Living near agricultural pesticide applications and the risk of adverse reproductive outcomes: a review of the literature.
Over the last decade, there has been growing concern about the possible health effects, including a number of adverse reproductive outcomes, from pesticide exposure of people living near agricultural fields. This systematic review evaluates the current epidemiological evidence on the association between living near agricultural pesticide applications and adverse reproductive outcomes, including congenital malformations, stillbirth, intrauterine growth retardation (IUGR), low birthweight, preterm birth and miscarriage. We identified and reviewed 25 studies from a systematic search of the main scientific databases and other sources published in 1950-2007. Study methods and main results were summarised and tabulated according to the year of study, design and type of adverse reproductive outcome. The levels of evidence for reproductive toxicity in humans contributed by each study were assessed and the main limitations associated with these studies discussed. Residential proximity to agricultural pesticide applications may be an important source of ambient environmental exposure, but because of the underlying methodological difficulties, the strength of evidence for its relationship with adverse reproductive outcomes is generally weak and varied between outcomes. The evidence suggested an association for congenital malformations, but because of methodological limitations, such as poor exposure measurement and potentially inadequate control of confounding, a firm conclusion remains beyond reach. For the other outcomes (stillbirth, IUGR, low birthweight, preterm birth and miscarriage) the evidence for any associations was equivocal at best, but some leads warrant further investigation. Improved exposure assessment methods are needed to obtain a more reliable assessment of any risks.


Hepatitis G virus.
A number of new hepatitis viruses (G, TT, SEN) were discovered late in the past century. We review the data available in the literature and our own findings suggesting that the new hepatitis G virus (HGV), disclosed in the late 1990s, has been rather well studied. Analysis of many studies dealing with HGV mainly suggests the lymphotropicity of this virus. HGV or GBV-C has been ascertained to influence course and prognosis in the HIV-infected patient. Until now, the frequent presence of GBV-C in coinfections, hematological diseases, and biliary pathology gives no grounds to determine it as an "accidental tourist" that is of no significance. The similarity in properties of GBV-C and hepatitis C virus (HCV) offers the possibility of using HGV, and its induced experimental infection, as a model to study hepatitis C and to develop a hepatitis C vaccine.


Effects of visceral adipose tissue reduction on CVD risk factors independent of weight loss: The Look AHEAD study.
To determine if the reduction of visceral adipose tissue (VAT) volume by lifestyle intervention improved risk factors for cardiovascular disease (CVD) independent of weight loss amount. Ancillary study of randomized-controlled trial. Data analysis using multivariable regression models. Participants of the Look AHEAD (Action for HEAlth in Diabetes) Fatty Liver Ancillary Study. Correlations between changes in VAT and in CVD risk factors, while adjusting for weight loss and treatment (intensive lifestyle intervention [ILI] vs. diabetes support and education [DSE]). Of 100 participants analyzed, 52% were women, and 36% were black, with a mean age of 61.1 years. In the DSE group, mean weight and VAT changed by 0.1 % (p=0.90) and 4.3% (p=0.39), respectively. In the ILI group, mean weight and VAT decreased by 8.0% (p<0.001) and 7.7% (p=0.01), respectively. Across both groups, mean weight decreased by 3.6% (p<0.001), and mean VAT decreased by 1.2% (p=0.22); the decrease in VAT was correlated with the increase in HDL-cholesterol (HDL-C; R=-0.37; p=0.03). There were no correlations between changes in VAT and blood pressure, triglycerides, LDL-C, glucose, or HbA1c. After adjusting for age, race, gender, baseline metabolic values, fitness, and treatment group, changes in HDL-C were not associated with changes in VAT, while weight changes were independently associated with decrease in glucose, HbA1c, and increase in HDL-C. VAT reduction was not correlated with improvements of CVD risk factors in a sample of overweight and obese adults with type 2 diabetes after adjusting for weight loss.


Differential cardioprotection with selective inhibitors of adenosine metabolism and transport: role of purine release in ischemic and reperfusion injury.
In a previous report, we have demonstrated that simultaneous inhibition of nucleoside transport and adenosine deaminase accumulates endogenous adenosine and protects the myocardium against stunning. The differential cardioprotective effects of erythro-9(2-hydroxy-3-nonyl)-adenine (EHNA), a potent inhibitor of adenosine deamination but not transport, and p-nitrobenzylthioinosine (NBMPR), a selective blocker of adenosine and inosine transport, are not known. Thirty-seven anaesthetized adult dogs were instrumented to monitor left ventricular performance using sonomicrometery. Dogs were randomly assigned into four groups. The control group (n = 8) received only the vehicle solution. Treated groups received saline containing 100 microM EHNA (EHNA-group, n = 7), 25 microM NBMPR (NBMPR-group, n = 7), or a combination of 100 microM EHNA and 25 microM NBMPR (EHNA/NBMPR-group, n = 10). Hearts were subjected to 30 min of normothermic global ischaemia and 60 min of reperfusion while on bypass. Adenine nucleotides, nucleosides, oxypurines and NAD+ were determined in extracts of transmural myocardial biopsies using HPLC. TTC staining revealed the absence of necrosis in this model. Drug administration did not affect myocardial ATP metabolism and cardiac function in the normal myocardium. Ischemia caused about 50% ATP depletion and accumulation of nucleosides. The ratio between adenosine/inosine at the end of ischemia was 1:10, 1:1, 1:1 and 10:1 in the control, EHNA-, NBMPR- and EHNA/NBMPR-group, respectively. Upon reperfusion, both nucleosides washed out from the myocardium in the control and EHNA-group while retained in the myocardium in the NBMPR and EHNA/NBMPR groups. Ventricular dysfunction 'stunning' persisted in the control group (52%) and in the EHNA-treated group (32%) after 30 min of reperfusion. Significant improvement of function was observed in the EHNA group only after 60 min of reperfusion. LV function recovered in the NBMPR- and EHNA/NBMPR-treated groups during reperfusion. ATP recovery occurred only when animals were pretreated with the combination of EHNA/NBMPR and remained depressed in the control group and EHNA and NBMPR-treated groups. At post mortem, TTC staining revealed the absence of myocardial necrosis. Superior myocardial protection was observed with inhibition of nucleoside transport by NBMPR alone or in combination with inhibition of adenosine deaminase by EHNA. Selective blockade of nucleoside transport by NBMPR is more cardioprotective than inhibition of adenosine deaminase alone in attenuating myocardial stunning. It is not known why EHNA partially inhibit adenosine deaminase, in vivo.


Detection of Legionella by quantitative-polymerase chain reaction (qPCR) for monitoring and risk assessment.
Culture and quantitative polymerase chain reaction (qPCR) assays for the detection of Legionella were compared on samples from a residential area before and after two interventions. A total of 84 samples were collected from shower hoses and taps as first flush samples and at constant temperature. Samples were grouped according to the origin of the sample, a) circulation water b) water from empty apartments c) water from shower hoses. The aims were to investigate the usefulness of qPCR compared to culture for monitoring remedial actions for elimination of Legionella bacteria and as a tool for risk assessment. In water collected from the apartments Legionella spp were detected by qPCR in the concentration range from LOQ to 9.6*105GU/L while L. pneumophila were detected in a range from LOQ to 6.8*105 GU/L. By culturing, the legionellae were detected in the range from below detection limit (> 10 CFU/L) to 1.6*106 CFU/L. In circulating water and in first flush water from shower hoses, culture and qPCR showed the same tendencies. The overall correlation between the bacteria number detected by culture and the two developed qPCR assays (L. spp and L. pneumophila) was relatively poor (r2 = 0.31 for culture and Legionella spp. assay, r2 = 0.20 for culture and L. pneumophila assay). Detection by qPCR was suitable for monitoring changes in the concentration of Legionella but the precise determination of bacteria is difficult. Risk assessment by qPCR only on samples without any background information regarding treatment, timing, etc is dubious. However, the rapid detection by qPCR of high concentrations of Legionella - especially Legionella pneumophila - is valuable as an indicator of risk, although it may be false positive compared to culture results. On the other hand, the detection of a low number of bacteria by qPCR is a strong indication for the absence of risk.


Synaptic relationships of the cerebral giant cells with motoneurones in the feeding system of Lymnaea stagnalis.
1. The cerebral giant cells (CGCs) of Lymnaea have a tonic, modulatory effect on the intensity of output from feeding motoneurones in the buccal ganglia. 2. Short latency, excitatory and probably monosynaptic connexions occur between the CGCs and three identified feeding motoneurones. Unitary excitatory postsynaptic potentials in these motoneurones, following CGC spikes, are of different sizes and durations, and hence have different summation properties. 3. The CGCs make long latency, excitatory polysynaptic connexions with four other feeding motoneurone types. 4. Bursts of spikes in the CGCs, resulting from phasic synaptic input, synchronous with the feeding cycle, amplify their modulatory effect on burst intensity in feeding motoneurones. 5. Thte for reinforcing their cyclic burst activity.


Increase of GKLF messenger RNA and protein expression during progression of breast cancer.
Genetic alterations found in carcinomas can alter specific regulatory pathways and provide a selective growth advantage by activation of transforming oncogenes. A subset of these genes, including wild-type alleles of GLI or c-MYC, and activated alleles of RAS or beta-catenin, exhibit transforming activity when expressed in diploid epithelial RK3E cells in vitro. By in vitro transformation of these cells, the zinc finger protein GKLF/KLF-4 was recently identified as a novel oncogene. Although GKLF is normally expressed in superficial, differentiating epithelial cells of the skin, oral mucosa, and gut, expression is consistently up-regulated in dysplastic epithelium and in squamous cell carcinoma of the oral cavity. In the current study, we used in situ hybridization, Northern blot analysis, and immunohistochemistry to detect GKLF at various stages of tumor progression in the breast, prostate, and colon. Overall, expression of GKLF mRNA was detected by in situ hybridization in 21 of 31 cases (68%) of carcinoma of the breast. Low-level expression of GKLF mRNA was observed in morphologically normal (uninvolved) breast epithelium adjacent to tumor cells. Increased expression was observed in neoplastic cells compared with adjacent uninvolved epithelium for 14 of 19 cases examined (74%). Ductal carcinoma in situ exhibited similar expression as invasive carcinoma, suggesting that GKLF is activated prior to invasion through the basement membrane. Expression as determined by Northern blot was increased in most breast tumor cell lines and in immortalized human mammary epithelial cells when these were compared with finite-life span human mammary epithelial cells. Alteration of GKLF expression was confirmed by the use of a novel monoclonal antibody that detected the protein in normal and neoplastic tissues in a distribution consistent with localization of the mRNA. In contrast to most breast tumors, expression of GKLF in tumor cells of colorectal or prostatic carcinomas was reduced or unaltered compared with normal epithelium. The results demonstrate that GKLF expression in epithelial compartments is altered in a tissue-type specific fashion during tumor progression, and suggest that increased expression of GKLF mRNA and protein may contribute to the malignant phenotype of breast tumors.


Functional cast-bracing for Colles' fractures. A comparison between cast-bracing and conventional plaster casts.
The use of Orthoplast cast-bracing to allow early hand function in the treatment of displaced Colles' fractures was investigated in 243 patients. They were randomly allocated into three groups: in the first a conventional Colles' type plaster was used; in the second an above-elbow cast-brace with the forearm in supination; and in the third a below-elbow cast-brace. Radiographic measurements were made at each stage of treatment, and the final anatomical result was scored using Sarmiento's (1975) criteria. Function was assessed at three months and at six months. The anatomical result was not influenced by the method of immobilisation but was related to the efficacy of reduction. Loss of position in the braces was no greater than in plaster. The functional result at three months also was uninfluenced by the method of immobilisation; it was, however, related to the severity of the initial displacement, and (to a lesser degree) to the anatomical result, an effect which was lost at six months. Early hand function and the supinated position advocated by Sarmiento were found to confer no anatomical or functional advantage; we could see no reason to change from the use of conventional plaster casts in the treatment of uncomplicated Colles' fractures.


Management of bladder, prostatic and pelvic floor disorders with botulinum neurotoxin.
Since its introduction in the late 1970s for the treatment of strabismus and blepharospasm, botulinum toxin (BoNT) has been increasingly used in the interventional treatment of several other disorders characterized by excessive or inappropriate muscle contractions. The use of this pluripotential agent has extended to a plethora of conditions including: focal dystonia; spasticity; inappropriate contraction in most sphincters of the body such as those associated with spasmodic dysphonia, esophageal achalasia, chronic anal fissure, and vaginismus; eye movement disorders; other hyperkinetic disorders including tics and tremors; autonomic disorders such as hyperhidrosis; genitourinary disorders such as overactive and neurogenic bladder, non-bacterial prostatitis and benign prostatic hyperplasia; and aesthetically undesirable hyperfunctional facial lines. In addition, BoNT is being investigated for the control of the pain, and for the management of tension or migraine headaches and myofascial pain syndrome. BoNT injections have several advantages over drugs and surgical therapies in the management of intractable or chronic disease. Systemic pharmacologic effects are rare; permanent destruction of tissue does not occur. Graded degrees of relaxation may be achieved by varying the dose injected; most adverse effects are transient. Finally, patient acceptance is high. In this paper, clinical experience over the last years with BoNT in urological impaired patients will be illustrated. Moreover, this paper presents current data on the use of BoNT to treat pelvic floor disorders.


LAP6/POLYKETIDE SYNTHASE A and LAP5/POLYKETIDE SYNTHASE B encode hydroxyalkyl α-pyrone synthases required for pollen development and sporopollenin biosynthesis in Arabidopsis thaliana.
Plant type III polyketide synthases (PKSs) catalyze the condensation of malonyl-CoA units with various CoA ester starter molecules to generate a diverse array of natural products. The fatty acyl-CoA esters synthesized by Arabidopsis thaliana ACYL-COA SYNTHETASE5 (ACOS5) are key intermediates in the biosynthesis of sporopollenin, the major constituent of exine in the outer pollen wall. By coexpression analysis, we identified two Arabidopsis PKS genes, POLYKETIDE SYNTHASE A (PKSA) and PKSB (also known as LAP6 and LAP5, respectively) that are tightly coexpressed with ACOS5. Recombinant PKSA and PKSB proteins generated tri-and tetraketide α-pyrone compounds in vitro from a broad range of potential ACOS5-generated fatty acyl-CoA starter substrates by condensation with malonyl-CoA. Furthermore, substrate preference profile and kinetic analyses strongly suggested that in planta substrates for both enzymes are midchain- and ω-hydroxylated fatty acyl-CoAs (e.g., 12-hydroxyoctadecanoyl-CoA and 16-hydroxyhexadecanoyl-CoA), which are the products of sequential actions of anther-specific fatty acid hydroxylases and acyl-CoA synthetase. PKSA and PKSB are specifically and transiently expressed in tapetal cells during microspore development in Arabidopsis anthers. Mutants compromised in expression of the PKS genes displayed pollen exine layer defects, and a double pksa pksb mutant was completely male sterile, with no apparent exine. These results show that hydroxylated α-pyrone polyketide compounds generated by the sequential action of ACOS5 and PKSA/B are potential and previously unknown sporopollenin precursors.


Plaque morphology (the PLAC Scale) on CT angiography: predicting long-term anatomical success of primary carotid stenting.
Carotid angioplasty and stenting has emerged as an alternative to carotid endarterectomy for the treatment of atherosclerotic carotid stenosis. Primary carotid stenting, performed using self-expanding stents alone without deliberate use of embolic protection devices and balloon angioplasty, has been shown to be effective and faster, cheaper, and potentially safer than conventional techniques. However, the long-term morphological results of this technique have not been established. The aim of this study was to determine whether preprocedural carotid plaque imaging at the site of maximal stenosis by using CT angiography (CTA) could predict the long-term morphological outcome of primary carotid stenting. One hundred eighty-one patients were treated over an 11-year period. Preprocedural CTA was performed in 102 of these. A morphological scale (the Predicting Long-term outcome with Angioplasty of the Carotid artery [PLAC] Scale), with grades from 0 to 4 and A or B, was used to evaluate the circumferential degree of plaque calcification, and the presence or absence of soft plaque. All patients were followed using duplex carotid ultrasound and plain radiographs. Satisfactory morphological outcome was defined as a peak systolic velocity < 120 cm/s and internal carotid artery/common carotid artery ratio < 1.4. The average follow-up duration was 29.7 months (median 24.5 months, range 0.3-87 months). Univariate logistic regression demonstrated that a low calcification grade (p < 0.001), less thick calcification (p < 0.001), and moderate amounts of soft plaque (p < 0.001) are factors that are highly associated with good long-term outcome. Multivariate analyses confirmed that these factors are independent of each other in predicting outcome. The long-term morphological outcome of primary carotid stenting was predicted with considerable accuracy by using a straightforward CTA carotid plaque grading scale.


The molecular biology of invertebrate voltage-gated Ca(2+) channels.
The importance of voltage-gated Ca(2+) channels in cellular function is illustrated by the many distinct types of Ca(2+) currents found in vertebrate tissues, a variety that is generated in part by numerous genes encoding Ca(2+) channel subunits. The degree to which this genetic diversity is shared by invertebrates has only recently become apparent. Cloning of Ca(2+) channel subunits from various invertebrate species, combined with the wealth of information from the Caenorhabditis elegans genome, has clarified the organization and evolution of metazoan Ca(2+) channel genes. Functional studies have employed novel structural information gained from invertebrate Ca(2+) channels to complement ongoing research on mammalian Ca(2+) currents, while demonstrating that the strict correspondence between pharmacological and molecular classes of vertebrate Ca(2+) channels does not fully extend to invertebrate tissues. Molecular structures can now be combined with physiological data to develop a more cogent system of categorizing invertebrate channel subtypes. In this review, we examine recent progress in the characterization of invertebrate Ca(2+) channel genes and its relevance to the diversity of invertebrate Ca(2+) currents.


Hyperthermia stimulates HIV-1 replication.
HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42-45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38-40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.


Gonadal steroids and humoral immunity.
Humoral immune responses are sexually dimorphic. Female individuals generally exhibit more-robust antibody responses to vaccines and, in the clinical setting as well as in experimental models, are more likely than male individuals to produce autoreactive antibodies of pathogenic potential. A number of differences between the sexes might account for these observations, including differences in the dosage of specific X-chromosome and Y-chromosomal genes, increased exposure of female individuals to antigenic stimulation in childbearing, and differences in circulating concentrations of gonadal steroid hormones. The role of gonadal steroids in modulating such humoral immune responses has been studied for nearly a century, but advances in our knowledge of B-lymphocyte development and function, the mechanisms of immune tolerance, and the molecular basis of gonadal steroid hormone action are now yielding new understanding of the influence of gonadal steroid hormones on the humoral immune system. This Review examines how oestrogens and androgens modulate B-lymphocyte development and function, focusing on the areas of B-cell production in the bone marrow, the maintenance of immune tolerance for self antigens, and the processes of immunoglobulin heavy chain gene somatic hypermutation and class switch recombination during maturation of cells involved in humoral immune responses.


Functional characterization of the Bag7, Lrg1 and Rgd2 RhoGAP proteins from Saccharomyces cerevisiae.
Rho proteins are down-regulated in vivo by specific GTPase activating proteins (RhoGAP). We have functionally studied three Saccharomyces cerevisiae putative RhoGAP. By first identifying Rho partners with a systematic two-hybrid approach and then using an in vitro assay, we have demonstrated that the Bag7 protein stimulated the GTPase activity of the Rho1 protein, Lrg1p acted on the Cdc42 and Rho2 GTPases and we showed that Rgd2p has a GAP activity on both Cdc42p and Rho5p. In addition, we brought the first evidence for the existence of a sixth functional Rho in yeast, the Cdc42/Rac-like GTPase Rho5.


Fungal pathogen uses sex pheromone receptor for chemotropic sensing of host plant signals.
For more than a century, fungal pathogens and symbionts have been known to orient hyphal growth towards chemical stimuli from the host plant. However, the nature of the plant signals as well as the mechanisms underlying the chemotropic response have remained elusive. Here we show that directed growth of the soil-inhabiting plant pathogen Fusarium oxysporum towards the roots of the host tomato (Solanum lycopersicum) is triggered by the catalytic activity of secreted class III peroxidases, a family of haem-containing enzymes present in all land plants. The chemotropic response requires conserved elements of the fungal cell integrity mitogen-activated protein kinase (MAPK) cascade and the seven-pass transmembrane protein Ste2, a functional homologue of the Saccharomyces cerevisiae sex pheromone α receptor. We further show that directed hyphal growth of F. oxysporum towards nutrient sources such as sugars and amino acids is governed by a functionally distinct MAPK cascade. These results reveal a potentially conserved chemotropic mechanism in root-colonizing fungi, and suggest a new function for the fungal pheromone-sensing machinery in locating plant hosts in a complex environment such as the soil.


Economic evaluation of neonatal intensive care of very-low-birth-weight infants.
We evaluated the economic aspects of neonatal intensive care of very-low-birth-weight infants, using outcomes and costs of care before and after the introduction of a regional neonatal-intensive-care program. Neonatal intensive care increased both survival rates and costs. For newborns weighing 1000 to 1499 g, the cost (in 1978 Canadian dollars) was $59,500 per additional survivor, $2,900 per life-year gained, and $3,200 per quality-adjusted life-year gained; intensive care resulted in a net economic gain when figures were undiscounted but a net economic loss when future costs, effects, and earnings were discounted at 5 per cent per annum. For infants weighing 500 to 999 g, the corresponding costs were $102,500 per additional survivor, $9,300 per life-year gained, and $22,400 per quality-adjusted life-year gained; intensive care resulted in a net economic loss. By every measure of economic evaluation, the impact of neonatal intensive care was more favorable among infants weighing 1000 to 1499 g than among those weighing 500 to 999 g. A judgment concerning the relative economic value of neonatal intensive care of very-low-birth-weight infants requires a comparison with other health programs.


Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.
Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy. In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks' gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks' gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581. Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51). Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy. Chief Scientist Office of the Scottish Government Health Directorate.


Sex difference in age at onset of schizophrenia.
The age at onset of schizophrenia was determined in 100 male and 100 female patients who unequivocally met DSM-III criteria for the illness. Three different indexes of onset were used: first treatment, first hospitalization, and the immediate family's first awareness of psychotic symptoms and signs. The mean age at onset of the male patients was approximately five years earlier than that of the female patients according to all three criteria. About nine of ten male patients, compared with only two of three female patients, became schizophrenic before the age of 30 years. The onset of psychosis after the age of 35 years occurred in 17% of women and in only 2% of men. About 10% of women gave no evidence of psychosis until after the age of 40 years. The reason for the sex difference is not readily apparent, but it could be a valuable clue to some of the causes of schizophrenia.


Pemetrexed with or without matuzumab as second-line treatment for patients with stage IIIB/IV non-small cell lung cancer.
This randomized phase II study investigated pemetrexed in combination with the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab compared with pemetrexed alone as second-line therapy for patients with advanced non-small cell lung cancer. Patients received pemetrexed 500 mg/m every 3 weeks either alone (n = 50) or in combination with matuzumab at either 800 mg weekly (n = 51) or 1600 mg every 3 weeks (n = 47). The primary end point was objective response, as assessed by an independent review committee. Tumor EGFR expression was detected in 87% of randomized patients. The objective response rate for the pooled matuzumab-treated arms was 11% compared with 5% for pemetrexed alone (p = 0.332). Apart from one patient in the pemetrexed alone group, all responses occurred in patients whose tumors expressed EGFR. The objective response rate for patients receiving weekly matuzumab was 16% compared with 2% for those receiving matuzumab every 3 weeks. There was also a trend for improved overall survival in patients receiving matuzumab weekly versus every 3 weeks (12.4 months versus 5.9 months, respectively, versus 7.9 months for pemetrexed alone). The combination of pemetrexed and matuzumab demonstrated an acceptable safety profile, with the most common grade 3/4 adverse event being neutropenia. Although the analysis on the pooled matuzumab-treated arms did not demonstrate a statistically significant improvement in objective response for the addition of matuzumab to pemetrexed compared with pemetrexed alone, the trends for improvement in objective response and overall survival for pemetrexed plus weekly matuzumab compared with pemetrexed alone warrant confirmation in additional clinical trials.


The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals.
Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine.


Nonlinear pulsed excitation of high-Q optical modes of plasmonic nanocavities.
We present a comprehensive theoretical and numerical analysis of the physical mechanisms pertaining to the nonlinear pulsed excitation of optical modes in plasmonic cavities made of metallic nanowires. Our analysis is based on extensive numerical simulations carried out both in the frequency and time domains. The numerical algorithm used in our study is based on the multiple scattering method and allows us to include in our analysis the effects of both the surface and bulk nonlinear polarizations generated at the second harmonic (SH). In particular, we investigate the physical properties of plasmonic modes excited at the SH as the result of the interaction of femtosecond optical pulses with plasmonic nanocavities. We show that such cavities have two distinct types of modes, namely, plasmonic cavity modes and multipole plasmon modes generated via the hybridization of modes of single nanowires. Our analysis reveals that the properties of the latter modes depend only weakly on the cavity geometry, whereas the lifetime and quality factor of plasmonic cavity modes vary considerably with the system parameters.


'Boots for my Sancho': structural vulnerability among Latin American day labourers in Berkeley, California.
This paper addresses the structural vulnerability of Latin American undocumented day labourers in Northern California, as it is expressed in conversations on street corners where they wait for work. The intimate aspects of migrant experience become exemplified in jokes about the Sancho - a hypothetical character who has moved in on a day labourer's family and who enjoys the money he sends home. Joking turns to more serious topics of nostalgia and tensions with family far away, elements that come together with the fears and threats of labour on the corner and affect the way day labourers see themselves. Sexuality is rearticulated in the absence of women and masculinity becomes enmeshed in the contingencies of unregulated work and long-term separation from the people the men support. Together, these elements result in the articulation of threat to the immigrant body itself, which is exemplified by anxieties over homosexual propositions on the corner.


[11C]MODAG-001-towards a PET tracer targeting α-synuclein aggregates.
Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases. Specificity and selectivity of [3H]MODAG-001 were tested in in vitro binding assays using recombinant fibrils. After carbon-11 radiolabeling, the pharmacokinetic and metabolic profile was determined in mice. Specific binding was quantified in rats, inoculated with αSYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM). [3H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils (Kd = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils (Kd = 19 ± 6.4 nM) as well as amyloid-β1-42 fibrils (Kd = 20 ± 10 nM). [11C]MODAG-001 showed an excellent ability to penetrate the mouse brain. Metabolic degradation was present, but the stability of the parent compound improved after selective deuteration of the precursor. (d3)-[11C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated αSYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated αSYN against background protein. MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties.


Optical absorption aspects of laser soldering for high density interconnects.
In laser soldering, one has direct control over the incident laser pulse energy and duration but only indirect control over the temperature profile of the parts to be soldered. To understand the conversion of incident laser energy into a substrate temperature profile, two processes need to be understood: first, the optical absorption as a function of temperature and, second, the temperature distribution as a function of absorbed energy. The optical absorption aspect is addressed here. A set of total reflectivity measurements for real surfaces of interest is presented along with analytical calculations of the temperature dependence of the optical absorption for both specular and rough surfaces.


Different responses to infectious hypodermal and hematopoietic necrosis virus (IHHNV) in Penaeus monodon and P. vannamei.
Infectious hypodermal and hematopoietic necrosis virus (IHHNV) is widespread in cultured Penaeus monodon and P. vannamei in Thailand. It causes runt-deformity syndrome that is characterized by physical abnormalities and stunted growth in P. vannamei, but causes no apparent disease in P. monodon. In both species, the virus may produce Cowdry Type A inclusions in tissues of ectodermal and mesodermal origin, but these are common in P. vannamei and rare in P. monodon. The virus can be more easily detected in both species by IHHNV-specific PCR primers. By in situ hybridization (ISH) using specific IHHNV probes, fixed phagocytes associated with myocardial cells tended to show strong positive reactions in both shrimp species. Ovarian and neural tissue (neurons in the nerve ganglia and glial cells in the nerve cord) were ISH positive for IHHNV only in P. vannamei. By transmission electron microscopy, necrotic cells were found in the gills of IHHNV-infected P. vannamei, while paracrystalline arrays of virions and apoptotic cells rather than necrotic cells were found in the lymphoid organ of IHHNV-infected P. monodon. Thus, it is possible that apoptosis in P. monodon contributes to the absence of clinical disease from IHHNV. These findings reveal different responses to IHHNV infection by the 2 shrimp species. A curious feature of IHHNV infection in P. monodon was inconsistency in the comparative viral load amongst tissues of different specimens, as detected by both ISH and real-time PCR. This inconsistency in apparent tissue preference and the reasons for different cellular responses between the 2 shrimp species remain unexplained.


A vaccinia-based single vector construct multi-pathogen vaccine protects against both Zika and chikungunya viruses.
Zika and chikungunya viruses have caused major epidemics and are transmitted by Aedes aegypti and/or Aedes albopictus mosquitoes. The "Sementis Copenhagen Vector" (SCV) system is a recently developed vaccinia-based, multiplication-defective, vaccine vector technology that allows manufacture in modified CHO cells. Herein we describe a single-vector construct SCV vaccine that encodes the structural polyprotein cassettes of both Zika and chikungunya viruses from different loci. A single vaccination of mice induces neutralizing antibodies to both viruses in wild-type and IFNAR-/- mice and protects against (i) chikungunya virus viremia and arthritis in wild-type mice, (ii) Zika virus viremia and fetal/placental infection in female IFNAR-/- mice, and (iii) Zika virus viremia and testes infection and pathology in male IFNAR-/- mice. To our knowledge this represents the first single-vector construct, multi-pathogen vaccine encoding large polyproteins, and offers both simplified manufacturing and formulation, and reduced "shot burden" for these often co-circulating arboviruses.


Heat shock factor binding in Alu repeats expands its involvement in stress through an antisense mechanism.
Alu RNAs are present at elevated levels in stress conditions and, consequently, Alu repeats are increasingly being associated with the physiological stress response. Alu repeats are known to harbor transcription factor binding sites that modulate RNA pol II transcription and Alu RNAs act as transcriptional co-repressors through pol II binding in the promoter regions of heat shock responsive genes. An observation of a putative heat shock factor (HSF) binding site in Alu led us to explore whether, through HSF binding, these elements could further contribute to the heat shock response repertoire. Alu density was significantly enriched in transcripts that are down-regulated following heat shock recovery in HeLa cells. ChIP analysis confirmed HSF binding to a consensus motif exhibiting positional conservation across various Alu subfamilies, and reporter constructs demonstrated a sequence-specific two-fold induction of these sites in response to heat shock. These motifs were over-represented in the genic regions of down-regulated transcripts in antisense oriented Alus. Affymetrix Exon arrays detected antisense signals in a significant fraction of the down-regulated transcripts, 50% of which harbored HSF sites within 5 kb. siRNA knockdown of the selected antisense transcripts led to the over-expression, following heat shock, of their corresponding down-regulated transcripts. The antisense transcripts were significantly enriched in processes related to RNA pol III transcription and the TFIIIC complex. We demonstrate a non-random presence of Alu repeats harboring HSF sites in heat shock responsive transcripts. This presence underlies an antisense-mediated mechanism that represents a novel component of Alu and HSF involvement in the heat shock response.


Zingiber officinale exhibits behavioral radioprotection against radiation-induced CTA in a gender-specific manner.
At the organismic level, exposure to radiation can produce taste aversion (CTA) learning and emesis, which have been proposed as behavioral endpoints that are mediated by harmful effects of radiations on peripheral systems, primarily the gastrointestinal system. Thus, the aim of the present investigation was to study the gastroprotective action of hydroalcoholic extract of zingiber rhizome (Zingiber officinale Rosc.) against radiation-induced conditioned taste aversion (CTA) in both male and female species of animals, for testing its potential as a behavioral radioprotector. Administration of zingiber extract 1 h before 2-Gy gamma-radiation was significantly effective in blocking the saccharin avoidance response, with 200 and 250 mg/kg b.wt. i.p., being the most effective doses for male and female rats, respectively. A comparison of the efficacy of zingiber extract with two antiemetic drugs, ondansteron and dexamethasone, revealed that the extract rendered comparable protection against radiation-induced CTA. Our experiments also confirmed the existence of sex dichotomy (i.e., the sex of animal greatly influenced response towards radiation exposure) in relation to behavioral responses (CTA) or differential metabolism. The observed gender variations were hypothesized to be a result of hormonal fluctuations and differences in pharmacological parameters in male and female rats. To correlate the mechanism of action, the free-radical-scavenging potential of zingiber extract to scavenge hydroxyl ion and nitric oxide was also tested, in cell-free system and a concentration of 1000 microg/ml, was found to be the most potent, which has been proposed as one the many activities assisting in its overall ability to modulate radiation-induced taste aversion. The results demonstrate that Z. officinale possesses antioxidant, radioprotective and neuromodulatory properties that can be effectively utilized for behavioral radioprotection and for efficiently mitigating radiation-induced CTA in both males and females species.


Avoidable waste of research related to inadequate methods in clinical trials.
To assess the waste of research related to inadequate methods in trials included in Cochrane reviews and to examine to what extent this waste could be avoided. A secondary objective was to perform a simulation study to re-estimate this avoidable waste if all trials were adequately reported. Methodological review and simulation study. Trials included in the meta-analysis of the primary outcome of Cochrane reviews published between April 2012 and March 2013. We collected the risk of bias assessment made by the review authors for each trial. For a random sample of 200 trials with at least one domain at high risk of bias, we re-assessed risk of bias and identified all related methodological problems. For each problem, possible adjustments were proposed that were then validated by an expert panel also evaluating their feasibility (easy or not) and cost. Avoidable waste was defined as trials with at least one domain at high risk of bias for which easy adjustments with no or minor cost could change all domains to low risk. In the simulation study, after extrapolating our re-assessment of risk of bias to all trials, we considered each domain rated as unclear risk of bias as missing data and used multiple imputations to determine whether they were at high or low risk. Of 1286 trials from 205 meta-analyses, 556 (43%) had at least one domain at high risk of bias. Among the sample of 200 of these trials, 142 were confirmed as high risk; in these, we identified 25 types of methodological problem. Adjustments were possible in 136 trials (96%). Easy adjustments with no or minor cost could be applied in 71 trials (50%), resulting in 17 trials (12%) changing to low risk for all domains. So the avoidable waste represented 12% (95% CI 7% to 18%) of trials with at least one domain at high risk. After correcting for incomplete reporting, avoidable waste due to inadequate methods was estimated at 42% (95% CI 36% to 49%). An important burden of wasted research is related to inadequate methods. This waste could be partly avoided by simple and inexpensive adjustments.


Killer whales redistribute white shark foraging pressure on seals.
Predatory behavior and top-down effects in marine ecosystems are well-described, however, intraguild interactions among co-occurring marine top predators remain less understood, but can have far reaching ecological implications. Killer whales and white sharks are prominent upper trophic level predators with highly-overlapping niches, yet their ecological interactions and subsequent effects have remained obscure. Using long-term electronic tagging and survey data we reveal rare and cryptic interactions between these predators at a shared foraging site, Southeast Farallon Island (SEFI). In multiple instances, brief visits from killer whales displaced white sharks from SEFI, disrupting shark feeding behavior for extended periods at this aggregation site. As a result, annual predations of pinnipeds by white sharks at SEFI were negatively correlated with close encounters with killer whales. Tagged white sharks relocated to other aggregation sites, creating detectable increases in white shark density at Ano Nuevo Island. This work highlights the importance of risk effects and intraguild relationships among top ocean predators and the value of long-term data sets revealing these consequential, albeit infrequent, ecological interactions.


Active regulation of receptor ratios controls integration of quorum-sensing signals in Vibrio harveyi.
Quorum sensing is a chemical signaling mechanism used by bacteria to communicate and orchestrate group behaviors. Multiple feedback loops exist in the quorum-sensing circuit of the model bacterium Vibrio harveyi. Using fluorescence microscopy of individual cells, we assayed the activity of the quorum-sensing circuit, with a focus on defining the functions of the feedback loops. We quantitatively investigated the signaling input-output relation both in cells with all feedback loops present as well as in mutants with specific feedback loops disrupted. We found that one of the feedback loops regulates receptor ratios to control the integration of multiple signals. Together, the feedback loops affect the input-output dynamic range of signal transmission and the noise in the output. We conclude that V. harveyi employs multiple feedback loops to simultaneously control quorum-sensing signal integration and to ensure signal transmission fidelity.


Sex determination in dioecious Silene latifolia. Effects of the Y chromosome and the parasitic smut fungus (Ustilago violacea) on gene expression during flower development.
We have embarked on a molecular cloning approach to the investigation of sex determination in Silene latifolia Poiret, a dioecious plant species with morphologically distinguishable sex chromosomes. One of our key objectives was to define a range of genes that are up-regulated in male plants in response to Y chromosome sex-determination genes. Here we present the characterization of eight male-specific cDNA sequences and classify these according to their expression dynamics to provide a range of molecular markers for dioecious male flower development. Genetically female S. latifolia plants undergo a partial sex reversal in response to infection by the parasitic smut fungus Ustilago violacea. This phenomenon has been exploited in these studies; male-specific cDNAs have been further categorized as inducible or noninducible in female plants by smut fungus infection. Analysis of the organ-specific expression of male-specific probes in male and female flowers has also identified a gene that is regulated in a sex-specific manner in nonreproductive floral tissues common to both male and female plants. This observation provides, to our knowledge, the first molecular marker for dominant effect of the Y chromosome in nonreproductive floral organs.


Direct and indirect effects of climate change on herbicide leaching--a regional scale assessment in Sweden.
Climate change is not only likely to improve conditions for crop production in Sweden, but also to increase weed pressure and the need for herbicides. This study aimed at assessing and contrasting the direct and indirect effects of climate change on herbicide leaching to groundwater in a major crop production region in south-west Sweden with the help of the regional pesticide fate and transport model MACRO-SE. We simulated 37 out of the 41 herbicides that are currently approved for use in Sweden on eight major crop types for the 24 most common soil types in the region. The results were aggregated accounting for the fractional coverage of the crop and the area sprayed with a particular herbicide. For simulations of the future, we used projections of five different climate models as model driving data and assessed three different future scenarios: (A) only changes in climate, (B) changes in climate and land-use (altered crop distribution), and (C) changes in climate, land-use, and an increase in herbicide use. The model successfully distinguished between leachable and non-leachable compounds (88% correctly classified) in a qualitative comparison against regional-scale monitoring data. Leaching was dominated by only a few herbicides and crops under current climate and agronomic conditions. The model simulations suggest that the direct effects of an increase in temperature, which enhances degradation, and precipitation which promotes leaching, cancel each other at a regional scale, resulting in a slight decrease in leachate concentrations in a future climate. However, the area at risk of groundwater contamination doubled when indirect effects of changes in land-use and herbicide use, were considered. We therefore concluded that it is important to consider the indirect effects of climate change alongside the direct effects and that effective mitigation strategies and strict regulation are required to secure future (drinking) water resources.


Coupled-mode analysis of a bent birefringent fiber.
A coupled-mode analysis is presented for a bent single-mode birefringent fiber. The coupling coefficients are given in closed forms. The effects of bending on the birefringence, the polarization dispersion, and the mode coupling in a bent birefringent fiber are discussed. Comparisons with other authors' work are also made by reducing our results to the case of a bent, isotropic, single-mode fiber.


How cancer cells attach to urinary bladder epithelium in vivo: study of the early stages of tumorigenesis in an orthotopic mouse bladder tumor model.
The majority of bladder cancers in humans are non-muscle-invasive cancers that recur frequently after standard treatment procedures. Mouse models are widely used to develop anti-tumor treatments. The purpose of our work was to establish an orthotopic mouse bladder tumor model and to explore early stages of implantation of cancerous MB49 cells in vivo using various labeling and microscopic techniques. To distinguish cancer cells from normal urothelial cells in mouse urinary bladders, we performed molecular characterization of MB49 cells before intravesical injection experiments. In this new approach we applied internalized metal nanoparticles to unequivocally discriminate cancer cells from normal cells. This method revealed that cancer cells attached to the urothelium or basal lamina within just 1 hour of intravesical injection, whereas small tumors and localized hyperplastic urothelial regions developed within two days. We found that cancer cells initially adhere to normal urothelial cells through filopodia and by focal contacts with basal lamina. This is the first in vivo characterization of intercellular contacts between cancerous and normal urothelial cells in the bladder. Our study yields new data about poorly known early events of tumorigenesis in vivo, which could be helpful for the translation into clinic.


Activity and expression of glutathione S-transferase pi in patients with amyotrophic lateral sclerosis.
Glutathione S-transferase (GST, EC 184.108.40.206) is an enzyme responsible for inactivation of a large variety of toxic, electrophilic compounds and organic peroxides. GST activity and GST pi expression were studied in patients with amyotrophic lateral sclerosis (ALS). Studies were conducted on cerebrospinal fluid (CSF), blood serum and peripheral blood mononuclear cells (PBMC) obtained from 40 ALS patients. CSF from 30 subjects without neurological diseases and blood from 40 healthy blood donors were used as controls. GST activity assayed with 1-chloro-2,4-dinitrobenzene (substrate for transferase activity) and cumene peroxide (substrate for peroxidase activity) was significantly decreased in PBMC of ALS patients, as well as the GST pi expression on both mRNA and protein level. The mean peroxidase activity was however significantly increased in CSF and serum of ALS patients with the specificity of 80% and 73%, and the sensitivity of 78% and 85%, respectively. It can thus be concluded that the protective barrier formed by GST is originally affected in peripheral blood of ALS patients, and may increase their vulnerability to toxic effects of electrophilic compounds and organic peroxides. Studies on a larger group are needed to answer the question whether GSH-Px determination may be implicated in the diagnosis of ALS.


Photodynamic therapy with verteporfin for corneal neovascularization.
To investigate the efficacy of photodynamic therapy (PDT) with verteporfin for the treatment of patients with corneal neovascularization. Retrospective interventional case series of 33 eyes of 32 patients with stable corneal neovascularization who were refractory to conventional treatment and were treated with single photodynamic therapy with verteporfin (6 mg/m(2)) at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia between January 1, 2007 and December 30, 2009. The mean age was 40.7 ± 19 years (range 16-76 years). The mean follow-up for all patients was 13.1 ± 5.5 months (range 6-24 months). The average amount of corneal neovascularization was 2.7 ± 1.9 (1-10). Corneal neovascularization was deep in 19 (57.6%) eyes and superficial in 14 (42.4%) eyes. Preoperative and postoperative visual acuity and intraocular pressure, and clinical outcome of the treatment were assessed. Statistical analysis was performed to investigate the association to potential risk factors, to assess the change in data and determine the risks for failure. A P-value less than 0.05 was statistically significant. At the last follow-up visit, 22 (66.7%) eyes showed a decrease in corneal neovascularization and evidence of vascular thrombosis. Complete vascular occlusion was achieved in 14 (42.4%) eyes, partial occlusion was achieved in 8 (24.2%) eyes, and the vessels were patent in 11 (33.3%) eyes. The corneal neovascularization score and depth of the vessels were found to be significant risk factors for failure (P = 0.0001 and 0.046, respectively). However, the diagnoses or causes of corneal neovascularisation were not statistically significant. No significant systemic or ocular complications associated with photodynamic therapy were observed. Photodynamic therapy with verteporfin was effective for the treatment of corneal neovascularization in the majority of the cases in this study.


Adenosine metabolism during phorbol myristate acetate-mediated induction of HL-60 cell differentiation: changes in expression pattern of adenosine kinase, adenosine deaminase, and 5'-nucleotidase.
Adenosine has potent immunosuppressive activity. Since the source of adenosine and the mechanism of its release in the immune system is largely unknown and may vary according to cell type, we have evaluated the relationship between adenosine metabolism and the enzymatic activities and mRNA levels of adenosine-metabolizing enzymes in myeloid and lymphoid cell lines. Induction of HL-60 cell differentiation along the macrophage lineage by PMA resulted in a reduction in the activities of adenosine deaminase (ADA), adenosine kinase (AK), and inosine monophosphate-specific cytosolic 5'-nucleotidase and an elevation of ecto-5'-nucleotidase (ecto-5'-NT). These changes were accompanied by an elevation of ecto-5'-NT mRNA and a decrease in ADA and AK mRNAs in a time-dependent fashion. Comparison of AK and ADA mRNA levels in several other leukemic cell lines revealed generally similar responses to PMA with much stronger suppression in immature T cells than in B cells. The metabolism of adenosine either through phosphorylation (AK) or deamination (ADA) was reduced in PMA-stimulated cells. Furthermore, the cumulative changes in enzyme expression resulted in a 2.5-fold increase in intracellular adenosine formation in PMA-stimulated cells. The inhibition of AK by 5'-iodotubercidin further increased adenosine formation by 6-fold over that in untreated cells. In accord with the increase in ecto-5'-NT activity, extracellular AMP dephosphorylation increased dramatically, but there was no increase in extracellular ATP degradation. These results indicate that a coordinated shift in adenosine-metabolizing enzyme levels during PMA-induced HL-60 cell differentiation is accompanied by a decrease in adenosine uptake and an increase in adenosine release.


Are probiotics a feasible intervention for prevention of diarrhoea in the developing world?
With more than 1.4 million of the 9 million child deaths being attributed to diarrhoea in 2008 and 49% of them occurring in five countries namely, India, Nigeria, Democratic Republic of the Congo, Pakistan and China, there is an urgent need for intervention to prevent and control diarrhoeal diseases. Of the various interventions, probiotics offer immense potential. The past decade has witnessed the validation of their utility for the prevention, treatment and management of a variety of infective and non infective disorders. The most investigated field continues to remain infectious diarrhoea and compelling evidence comes from randomized placebo controlled trials. While results from these studies are encouraging most of them reflect the outcomes of the developed world. Developing countries like India continue to struggle with nutritional and health challenges and bear the greatest burden of diarrhoea. A paucity of data from the developing countries limits the definite recommendation of probiotics. In these countries curd, often confused for a probiotic, is practiced as an integral part of the culture. While the nutritional benefits of these products cannot be understated, it is still uncertain whether these products can be classified as a probiotic. The emergence of probiotic foods which are scientifically validated for their efficacy and impart defined health benefits offer an excellent opportunity to improve public health. A recent randomized controlled trial conducted by the National Institute of Cholera and Enteric Diseases in Kolkata, India demonstrated a protective efficacy of 14% in preventing diarrhoea among children who received a probiotic. For the developing world however the vision for probiotics would mean a fundamental change in perception and developing a well planned strategy to allow interventions like probiotics to permeate to impoverished settings, where the assault of micro organisms is on a daily basis. This would mean that probiotics are ingrained into the public health system without being seen as a medicine.


Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.
Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.


Utility of a new model to diagnose an alcohol basis for steatohepatitis.
Distinguishing an alcohol basis from a nonalcoholic basis for the clinical and histologic spectrum of steatohepatitic liver disease is difficult because of unreliability of alcohol consumption history. Unfortunately, various biomarkers have had limited utility in distinguishing alcoholic liver disease (ALD) from nonalcoholic fatty liver disease (NAFLD). Thus, the aim of our study was to create and validate a model to diagnose ALD in patients with steatohepatitis. A cross-sectional cohort study was performed at the Mayo Clinic, Rochester, Minnesota, to create a model using multivariable logistic regression analysis. This model was validated in 3 independent data sets comprising patients of varying severity of steatohepatitis spanning over 10 years. Logistic regression identified mean corpuscular volume, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, body mass index, and gender as the most important variables that separated patients with ALD from NAFLD. These variables were used to generate the ALD/NAFLD Index (ANI), with ANI of greater than zero incrementally favoring ALD and ANI of less than zero incrementally favoring a diagnosis of NAFLD, thus making ALD unlikely. ANI had a c-statistic of 0.989 in the derivation sample, and 0.974, 0.989, 0.767 in the 3 validation samples. ANI performance characteristics were significantly better than several conventional and recently proposed biomarkers used to differentiate ALD from NAFLD, including the histopathologic marker protein tyrosine phosphatase 1b, AST/ALT ratio, gamma-glutamyl transferase, and carbohydrate-deficient transferrin. ANI, derived from easily available objective variables, accurately differentiates ALD from NAFLD in hospitalized, ambulatory, and pretransplantation patients and compares favorably with other traditional and proposed biomarkers.


Carbohydrate intake and short-term regulation of leptin in humans.
The response of serum leptin to short (4 days) and prolonged (28 days) energy restriction (50% reduction in energy intake) was determined in 18 (9 male, 9 female) moderately obese humans (body mass index 32.0 +/- 0.6 kg/m2 mean +/- SEM), 9 of whom had mild non-insulin-dependent diabetes mellitus (NIDDM). Body composition was assessed before and at the end of the energy restriction using DEXA. The subjects lost a measured 2.6 +/- 0.4 kg of body fat after 28 days and an estimated 0.3 kg at 4 days. Serum leptin fell to 64 +/- 3% of baseline levels at day 4 and further to 46 +/- 4% at day 28. In a multiple correlation analysis, the change in leptin concentration at day 4 was significantly related to the change in dietary carbohydrate intake (partial r = 0.68, p < 0.005) but not to changes in fat (r = 0.12) or protein (r = 0.02) intakes. There was a 1:1 relationship between the changes in leptin and dietary carbohydrate (regression slope = 1.0 +/- 0.3). Gender, or the presence of NIDDM had no effects on these responses. This pronounced fall in serum leptin in association with reduced carbohydrate intake before substantial loss of body fat suggests a role for leptin in defending the body's carbohydrate stores and implicates leptin in the satiating effects of carbohydrate. Dietary or other interventions which maintain leptin levels during weight reduction may lead to improvements in weight loss.


Bovine spongiform encephalopathy: epidemiological features 1985 to 1990.
Following the identification of bovine spongiform encephalopathy (BSE) in the British cattle population in 1986 epidemiological studies were launched. This paper provides an updated account of the epidemiological features of BSE from 1985, when the first cases, based on clinical histories, occurred, until 1990. The number of cases up to December 1989 represents an annual incidence of 3.9 confirmed cases per 1000 adult animals in Great Britain. Many more dairy herds were affected than beef suckler herds, a difference attributable to the difference in feeding practices between the two herd types. The geographical variation in incidence previously described has persisted with the highest incidence in the south and east of England. Other features of the epidemiology, including the low within-herd incidence, remained unaltered from the earlier findings. The results support the previously suggested hypothesis that the outbreak of BSE was due to the sudden exposure of the cattle population to a scrapie-like agent in 1981/82. There was no evidence of direct transmission between cattle during the period considered.


Absence of bone sialoprotein (BSP) alters profoundly hematopoiesis and upregulates osteopontin.
Matrix proteins of the SIBLING family interact with bone cells, extracellular matrix and mineral and are thus in a key position to regulate the microenvironment of the bone tissue, including its hematopoietic component. In this respect, osteopontin (OPN) has been implicated in the hematopoietic stem cell (HSC) niche as negative regulator of the HSC function. We investigated the impact on hematopoietic regulation of the absence of the cognate bone sialoprotein (BSP). BSP knockout (-/-) mice display increased bone marrow cellularity, and an altered commitment of hematopoietic precursors to myeloid lineages, leading in particular to an increased frequency of monocyte/macrophage cells. The B cell pool is increased in -/- bone marrow, and its composition is shifted toward more mature lymphocyte stages. BSP-null mice display a decreased HSC fraction among LSK cells and a higher percentage of more committed progenitors as compared to +/+. The fraction of proliferating LSK progenitors is higher in -/- mice, and after PTH treatment the mutant HSC pool is lower than in +/+. Strikingly, circulating levels of OPN as well as its expression in the bone tissue are much higher in the -/-. Thus, a BSP-null bone microenvironment affects the hematopoietic system both quantitatively and qualitatively, in a manner in part opposite to the OPN knockout, suggesting that the effects might in part reflect the higher OPN expression in the absence of BSP.


S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function.
Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.


Differential infection patterns of CD4+ T cells and lymphoid tissue viral burden distinguish progressive and nonprogressive lentiviral infections.
Nonhuman primate natural hosts for simian immunodeficiency viruses (SIV) develop a nonresolving chronic infection but do not develop AIDS. Mechanisms to explain the nonprogressive nature of SIV infection in natural hosts that underlie maintained high levels of plasma viremia without apparent loss of target cells remain unclear. Here we used comprehensive approaches (ie, FACS sorting, quantitative RT-PCR, immunohistochemistry, and in situ hybridization) to study viral infection within subsets of peripheral blood and lymphoid tissue (LT) CD4(+) T cells in cohorts of chronically SIV-infected rhesus macaques (RMs), HIV-infected humans, and SIVsmm-infected sooty mangabeys (SMs). We find: (1) infection frequencies among CD4(+) T cells in chronically SIV-infected RMs are significantly higher than those in SIVsmm-infected SMs; (2) infected cells are found in distinct anatomic LT niches and different CD4(+) T-cell subsets in SIV-infected RMs and SMs, with infection patterns of RMs reflecting HIV infection in humans; (3) T(FH) cells are infected at higher frequencies in RMs and humans than in SMs; and (4) LT viral burden, including follicular dendritic cell deposition of virus, is increased in RMs and humans compared with SMs. These data provide insights into how natural hosts are able to maintain high levels of plasma viremia while avoiding development of immunodeficiency.


Improving the use of research evidence in guideline development: 13. Applicability, transferability and adaptation.
The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the thirteenth of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. We reviewed the literature on applicability, transferability, and adaptation of guidelines. We searched five databases for existing systematic reviews and relevant primary methodological research. We reviewed the titles of all citations and retrieved abstracts and full text articles if the citations appeared relevant to the topic. We checked the reference lists of articles relevant to the questions and used snowballing as a technique to obtain additional information. We used the definition "coming from, concerning or belonging to at least two or all nations" for the term international. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. We did not identify systematic reviews addressing the key questions. We found individual studies and projects published in the peer reviewed literature and on the Internet. Should WHO develop international recommendations? Resources for developing high quality recommendations are limited. Internationally developed recommendations can facilitate access to and pooling of resources, reduce unnecessary duplication, and involve international scientists. Priority should be given to international health problems and problems that are important in low and middle-income countries, where these advantages are likely to be greatest. Factors that influence the transferability of recommendations across different settings should be considered systematically and flagged, including modifying factors, important variation in needs, values, costs and the availability of resources. What should be done centrally and locally? The preparation of systematic reviews and evidence profiles should be coordinated centrally, in collaboration with organizations that produce systematic reviews. Centrally developed evidence profiles should be adaptable to specific local circumstances. Consideration should be given to models that involve central coordination with work being undertaken by centres located throughout the world. While needs, availability of resources, costs, the presence of modifying factors and values need to be assessed locally, support for undertaking these assessments may be needed to make guidelines applicable. WHO should provide local support for adapting and implementing recommendations by developing tools, building capacity, learning from international experience, and through international networks that support evidence-informed health policies, such as the Evidence-informed Policy Network (EVIPNet). How should recommendations be adapted? WHO should provide detailed guidance for adaptation of international recommendations. Local adaptation processes should be systematic and transparent, they should involve stakeholders, and they should report the key factors that influence decisions, including those flagged in international guidelines, and the reasons for any modifications that are made.


Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.
We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.


Associating a negatively charged GdDOTA-derivative to the Pittsburgh compound B for targeting Aβ amyloid aggregates.
We have conjugated the tetraazacyclododecane-tetraacetate (DOTA) chelator to Pittsburgh compound B (PiB) forming negatively charged lanthanide complexes, Ln(L4), with targeting capabilities towards aggregated amyloid peptides. The amphiphilic Gd(L4) chelate undergoes micellar aggregation in aqueous solution, with a critical micellar concentration of 0.68 mM, lower than those for the neutral complexes of similar structure. A variable temperature (17)O NMR and NMRD study allowed the assessment of the water exchange rate, k ex (298) = 9.7 × 10(6) s(-1), about the double of GdDOTA, and for the description of the rotational dynamics for both the monomeric and the micellar forms of Gd(L4). With respect to the analogous neutral complexes, the negative charge induces a significant rigidity of the micelles formed, which is reflected by slower and more restricted local motion of the Gd(3+) centers as evidenced by higher relaxivities at 20-60 MHz. Surface Plasmon Resonance results indicate that the charge does not affect significantly the binding strength to Aβ1-40 [K d = 194 ± 11 μM for La(L4)], but it does enhance the affinity constant to human serum albumin [K a = 6530 ± 68 M(-1) for Gd(L4)], as compared to neutral counterparts. Protein-based NMR points to interaction of Gd(L4) with Aβ1-40 in the monomer state as well, in contrast to neutral complexes interacting only with the aggregated form. Circular dichroism spectroscopy monitored time- and temperature-dependent changes of the Aβ1-40 secondary structure, indicating that Gd(L4) stabilizes the random coil relative to the α-helix and β-sheet. TEM images confirm that the Gd(L4) complex reduces the formation of aggregated fibrils.


Cognitive remediation improves memory and psychosocial functioning in first-episode psychiatric out-patients.
Cognitive remediation (CR) is an effective treatment for several psychiatric disorders. To date, there have been no published studies examining solely first-episode psychiatric cohorts, despite the merits demonstrated by early intervention CR studies. The current study aimed to assess the effectiveness of CR in patients with a first-episode of either major depression or psychosis. Method Fifty-five patients (mean age = 22.8 years, s.d. = 4.3) were randomly assigned to either CR (n = 28) or treatment as usual (TAU; n = 27). CR involved once-weekly 2-h sessions for a total of 10 weeks. Patients were comprehensively assessed before and after treatment. Thirty-six patients completed the study, and analyses were conducted using an intent-to-treat (ITT) approach with all available data. In comparison to TAU, CR was associated with improved immediate learning and memory controlling for diagnosis and baseline differences. Similarly, CR patients demonstrated greater improvements than TAU patients in psychosocial functioning irrespective of diagnosis. Delayed learning and memory improvements mediated the effect of treatment on psychosocial functioning at a marginal level. CR improves memory and psychosocial outcome in first-episode psychiatric out-patients for both depression and psychosis. Memory potentially mediated the functional gains observed. Future studies need to build on the current findings in larger samples using blinded allocation and should incorporate longitudinal follow-up and assessment of potential moderators (e.g. social cognition, self-efficacy) to examine sustainability and the precise mechanisms of CR effects respectively.


Profession, market and class: nurse migration and the remaking of division and disadvantage.
This article aims to analyse the part played by successive waves of nurse migration in changing patterns of division and disadvantage within nursing. We argue that migration has in part acted to reinforce disadvantage based on class and gender, race and ethnicity and identify the influence of changes in nursing structure and commercialization of care in these processes. BACKGROUND, DESIGN AND METHODS: The historical analysis of division within nursing and the impact of migration are based on secondary sources (literature review) and primary research undertaken by ourselves and colleagues. The paper develops a concept of 'remaking' disadvantage drawing on analysis in social history of the interplay between agency and economic position in the 'making' of class. It uses the extended case method to focus on the residential care sector, showing how global and national influences operate at the frontline of service delivery. We show how social class and gender, race and ethnicity have interacted and are reflected in the division of labour within nursing. We demonstrate how the employment conditions of nurse migrants have reinforced patterns of disadvantage. The case study of the residential care home sector deepens our analysis of intersecting sources of professional disadvantage including aspects of commercialization, in a sector where they have severe effects for vulnerable staff and patients. In the UK, migrant professional nurses have repeatedly acted both as a highly valued labour force on whom patients and clients rely and as involuntary contributors to remaking disadvantage. This situation is sustained by the current international labour market and rising commercialization which facilitate nurse migration and the segmentation of care work based on a 'pecking order' of specialties that reinforce existing divisions of social class, gender and race within nursing. Migrant nurses play a key role in the delivery of 'frontline' care to patients. The role many currently play reinforces disadvantage within nursing in ways that are problematic for the profession, patients and clients. The recognition and valuing of their skills is critical to the promotion of their own morale which in turn has an impact on their relationship with colleagues and the delivery of patient and client care.


SLAM Project - Long Term Ecological Study of the Impacts of Climate Change in the natural forest of Azores: I - the spiders from native forests of Terceira and Pico Islands (2012-2019).
Long-term monitoring of invertebrate communities is needed to understand the impact of key biodiversity erosion drivers (e.g. habitat fragmentation and degradation, invasive species, pollution, climatic changes) on the biodiversity of these high diverse organisms.The data we present are part of the long-term project SLAM (Long Term Ecological Study of the Impacts of Climate Change in the natural forest of Azores) that started in 2012, aiming to understand the impact of biodiversity erosion drivers on Azorean native forests (Azores, Macaronesia, Portugal). In this contribution, the design of the project, its objectives and the first available data for the spider fauna of two Islands (Pico and Terceira) are described.Passive flight interception SLAM traps (Sea, Land and Air Malaise traps) were used to sample native forest plots in several Azorean islands, with one trap being set up at each plot and samples taken every three months following the seasons.The key objectives of the SLAM project are: 1) collect long-term ecological data to evaluate species distributions and abundance at multiple spatial and temporal scales, responding to the Wallacean and Prestonian shortfalls, 2) identify biodiversity erosion drivers impacting oceanic indigenous assemblages under global change for conservation management purpose, 3) use species distribution and abundance data in model-based studies of environmental change in different islands, 4) contribute to clarifying the potential occurrence of an "insect decline" in Azores and identifying the spatial and temporal invasion patterns of exotic arthropod species, 5) contribute with temporal data to re-assess the Red-list status of Azorean endemic arthropods and 6) perform studies about the relationship between diversity (taxonomic, functional and phylogenetic) and ecosystem function. The project SLAM (Long Term Ecological Study of the Impacts of Climate Change in the natural forest of Azores) is described in detail.Seasonal distribution and abundance data of Azorean spiders, based on a long-term study undertaken between 2012 and 2019 in two Azorean Islands (Terceira and Pico), is presented. A total of 14979 specimens were collected, of which 6430 (43%) were adults. Despite the uncertainty of juvenile identification, juveniles are also included in the data presented in this paper, since the low diversity allows a relatively precise identification of this life-stage in Azores.A total of 57 species, belonging to 50 genera and 17 families, were recorded from the area, which constitutes baseline information of spiders from the studied sites for future long-term comparisons. Linyphiidae were the richest and most abundant family, with 19 (33%) species and 5973 (40%) specimens. The ten most abundant species are composed mostly of endemic or native non-endemic species and only one exotic species (Tenuiphantestenuis (Blackwall, 1852)). Those ten most abundant species include 84% of all sampled specimens and are clearly the dominant species in the Azorean native forests. Textrixcaudata L. Koch, 1872 was firstly reported from Terceira and Pico Islands, Araneusangulatus Clerck, 1757 was firstly reported from Terceira Island, Nerieneclathrata (Sundevall, 1830) and Macaroerisdiligens (Blackwall, 1867) were firstly reported from Pico Island.This publication contributes not only to a better knowledge of the arachnofauna present in native forests of Terceira and Pico, but also to understand the patterns of abundance and diversity of spider species, both seasonally and between years.


Bones of contention: bone mineral density recovery in celiac disease--a systematic review.
Metabolic bone disease is a frequent co-morbidity in newly diagnosed adults with celiac disease (CD), an autoimmune disorder triggered by the ingestion of dietary gluten. This systematic review of studies looked at the efficacy of the gluten-free diet, physical activity, nutrient supplementation, and bisphosphonates for low bone density treatment. Case control and cohort designs were identified from PubMed and other academic databases (from 1996 to 2015) that observed newly diagnosed adults with CD for at least one year after diet treatment using the dual-energy x-ray absorptiometry (DXA) scan. Only 20 out of 207 studies met the inclusion criteria. Methodological quality was assessed using the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) statement checklist. Gluten-free diet adherence resulted in partial recovery of bone density by one year in all studies, and full recovery by the fifth year. No treatment differences were observed between the gluten-free diet alone and diet plus bisphosphonates in one study. For malnourished patients, supplementation with vitamin D and calcium resulted in significant improvement. Evidence for the impact of physical activity on bone density was limited. Therapeutic strategies aimed at modifying lifestyle factors throughout the lifespan should be studied.


Preventive effects of Escherichia coli strain Nissle 1917 on acute and chronic intestinal inflammation in two different murine models of colitis.
Escherichia coli strain Nissle 1917 (EcN) is as effective in maintaining remission in ulcerative colitis as is treatment with mesalazine. This study aims to evaluate murine models of acute and chronic intestinal inflammation to study the antiinflammatory effect of EcN in vivo. Acute colitis was induced in mice with 2% dextran-sodium sulfate (DSS) in drinking water. EcN was administered from day -2 to day +7. Chronic colitis was induced by transfer of CD4(+) CD62L(+) T lymphocytes from BALB/c mice in SCID mice. EcN was administered three times/week from week 1 to week 8 after cell transfer. Mesenteric lymph node (MLN) cytokine secretion (of gamma interferon [IFN-gamma], interleukin 5 [IL-5], IL-6, and IL-10) was measured by enzyme-linked immunosorbent assay. Histologic sections of the colon were analyzed by using a score system ranging from 0 to 4. Intestinal contents and homogenized MLN were cultured, and the number of E. coli-like colonies was determined. EcN was identified by repetitive extragenic palindromic (REP) PCR. EcN administration to DSS-treated mice reduced the secretion of proinflammatory cytokines (IFN-gamma, 32,477 +/- 6,377 versus 9,734 +/- 1,717 [P = 0.004]; IL-6, 231 +/- 35 versus 121 +/- 17 [P = 0.02]) but had no effect on the mucosal inflammation. In the chronic experimental colitis of the transfer model, EcN ameliorated the intestinal inflammation (histology score, 2.7 +/- 0.2 versus 1.9 +/- 0.3 [P = 0.02]) and reduced the secretion of proinflammatory cytokines. Translocation of EcN and resident E. coli into MLN was observed in the chronic colitis model but not in healthy controls. Administration of EcN ameliorated acute and chronic experimental colitis by modifying proinflammatory cytokine secretion but had no influence on the acute DSS-induced colitis. In this model, preexisting colitis was necessary for translocation of EcN and resident E. coli into MLN.


Validation of Field Methods to Assess Body Fat Percentage in Elite Youth Soccer Players.
This study determined the most effective field method for quantifying body fat percentage in male elite youth soccer players and developed prediction equations based on anthropometric variables. Forty-four male elite-standard youth soccer players aged 16.3-18.0 years underwent body fat percentage assessments, including bioelectrical impedance analysis and the calculation of various skinfold-based prediction equations. Dual X-ray absorptiometry provided a criterion measure of body fat percentage. Correlation coefficients, bias, limits of agreement, and differences were used as validity measures, and regression analyses were used to develop soccer-specific prediction equations. The equations from Sarria et al. (1998) and Durnin & Rahaman (1967) reached very large correlations and the lowest biases, and they reached neither the practically worthwhile difference nor the substantial difference between methods. The new youth soccer-specific skinfold equation included a combination of triceps and supraspinale skinfolds. None of the practical methods compared in this study are adequate for estimating body fat percentage in male elite youth soccer players, except for the equations from Sarria et al. (1998) and Durnin & Rahaman (1967). The new youth soccer-specific equation calculated in this investigation is the only field method specifically developed and validated in elite male players, and it shows potentially good predictive power.


Using quantum dots to tag subsurface damage in lapped and polished glass samples.
Grinding, lapping, and polishing are finishing processes used to achieve critical surface parameters in a variety of precision optical and electronic components. As these processes remove material from the surface through mechanical and chemical interactions, they may induce a damaged layer of cracks, voids, and stressed material below the surface. This subsurface damage (SSD) can degrade the performance of a final product by creating optical aberrations due to diffraction, premature failure in oscillating components, and a reduction in the laser induced damage threshold of high energy optics. As these defects lie beneath the surface, they are difficult to detect, and while many methods are available to detect SSD, they can have notable limitations regarding sample size and type, preparation time, or can be destructive in nature. The authors tested a nondestructive method for assessing SSD that consisted of tagging the abrasive slurries used in lapping and polishing with quantum dots (nano-sized fluorescent particles). Subsequent detection of fluorescence on the processed surface is hypothesized to indicate SSD. Quantum dots that were introduced to glass surfaces during the lapping process were retained through subsequent polishing and cleaning processes. The quantum dots were successfully imaged by both wide field and confocal fluorescence microscopy techniques. The detected fluorescence highlighted features that were not observable with optical or interferometric microscopy. Atomic force microscopy and additional confocal microscope analysis indicate that the dots are firmly embedded in the surface but do not appear to travel deep into fractures beneath the surface. Etching of the samples exhibiting fluorescence confirmed that SSD existed. SSD-free samples exposed to quantum dots did not retain the dots in their surfaces, even when polished in the presence of quantum dots.


Oral Health of Parkinson's Disease Patients: A Case-Control Study.
The aim of the study was to examine the oral health status of Parkinson's disease (PD) patients, to compare their oral health status to that of a control group, and to relate it to the duration and severity of PD. Materials and Methods. 74 PD patients and 74 controls were interviewed and orally examined. Among PD patients, the duration and the Hoehn and Yahr stage (HY) of the disease were registered. Results. More PD patients than controls reported oral hygiene care support as well as chewing/biting problems, taste disturbance, tooth mobility, and xerostomia, whereas dentate patients had more teeth with carious lesions, tooth root remnants, and biofilm. Both longer duration and higher HY were associated with more chewing problems and, in dentates, more teeth with restorations. In dentates, longer duration of the disease was associated with higher number of mobile teeth. Higher HY was associated with more oral hygiene care support as well as biting problems and, in dentates, more teeth with carious lesions and tooth root remnants. Conclusions. Comparatively, PD patients had weakened oral health status and reduced oral hygiene care. Both duration and severity of the disease were associated with more oral health and hygiene care problems.


Effects of Organic Pollutants on Bacterial Communities Under Future Climate Change Scenarios.
Coastal ecosystems are highly dynamic and can be strongly influenced by climate change, anthropogenic activities (e.g., pollution), and a combination of the two pressures. As a result of climate change, the northern hemisphere is predicted to undergo an increased precipitation regime, leading in turn to higher terrestrial runoff and increased river inflow. This increased runoff will transfer terrestrial dissolved organic matter (tDOM) and anthropogenic contaminants to coastal waters. Such changes can directly influence the resident biology, particularly at the base of the food web, and can influence the partitioning of contaminants and thus their potential impact on the food web. Bacteria have been shown to respond to high tDOM concentration and organic pollutants loads, and could represent the entry of some pollutants into coastal food webs. We carried out a mesocosm experiment to determine the effects of: (1) increased tDOM concentration, (2) organic pollutant exposure, and (3) the combined effect of these two factors, on pelagic bacterial communities. This study showed significant responses in bacterial community composition under the three environmental perturbations tested. The addition of tDOM increased bacterial activity and diversity, while the addition of organic pollutants led to an overall reduction of these parameters, particularly under concurrent elevated tDOM concentration. Furthermore, we identified 33 bacterial taxa contributing to the significant differences observed in community composition, as well as 35 bacterial taxa which responded differently to extended exposure to organic pollutants. These findings point to the potential impact of organic pollutants under future climate change conditions on the basal coastal ecosystem, as well as to the potential utility of natural bacterial communities as efficient indicators of environmental disturbance.


Combined large and small subunit ribosomal RNA phylogenies support a basal position of the acoelomorph flatworms.
The phylogenetic position of the phylum Platyhelminthes has been re-evaluated in the past decade by analysis of diverse molecular datasets. The consensus is that the Rhabditophora + Catenulida, which includes most of the flatworm taxa, are not primitively simple basal bilaterians but are related to coelomate phyla such as molluscs. The status of two other groups of acoelomate worms, Acoela and Nemertodermatida, is less clear. Although many characteristics unite these two groups, initial molecular phylogenetic studies placed the Nemertodermatida within the Rhabditophora, but placed the Acoela at the base of the Bilateria, distant from other flatworms. This contradiction resulted in scepticism about the basal position of acoels and led to calls for further data. We have sequenced large subunit ribosomal RNA genes from 13 rhabditophorans + catenulids, three acoels and one nemertodermatid, tripling the available data. Our analyses strongly support a basal position of both acoels and nemertodermatids. Alternative hypotheses are significantly less well supported by the data. We conclude that the Nemertodermatida and Acoela are basal bilaterians and, owing to their unique body plan and embryogenesis, should be recognized as a separate phylum, the Acoelomorpha.