p, a pheromone-regulated multispanning membrane protein, facilitates plasma membrane fusion during yeast mating.
Cell fusion occurs throughout development, from fertilization to organogenesis. The molecular mechanisms driving plasma membrane fusion in these processes remain unknown. While yeast mating offers an excellent model system in which to study cell fusion, all genes previously shown to regulate the process act at or before cell wall breakdown; i.e., well before the two plasma membranes have come in contact. Using a new strategy in which genomic data is used to predict which genes may possess a given function, we identified PRM1, a gene that is selectively expressed during mating and that encodes a multispanning transmembrane protein. Prm1p localizes to sites of cell-cell contact where fusion occurs. In matings between Deltaprm1 mutants, a large fraction of cells initiate zygote formation and degrade the cell wall separating mating partners but then fail to fuse. Electron microscopic analysis reveals that the two plasma membranes in these mating pairs are tightly apposed, remaining separated only by a uniform gap of approximately 8 nm. Thus, the phenotype of Deltaprm1 mutants defines a new step in the mating reaction in which membranes are juxtaposed, possibly through a defined adherence junction, yet remain unfused. This phenotype suggests a role for Prm1p in plasma membrane fusion.


Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation.
Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which likely contributes to the increased susceptibility to infection in these patients.


Gender difference in the association of dietary patterns and metabolic parameters with obesity in young and middle-aged adults with dyslipidemia and abnormal fasting plasma glucose in Taiwan.
The increasing prevalence of obesity has become a pandemic problem, and dietary patterns are one of the important factors causing obesity. Although the correlation between dietary patterns and obesity has been well explored, the gender difference on the association between dietary patterns and obesity remains unclear. The objective of this study examined whether gender difference existed in the relationship of dietary patterns with metabolic parameters and specific indices of adiposity among young and middle-aged adults with dyslipidemia and abnormal fasting plasma glucose (FPG) in Taiwan. A total of 14,087 subjects aged between 20 and 50 years with dyslipidemia and abnormal FPG were recruited in Taiwan between 2001 and 2010 for a cross-sectional study. Dyslipidemia was defined primarily according to the National Cholesterol Education Program Adult Treatment Panel III guidelines with minor modification. Abnormal FPG level was defined by the American Diabetes Association. Principal component analysis was conducted to identify dietary patterns. Multivariate logistic regression analysis was performed to evaluate the association of dietary patterns and metabolic parameters with different indices of adiposity including general obesity, central obesity, and high body fat, stratified by gender. Two dietary patterns derived from principal component analysis were the prudent dietary pattern and the western dietary pattern. Both men and women in the highest quartile of the western dietary pattern had a significantly increased odds ratio of general obesity, central obesity, and high body fat. However, only male subjects in the higher quartiles of the prudent dietary pattern had a significantly decreased odds ratio of all indices of obesity. Both men and women with higher high-density lipoprotein cholesterol and total cholesterol levels had a significantly reduced odds ratio of general and central obesity, while those with higher triglycerides and FPG levels had a significantly increased odds ratio of general and central obesity. Higher low-density lipoprotein cholesterol level was significantly associated with an elevated odds ratio of high body fat, while higher total cholesterol level was significantly correlated with a reduced odds ratio of high body fat only in women. Gender difference exists in the association of dietary patterns and metabolic parameters with obesity and body fat in young and middle-aged adults with dyslipidemia and abnormal FPG in Taiwan.


Stem cell-based neuroprotective and neurorestorative strategies.
Stem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from the adult hippocampal and subventricular regions possess the utilizing potential to develop the transplantation strategies and to screen the candidate agents for neurogenesis, neuroprotection, and neuroplasticity in neurodegenerative diseases. In this article, we review the roles of NSCs and other stem cells in neuroprotective and neurorestorative therapies for neurological and psychiatric diseases. We show the evidences that NSCs play the key roles involved in the pathogenesis of several neurodegenerative disorders, including depression, stroke and Parkinson's disease. Moreover, the potential and possible utilities of induced pluripotent stem cells (iPS), reprogramming from adult fibroblasts with ectopic expression of four embryonic genes, are also reviewed and further discussed. An understanding of the biophysiology of stem cells could help us elucidate the pathogenicity and develop new treatments for neurodegenerative disorders. In contrast to cell transplantation therapies, the application of stem cells can further provide a platform for drug discovery and small molecular testing, including Chinese herbal medicines. In addition, the high-throughput stem cell-based systems can be used to elucidate the mechanisms of neuroprotective candidates in translation medical research for neurodegenerative diseases.


[Evaluation of 115 consecutive patients with blunt renal trauma by using the classification for renal injury of Japanese Association for the Surgery of Trauma].
To evaluate the clinical usefulness of the classification for renal injury, proposed by Japanese Association for the Surgery of Trauma (JAST). JAST classification for renal injuries consists of categories as: Type I (subcapsular injury); Type II (superficial injury); type III (deep injury); type IV (pedicle injury). Type III injuries are subclassified into: IIIa (deep laceration); IIIb (transection); IIIc (fragmentation). Type IV are subclassified as: IVa (M), IVa (S) (the occlusion of main or segmental renal artery); IVb (renal vessels laceration). Each of the degrees of severity in hemorrhage (H factor) and extravasation of urine (U factor) should be appended as: H0, U0 (not recognized); H1, U1 (remaining within perinephric space); H2, U2 (extending through Gerota's fascia); H3, U3 (extending to contralateral side). We examined the initial management and overall outcome of blunt renal injuries recorded at our institute. All patients were classified according to the JAST criteria. Statistical analyses were applied to find the correlations between type and H factor, and between type and U factor. We also determined which parameter (type, H or U) is the most significant factor responsible for the outcome of treatment in the injured kidney. One hundred and fifteen consecutive cases of blunt renal injuries from 1982 to 1999 were investigated. Significant correlations were observed between type (I-IIIc) and H factor, and also between type (IIIa-IIIc) and U factor. Twenty-nine patients (25%) underwent immediate surgical exploration; 1 (2%) in type I or II or IVa (S), 5 (18%) in IIIa, 4 (50%) in IIIb, 7 (100%) in IIIc and 12 (100%) in IVa (M) or IVb. Among the 86 conservatively-managed patients, TAE or surgical intervention was required later in six patients. Nineteen (17%) patients were nephrectomized. The renal loss rates were 0% in type I or II or IVa (S), 7% in IIIa, 25% in IIIb, 57% in IIIc and 92% in IVa (M) or IVb, respectively. The differences of severities of the type and the H factor are statistically significant between the groups of injured kidney preserved and lost. Logistic regression analysis suggested that the type was an independent factor predicting outcomes of injured kidneys. It seemed that the type category is most useful when managing patients with renal injuries and also evaluating outcomes of them.


Progress in Vaccine-Preventable and Respiratory Infectious Diseases-First 10 Years of the CDC National Center for Immunization and Respiratory Diseases, 2006-2015.
The need for closer linkages between scientific and programmatic areas focused on addressing vaccine-preventable and acute respiratory infections led to establishment of the National Center for Immunization and Respiratory Diseases (NCIRD) at the Centers for Disease Control and Prevention. During its first 10 years (2006-2015), NCIRD worked with partners to improve preparedness and response to pandemic influenza and other emergent respiratory infections, provide an evidence base for addition of 7 newly recommended vaccines, and modernize vaccine distribution. Clinical tools were developed for improved conversations with parents, which helped sustain childhood immunization as a social norm. Coverage increased for vaccines to protect adolescents against pertussis, meningococcal meningitis, and human papillomavirus-associated cancers. NCIRD programs supported outbreak response for new respiratory pathogens and oversaw response of the Centers for Disease Control and Prevention to the 2009 influenza A(H1N1) pandemic. Other national public health institutes might also find closer linkages between epidemiology, laboratory, and immunization programs useful.


Effects of a fruit/berry/vegetable supplement on muscle function and oxidative stress.
This study tested the effectiveness of a fruit, berry, and vegetable concentrate (FVC), Juice Plus+® (NSA LLC, Collierville, TN), supplement on muscle function and oxidative stress in response to an acute bout of eccentric exercise (EE). Forty-one healthy volunteers (age = 18-35 yr) were randomly assigned to either a placebo (P) or an FVC treatment taking capsules for 28 d (6 d(-1)) before EE and for the next 4 d. All subjects completed four sets of 12 repetitions of eccentric elbow flexion with their nondominant arm. Blood, muscle soreness (MS), range of motion (ROM), and maximal isometric force (MIF) of the elbow flexors were obtained before and immediately after exercise and at 2, 6, 24, 48, and 72 h postexercise. Plasma was analyzed for creatine kinase (CK), lipid hydroperoxides, malondialdehyde (MDA), and protein carbonyls (PC). Glutathione ratio was determined from whole-blood extracts. MS, ROM, MIF, and plasma CK demonstrated significant time effects independent of treatment. MS and plasma CK increased over time, whereas ROM and MIF decreased over time. There was a significant time and time × treatment effect for plasma PC and MDA. PC and MDA increased over time in the P group (P < 0.01) but were not significantly altered in the FVC-treated group at any time. No significant changes were noted in lipid hydroperoxides. The glutathione ratio was elevated immediately postexercise in both groups (P < 0.01) and elevated 6 h postexercise with P compared with the FVC-treated group (P < 0.05). This study reports that 4 wk of pretreatment with an FVC can attenuate blood oxidative stress markers induced by EE but had no significant impact on the functional changes related to pain and muscle damage.


Transfer of recombinant plasmids containing the gene for DpnII DNA methylase into strains of Streptococcus pneumoniae that produce DpnI or DpnII restriction endonucleases.
Plasmid transfer via the transformation pathway of Streptococcus pneumoniae was weakly restricted by the DpnI or DpnII restriction endonuclease, either of which gave a reduction only to 0.4, compared with phage infection, which was restricted to 10(-5). The greater sensitivity of plasmid transfer compared with chromosomal transformation, which was not at all restricted, can be attributed to partially double-stranded intermediates formed from two complementary donor fragments. However, clustering of potential restriction sites in the plasmids increased the probability of escape from restriction. The recombinant plasmid pMP10 , in which the gene for the DpnII DNA methylase was cloned, can be transferred to strains that contain neither restriction enzyme or that contain DpnII as readily as can the vector pMP5 . Introduction of pMP10 raised the level of methylase by five times the level normally present in DpnII strains. Transfer of pMP10 to DpnI -containing strains was infrequent, presumably owing to the suicidal methylation of DNA which rendered it susceptible to the host endonuclease. The few clones in which pMP10 was established had lost DpnI . Loss of the plasmid after curing of the cell eliminated the methylase but did not restore DpnI . Although this loss of DpnI could result from spontaneous mutation, its relatively high frequency, 0.1% suggested that the loss was due to a regulatory shift.


Breast cancer-specific TRAIL expression mediated by miRNA response elements of let-7 and miR-122.
Breast cancer is a highly aggressive malignancy and always has a poor prognosis. The current therapeutic strategies including surgery, chemotherapy and radiotherapy benefit little for patients survival. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in a wide range of cancer cells, such as breast cancer, it also has cytotoxicity to normal cells. To improve the selectivity of TRAIL expression to breast cancer cells, we inserted miRNA response elements (MREs) of let-7 and miR-122 into a TRAIL-expressing adenoviral vector (Ad-TRAIL-MRE-7-122) to restrict its expression within breast cancer cells. qPCR assay confirmed that the levels of let-7 and miR-122 were downregulated in breast cancer samples and cell lines, compared with normal tissues and cell lines. Luciferase assay indicated that MREs of let-7 and miR-122 was able to confer luciferase expression with the selectivity to breast cancer. Ad-TRAIL-MRE-7-122 highly expressed TRAIL in breast cancer cells, but not in normal cells. The breast cancer-specific apoptosis was detected after the infection of Ad-TRAIL-MRE-7-122. The viability of breast cancer cells, rather than normal cells, was reduced by the treatment of Ad-TRAIL-MRE-7-122. Animal experiments further confirmed that Ad-TRAIL-MRE-7-122 and Ad-TRAIL both greatly impeded the growth of breast cancer xenograft in mice. Taken together, we constructed a TRAIL-expressing recombinant adenovirus regulated by MREs of let-7 and miR-122 and showed evidences that this strategy may be promising for breast cancer treatment.


Deep-ultraviolet laser ablation sampling for proteomic analysis of tissue.
Deep-ultraviolet laser ablation with a pulsed 193 nm ArF excimer laser was used to remove localized regions from tissue sections from which proteins were extracted for spatially resolved proteomic analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). The ability to capture intact proteins by ablation at 193 nm wavelength was verified by matrix-assisted laser desorption ionization (MALDI) of the protein standard bovine serum albumin (BSA), which showed that BSA was ablated and captured without fragmentation. A Bradford assay of the ablated and captured proteins indicated 90% efficiency for transfer of the intact protein at a laser fluence of 3 kJ/m2. Rat brain tissue sections mounted on quartz microscope slides and ablated in transmission mode yielded 2 μg protein per mm2 as quantified by the Bradford assay. Tissue areas ranging from 0.06 mm2 to 1 mm2 were ablated and the ejected material was collected for proteomic analysis. Extracted proteins were digested and the resulting peptides were analyzed by LC-MS/MS. The proteins extracted from the ablated areas were identified and the average number of identified proteins ranged from 85 in the 0.06 mm2 area to 2400 in the 1 mm2 area of a 50 μm thick tissue. In comparison to infrared laser ablation of equivalent sampled areas, both the protein mass and number of proteins identified using DUV laser ablation sampling were approximately four times larger.


Three-Dimensional Printed Porous Titanium Screw with Bioactive Surface Modification for Bone-Tendon Healing: A Rabbit Animal Model.
The interference screw fixation method is used to secure a graft in the tibial tunnel during anterior cruciate ligament reconstruction surgery. However, several complications have been reported, such as biodegradable screw breakage, inflammatory or foreign body reaction, tunnel enlargement, and delayed graft healing. Using additive manufacturing (AM) technology, we developed a titanium alloy (Ti6Al4V) interference screw with chemically calcium phosphate surface modification technology to improve bone integration in the tibial tunnel. After chemical and heat treatment, the titanium screw formed a dense apatite layer on the metal surface in simulated body fluid. Twenty-seven New Zealand white rabbits were randomly divided into control and additive manufactured (AMD) screw groups. The long digital extensor tendon was detached and translated into a tibial plateau tunnel (diameter: 2.0 mm) and transfixed with an interference screw while the paw was in dorsiflexion. Biomechanical analyses, histological analyses, and an imaging study were performed at 1, 3, and 6 months. The biomechanical test showed that the ultimate pull-out load failure was significantly higher in the AMD screw group in all tested periods. Micro-computed tomography analyses revealed early woven bone formation in the AMD screw group at 1 and 3 months. In conclusion, AMD screws with bioactive surface modification improved bone ingrowth and enhanced biomechanical performance in a rabbit model.


ALE meta-analysis on facial judgments of trustworthiness and attractiveness.
Faces convey a multitude of information in social interaction, among which are trustworthiness and attractiveness. Humans process and evaluate these two dimensions very quickly due to their great adaptive importance. Trustworthiness evaluation is crucial for modulating behavior toward strangers; attractiveness evaluation is a crucial factor for mate selection, possibly providing cues for reproductive success. As both dimensions rapidly guide social behavior, this study tests the hypothesis that both judgments may be subserved by overlapping brain networks. To this end, we conducted an activation likelihood estimation meta-analysis on 16 functional magnetic resonance imaging studies pertaining to facial judgments of trustworthiness and attractiveness. Throughout combined, individual, and conjunction analyses on those two facial judgments, we observed consistent maxima in the amygdala which corroborates our initial hypothesis. This finding supports the contemporary paradigm shift extending the amygdala's role from dominantly processing negative emotional stimuli to processing socially relevant ones. We speculate that the amygdala filters sensory information with evolutionarily conserved relevance. Our data suggest that such a role includes not only "fight-or-flight" decisions but also social behaviors with longer term pay-off schedules, e.g., trustworthiness and attractiveness evaluation.


Contagion of Cooperation in Static and Fluid Social Networks.
Cooperation is essential for successful human societies. Thus, understanding how cooperative and selfish behaviors spread from person to person is a topic of theoretical and practical importance. Previous laboratory experiments provide clear evidence of social contagion in the domain of cooperation, both in fixed networks and in randomly shuffled networks, but leave open the possibility of asymmetries in the spread of cooperative and selfish behaviors. Additionally, many real human interaction structures are dynamic: we often have control over whom we interact with. Dynamic networks may differ importantly in the goals and strategic considerations they promote, and thus the question of how cooperative and selfish behaviors spread in dynamic networks remains open. Here, we address these questions with data from a social dilemma laboratory experiment. We measure the contagion of both cooperative and selfish behavior over time across three different network structures that vary in the extent to which they afford individuals control over their network ties. We find that in relatively fixed networks, both cooperative and selfish behaviors are contagious. In contrast, in more dynamic networks, selfish behavior is contagious, but cooperative behavior is not: subjects are fairly likely to switch to cooperation regardless of the behavior of their neighbors. We hypothesize that this insensitivity to the behavior of neighbors in dynamic networks is the result of subjects' desire to attract new cooperative partners: even if many of one's current neighbors are defectors, it may still make sense to switch to cooperation. We further hypothesize that selfishness remains contagious in dynamic networks because of the well-documented willingness of cooperators to retaliate against selfishness, even when doing so is costly. These results shed light on the contagion of cooperative behavior in fixed and fluid networks, and have implications for influence-based interventions aiming at increasing cooperative behavior.


Development and first assessment of a questionnaire for health care utilization and costs for cardiac patients.
The valid and reliable measurement of health service utilization, productivity losses and consequently total disease-related costs is a prerequisite for health services research and for health economic analysis. Although administrative data sources are usually considered to be the most accurate, their use is limited as some components of utilization are not systematically captured and, especially in decentralized health care systems, no single source exists for comprehensive utilization and cost data. The aim of this study was to develop and test a questionnaire for the measurement of disease-related costs for patients after an acute cardiac event (ACE). To design the questionnaire, the literature was searched for contributions to the assessment of utilization of health care resources by patient-administered questionnaires. Based on these findings, we developed a retrospective questionnaire appropriate for the measurement of disease-related costs over a period of 3 months in ACE patients. Items were generated by reviewing existing guidelines and by interviewing medical specialists and patients. In this study, the questionnaire was tested on 106 patients, aging 35-65 who were admitted for rehabilitation after ACE. It was compared with prospectively measured data; selected items were compared with administrative data from sickness funds. The questionnaire was accepted well (response rate = 88%), and respondents completed the questionnaire in an average time of 27 minutes. Concordance between retrospective and prospective data showed an intraclass correlation (ICC) ranging between 0.57 (cost of medical intake) and 0.9 (hospital days) with the other main items (physician visits, days off work, medication) clustering around 0.7. Comparison between self-reported and administrative data for days off work and hospitalized days were possible for n = 48. Respective ICCs ranged between 0.92 and 0.94, although differences in mean levels were observed. The questionnaire was accepted favorably and correlated well with alternative measurement approaches. This first assessment showed promising characteristics of this questionnaire in different aspects of validity for patients with ACE. However, additional research and more extensive tests in other patient groups would be worthwhile.


New Insight into a Cancer Theranostic Probe: Efficient Cell-Specific Delivery of SN-38 Guided by Biotinylated Poly(vinyl alcohol).
An optically modulated "turn-on" theranostic prodrug TP1 has been explored and formulated with biotinylated poly(vinyl alcohol) (biotinPVA) to obtain desired pharmacokinetics. TP1, consisting of the antineoplastic camptothecin analogue SN-38, and the fluorescent dye rhodol green have been covalently conjugated through a disulfide bond. Glutathione triggering the release of drug and fluorophore has been well established by UV-vis measurements through mass spectral analysis in physiological conditions. The biocompatible biotinPVA formulated prodrug (PTP1) showed remarkably higher stability against blood serum and cell-specific activation in contrast to that of TP1. Significantly, PTP1 permits monitoring of the delivery and release of well-known topoisomerase I inhibitor SN-38 by modulating fluorescence signal at λem 550 nm within intracellular milieus. Moreover, theranostic probe PTP1 exhibited dose-dependent antiproliferative activity against receptor-positive HeLa cells, whereas it did not show such an effect against receptor-negative NIH3T3 cells. Finally, the cell-specific antiproliferative activity of PTP1 via the apoptotic pathway is an efficient approach in cancer theranostics. Thus, futuristic PTP1 could be a promising agent in which diagnostic and prognostic data will be monitored synergistically.


Two-year outcome of social skills training and group psychotherapy for outpatients with schizophrenia.
The authors evaluated the effectiveness of behaviorally oriented social skills training and supportive group therapy for improving the social adjustment of schizophrenic patients living in the community and for protecting them against psychotic relapse. Eighty male outpatients with schizophrenia were stabilized with a low dose of fluphenazine decanoate (5 to 10 mg every 14 days), which was supplemented with oral fluphenazine (5 mg twice daily) or a placebo when they first met criteria for a prodromal period. (Half of the patients did so at some time during the study.) Patients were randomly assigned to receive either social skills training or supportive group therapy twice weekly for 6 months and then weekly for the next 18 months. Rates of psychotic exacerbation were monitored, as were scores on the Social Adjustment Scale II. There were significant main effects favoring social skills training over supportive group therapy on two of the six Social Adjustment Scale II cluster totals examined (personal well-being and total) and significant interactions between psychosocial treatment and drug treatment for three items (external family, social and leisure activities, and total). In each case, these interactions indicated that the advantage of social skills training over supportive group therapy was greatest when it was combined with active drug supplementation. Social skills training did not significantly decrease the risk of psychotic exacerbation in the full group, but an advantage was observed (post hoc) among patients who received placebo supplementation. These findings suggest that social skills training resulted in greater improvement in certain measures of social adjustment than supportive group therapy. The greatest improvement in social outcomes occurred when social skills training was combined with a pharmacological strategy of active drug supplementation at the time prodromal worsening of psychotic symptoms was first observed. However, these improvements were modest in absolute terms and confined to certain subgroups of patients.


Investigating the risk of cancer in 1990-1991 US Gulf War veterans with the use of state cancer registry data.
The purpose of this study was to determine whether proportional cancer incidence is greater among Gulf War veterans compared with non-Gulf War veterans. Files obtained from the Defense Manpower Data Center included data for 621,902 veterans who were deployed to the Persian Gulf during the 1990 to 1991 Gulf War (August 2, 1990, to March 1, 1991) and 746,248 non-Gulf War veteran controls. Identification of veterans who received a cancer diagnosis between 1991 and 2006 was accomplished through record linkage of the Defense Manpower Data Center dataset with files from 28 state cancer registries and the Department of Veterans Affairs Central Cancer Registry. By the use of logistic regression, proportional incidence ratios adjusted for demographic and military characteristics were calculated by comparing the proportion of a specific cancer among all cancers in the Gulf War veterans to the proportion of that specific cancer among all cancers in the non-Gulf War veterans. Only lung cancer showed a statistically significant relative excess among Gulf War veterans compared with non-Gulf War veterans (adjusted proportional incidence ratios, 1.15; 95% confidence interval, 1.03-1.29). When adjusted for race, age, and sex, the overall proportion of cancers among Gulf War and non-Gulf War veterans was similar (odds ratio, 0.99; 95% CI, 0.96-1.02). With the exception of lung cancer, there is little evidence of excess risk of cancer associated with Gulf War deployment. A follow-up study is warranted to confirm this finding and to evaluate the role of greater smoking rates among deployed personnel.


Student drinking patterns and blood alcohol concentration on commercially organised pub crawls in the UK.
Commercial student pub crawls are associated with high levels of alcohol consumption, and are of growing concern amongst public health and student bodies. However, little is currently known about drinking behaviours whilst participating in these events. A questionnaire was implemented amongst 227 students attending commercial pub crawls across three UK events. Questions established alcohol consumption patterns up to the point of interview and throughout the remaining night out, and pub crawl experience. Breathalyser tests were used to measure breath alcohol concentration (converted to blood alcohol concentration [BAC]) at interview. Analyses used chi squared, Mann-Whitney U, Kruskal-Wallis and logistic regression. 94.3% of participants had consumed alcohol, 90.9% of whom reported preloading. Drinkers reported consuming a median of 10.0 alcohol units (80g of pure alcohol) up to the point of interview (range one-40.6), with estimated total consumption over the evening exceeding 16units (range three-70.6). Median BAC of drinkers at the time of interview was 0.10%BAC (range 0.00-0.27). High BAC (>0.08%; at interview) was associated with having not eaten food in the four hours prior (AOR 4.8, p<0.01), time spent drinking (AOR 1.4, p<0.01) and number of units drank per hour (AOR 1.2, p<0.01). Measures to prevent high levels of alcohol consumption before and during commercial pub crawls should aim to alter drinking behaviours such as preloading and rapid and excessive drinking. Organisers, local authorities, universities and students should all be involved in ensuring the effective management of pub crawls, including implementation of harm prevention measures.


Optical properties of solid-core photonic crystal fibers filled with nonlinear absorbers.
A theoretical and experimental investigation of the transmission of solid-core photonic crystal fibers (PCFs) filled with nonlinear absorbers shows a sharp change in the threshold for optical limiting and in leakage loss as the refractive index of the material in the holes approaches that of the glass matrix. Theoretical calculations of the mode profiles and leakage loss of the PCF are in agreement with experimental results and indicate that the change in limiting response is due to the interaction of the evanescent field of the guided mode with the nonlinear absorbers in the holes.


Inhibitors targeting the influenza virus hemagglutinin.
The annual flu season causes thousands of deaths and millions of hospitalizations, which pose a great burden to global health and economy. Moreover, a flu pandemic arising from reassortment viruses, such as H5N1 and H1N1, raises even greater concern due to the lack of effective vaccines at the initial stage of flu outbreak. The influenza virus is the causative agent of flu infection. Currently there are four drugs in use to combat influenza infection. Amantadine and rimantadine are M2 proton channel blockers that inhibit virus uncoating; oseltamivir and zanamivir are neuraminidase (NA) inhibitors that inhibit virus release. However, recent years have witnessed a drastic increase in instances of drug resistance, and flu strains that are resistant to both classes of drugs have been reported. Thus, there is a pressing need to develop the next generation of anti-influenza drugs. Among a handful of anti-influenza drug targets, the viral fusion protein hemagglutinin (HA) is one of the most advanced. This review discusses the biological roles of HA during viral replication and highlights peptide- and small molecule-based HA inhibitors, including recent computationally designed HA binders. The text is organized into four sections based on the maturation stages of HA: inhibitors targeting the glycosylation of HA, the proteolytic activation of HA, the attachment of HA to host cell receptors, and peptide- and small molecule-based inhibitors targeting HA-mediated membrane fusion. Of particular interest are advances in the areas of developing dual inhibitors targeting both HA and NA and broad-spectrum HA inhibitors targeting both groups of HAs.


Missed opportunities among HIV-positive women to control viral replication during pregnancy and to have a vaginal delivery.
Most national guidelines for the prevention of mother-to-child transmission of HIV in Europe updated between 2001 and 2010 recommend vaginal deliveries for women with undetectable or very low viral load (VL). Our aim was to explore the impact of these new guidelines on the rates of vaginal deliveries among HIV-positive women in Europe. In a pooled analysis of data on HIV-positive pregnant women enrolled in the Swiss Mother & Child HIV Cohort Study and the European Collaborative Study 2000 to 2010, deliveries were classified as occurring pre- or postpublication of national guidelines recommending vaginal delivery. Overall, 2663 women with 3013 deliveries were included from 10 countries; 28% women were diagnosed with HIV during pregnancy. Combination antiretroviral therapy was used in most pregnancies (2020, 73%), starting during the first or second trimester in 78% and during the third trimester in 22%; in 25% pregnancies, the woman conceived on combination antiretroviral therapy. Overall, in 86% pregnancies, a VL < 400 copies per milliliter was achieved before delivery. The proportion of vaginal deliveries increased from 17% (414/2377) before the change in guidelines to 52% (313/600) after; elective Caesarean section rates decreased from 65% to 27%. The proportion of women with undetectable VL having a Caesarean section was 55% after implementation of new guidelines. We observed a decrease of late preterm deliveries from 16% (377/2354) before to 7% (42/599) after the change in guidelines (P < 0.001). There are still missed opportunities for women with HIV to fully suppress their VL and to deliver vaginally in Europe.


Building an Extracorporeal Cardiopulmonary Resuscitation Program at a High-volume Extracorporeal Membrane Oxygenation Center.
Extracorporeal Cardiopulmonary Resuscitation (ECPR) is an emerging approach to cardiac arrest. We present two contrasting cases from a high-volume extracorporeal membrane oxygenation (ECMO) center (defined as greater than 30 ECMO cases per year) without a 24/7 ECPR program to highlight how to establish an ECPR program with a focus on patient selection and outcome optimization. In one case, a patient presented with cardiac arrest during initial triage for chest pain within the emergency department, and in the other case, a patient experienced an out-of-hospital cardiac arrest with prolonged no-flow and low-flow time. Despite the lack of a 24/7 ECPR program at the presenting center, both patients received an ECPR evaluation, as both patients presented while all services necessary for ECMO cannulation were available. The in-hospital cardiac arrest patient was successfully cannulated for ECMO during cardiopulmonary resuscitation and survived with few complications. The out-of-hospital cardiac arrest patient was deemed a poor candidate for ECPR and expired soon after presentation. These two cases highlight the complex decision-making in ECPR and further illustrate how to create ECPR protocols at a high-volume ECMO center before resources are available for a 24/7 ECPR program.