Short-patch correction of C/C mismatches in human cells.
We examined whether the human nucleotide excision repair complex, which is specialized on the removal of bulky DNA adducts, also displays a correcting activity on base mismatches. The cytosine/cytosine (C/C) lesion was used as a model substrate to monitor the correction of base mismatches in human cells. Fibroblasts with different repair capabilities were transfected with shuttle vectors that contain a site-directed C/C mismatch in the replication origin, accompanied by an additional C/C mismatch in one of the flanking sequences that are not essential for replication. Analysis of the vector progeny obtained from these doubly modified substrates revealed that C/C mismatches were eliminated before DNA synthesis not only in the repair-proficient background, but also when the target cells carried a genetic defect in long-patch mismatch repair, in nucleotide excision repair, or when both pathways were deleted. Furthermore, cells deficient for long-patch mismatch repair as well as a cell line that combines mismatch and nucleotide excision repair defects were able to correct multiple C/C mispairs, placed at distances of 21-44 nt, in an independent manner, such that the removal of each lesion led to individual repair patches. These results support the existence of a concurrent short-patch mechanism that rectifies C/C mismatches.


Improving medical diagnosis reliability using Boosted C5.0 decision tree empowered by Particle Swarm Optimization.
Improving accuracy of supervised classification algorithms in biomedical applications is one of active area of research. In this study, we improve the performance of Particle Swarm Optimization (PSO) combined with C4.5 decision tree (PSO+C4.5) classifier by applying Boosted C5.0 decision tree as the fitness function. To evaluate the effectiveness of our proposed method, it is implemented on 1 microarray dataset and 5 different medical data sets obtained from UCI machine learning databases. Moreover, the results of PSO + Boosted C5.0 implementation are compared to eight well-known benchmark classification methods (PSO+C4.5, support vector machine under the kernel of Radial Basis Function, Classification And Regression Tree (CART), C4.5 decision tree, C5.0 decision tree, Boosted C5.0 decision tree, Naive Bayes and Weighted K-Nearest neighbor). Repeated five-fold cross-validation method was used to justify the performance of classifiers. Experimental results show that our proposed method not only improve the performance of PSO+C4.5 but also obtains higher classification accuracy compared to the other classification methods.


Treatment of vesicoureteric reflux by endoscopic injection of Teflon. 1984.
Thirteen girls with grade III-V vesicoureteric reflux were treated by endoscopic injection of Teflon paste behind the intravesical ureter. Fourteen of the 18 treated ureters showed complete absence of reflux after one injection of Teflon. Three ureters required a second injection of Teflon for successful treatment of the reflux. One ureter with grade IV reflux was converted to grade II reflux. Properly carried out, this procedure corrects reflux. It takes less than 15 minutes, may be done as a day procedure, and avoids open surgery. There have been no complications. (Reprinted with permission from Br Med J, 289: 7-9, 1984)


Increased response to cholesterol feeding in apolipoprotein C1-deficient mice.
The function of apolipoprotein (apo) C1 in vivo is not well understood. From in vitro studies it has been reported that an excess of apoC1 relative to apoE inhibits receptor-mediated uptake of remnant lipoproteins [Sehayek and Eisenberg (1991) J. Biol. Chem. 266, 22453-22459]. In order to gain a better understanding of the role of apoC1 in lipoprotein metabolism in vivo, we have generated apoC1-deficient mice by gene targeting in embryonic stem cells. Homozygous mutant mice are viable and do not show overt abnormalities. Serum triacylglycerol levels are increased by 60% on both a standard mouse diet and a mild hypercholesterolaemic diet compared with controls. Total serum cholesterol levels are similar to controls on the two diets. However, the level of high-density lipoprotein cholesterol in the apoC1-deficient mice fed on the mild hypercholesterolaemic diet is slightly decreased, which is accompanied by a 3-fold increase in very-low-density plus low-density lipoprotein (VLDL+LDL) cholesterol. On a severe atherogenic diet, the homozygous apoC1-deficient mice become hypercholesterolaemic, with a serum cholesterol level of 10.7 +/- 3.3 mM compared with 6.7 +/- 1.8 mM and 5.1 +/- 1.6 mM in heterozygous and control mice respectively. The increase in cholesterol is mainly confined to the VLDL+LDL-sized fractions. Binding experiments revealed that lipoproteins lacking apoC1 with d < 1.006 g/ml are poor competitors for 125I-labelled LDL binding to the LDL receptor on HepG2 cells. This suggests that total apoC1 deficiency leads to impaired receptor-mediated clearance of remnant lipoproteins rather than enhanced uptake, as was expected from data reported in the literature.


Phosphorylation of Akt and ERK1/2 is required for VEGF-A/VEGFR2-induced proliferation and migration of lymphatic endothelium.
There is growing evidence that vascular endothelial growth factor-A (VEGF-A), a ligand of the receptor tyrosine kinases VEGFR1 and VEGFR2, promotes lymphangiogenesis. However, the underlying mechanisms by which VEGF-A induces the growth of lymphatic vessels remain poorly defined. Here we report that VEGFR2, not VEGFR1, is the primary receptor regulating VEGF-A-induced lymphangiogenesis. We show that specific inhibition of VEGF-A/VEGFR2 signaling with the fully human monoclonal antibody r84 significantly inhibits lymphangiogenesis in MDA-MB-231 tumors. In vitro experiments with primary human dermal lymphatic endothelial cells (LECs) demonstrate that blocking VEGF-A activation of VEGFR2, not VEGFR1, significantly inhibits VEGF-A-induced proliferation and migration of LECs. We show that VEGF-A stimulation of LECs leads to the phosphorylation of VEGFR2 (Tyr 951, 1054, 1059, 1175, and 1214) which subsequently triggers PKC dependent phosphorylation of ERK1/2 and PI3-K dependent phosphorylation of Akt. Additionally, we demonstrate that inhibitors that suppress the phosphorylation of ERK1/2 and Akt significantly block VEGF-A- induced proliferation and migration of LECs. Together, these results shed light on the mechanisms regulating VEGF-A-induced proliferation and migration of LECs, reveal that VEGFR2 is the primary signaling VEGF-A receptor on lymphatic endothelium, and suggest that therapeutic agents targeting the VEGF-A/VEGFR2 axis could be useful in blocking the pathological formation of lymphatic vessels.


Three-dimensional sonography of prenatal skull base development.
To explore longitudinally the development of the fetal skull base using three-dimensional (3D) sonography. Serial 3D sonographic measurements of anterior skull base length, posterior cranial fossa length and skull base angle were made in 126 normal singleton pregnancies at 18-34 weeks of gestation. In a sub-study of 22 pregnancies, intraobserver variability was determined. Regression analysis for repeated measurements was performed by means of the random coefficients model. Results from an earlier publication on brain volume were extended to the total patient cohort. Measurements were technically successful in 69-94% of cases. The coefficient of variation for differences between repeated tests within women was 3.5-7.6% and between repeated analyses of the same recorded volume it was 3.0-5.1%. A statistically significant gestational age-related increase was established for both the anterior skull base length and the posterior cranial fossa length and the skull base angle showed a small but significant flexion of about 6 degrees . A higher increment in posterior cranial fossa length relative to anterior skull base angle was established. A significant quadratic relationship could be established for both anterior skull base length (P < 0.0001) and posterior cranial fossa length (P < 0.0001) but not for skull base angle, relative to brain volume. The reproducibility was acceptable for all fetal skull base measurements. The more pronounced growth in posterior cranial fossa length relative to anterior skull base length is influenced by brain growth. The small flexion of the skull base angle, however, may be caused by other factors. Published by John Wiley & Sons, Ltd.


Social network fragmentation and community health.
Community health interventions often seek to intentionally destroy paths between individuals to prevent the spread of infectious diseases. Immunizing individuals through direct vaccination or the provision of health education prevents pathogen transmission and the propagation of misinformation concerning medical treatments. However, it remains an open question whether network-based strategies should be used in place of conventional field approaches to target individuals for medical treatment in low-income countries. We collected complete friendship and health advice networks in 17 rural villages of Mayuge District, Uganda. Here we show that acquaintance algorithms, i.e., selecting neighbors of randomly selected nodes, were systematically more efficient in fragmenting all networks than targeting well-established community roles, i.e., health workers, village government members, and schoolteachers. Additionally, community roles were not good proxy indicators of physical proximity to other households or connections to many sick people. We also show that acquaintance algorithms were effective in offsetting potential noncompliance with deworming treatments for 16,357 individuals during mass drug administration (MDA). Health advice networks were destroyed more easily than friendship networks. Only an average of 32% of nodes were removed from health advice networks to reduce the percentage of nodes at risk for refusing treatment in MDA to below 25%. Treatment compliance of at least 75% is needed in MDA to control human morbidity attributable to parasitic worms and progress toward elimination. Our findings point toward the potential use of network-based approaches as an alternative to role-based strategies for targeting individuals in rural health interventions.


Experiences of habit formation: a qualitative study.
Habit formation is an important goal for behaviour change interventions because habitual behaviours are elicited automatically and are therefore likely to be maintained. This study documented experiences of habit development in 10 participants enrolled on a weight loss intervention explicitly based on habit-formation principles. Thematic analysis revealed three themes: Strategies used to support initial engagement in a novel behaviour; development of behavioural automaticity; and selecting effective cues to support repeated behaviour. Results showed that behaviour change was initially experienced as cognitively effortful but as automaticity increased, enactment became easier. Habits were typically formed in work-based contexts. Weekends and vacations temporarily disrupted performance due to absence of associated cues, but habits were reinstated on return to work. Implications for theory and practice are discussed.


Quantum and classical dynamics of Langmuir wave packets.
The quantum Zakharov system in three spatial dimensions and an associated Lagrangian description, as well as its basic conservation laws, are derived. In the adiabatic and semiclassical cases, the quantum Zakharov system reduces to a quantum modified vector nonlinear Schrödinger (NLS) equation for the envelope electric field. The Lagrangian structure for the resulting vector NLS equation is used to investigate the time dependence of the Gaussian-shaped localized solutions, via the Rayleigh-Ritz variational method. The formal classical limit is considered in detail. The quantum corrections are shown to prevent the collapse of localized Langmuir envelope fields, in both two and three spatial dimensions. Moreover, the quantum terms can produce an oscillatory behavior of the width of the approximate Gaussian solutions. The variational method is shown to preserve the essential conservation laws of the quantum modified vector NLS equation. The possibility of laboratory tests in the next generation intense laser-solid plasma compression experiment is discussed.


Alternative transcription of sodium/bicarbonate transporter SLC4A7 gene enhanced by single nucleotide polymorphisms.
Genome-wide association studies have identified the single nucleotide polymorphism (SNP) rs3278 in the human SLC4A7 gene as one of the marker loci for addiction vulnerability. This marker is located in an intron of the gene, and its genomic role has been unknown. In this study, we examined rs3278 and three adjacent SNPs prevalent in alcoholics for their effects on an alternative promoter that would lead to the production of the NH2-terminally truncated protein NBCn1ΔN450, missing the first 450 amino acids. Analysis of the transcription start site database and a promoter prediction algorithm identified a cluster of three promoters in intron 7 and two short CpG-rich sites in intron 6. The promoter closest to rs3278 showed strong transcription activity in luciferase reporter gene assays. Major-to-minor allele substitution at rs3278 resulted in increased transcription activity. Equivalent substitutions at adjacent rs3772723 (intron 7) and rs13077400 (exon 8) had negligible effect; however, the substitution at nonsynonymous rs3755652 (exon 8) increased the activity by more than twofold. The concomitant substitution at rs3278/rs3755652 produced an additive effect. The rs3755652 had more profound effects on the promoter than the upstream regulatory CpG sites. The amino acid change E326K caused by rs3755652 had negligible effect on transporter function. In HEK 293 cells, NBCn1ΔN450 was expressed in plasma membranes, but at significantly lower levels than the nontruncated NBCn1-E. The pH change mediated by NBCn1ΔN450 was also low. We conclude that rs3278 and rs3755652 stimulate an alternative transcription of the SLC4A7 gene, increasing the production of a defective transporter.


Malignancy in Pediatric-onset Systemic Lupus Erythematosus.
To determine cancer incidence in a large pediatric-onset systemic lupus erythematosus (SLE) population. Data were examined from 12 pediatric SLE registries in North America. Patients were linked to their regional cancer registries to detect cancers observed after cohort entry, defined as date first seen in the clinic. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year-specific cancer rates. The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated, with 95% CI. A total of 1168 patients were identified from the registries. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years, resulting in a total observation period of 8839 years spanning the calendar period 1974-2009. During followup, fourteen invasive cancers occurred (1.6 cancers per 1000 person-yrs, SIR 4.13, 95% CI 2.26-6.93). Three of these were hematologic (all lymphomas), resulting in an SIR for hematologic cancers of 4.68 (95% CI 0.96-13.67). SIR were increased for both male and female patients, and across age groups. Although cancer remains a relatively rare outcome in pediatric-onset SLE, our data do suggest an increase in cancer for patients followed an average of 7.6 years. About one-fifth of the cancers were hematologic. Longer followup, and study of drug effects and disease activity, is warranted.


SNP rs403212791 in exon 2 of the MTNR1A gene is associated with reproductive seasonality in the Rasa aragonesa sheep breed.
The aim of this study was to characterize and identify causative SNPs in the MTNR1A gene responsible for the reproductive seasonality traits in the Rasa aragonesa sheep breed. A total of 290 ewes (155, 84 and 51 mature, young and ewe lambs, respectively) from one flock were controlled from January to August. The following three reproductive seasonality traits were considered: the total days of anoestrus (TDA) and the progesterone cycling months (P4CM); both ovarian function seasonality traits based on blood progesterone levels; and the oestrus cycling months (OCM) based on oestrous detection, which indicate behavioural signs of oestrous. We have sequenced the total coding region plus 733 and 251 bp from the promoter and 3'-UTR regions, respectively, from the gene in 268 ewes. We found 9 and 4 SNPs associated with seasonality traits in the promoter (for TDA and P4CM) and exon 2 (for the three traits), respectively. The SNPs located in the gene promoter modify the putative binding sites for various trans-acting factors. In exon 2, two synonymous SNPs affect RFLP sites, rs406779174/RsaI (for the three traits) and rs430181568/MnlI (for OCM), and they have been related with seasonal reproductive activity in previous association studies with other breeds. SNP rs400830807, which is located in the 3'-UTR, was associated with the three traits, but this did not modify the putative target sites for ovine miRNAs according to in silico predictions. Finally, the SNP rs403212791 (NW_014639035.1: g.15099004G > A), which is also associated with the three seasonality phenotypes, was the most significant SNP detected in this study and was a non-synonymous polymorphism, leading a change from an Arginine to a Cysteine (R336C). Haplotype analyses confirmed the association results and showed that the effects found for the seasonality traits were caused by the SNPs located in exon 2. We have demonstrated that the T allele in the SNP rs403212791 in the MNTR1A gene is associated with a lower TDA and higher P4CM and OCM values in the Rasa Aragonesa breed.


Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood.
Polycystic ovary syndrome (PCOS) is a prevalent hyperandrogenic infertility and cardiometabolic disorder that increases a woman's lifetime risk of type 2 diabetes mellitus. It is heritable and intensely familial. Progress toward a cure has been delayed by absence of an etiology. Evidence is mounting, however, for in utero T excess, together with gestational hyperglycemia, contributing to either early differentiation of PCOS or phenotypic amplification of its genotypes. Abnormal endocrine, ovarian, and hyperinsulinemic traits are detectable as early as 2 months of age in daughters of women with PCOS, with adiposity enhancement of hyperinsulinemia during childhood potentially contributing to hyperandrogenism and LH excess by adolescence. These findings encourage increasing clinical focus on early childhood markers for adiposity and hyperinsulinemia accompanying ovarian and adrenal endocrine abnormalities that precede a diagnosable PCOS phenotype. They raise the possibility for lifestyle or therapeutic intervention before and during pregnancy or during childhood and adolescence alleviating the manifestations of a familial genetic predisposition to PCOS.


Indicators of life-threatening malaria in African children.
About 90 percent of the deaths from malaria are in African children, but criteria to guide the recognition and management of severe malaria have not been validated in them. We conducted a prospective study of all children admitted to the pediatric ward of a Kenyan district hospital with a primary diagnosis of malaria. We calculated the frequency and mortality rate for each of the clinical and laboratory criteria in the current World Health Organization (WHO) definition of severe malaria, and then used logistic-regression analysis to identify the variables with the greatest prognostic value. We studied 1844 children (mean age, 26.4 months) with a primary diagnosis of malaria. Not included were 18 children who died on arrival and 4 who died of other causes. The mortality rate was 3.5 percent (95 percent confidence interval, 2.7 to 4.3 percent), and 84 percent of the deaths occurred within 24 hours of admission. Logistic-regression analysis identified four key prognostic indicators: impaired consciousness (relative risk, 3.3; 95 percent confidence interval, 1.6 to 7.0), respiratory distress (relative risk, 3.9; 95 percent confidence interval, 2.0 to 7.7), hypoglycemia (relative risk, 3.3; 95 percent confidence interval, 1.6 to 6.7), and jaundice (relative risk, 2.6; 95 percent confidence interval, 1.1 to 6.3). Of the 64 children who died, 54 were among those with impaired consciousness (n = 336; case fatality rate, 11.9 percent) or respiratory distress (n = 251; case fatality rate, 13.9 percent), or both. Hence, this simple bedside index identified 84.4 percent of the fatal cases, as compared with the 79.7 percent identified by the current WHO criteria. In African children with malaria, the presence of impaired consciousness or respiratory distress can identify those at high risk for death.


Use of infrared thermography in the detection of superficial phlebitis in adult intensive care unit patients: A prospective single-center observational study.
Common methods to detect phlebitis may not be sufficient for patients in the intensive care unit (ICU). The goal of this study was to investigate the feasibility of infrared (IR) thermography to objectively detect phlebitis in adult ICU patients. We included a total of 128 adult ICU-patients in a pilot and subsequent validation study. Median [interquartile range] age was 62 [54-71] years and 88 (69%) patients were male. Severity of phlebitis was scored using the visual infusion phlebitis (VIP)-score, ranging from 0 (no phlebitis) to 5 (thrombophlebitis). The temperature difference (ΔT) between the insertion site and a proximal reference point was measured with IR thermography. In 78 (34%) catheters early phlebitis and onset of moderate phlebitis was observed (VIP-score of 1-3). In both the pilot and the validation study groups ΔT was significantly higher when the VIP-score was ≥1 compared to a VIP-score of 0 (p<0.01 and p<0.001, respectively). Multivariate analysis identified ΔT (p<0.001) and peripheral venous catheter (PVC) dwell time (p = 0.001) as significantly associated with phlebitis. IR thermography may be a promising technique to identify phlebitis in the ICU. An increased ΔT as determined with thermography may be a risk factor for phlebitis.


[A psychiatrist is not always the one and only specialist needed by patients with psychiatric symptoms].
We present three cases in which psychiatric symptoms were misinterpreted and somatic investigation was incomplete. Some of the symptoms encountered in mental health care such as anxiety, confusion and even attempted suicide, are caused by an underlying somatic disorder. In most cases, particularly when patients have a known past psychiatric history, insufficient attention is given to possible somatic causes of psychiatric symptoms. Since psychiatric and somatic symptoms can clearly overlap, we believe that health professionals, particularly psychiatrists, should take a broad clinical view and give close attention to the possibility that a patient's psychiatric symptoms may have somatic causes.


Spatial structure increases the waiting time for cancer.
Cancer results from a sequence of genetic and epigenetic changes which lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells, and thus, to a selective advantage of pre-cancerous cells. The notion of cancer progression as an evolutionary process has been experiencing increasing interest in recent years. Many efforts have been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a well-mixed cell population, even though pre-cancerous cells often evolve in highly structured epithelial tissues. In this study, we propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to assess two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones, decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale L(c). These characteristic features of clonal interference may help to predict the onset of cancers with pronounced spatial structure and to interpret spatially-sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progression of colon cancer, and possibly other cancers where spatial structure matters.


Diagnostic DNA amplification no respite for the elusive parasite.
In the [Formula: see text] years since its addition to the 'molecular biology bag of tricks', in vitro DNA amplification by the polymerase chain reaction has made a considerable impact on medical research. A breakthrough into the field of molecular parasitology is now imminent - especially through the use of thermostoble DNA polymerise. In this introduction Maarten de Brujin discusses the general principles of the method together with recent technical improvements, suggesting some potential applications for diagnosis of parasitic diseases and some of the pitfalls that may be anticipated.


Sodium-coupled neurotransmitter transport: structure, function and regulation.
The removal of neurotransmitters by their transporters--located in the plasma membranes of nerve terminals and glial cells--plays an important role in the termination of synaptic transmission. In the last 3 years, many neurotransmitter transporters have been cloned. Structurally and functionally they can be divided into two groups: glutamate transporters, of which to date three have been cloned, couple the flow of glutamate to that of sodium and potassium. The second group of transporters includes those for GABA, glycine, taurine, norepinephrine, dopamine and serotonin. They are sodium- and chloride-dependent, but do not require potassium for function. One of these, the GABAA transporter, encoded by GAT-1, is perhaps the best characterized. It has been purified and reconstituted and has a molecular mass of around 80 kDa, of which 10-15 kDa is sugar. Amino and carboxyl termini (around 50 amino acids each) are not required for function. The transporter is protected against proteolysis at multiple sites by GABA, provided that the two cosubstrates--sodium and chloride--are present. Several amino acid residues that are critical for function have been identified in the GABA transporter. These include arginine-69 and tryptophan-222 located in the first and fourth putative transmembrane helices, respectively. The first is possibly involved in the binding of chloride. The tryptophan appears to serve as a binding site for the amino group of GABA.


Nutlin-3, A p53-Mdm2 Antagonist for Nasopharyngeal Carcinoma Treatment.
Nasopharyngeal carcinoma (NPC) is a form of head and neck cancer of multifactorial etiologies that is highly prevalent among men in the population of Southern China and Southeast Asia. NPC has claimed many thousands of lives worldwide; but the low awareness of NPC remains a hindrance in early diagnosis and prevention of the disease. NPC is highly responsive to radiotherapy and chemotherapy, but radiocurable NPC is still dependent on concurrent treatment of megavoltage radiotherapy with chemotherapy. Despite a significant reduction in loco-regional and distant metastases, radiotherapy alone has failed to provide a significant improvement in the overall survival rate of NPC, compared to chemotherapy. In addition, chemo-resistance persists as the major challenge in the management of metastatic NPC although the survival rate of advanced metastatic NPC has significantly improved with the administration of chemotherapy adjunctive to radiotherapy. In this regard, targeted molecular therapy could be explored for the discovery of alternative NPC therapies. Nutlin-3, a small molecule inhibitor that specifically targets p53-Mdm2 interaction offers new therapeutic opportunities by enhancing cancer cell growth arrest and apoptosis through the restoration of the p53-mediated tumor suppression pathway while producing minimal cytotoxicity and side effects. This review discusses the potential use of Nutlin-3 as a p53-activating drug and the future directions of its clinical research for NPC treatment.


Impact of air pollution on hospital admissions in Southwestern Ontario, Canada: generating hypotheses in sentinel high-exposure places.
Southwestern Ontario (SWO) in Canada has been known as a 'hot spot' in terms of environmental exposure and potential effects. We chose to study 3 major cities in SWO in this paper. We compared age-standardized hospital admission ratios of Sarnia and Windsor to London, and to generate hypotheses about potential pollutant-induced health effects in the 'Chemical Valley', Sarnia. The number of daily hospital admissions was obtained from all hospitals in London, Windsor and Sarnia from January 1, 1996 to December 31, 2000. We used indirect age adjustment method to obtain standardized admissions ratios for males and females and we chose London as the reference population. This process of adjustment was to apply the age-specific admission rates of London to the population of Sarnia and Windsor in order to yield expected admissions. The observed number of admissions was then compared to the expected admissions in terms of a ratio. These standardized admissions ratios and their corresponding confidence intervals were calculated for Sarnia and Windsor. Our findings showed that Sarnia and Windsor had significantly higher age-adjusted hospital admissions rates compared to London. This finding was true for all admissions, and especially pronounced for cardiovascular and respiratory admissions. For example, in 1996, the observed number of admissions in Sarnia was 3.11 (CI: 2.80, 3.44) times for females and 2.83 (CI: 2.54, 3.14) times for males as would be expected by using London's admission rates. Since hospital admissions rates were significantly higher in 'Chemical Valley' as compared to both London and Windsor, we hypothesize that these higher rates are pollution related. A critical look at the way ambient air quality and other pollutants are monitored in this area is warranted. Further epidemiological research is needed to verify our preliminary indications of harmful effects in people living in 'Chemical Valley'.


Bowel preparation prior to laparoscopic colorectal resection: what is the current practice?
Much has been published on the role of mechanical bowel preparation (MBP) in open colorectal resection; however, the current study shows little evidence on the use of MBP prior to laparoscopic colorectal resections. In contrast to open procedures, MBP could influence the diameter of the bowel and thus the exposure of the surgical field in laparoscopy. This study aimed to assess the current practice of Dutch laparoscopic surgeons regarding MBP prior to colorectal resections. In January 2010, members of the Dutch Association for Endoscopic Surgery were invited to fill out an online questionnaire investigating whether MBP is prescribed prior to laparoscopic colorectal surgery, and which considerations are taken into account when choosing or omitting MBP. The 82 (49%) returned questionnaires showed that 20% of respondents prescribe MBP prior to colonic resections, while 63% prescribe MBP prior to rectal resections. The most common reasons for giving MBP were the construction of a protective ileostoma (22%), improvement of the surgical field exposure (16%), and "other reasons" specified by free text (21%). The three most common reasons for conversion were inadequate surgical field exposure (88%), locally advanced tumor (68%), and adhesions (29%). Concerning the question which stages of the operation are influenced by MBP, 29% of respondents believed that the diameter of the small bowel was influenced by MBP, 29% indicated that the exposure of the surgical field was influenced by MBP, and 52% did not believe that any of the stages of the operation were influenced by MBP. The results of this questionnaire indicate that the implementation of MBP in laparoscopic colorectal surgery is based on individual preferences in the Netherlands. This emphasizes the need of new studies investigating the role of MBP on surgical field exposure in colorectal laparoscopic surgery.


Robotic exoskeleton embodiment in post-stroke hemiparetic patients: an experimental study about the integration of the assistance provided by the REFLEX knee exoskeleton.
Hemiparetic gait is the most common motor-disorder after stroke and, in spite of rehabilitation efforts, it is persistent in 50% of community dwelling stroke-survivors. Robotic exoskeletons have been proposed as assistive devices to support impaired joints. An example of these devices is the REFLEX knee exoskeleton, which assists the gait of hemiparetic subjects and whose action seems to be properly embodied by stroke survivors, who were able to adapt the motion of their non-assisted limbs and, therefore, reduce their compensation mechanisms. This paper presents an experimental validation carried out to deepen into the effects of REFLEX's assistance in hemiparetic subjects. Special attention was paid to the effect produced in the muscular activity as a metric to evaluate the embodiment of this technology. Significant differences were obtained at the subject level due to the assistance; however, the high dispersion of the measured outcomes avoided extracting global effects at the group level. These results highlight the need of individually tailoring the action of the robot to the individual needs of each patient to maximize the beneficial outcomes. Extra research effort should be done to elucidate the neural mechanisms involved in the embodiment of external devices by stroke survivors.


Immune privilege is extended, then withdrawn, from allogeneic tumor cell grafts placed in the subretinal space.
To determine whether the subretinal space can extend immune privilege to allogeneic tumor cell grafts that do not possess their own inherent immune privilege. P815 tumor cells were injected into the anterior chamber (AC), the subretinal (SR) space, or subconjunctivally in eyes of BALB/c (allogeneic), SCID (immune incompetent), normal DBA/2 (syngeneic), or DBA/2 mice presensitized with P815 cells transfected with interleukin-12 and B7.1. Tumor growth was observed clinically and histologically for up to 50 days. BALB/c recipients were tested for suppression of DBA/2-specific delayed hypersensitivity and concomitant immunity. The SR space of tumor-containing eyes was assessed for its capacity to support ovalbumin (OVA)-specific anterior chamber associated immune deviation (ACAID). P815 cells injected into the SR space of presensitized and normal DBA/2 and SCID mice grew progressively, resulting eventually in recipient death. Tumor cells injected into the SR space of eyes of BALB/c mice grew progressively until day 14, followed by tumor regression resulting in phthisis bulbi (14/35) or tumor elimination (19/35) with preserved ocular anatomy by day 35. Despite elimination of tumors from the SR space, BALB/c recipients exhibited DBA/2-specific ACAID and concomitant immunity. In addition, OVA injected into the SR space of eyes from which tumor has been eliminated induced ACAID. Various parameters of immune privilege, originally described for the AC, are characteristic of immune privilege within the SR space. However, because P815 cells placed in the AC prove lethal for BALB/c recipients, but P815 cells placed in the SR space resolve without jeopardizing the host's life, immune privilege in the SR space can be distinguished from immune privilege in the AC, and this may have implications for grafts of retinal tissue placed within the SR space.


Connecting brains to robots: an artificial body for studying the computational properties of neural tissues.
We have created a hybrid neuro-robotic system that establishes two-way communication between the brain of a lamprey and a small mobile robot. The purpose of this system is to offer a new paradigm for investigating the behavioral, computational, and neurobiological mechanisms of sensory-motor learning in a unified context. The mobile robot acts as an artificial body that delivers sensory information to the neural tissue and receives command signals from it. The sensory information encodes the intensity of light generated by a fixed source. The closed-loop interaction between brain and robot generates autonomous behaviors whose features are strictly related to the structure and operation of the neural preparation. We provide a detailed description of the hybrid system, and we present experimental findings on its performance. In particular, we found (a) that the hybrid system generates stable behaviors, (b) that different preparations display different but systematic responses to the presentation of an optical stimulus, and (c) that alteration of the sensory input leads to short- and long-term adaptive changes in the robot responses. The comparison of the behaviors generated by the lamprey's brain stem with the behaviors generated by network models of the same neural system provides us with a new tool for investigating the computational properties of synaptic plasticity.


DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity.
Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail. Here, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics.


Modifying the Morphology of Silicon Surfaces by Laser Induced Liquid Assisted Colloidal Lithography.
Single, or isolated small arrays of, spherical silica colloidal particles (with refractive index ncolloid = 1.47 and radius R = 350 nm or 1.5 μm) were placed on a silicon substrate and immersed in carbon tetrachloride (nliquid = 1.48) or toluene (nliquid = 1.52). Areas of the sample were then exposed to a single laser pulse (8 ps duration, wavelength λ = 355 nm), and the spatial intensity modulation of the near field in the vicinity of the particles revealed via the resulting patterning of the substrate surface. In this regime, ncolloid < nliquid and the near-field optical intensification is concentrated at and beyond the edge of the particle. Detailed experimental characterization of the irradiated Si surface using atomic force microscopy reveals contrasting topographies. The same optical behavior is observed with both liquids, i.e., the incident laser light diverges on interaction with the colloidal particle, but the resulting interaction with the substrate is liquid dependent. Topographic analysis indicates localized ablation and patterning of the Si substrate when using toluene, whereas the patterning induced under carbon tetrachloride is on a larger scale and extends well below the original substrate surface-hinting at a laser induced photochemical contribution to the surface patterning.


Community-acquired CTX-M-15-type ESBL-producing Escherichia coli meningitis: a case report and literature review.
In this report, a case of community-acquired acute bacterial meningitis (CA-ABM) caused by CTX-M-15-producing Escherichia coli in an elderly male patient was presented in the light of literature. Cultures of cerebrospinal fluid, blood, ear discharge, and stool samples yielded CTX-M-15-producing E. coli in-vitro, which was resistant to the extended-spectrum cephalosporins and ciprofloxacin and susceptible to imipenem, meropenem and amikacin. Meningitis was treated with parenteral meropenem plus parenteral and intraventricular amikacin administration. Since bacterial meningitis is a life-threatening infection, empiric antibiotic therapy with carbapenem can be started before the culture results are obtained, mainly in areas where the ESBL epidemiology is well known.


Effects of arginine, S-adenosylmethionine and polyamines on nerve regeneration.
Axon growth and axon regeneration are complex processes requiring an adequate supply of certain metabolic precursors and nutrients. This article reviews the studies examining some of the processes of protein modification fundamental to both nerve regeneration and to the continuous and adequate supply of specific factors such as arginine, S-adenosylmethionine and polyamines. The process of arginylation notably increases following nerve injury and during subsequent regeneration of the nerve, with the most likely function of arginine-modification of nerve proteins being the degradation of proteins damaged through injury. It appears that defective methyl group metabolism may be one of the leading causes of demyelination, as suggested by the observation of reduced cerebrospinal fluid concentrations of s-adenosylmethionine (SAMe) and 5-methyltetrahydrofolate, the key metabolites in methylation processes, in patients with a reduction in myelination of corticospinal tracts. Polyamine synthesis, which depends strongly on the availability of both SAMe and arginine, markedly increases in neurons soon after an injury. This "polyamine-response" has been found to be essential for the survival of the parent neurons after injury to their axons. Polyamines probably exert their effects through involvement in DNA, RNA and protein synthesis, or through post-translational modifications that are indicated as the most relevant events of the "axon reaction." Nerve regeneration requires the presence of arginine, s-adenosylmethionine, and polyamines. Further studies are needed to explore the mechanisms involved in these processes.


Metabolic and endocrine changes in persons aging with spinal cord injury.
Persons with spinal cord injury (SCI) have secondary medical disabilities that impair their ability to function. With paralysis, dramatic deleterious changes in body composition occur acutely with further adverse changes ensuing with increasing duration of injury. Lean mass, composed of skeletal muscle and bone, is lost and adiposity is relatively increased. The body composition changes may be further exacerbated by associated reductions in anabolic hormones, testosterone, and growth hormone. Individuals with SCI also have decreased levels of activity. These body composition and activity changes are associated with insulin resistance, disorders in carbohydrate and lipid metabolism, and may be associated with premature cardiovascular disease. Although limited information is available, upper body exercise and cycle ergometry of the lower extremities by functional electrical stimulation (FES) have been reported to have a salutary effect on these body composition and metabolic sequelae of paralysis. Perhaps other innovative, externally mediated forms of active exercise of the paralyzed extremities will result in an increased functional capacity, metabolic improvement, and reduction of atherosclerotic vascular disease.


Low transmission areas of schistosomiasis in Venezuela: consequences on the diagnosis, treatment, and control.
Schistosomiasis low transmission areas as Venezuela, can be defined as those where the vector exists, the prevalence of active cases is under 25%, individuals with mild intensity of infection predominate and are mostly asymptomatic. These areas are the consequence of effective control programs, however, "silent" epidemiological places are difficult to trace, avoiding the opportune diagnosis and treatment of infected persons. Clinic and abdominal ultrasound have not shown to discriminate infected from uninfected persons in areas where besides Schistosoma mansoni, intestinal parasites are the rule. Under these conditions, serology remains as a very valuable diagnostic tool, since it gives a closer approximation to the true prevalence. In this sense, circumoval precipitin test, ELISA-SEA with sodium metaperiodate, and alkaline phosphatase immunoassay joined to coprology allow the identification of the "schistosomiasis cases". In relation to public health, schistosomiasis has been underestimated by the sanitary authorities and the investment on its control is being transferred to other diseases of major social and political relevance neglecting sanitary efforts and allowing growth of snail population. Some strategies of diagnosis and control should be done before schistosomiasis reemergence occurs in low transmission areas.


Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar.
Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.


Interacting Qubit-Photon Bound States with Superconducting Circuits.
Qubits strongly coupled to a photonic crystal give rise to qubit-photon dressed bound states. These bound states, comprising the qubits and spatially localized photonic modes induced around the qubits, are the basis for many exotic physical scenarios. The localization of these states changes with qubit detuning from the photonic crystal band edge, offering an avenue of in situ control of bound-state interaction. Here, we present experimental results from a device with two transmon qubits coupled to a superconducting microwave photonic crystal and realize tunable on-site and interbound state interactions. We observe a fourth-order two-photon virtual process between bound states indicating strong coupling between the photonic crystal and transmon qubits. Because of their localization-dependent interaction, these states offer the ability to realize one-dimensional chains of bound states with tunable and potentially long-range interactions that preserve the qubits' spatial organization. The widely tunable, strong, and robust interactions demonstrated with this system are promising benchmarks towards realizing larger, more complex systems that use bound states to build and study quantum spin models.


Timing of tactile and visuo-tactile events is impaired in patients with cervical dystonia.
Psychophysical studies show alterations of cross-modal integration and timing processes in patients with generalized and focal hand dystonia. Here we assess the capability of 10 cervical dystonia patients, 5 patients with cervical pain but no dystonia, and 10 healthy controls to determine whether pairs of visual, tactile or visuo-tactile stimuli were simultaneous or sequential (TD threshold) and which stimulus preceded the other (temporal order judgement, TOJ). Visual stimuli consisted of light emitting diodes and tactile stimuli of non-noxious electrical shocks delivered to the hands. Intervals between stimuli were increased from 0 to 400 ms in steps of 10 ms. Cervical dystonia patients had a clear impairment of tactile and visuo-tactile temporal discrimination compared with patients with cervical pain but no dystonia who performed as well as healthy subjects. This suggests that deficits of temporal discrimination in cervical dystonia patients are not due to the possible distracting effect of unpleasant sensations or pain. Comparisons with previous studies show that deficits in cervical dystonia were more severe than in focal hand dystonia and less severe than in generalized dystonia. Thus, impairment of sensory timing may be a marker of disease, which varies along a continuum in the different forms of dystonia.


Prevalence and type distribution of high-risk human papillomavirus in patients with cervical cancer: a population-based study.
Cervical cancer is the greater cause of cancer death in women in many developing countries. Persistent infection with human papilloma virus (HPV), primarily high risk types 16 and 18, is recognized as a causal and essential factor for the development of cervical cancer. We aimed to determine the distribution of high-risk HPV genotypes in archival biopsies with cervical carcinoma in patients from Mazandaran Province, Northern Iran. A total of 98 paraffin-embedded cervical samples consisted of 63 Squamous Cell Carcinomas (SCC), 4 Adenocarcinomas, 19 Cervical Interaepithelial Neoplasia grade I (CIN-I), 4 CIN-II and 8 CIN-III diagnosed during 2009-2011, were selected to perform high risk HPV genotyping using AmpliSens(R) HPV HCR DNA genotyping kit. The prevalence of HPV infections was assessed in low and high grade cervical lesions by age. Of the 98 cervical samples analysed by DNA PCR, 78 (79.59%) were positive for HPV DNA. HPV was detected in the 52 of SCC, 4 of Adenocarcinomas, 14 of CIN-I, 4 of CIN-II, and 4 of CIN-III for HPV. From the 78 HPV positive samples, 23 (29.5%) samples were positive for HPV type 16, 32 (41%) were positive for HPV 18, 19 (24.4%) were positive for HPV 45, and 4 (5.1%) of cervical specimens were positive for HPV 39. This study provides valuable baseline data for future assessment of the impact of current prophylactic vaccination programs that is protective against the two most common oncogenic types of HPV found in cervical cancer, HPV-16 and HPV-18, but not against other high-risk mucosal HPVs, 39 and 45, reported in this population.


Calcium carbonate phosphate binding ion exchange filtration and accelerated denitrification improve public health standards and combat eutrophication in aquatic ecosystems.
Cultural eutrophication, the process by which a lake becomes rich in dissolved nutrients as a result of point and nonpoint pollutant sources, is a major cause of the loss of natural lake ecosystems throughout the world. The process occurs naturally in all lakes, but phosphate-rich nutrient runoff from sources such as storm drains and agricultural runoff is a major cause of excess phosphate-induced eutrophication. Especially in Madrona Marsh, one of the last remaining vernal marshes in the greater Los Angeles area, California, cultural eutrophication has become a major problem. In this study, calcium carbonate was found to be an excellent phosphate binder, reducing up to 70% of the phosphates in a given sample of water, and it posed relatively negligent ecological repercussions. This study involved the testing of this principle in both the laboratory and the real ecosystem. A calcium carbonate lacing procedure was first carried out to determine its efficacy in Madrona Marsh. Through this, ammonia was found to interfere with the solubility of calcium carbonate and therefore to be a hindrance to the reduction of phosphate. Therefore, various approaches for reduction of ammonia were tested, including aeration, use of fiber growth media, and plants, mainly Caulerpa verticellata, chosen for it hardiness, primarily in an attempt to increase population of Nitrobacter and Nitrosomonas. All were successful in moderately reducing ammonia levels. In addition, soil sampling, sediment analysis, microscopic plant analysis, microorganism and macroinvertebrate identification, and rate law formulations were conducted. The effect of phosphate and ammonia reduction on the populations of enterobacteria was also an important focus of this experiment. Varying concentrations of phosphate, ammonia, and calcium carbonate in conjunction with phosphate were tested in Madrona Marsh to determine their effects on the populations of enteropathogens on nonspecific blood agar, MacConkey agar, and Hektoen agar. Initial analyses suggest a strong correlation between phosphate concentrations and bacterial populations; a 66% decrease in phosphate resulted in a 35% reduction in bacterial populations and a 45% reduction in enteropathogenic populations. Likewise, a strong correlation was shown between calcium carbonate concentrations and bacterial reduction greater than that which can be attributed to the phosphate reduction alone. This was followed by the construction of various phosphate binding calcium carbonate filters, which used the ion exchange principle, including a spring loading filter, PVC pipe filter, and a galvanized filter. All were tested with the aid of Stoke's law formulation. The experiment was extremely successful in designing a working phosphate-binding and ammonia-reducing filter, and a large-scale agitator-clarifier filter system is currently being planned for construction in Madrona Marsh; this filter will reduce phosphate and ammonia levels substantially in the following years, bringing ecological, economical, and health-related improvements to the overall ecosystem and habitat.


Clinical spectrum of infections in patients with HTLV-III-associated diseases.
Infectious complications are the cause of death in the overwhelming majority of patients with the acquired immunodeficiency syndrome (AIDS). These infectious complications are outstanding in severity and number. Infecting organisms are mainly those which take advantage of defective T-cell function. Many cause latent infections which can reactivate and cause disease in AIDS patients because of immunosuppression. Serological diagnosis of infections in AIDS patients is complicated because of the defect in B-cell function; rising antibody titers are not observed in most patients with infectious complications. The natural history of AIDS is one of repeated infections leading to a fatal outcome. However, treatment for most of the bacterial, fungal, and parasitic infections is effective. Treatment of some of these infections must be prolonged indefinitely because of the tendency to relapse.


Consistency and Variability in Children's Word Learning Across Languages.
Why do children learn some words earlier than others? The order in which words are acquired can provide clues about the mechanisms of word learning. In a large-scale corpus analysis, we use parent-report data from over 32,000 children to estimate the acquisition trajectories of around 400 words in each of 10 languages, predicting them on the basis of independently derived properties of the words' linguistic environment (from corpora) and meaning (from adult judgments). We examine the consistency and variability of these predictors across languages, by lexical category, and over development. The patterning of predictors across languages is quite similar, suggesting similar processes in operation. In contrast, the patterning of predictors across different lexical categories is distinct, in line with theories that posit different factors at play in the acquisition of content words and function words. By leveraging data at a significantly larger scale than previous work, our analyses identify candidate generalizations about the processes underlying word learning across languages.


Differences in acute retroviral syndrome by HIV-1 subtype in a multicentre cohort study in Africa.
Symptoms of acute retroviral syndrome (ARS) may be used to identify patients with acute HIV-1 infection who seek care. ARS symptoms in African adults differ by region. We assessed whether reporting of ARS was associated with HIV-1 subtype in a multicentre African cohort study representing countries with predominant HIV-1 subtypes A, C, and D. ARS symptoms were assessed in adults enrolling within 6 weeks after the estimated date of infection in an acute and early HIV-1 infection cohort study. HIV-1 subtype was determined by POL genotyping. We used log-binomial regression to compare ARS symptom prevalence among those with subtype A vs. C or D, adjusting for sex, time since enrolment, and enrolment viral load. Among 183 volunteers ascertained within 6 weeks after estimated date of infection, 77 (42.0%) had subtype A, 83 (45.4%) subtype C, and 23 (12.6%) subtype D infection. Individuals with subtype A were 1.40 (95% confidence interval: 1.17, 1.68) times as likely as individuals with subtypes C or D to report any ARS symptoms; each individual symptom other than rash was also more prevalent in subtype A than in subtype C or D, with prevalence ratios ranging from 1.94 (1.40, 2.70) for headache to 4.92 (2.24, 10.78) for lymphadenopathy. Individuals with subtype A were significantly more likely than individuals with subtypes C or D to report any ARS symptoms. HIV-1 subtypes may help explain differences in ARS that have been observed across regions in Africa, and may impact the yield of symptom-based screening strategies for acute HIV infection detection.


The influence of penicillamine/cysteine mutation on the metal complexes of peptides.
N-Terminally free but C-terminally amidated peptides Pen-SSACS-NH2 and CSSA-Pen-S-NH2 containing l-penicillamine (Pen) in sequence have been synthesized and their nickel(ii), zinc(ii) and cadmium(ii) complexes were studied by potentiometric and spectroscopic measurements. This study is the first example of the synthesis and metal complexes of peptides containing penicillamine in a peptide sequence constructed from natural amino acids. The data were compared to those of the two cysteine counterparts, CSSACS-NH2. It was found that the replacement of l-cysteine with l-penicillamine has a significant impact on the complex formation processes with nickel(ii) ions. The major differences include the suppression of polynuclear complex formation, the enhanced metal binding affinity of the amino terminus and the increased tendency for the formation of amide bonded species. The tridentate (NH2,S-,S-) coordination was characteristic of the zinc(ii) and cadmium(ii) complexes in the case of all three peptides containing two thiolate functions.


Persons with chronic widespread pain experience excess mortality: longitudinal results from UK Biobank and meta-analysis.
It is uncertain whether persons with chronic widespread pain (CWP) experience premature mortality. Using the largest study conducted, we determine whether such a relationship exists, estimate its magnitude and establish what factors mediate any relationship. UK Biobank, a cohort study of 0.5 million people aged 40-69 years, recruited throughout Great Britain in 2006-2010. Participants reporting 'pain all over the body' for >3 months were compared with persons without chronic pain. Information on death (with cause) was available until mid-2015. We incorporated these results in a meta-analysis with other published reports to calculate a pooled estimate of excess risk. 7130 participants reported CWP and they experienced excess mortality (mortality risk ratio 2.43, 95%CI 2.17 to 2.72). Specific causes of death in excess were cancer (1.73adjusted age and sex, 95% CI 1.46 to 2.05), cardiovascular (3.24adjusted age and sex, 95% CI 2.55 to 4.11), respiratory (5.66adjusted age and sex, 95% CI 4.00 to 8.03) and other disease-related causes (4.04adjusted age and sex, 95% CI 3.05 to 5.34). Excess risk was substantially reduced after adjustment for low levels of physical activity, high body mass index, poor quality diet and smoking. In meta-analysis, all studies showed significant excess all-cause (combined estimate 1.59 (95% CI 1.05 to 2.42)), cardiovascular and cancer mortality. Evidence is now clear that persons with CWP experience excess mortality. UK Biobank results considerably reduce uncertainty around the magnitude of excess risk and are consistent with the excess being explained by adverse lifestyle factors, which could be targeted in the management of such patients.


Interfacial engineering in graphene bandgap.
Graphene exhibits superior mechanical strength, high thermal conductivity, strong light-matter interactions, and, in particular, exceptional electronic properties. These merits make graphene an outstanding material for numerous potential applications. However, a graphene-based high-performance transistor, which is the most appealing application, has not yet been produced, which is mainly due to the absence of an intrinsic electronic bandgap in this material. Therefore, bandgap opening in graphene is urgently needed, and great efforts have been made regarding this topic over the past decade. In this review article, we summarise recent theoretical and experimental advances in interfacial engineering to achieve bandgap opening. These developments are divided into two categories: chemical engineering and physical engineering. Chemical engineering is usually destructive to the pristine graphene lattice via chemical functionalization, the introduction of defects, doping, chemical bonds with substrates, and quantum confinement; the latter largely maintains the atomic structure of graphene intact and includes the application of an external field, interactions with substrates, physical adsorption, strain, electron many-body effects and spin-orbit coupling. Although these pioneering works have not met all the requirements for electronic applications of graphene at once, they hold great promise in this direction and may eventually lead to future applications of graphene in semiconductor electronics and beyond.


Eco-friendly yield-scaled global warming potential assists to determine the right rate of nitrogen in rice system: A systematic literature review.
Rice paddies are one of the largest greenhouse gases (GHGs) facilitators that are predominantly regulated by nitrogen (N) fertilization. Optimization of N uses based on the yield has been tried a long since, however, the improvement of the state-of-the-art technologies and the stiffness of global warming need to readjust N rate. Albeit, few individual studies started to, herein attempted as a systematic review to generalize the optimal N rate that minimizes global warming potential (GWP) concurrently provides sufficient yield in the rice system. To satisfy mounted food demand with inadequate land & less environmental impact, GHGs emissions are increasingly evaluated as yield-scaled basis. This systematic review (20 published studies consisting of 21 study sites and 190 observations) aimed to test the hypothesis that the lowest yield-scaled GWP would provide the minimum GWP of CH4 and N2O emissions from rice system at near optimal yields. Results revealed that there was a strong polynomial quadratic relationship between CH4 emissions and N rate and strong positive correlation between N2O emissions and N rate. Compared to control the low N dose emitted less (23%) CH4 whereas high N dose emitted higher (63%) CH4 emission. The highest N2O emission observed at moderated N level. In total GWP, about 96% and 4%, GHG was emitted as CH4 and N2O, respectively. The mean GWP of CH4 and N2O emissions from rice was 5758 kg CO2 eq ha-1. The least yield-scaled GWP (0.7565 (kg CO2 eq. ha-1)) was recorded at 190 kg N ha-1 that provided the near utmost yield. This dose could be a suitable dose in midseason drainage managed rice systems especially in tropical and subtropical climatic conditions. This yield-scaled GWP supports the concept of win-win for food security and environmental aspects through balancing between viable rice productivity and maintaining convincing greenhouse gases.


Novel costimulators in the immune gene therapy of cancer.
One of the major goals of cancer immunotherapy is the induction of tumour-specific T-lymphocyte responses that will be effective in the rejection of established tumours. The prospects for such therapy rely on the identification of tumour antigens, and although there is persuasive evidence for the presence of such antigens,1,2 the occurrence of the disease does illustrate that the immune system is at least, on some occasions, unable to recognise and destroy these targets. Tumour antigens may be novel proteins (from genetic lesions or viral infections), modified existing antigens (eg, abnormally glycosylated cell surface proteins), or inappropriately expressed normal gene products (eg, CA125, carcinoembryonic antigen, and alpha-fetoprotein).1 Involvement of the immune system in the normal surveillance and suppression of cancer is further suggested by the increased incidence of tumours in immunocompromised patients.3 However, recent evidence has shown that, at least in model systems, cancer cells can be modulated in such a way that they stimulate cells of the immune system to recognise and destroy these malignant cells. This review summarizes the costimulatory molecules involved in the activation of such cells, the principles and mechanisms underlying their activation, and how such knowledge can be used to persuade the immune system to challenge cancer.


Essential polyunsaturated fatty acids in plasma and erythrocytes of children with inborn errors of amino acid metabolism.
Essential fatty acids (EFAs), and their longer-chain more-unsaturated derivatives (LCPUFAs) in particular, are essential for normal growth and cognitive development during childhood. Children with inborn errors of amino acid metabolism represent a risk population for a reduced LCPUFA status because their diet is low in EFAs and LCPUFAs. We have investigated the EFA and LCPUFA status of children with various amino acid metabolism disorders (not PKU) under treatment. Fatty acid profiles of plasma and erythrocyte phospholipids of 33 patients (aged 0-18 years) and 38 matched controls were determined by gas-liquid chromatography. Food-frequency questionnaires were used to assess the mean fatty acid intake. The dietary intake of the EFAs linoleic acid (LA) and alpha-linolenic acid (ALA) was comparable in both groups, while the LCPUFA intake was much lower in patients. This was associated with lower relative concentrations (% of total fatty acids) of n-3 docosahexaenoic acid (DHA) in plasma and erythrocyte phospholipids. Concentrations of arachidonic acid (AA) did not differ. The same was observed for the two EFAs LA and ALA. Thus, as compared to healthy controls, children with amino acid metabolism disorders have a lower intake of LCPUFAs and have lower concentrations of DHA but not of AA in plasma and erythrocyte phospholipids. This suggests that endogenous AA synthesis might guarantee an adequate AA status. The lower DHA status, however, warrants further investigations regarding the impact of DHA supplementation on growth and development of these children.


Timing of adjuvant chemotherapy after limb amputation and effect on outcome in dogs with appendicular osteosarcoma without distant metastases.
To determine an optimal time interval between amputation and initiation of adjuvant chemotherapy (TIamp-chemo) in dogs with appendicular osteosarcoma without distant metastases and whether TIamp-chemo was associated with outcome. 168 client-owned dogs treated at 9 veterinary oncology centers. Data were collected from the dogs' medical records concerning potential prognostic variables and outcomes. Dogs were grouped as to whether they received chemotherapy within 3, 5, 7, 10, 15, 20, 30, or > 30 days after amputation of the affected limb. Analyses were performed to identify variables associated with time to tumor progression and survival time after limb amputation and to determine an optimal TIamp-chemo. Median TIamp-chemo was 14 days (range, 1 to 210 days). Median time to tumor progression for dogs with a TIamp-chemo ≤ 5 days (375 days; 95% CI, 162 to 588 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (202 days; 95% CI, 146 to 257 days). Median overall survival time for dogs with a TIamp-chemo ≤ 5 days (445 days; 95% CI, 345 to 545 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (239 days; 95% CI, 186 to 291 days). Findings indicated that early (within 5 days) initiation of adjuvant chemotherapy after limb amputation was associated with a significant and clinically relevant survival benefit for dogs with appendicular osteosarcoma without distant metastases. These results suggested that the timing of chemotherapy may be an important prognostic variable.


WITHDRAWN: Low level laser therapy (Classes III) for treating osteoarthritis.
Osteoarthritis (OA) affects a large portion of the population. Low Level Laser Therapy (LLLT) is a light source that generates extremely pure light, of a single wavelength. The effect is not thermal, but rather related to photochemical reactions in the cells. LLLT was introduced as an alternative non-invasive treatment for OA about 30 years ago, but its effectiveness has to be examined more closely, especially in the treatment of OA. To assess the effectiveness of class III LLLT for osteoarthritis when irradiation is directed at the osteoarthritic joint capsule. Searches were conducted in the following databases: MEDLINE, EMBASE, the Cochrane Musculoskeletal registry, the Rehabilitation and Related Therapies field registry and the Cochrane Controlled Trials Register up to May, 2005. Following an a prior protocol, only controlled clinical trials of LLLT for the treatment of patients with a clinical diagnosis of OA were eligible. Abstracts lacking data were excluded unless further data could be obtained from the authors. Two reviewers independently selected trials and extracted data using predetermined forms. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed; in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI), whereas the difference between the treatment and control groups was weighted by the inverse of the variance. Standardized mean differences (SMD) were calculated by dividing the difference between treatment and control by the baseline variance, and were used in the analysis of pain because different scales were used to measure it. Dichotomous outcomes were analyzed with relative risk (RR). Eight trials were included with 233 patients randomized to laser and 172 patients to placebo laser. Treatment duration ranged from two to six weeks. Pain was assessed in seven trials. When the results were pooled from different pain scales used in these seven trials, a statistically significant difference in favor of laser treatment was found with a SMD of -0.28 (95% CI: -0.48 to -0.09). One of these studies also measured pain during movement and found a statistically significant difference in favor of laser treatment with a WMD of -1.16 (95% CI: -2.02 to -0.30). Two studies found significant results for increased knee range of motion. Two others studies found a statistically significant difference in favor of laser treatment for patient-assessed global disease activity with laser compared to placebo (RR 1.70, 95%CI: 1.1. to 2.63). One trial evaluated the effectiveness of laser treatment in temporomandibular joint OA and found a statistically significant difference (WMD 38.69, 95% CI: 29.25 to 48.13) using the change in VAS score to measure pain. One study found a statistically significant difference in favor of laser treatment at the end of treatment and at 4 and 8 weeks post-treatment for morning stiffness. Other outcome measures of joint tenderness and strength did not yield significant differences. Five trials included in this review showed a statistically significant difference favoring laser treatment when compared to placebo for at least one outcome measure. Three trials did not report beneficial effects. The varying results of these trials may be due to the method of laser application and/or other features of LLLT application. Clinicians and researchers should consistently report the characteristics of LLLT devices and application techniques used. New trials on LLLT should make use of standardized, validated outcomes. There is clearly a need to investigate the effects of different dosages on LLLT effectiveness for OA in future randomized, controlled clinical trials. Also, more studies should be done to investigate the anti-inflammatory action of laser as well as the appropriate parameters needed to achieve an anti-inflammatory effect.


Secular trends in fracture incidence in the UK between 1990 and 2012.
We studied sex-specific incidence rates in a population 50 years or older in the UK. In the period of 1990-2012, the overall rate of fracture did not change, but there were marked secular alterations in the rates of individual fracture types, particularly hip and spine fractures in the elderly. There is increasing evidence of secular changes in age- and sex- adjusted fracture incidence globally. Such observations broadly suggest decreasing rates in developed countries and increasing rates in transitioning populations. Since altered fracture rates have major implications for healthcare provision and planning, we investigated secular changes to age- and sex-adjusted fracture risk amongst the UK population aged 50 years or above from 1990 till 2012. We undertook a retrospective observational study using the Clinical Practice Research Datalink (CPRD), which contains the health records of 6.9 % of the UK population. Site-specific fracture incidence was calculated by calendar year for men and women separately, with fracture type categorised according to ICD-9 classification. Linear regression analysis was used to calculate mean annualised change in absolute incidence. For presentational purposes, mean rates in the first 5 years and last 5 years of the period were calculated. Overall fracture incidence was unchanged in both women and men from 1990 to 2012. The incidence of hip fracture remained stable amongst women (1990-1994 33.8 per 10,000 py; 2008-2012 33.5 per 10,000 py; p trend annualised change in incidence = 0.80) but rose in men across the same period (10.8 to 13.4 per 10,000 py; p = 0.002). Clinical vertebral fractures became more common in women (8.9 to 11.8 per 10,000 py; p = 0.005) but remained comparable in men (4.6 to 5.9 per 10,000 py; p = 0.72). Similarly, the frequency of radius/ulna fractures did not change in men (9.6 to 9.6 per 10,000 py; p = 0.25), but, in contrast, became less frequent in women (50.4 to 41.2 per 10,000 py; p = 0.001). Secular trends amongst fractures of the carpus, scapula, humerus, foot, pelvis, skull, clavicle, ankle, patella, and ribs varied according to fracture site and sex. Although overall sex-specific fracture incidence in the UK population 50 years or over appears to have remained stable over the last two decades, there have been noticeable changes in rates of individual fracture types. Given that the impact of a fracture on morbidity, mortality, and health economy varies according to fracture site, these data inform the provision of healthcare services in the UK and elsewhere.


Affect Following First Exercise Session as a Predictor of Treatment Response in Depression.
Remission rates are low with first-step or even second-step antidepressant treatments. Furthermore, despite extensive investments from National Institutes of Health and from industry, novel treatments are not yet available in clinical care for depression. Predictors of treatment response very early in the course of treatment can avoid unnecessarily lengthy trials with ineffective treatments and reduce the trial and error process. This article examines the expression of positive affect immediately following an acute exercise session at the end of the first exercise session as a predictor of treatment response in the National Institute of Mental Health-funded TREAD (Treatment with Exercise Augmentation for Depression) study, which was conducted from April 2003 to August 2007. 122 subjects with DSM-IV-diagnosed major depressive disorder were randomized to public health dose (16 kcal/kg/wk) or low dose (4 kcal/kg/wk) of exercise for 12 weeks. Affect following the first exercise session was assessed using the Positive and Negative Affect Scale (PANAS), and depressive symptoms were assessed weekly using the Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) (primary outcome measure). The PANAS composite affect score (positive-negative total) predicted change in IDS-C score (P < .05), as well as treatment response (P < .02) and remission (P < .03) for those in the high-dose group but not in the low-dose group. These findings suggest that the composite positive affect following the first exercise session has clinical utility to predict treatment response to exercise in depression and match the "right patient" with the "right" treatment. ClinicalTrials.gov identifier: NCT00076258.


Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis.
Neoplastic growth is usually dependent on blood supply, and it is commonly accepted that this is provided by the formation of new vessels. However, tumors may be able to grow without neovascularization if they find a suitable vascular bed available. We have investigated the pattern of vascularization in a series of 500 primary stage I non-small-cell lung carcinomas. Immunostaining of endothelial cells has highlighted four distinct patterns of vascularization. Three patterns (which we called basal, papillary, and diffuse) have in common the destruction of normal lung and the production of newly formed vessels and stroma. The fourth pattern, which we called alveolar or putative nonangiogenic, was observed in 16% (80/500) of the cases and is characterized by lack of parenchymal destruction and absence of both tumor associated stroma and new vessels. The only vessels present were the ones in the alveolar septa, and their presence highlighted, through the whole tumor, the lung alveoli filled up by the neoplastic cells. This observation suggests that, if an appropriate vascular bed is available, a tumor can exploit it and grows without inducing neo-angiogenesis. This could have implications for strategies aimed at inhibiting tumor growth by vascular targeting or inhibition of angiogenesis.


Targeted identification of glycosylated proteins in the gastric pathogen Helicobacter pylori (Hp).
Virulence of the gastric pathogen Helicobacter pylori (Hp) is directly linked to the pathogen's ability to glycosylate proteins; for example, Hp flagellin proteins are heavily glycosylated with the unusual nine-carbon sugar pseudaminic acid, and this modification is absolutely essential for Hp to synthesize functional flagella and colonize the host's stomach. Although Hp's glycans are linked to pathogenesis, Hp's glycome remains poorly understood; only the two flagellin glycoproteins have been firmly characterized in Hp. Evidence from our laboratory suggests that Hp synthesizes a large number of as-yet unidentified glycoproteins. Here we set out to discover Hp's glycoproteins by coupling glycan metabolic labeling with mass spectrometry analysis. An assessment of the subcellular distribution of azide-labeled proteins by Western blot analysis indicated that glycoproteins are present throughout Hp and may therefore serve diverse functions. To identify these species, Hp's azide-labeled glycoproteins were tagged via Staudinger ligation, enriched by tandem affinity chromatography, and analyzed by multidimensional protein identification technology. Direct comparison of enriched azide-labeled glycoproteins with a mock-enriched control by both SDS-PAGE and mass spectrometry-based analyses confirmed the selective enrichment of azide-labeled glycoproteins. We identified 125 candidate glycoproteins with diverse biological functions, including those linked with pathogenesis. Mass spectrometry analyses of enriched azide-labeled glycoproteins before and after cleavage of O-linked glycans revealed the presence of Staudinger ligation-glycan adducts in samples only after beta-elimination, confirming the synthesis of O-linked glycoproteins in Hp. Finally, the secreted colonization factors urease alpha and urease beta were biochemically validated as glycosylated proteins via Western blot analysis as well as by mass spectrometry analysis of cleaved glycan products. These data set the stage for the development of glycosylation-based therapeutic strategies, such as new vaccines based on natively glycosylated Hp proteins, to eradicate Hp infection. Broadly, this report validates metabolic labeling as an effective and efficient approach for the identification of bacterial glycoproteins.


Spinal dural arteriovenous fistulas: experience with endovascular and surgical therapy.
Although the pathophysiology of spinal dural arteriovenous fistulas (AVFs) has recently been elucidated, the optimal treatment strategy for these lesions has yet to be defined. Current management techniques include endovascular embolization or microsurgical obliteration. The authors reviewed the records and angiograms of all patients with spinal dural AVFs treated at Massachusetts General Hospital over a 6-year period (1992-1998). During this period, it was intended initially to treat all patients with embolization and to reserve surgery for those in whom endovascular treatment failed or in cases in which pretreatment evaluation suggested that endovascular therapy would be ineffective or unsafe. A total of 26 patients with spinal dural AVFs were treated: there were 22 men and 4 women with a mean age of 65 years (range 39-79 years). Lesions were located in the following areas: five in foramen magnum/cervical, 13 in thoracic, five in lumbar, and three in sacral. Twenty-three (88%) of 26 patients underwent embolization and three (12%) of 23 patients underwent surgery as the primary mode of treatment. Of the 23 patients in whom embolization was performed or attempted, nine (39%) ultimately required surgery. All patients were stabilized or improved following definitive treatment, as assessed by the Aminoff-Logue scores. There was one death secondary to a myocardial infarction. These data demonstrate that endovascular therapy can be successful as an initial treatment for the majority of patients; however, there is a 39% failure rate, which is not observed following surgical therapy. Once a definitive therapy has been achieved using either technique virtually all patients are either stabilized or improved.


Identification and Management of Atherosclerotic Cardiovascular Disease Risk in South Asian Populations in the U.S.
South Asians (SAs, individuals with ancestry from Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka) are among the fastest growing ethnic subgroups in the United States. SAs typically experience a high prevalence of diabetes, abdominal obesity, and hypertension, among other cardiovascular disease risk factors, which are often under recognized and undermanaged. The excess coronary heart disease risk in this growing population must be critically assessed and managed with culturally appropriate preventive services. Accordingly, this scientific document prepared by a multidisciplinary group of clinicians and investigators in cardiology, internal medicine, pharmacy, and SA-centric researchers describes key characteristics of traditional and nontraditional cardiovascular disease risk factors, compares and contrasts available risk assessment tools, discusses the role of blood-based biomarkers and coronary artery calcium to enhance risk assessment and prevention strategies, and provides evidenced-based approaches and interventions that may reduce coronary heart disease disparities in this higher-risk population.


Assisted reproduction and distributive justice.
The Canadian province of Quebec recently amended its Health Insurance Act to cover the costs of In Vitro Fertilization (IVF). The province of Ontario recently de-insured IVF. Both provinces cited cost-effectiveness as their grounds, but the question as to whether a public health insurance system ought to cover IVF raises the deeper question of how we should understand reproduction at the social level, and whether its costs should be a matter of individual or collective responsibility. In this article I examine three strategies for justifying collective provisions in a liberal society and assess whether public reproductive assistance can be defended on any of these accounts. I begin by considering, and rejecting, rights-based and needs-based approaches. I go on to argue that instead we ought to address assisted reproduction from the perspective of the contractarian insurance-based model for public health coverage, according to which we select items for inclusion based on their unpredictability in nature and cost. I argue that infertility qualifies as an unpredictable incident against which rational agents would choose to insure under ideal conditions and that assisted reproduction is thereby a matter of collective responsibility, but only in cases of medical necessity or inability to pay. The policy I endorse by appeal to this approach is a means-tested system of coverage resembling neither Ontario nor Quebec's, and I conclude that it constitutes a promising alternative worthy of serious consideration by bioethicists, political philosophers, and policy-makers alike.


Major complications after distal biceps tendon repairs: retrospective cohort analysis of 970 cases.
The major complication and reoperation rates after distal biceps repair are poorly defined. The purpose of this large retrospective cohort study of distal biceps repairs performed by multiple surgeons within a large orthopedic group was to more clearly define the rates and risk factors of clinically impactful major complications and reoperations. All distal biceps tendon repairs performed from January 2005 through April 2017 with a minimum 2-month follow-up were identified using Current Procedural Terminology code 24342. We included 970 patients. The primary outcome measure was the total major complication rate. Reoperations, minor complications, and risk factors were also tracked. Repairs were performed via a single anterior incision in 652 cases and a 2-incision exposure in 318 cases. A 7.5% major complication rate and 4.5% reoperation rate were observed overall. Major complications occurred at the following rates: proximal radioulnar synostosis, 1.0%; heterotopic ossification or loss of range of motion with reoperation, 0.9%; tendon rerupture, 1.6%; deep infection, 0.5%; posterior interosseous nerve palsy, 1.9%; and complex regional pain syndrome, 0.6%. The 2-incision exposure was identified as a significant risk factor for the development of proximal radioulnar synostosis when compared with single-incision repair techniques (P = .0003; odds ratio, 19), occurring in 2.8% of 2-incision exposure cases. Lateral antebrachial cutaneous nerve neuritis or numbness and radial sensory nerve neuritis or numbness were documented more frequently in the postoperative period among patients treated with a single-incision exposure (P < .0001 and P = .034, respectively). Distal biceps repair is associated with a 7.5% major complication rate and 4.5% reoperation rate. The use of a 2-incision technique for repair increases the risk of radioulnar synostosis.


Thyrotropin-releasing hormone receptor activation in the spinal cord increases blood pressure and sympathetic tone to the vasculature and the adrenals.
Cardiovascular and regional hemodynamic effects of the intrathecal (i.t.) administration of a thyrotropin-releasing hormone (TRH) analog, MK-771 (L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide), were studied in rats. MK-771 (0.01-5.0 micrograms i.t.) caused dose-related increases in mean arterial pressure (MAP) and heart rate (HR). TRH (10 micrograms i.t.), but not TRH-free acid, produced similar cardiovascular effects. The MAP response to MK-771 (i.t.) remained primarily intact after cervical spinal cord transection, whereas the HR response was attenuated (37% of control). The MAP response to MK-771 was blocked by peripheral administration of pentolinium or phentolamine, and was partially attenuated by adrenalectomy. The HR response was reduced by pentolinium or atropine. Assessment of changes in regional blood flow and vascular resistance with the radioactive microsphere technique showed that MK-771 increased total peripheral resistance and vasoconstricted cutaneous, skeletal muscle, adrenal, renal and intestinal vascular beds. Cardiac output and stroke volume were not altered. MK-771 had no effect on vascular resistance locally or in other central nervous system structures. However, blood flow was elevated by MK-771 in spinal cord and brain. These data show that TRH receptor activation in the thoracic spinal cord, presumably in the intermediolateral cell column, elevated MAP by increased sympathetic activity to the peripheral vasculature and the adrenals. However, the HR response to TRH receptor activation required a supra-spinal component and was mediated in part by vagal inhibition.


Cord blood 25(OH)-vitamin D deficiency and childhood asthma, allergy and eczema: the COPSAC2000 birth cohort study.
Epidemiological studies have suggested an association between maternal vitamin D dietary intake during pregnancy and risk of asthma and allergy in the offspring. However, prospective clinical studies on vitamin D measured in cord blood and development of clinical end-points are sparse. To investigate the interdependence of cord blood 25-hydroxyvitamin D (25(OH)-Vitamin D) level and investigator-diagnosed asthma- and allergy-related conditions during preschool-age. Cord blood 25(OH)-Vitamin D level was measured in 257 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) at-risk mother-child cohort. Troublesome lung symptoms (TROLS), asthma, respiratory infections, allergic rhinitis, and eczema, at age 0-7 yrs were diagnosed exclusively by the COPSAC pediatricians strictly adhering to predefined algorithms. Objective assessments of lung function and sensitization were performed repeatedly from birth. After adjusting for season of birth, deficient cord blood 25(OH)-Vitamin D level (<50 nmol/L) was associated with a 2.7-fold increased risk of recurrent TROLS (HR = 2.65; 95% CI = 1.02-6.86), but showed no association with respiratory infections or asthma. We saw no association between cord blood 25(OH)-Vitamin D level and lung function, sensitization, rhinitis or eczema. The effects were unaffected from adjusting for multiple lifestyle factors. Cord blood 25(OH)-Vitamin D deficiency associated with increased risk of recurrent TROLS till age 7 years. Randomized controlled trials of vitamin D supplementation during pregnancy are needed to prove causality.


Effectiveness analyses may underestimate protection of infants after group C meningococcal immunization.
Group C meningococcal conjugate-vaccine effectiveness in the United Kingdom declines from ~90% in the first year to 0% between 1 and 4 years after immunization in infants immunized at 2, 3, and 4 months of age and to 61% in toddlers given a single dose. Confidence intervals are wide, and the extent of protection is uncertain. Serum samples were obtained from children 3-5 years of age who were participants in a preschool booster-vaccine trial. Serum bactericidal activity was measured with human complement. Group C anticapsular antibody concentrations were measured by a radioantigen binding assay. Passive protection was analyzed in an infant rat bacteremia model. Serum samples from UK children who had been immunized 2-3 years earlier as infants or toddlers had higher levels of radioantigen binding, bactericidal activity, and passive protection than did historical control serum samples from unimmunized children (P<.05). A higher proportion of children immunized as infants had serum bactericidal activity titers > or =1 : 4 (considered to be protective) than those immunized as toddlers (61% vs. 24%; P<.01), but there were no significant differences in the proportion of serum samples conferring passive protection (50% and 41%, respectively; P=.4). We found no evidence of lower immunity in children immunized as infants than as toddlers. On the basis of serum bactericidal activity and/or passive protection, 40%-50% of both age groups are protected at 2-3 years after immunization, which was significantly greater than in unimmunized historical controls (<5%).


The support needs of parent caregivers of children with a life-limiting illness and approaches used to meet their needs: A scoping review.
Provision of paediatric palliative care is complex and optimally covers meeting the individual needs of a heterogenous population of children and their parent caregivers throughout a life-limiting illness. It is unclear whether existing approaches comprehensively address parent caregivers' needs. To examine support needs of parents caring for children with life limiting illnesses and identify specific approaches used to identify and address needs. A scoping review. MEDLINE, EMBASE, PsycINFO, CINAHL and ProQuest Central, were searched for peer reviewed English language full text research published from 2008 to 2019. Study quality appraisal was undertaken. Fourteen quantitative, 18 qualitative and 12 mixed methods studies were synthesised and themed using summative content analysis and mapped to the Parent Supportive Care Needs Framework (PSCNF). Themes were communication, choice, information, practical, social, psychological, emotional and physical. Communication and choice were central and additional to domains of the PSCNF. Unmet were needs for supporting siblings, for respite care, out of hours, psychological, home and educational support. Six articles reported using instruments to identify parent carer support needs. Support needs of parent caregivers of children with life limiting illnesses are substantial and heterogenous. While studies report evidence of burden and distress in parent caregivers, this rarely translates into improvements in practice through the development of interventions. A systematic and regular assessment of individual parent caregiver support needs is required by using instruments appropriate to use in clinical practice to move the focus to palliative care interventions and improved services for parents.


Quantitative orientation-independent differential interference contrast microscope with fast switching shear direction and bias modulation.
We describe a quantitative orientation-independent differential interference contrast (DIC) microscope, which allows bias retardation to be modulated and shear directions to be switched rapidly without any mechanical movement. The shear direction is switched by a regular liquid-crystal cell sandwiched between two standard DIC prisms. Another liquid-crystal cell modulates the bias. Techniques for measuring parameters of DIC prisms and calibrating the bias are shown. Two sets of raw DIC images with the orthogonal shear directions are captured within 1 s. Then the quantitative image of optical path gradient distribution within a thin optical section is computed. The gradient data are used to obtain a quantitative distribution of the optical path, which represents the refractive index gradient or height distribution. Computing enhanced regular DIC images with any desired shear direction is also possible.


Plasmodium falciparum proteinases: cloning of the putative gene coding for the merozoite proteinase for erythrocyte invasion (MPEI) and determination of hydrolysis sites of spectrin by Pf37 proteinase.
Numerous proteinase activities have been shown to be essential for the survival of Plasmodium falciparum. One approach to antimalarial chemotherapy, would be to block specifically one or several of these activities, by using compounds structurally analogous to the substrates of these proteinases. Such a strategy requires a detailed knowledge of the active site of the proteinase, in order to identify the best substrate for the proteinase. Aiming at developing such a strategy, two proteinases previously identified in our laboratory, were chosen for further characterization of their molecular structure and properties: the merozoite proteinase for erythrocytic invasion (MPEI), involved in the erythrocyte invasion by the merozoites, and the Pf37 proteinase, which hydrolyses human spectrin in vitro.