NH4+-induced down-regulation of the Saccharomyces cerevisiae Gap1p permease involves its ubiquitination with lysine-63-linked chains.
Addition of ammonium ions to yeast cells growing on proline as the sole nitrogen source induces internalization of the general amino acid permease Gap1p and its subsequent degradation in the vacuole. An essential step in this down-regulation is Gap1p ubiquitination through a process requiring the Npi1p/Rsp5p ubiquitin ligase. We show in this report that NPI2, a second gene required for NH4+-induced down-regulation of Gap1p, codes for the ubiquitin hydrolase Doa4p/Ubp4p/Ssv7p and that NH4+-induced Gap1p ubiquitination is strongly reduced in npi2 cells. The npi2 mutation results in substitution of an aromatic amino acid located in a 33-residue sequence shared by some ubiquitin hydrolases of the Ubp family. In this mutant, as in doa4(delta) cells, the amount of free monomeric ubiquitin is at least four times lower than in wild-type cells. Both ubiquitination and down-regulation of the permease can be restored in npi2 cells by over-expression of ubiquitin. In proline-grown wild-type and npi2/doa4 cells overproducing ubiquitin, Gap1p appears to be mono-ubiquitinated at two lysine acceptor sites. Addition of NH4+ triggers rapid poly-ubiquitination of Gap1p, the poly-ubiquitin chains being specifically formed by linkage through the lysine 63 residue of ubiquitin. Gap1p is thus ubiquitinated differently from the proteins targeted by ubiquitination for proteolysis by the proteasome, but in the same manner as the uracil permease, also subject to ubiquitin-dependent endocytosis. When poly-ubiquitination through Lys63 is blocked, the Gap1p permease still undergoes NH4+-induced down-regulation, but to a lesser extent.


The context and meaning of placebos for complementary medicine.
Calls for placebo-controlled randomised trials in complementary and alternative medicine (CAM) are entirely reasonable. However, they present major methodological problems, particularly when we understand so little about the underlying biological mechanisms involved for many of these therapies. Designing a placebo in CAM is frequently dependent on unsubstantiated assumptions about the specificity of a particular CAM intervention. In this paper we address the development and application of placebos to clinical trials of homeopathy, acupuncture, kinesiology, Chinese herbal medicine and healing. Each therapy-based vignette is authored by a researcher from the Complementary and Integrated Medicine Research Unit at the University of Southampton who has specific expertise in the field. The essential research question within this review is; can we legitimately claim to have placebos for these particular CAM interventions? In some areas of CAM the debate has become very involved and sophisticated, for instance in acupuncture but for other areas, such as healing, our understanding of placebos is currently limited and very naïve. For instance, if acupuncture is not point specific, then many so-called 'placebo-controlled' acupuncture trials are both misconceived and misleading. We have addressed this debate in what we hope is a thoughtful and rigorous manner with a view to developing realistic, reliable and credible placebos for randomised controlled studies when and where possible. However, our conclusions suggest that we are some way from developing valid, credible and reliable placebos for most CAM therapies.


TSH release during the estrous cycle of the rat: variations in responsiveness to cervicovaginal stimulation.
Serum TSH, LH and FSH were measured at various times during the day, during the estrous cycle of the rat. Proestrous surges of FSH and LH were detected as previously reported. TSH values fell to low levels in the late afternoon on each day of the cycle. There was a significant elevation of TSH at 13.00 h on both proestrus and estrus. The elevation of TSH on proestrus was accompanied by a significant fall in pituitary TSH stores. LH stores were also significantly depleted by 19.00 h on proestrus. Cervicovaginal stimulation by a glass rod provoked a significant rise in serum TSH 3 h after stimulation at 10.00 h on estrus but not on other days of the cycle. Responsiveness to a test dose of TRH varied during the cycle. It was maximal on proestrus and declined to minimum values on diestrus day II. Values were further lowered after ovariectomy but were restored to diestrus day II levels by treatment with estradiol. It is concluded that there are important cyclic variations in TSH release in the female rat, that cervicovaginal stimulation can provoke TSH release on estrus and that these changes are associated with altered responsiveness to TRH. We conclude that ovarian steroids modulate the release of TSH from the pituitary and affect the responsiveness to cervicovaginal stimulation. These changes are presumably brought about by alterations in TRH release and in responsiveness of the pituitary to the neurohormone.


Completing the FACE of elevated CO₂ research.
We appraise the present geographical extent and inherent knowledge limits, following two decades of research on elevated CO2 responses in plant communities, and ask whether such research has answered the key question in quantifying the limits of compensatory CO2 uptake in the major biomes. Our synthesis of all ecosystem-scale (between 10 m(2) and 3000 m(2) total experimental plot area) elevated CO2 (eCO2) experiments in natural ecosystems conducted worldwide since 1987 (n=151) demonstrates that the locations of these eCO2 experiments have been spatially biased, targeting primarily the temperate ecosystems of northern America and Europe. We consider the consequences, suggesting fundamentally that this limits the capacity of the research to understand how the world's major plant communities will respond to eCO2. Most notably, our synthesis shows that this research lacks understanding of impacts on tropical forests and boreal regions, which are potentially the most significant biomes for C sink and storage activity, respectively. Using a meta-analysis of the available data across all biomes, we show equivocal increases in net primary productivity (NPP) from eCO2 studies, suggesting that global validation is needed, especially in the most important biomes for C processing. Further, our meta-analysis identifies that few research programs have addressed eCO2 effects on below-ground C storage, such that at the global scale, no overall responses are discernable. Given the disparity highlighted in the distribution of eCO2 experiments globally, we suggest opportunities for newly-industrialized or developing nations to become involved in further research, particularly as these countries host some of the most important regions for tropical or sub-tropical forest systems. Modeling approaches that thus far have attempted to understand the biological response to eCO2 are constrained with respect to collective predictions, suggesting that further work is needed, which will link models to in situ eCO2 experiments, in order to understand how the world's most important regions for terrestrial C uptake and storage will respond to a future eCO2 atmosphere.


Plasma Cholesterol-Lowering Activity of Lard Functionalized with Mushroom Extracts Is Independent of Niemann-Pick C1-like 1 Protein and ABC Sterol Transporter Gene Expression in Hypercholesterolemic Mice.
Interest in food matrices supplemented with mushrooms as hypocholesterolemic functional foods is increasing. This study was to (i) investigate the hypocholesterolemic activity of lard functionalized with mushroom extracts (LF) including fungal β-glucans, water-soluble polysaccharides, or ergosterol and (ii) examine the LF influence on transcriptional mechanisms involved in cholesterol metabolism. mRNA levels of 17 cholesterol-related genes were evaluated in jejunum, cecum, and liver of high cholesterol-fed mice. The four tested LFs decreased plasma cholesterol by 22-42%, HDLc by 18-40%, and LDLc by 27-51%, and two of them increased mRNA levels of jejunal Npc1l1 and Abcg5 and hepatic Npc1l1. mRNA levels of other cholesterol-related genes were unchanged. These findings suggest that LF may have potential as a dietary supplement for counteracting diet-induced hypercholesterolemia and could be a source for the development of novel cholesterol-lowering functional foods. However, the cholesterol-lowering effect was unrelated to transcriptional changes, suggesting that post-transcriptional mechanisms could be involved.


Demography, not inheritance, drives phenotypic change in hunted bighorn sheep.
Selective harvest, such as trophy hunting, can shift the distribution of a quantitative character such as body size. If the targeted character is heritable, then there will be an evolutionary response to selection, and where the trait is not, then any response will be plastic or demographic. Identifying the relative contributions of these different mechanisms is a major challenge in wildlife conservation. New mathematical approaches can provide insight not previously available. Here we develop a size- and age-based two-sex integral projection model based on individual-based data from a long-term study of hunted bighorn sheep (Ovis canadensis) at Ram Mountain, Canada. We simulate the effect of trophy hunting on body size and find that the inheritance of body mass is weak and that any perceived decline in body mass of the bighorn population is largely attributable to demographic change and environmental factors. To our knowledge, this work provides the first use of two-sex integral projection models to investigate the potential eco-evolutionary consequences of selective harvest.


Dietary flaxseed meal reduces proteinuria and ameliorates nephropathy in an animal model of type II diabetes mellitus.
Evidence is emerging that varying the type or source of dietary protein intake can have beneficial effects on chronic renal disease. Consumption of soybean and soy-based food products, as the source of plant protein, can retard the development and progression of chronic renal disease. We studied the obese spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat, a model of obesity and type II diabetes mellitus that consistently develops nephropathy resembling diabetic nephropathy. We specifically sought to determine whether changing the source of protein intake from animal protein, casein, to plant protein in the form of either soy protein concentrate or flaxseed protein in the diet has a different impact on renal function and nephropathy in this model. Male obese SHR/N-cp rats were randomly assigned to one of three diets containing either 20% casein, 20% soy protein concentrate, or 20% flaxseed meal. Except for the protein source, all three diets were identical and contained similar amounts of protein, fat, carbohydrates, minerals, and vitamins. All animals were maintained on these diets for 6 months. At the end of the study, blood sampling and 24-hour urine collections were performed for renal functional measurements, and the kidneys were harvested and examined for histologic evaluation. All three groups had similar amounts of food intake and body weight gain and exhibited fasting hyperglycemia and hyperinsulinemia. Plasma glucose levels did not differ among the three groups, but plasma insulin concentration was significantly lower in rats fed flaxseed meal than those fed either casein or soy protein concentrate. Mean plasma creatinine, creatinine clearance, and urinary urea excretion also did not differ significantly between the three groups. By contrast, urinary protein excretion was significantly lower (P < 0.01) in rats fed flaxseed than in rats fed either casein or soy protein concentrate. Morphologic analysis of renal structural lesions showed that the percentage of abnormal glomeruli with mesangial expansion and the tubulointerstitial score (an index of severity of tubulointerstitial damage) were significantly reduced in rats fed flaxmeal compared to those fed casein or soy protein concentrate. We conclude that dietary protein substitution with flaxseed meal reduces proteinuria and glomerular and tubulointerstitial lesions in obese SHR/N-cp rats and that flaxseed meal is more effective than soy protein in reducing proteinuria and renal histologic abnormalities in this model. The reduction in proteinuria and renal injury was independent of the amount of protein intake and glycemic control. Which dietary component(s) present in flaxseed meal is (are) responsible for the renal protective effect remains to be determined.


Small molecule additive enhances cell uptake of 5-aminolevulinic acid and conversion to protoporphyrin IX.
Administration of exogenous 5-aminolevulinic acid (5-ALA) to cancerous tissue leads to intracellular production of photoactive protoporphyrin IX, a biosynthetic process that enables photodynamic therapy and fluorescence-guided surgery of cancer. Cell uptake of 5-ALA is limited by its polar structure and there is a need for non-toxic chemical additives that can enhance its cell permeation. Two zinc-bis(dipicolylamine) (ZnBDPA) compounds were evaluated for their ability to promote uptake of 5-ALA into Chinese Hamster Ovary (CHO-K1) cells and produce protoporphyrin IX. One of the ZnBDPA compounds was found to be quite effective, and a systematic comparison of cells incubated with 5-ALA (100 μM) for 6 hours showed that the presence of this ZnBDPA compound (10 μM) produced 3-fold more protoporphyrin IX than cells treated with 5-ALA alone. The results of mechanistic studies suggest that the ZnBDPA compound does not interact strongly with the 5-ALA. Rather, the additive is membrane active and transiently disrupts the cell membrane, permitting 5-ALA permeation. The membrane disruption is not severe enough to induce cell toxicity or allow passage of larger macromolecules like plasmid DNA.


Teigne Tondante and Mahon Brothers: Two Laymen "Physicians" of Hôpital Saint-Louis, Paris.
In the early and mid-nineteenth century Europe, ringworm of the scalp was a vexing problem. It affected children in such numbers that the famous Hôpital Saint-Louis of Paris had a separate Tinea School. Before advent of radiation method of epilation, painful method of peeling was the mainstay of management. A family bearing title Mahon with no conventional medical training and qualification developed a secret method of epilation which was far superior to the existing method of treatment. Two brothers of this family, whose identity is obscure in the history of dermatology, were given the charge of treatment of such cases in various hospitals of France. Though they were not physician per se, their observations surprise us even today. Mahon the junior wrote a book on ringworm which is the first ever monograph on the subject. They also described favus of the nail and named ringworm of the scalp.


Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice.
The Notch pathway is an evolutionary conserved, intercellular signaling pathway that plays an important role in cell fate specification and the embryonic development of many organs, including the liver. In humans, mutations in the Notch receptor ligand Jagged1 gene result in defective intrahepatic bile duct (IHBD) development in Alagille syndrome. Developmental abnormalities of IHBD in mice doubly heterozygous for Jagged1 and Notch2 mutations propose that interactions of Jagged1 and its receptor Notch2 are crucial for normal IHBD development. Because different cell types in the liver are involved in IHBD development and morphogenesis, the cell-specific role of Notch signaling is not entirely understood. We investigated the effect of combined or single targeted disruption of Notch1 and Notch2 specifically in hepatoblasts and hepatoblast-derived lineage cells on liver development using AlbCre transgenic mice. Hepatocyte differentiation and homeostasis were not impaired in mice after combined deletion of Notch1 and Notch2 (N1N2(F/F)AlbCre). However, we detected irregular ductal plate structures in N1N2(F/F)AlbCre newborns, and further postnatal development of IHBD was severely impaired characterized by disorganized ductular structures accompanied by portal inflammation, portal fibrosis, and foci of hepatocyte feathery degeneration in adulthood. Further characterization of mutant mice with single deletion of Notch1 (N1(F/F)AlbCre) or Notch2 (N2(F/F)AlbCre) showed that Notch2 but not Notch1 is indispensable for normal perinatal and postnatal IHBD development. Further reduction of Notch2 gene dosage in Notch2 conditional/mutant (N2(F/LacZ)AlbCre) animals further enhanced IHBD abnormalities and concomitant liver pathology. Notch2 is required for proper IHBD development and morphogenesis.


Toxicity and Detoxification Mechanism of Black Pepper and Its Major Constituent in Controlling Rhynchophorus ferrugineus Olivier (Curculionidae: Coleoptera).
The survival, feeding response, and detoxification mechanism of Rhynchophorus ferrugineus Olivier, a key pest responsible for destruction of date palm, was examined with different extracts of Piper nigrum and its major constituent (piperine) identified by GC-MS. In the present study, toxicity of different extracts of black pepper was evaluated by incorporating diffferent doses of extracts into the artificial diet of red palm weevil larvae. All extracts showed dose-dependent insecticidal activity to the tested eighth-instar red palm weevil larvae. Among all the extracts, maximum larvicidal activity was exhibited by chloroform (LD50 = 342.62 mg/l), followed by dichloromethane (LD50 = 357.78 mg/l), acetone (LD50 = 372.57 mg/l), and ethanol (LD50 = 408.88 mg/l). However, piperine, a major constituent of all black pepper extracts identified by GC-MS in the present work, was found to be the most potent treatment exhibiting the least LD50 (219.88 mg/l). In addition, nutritional indices evaluated by calculating the efficiency of the conversion of ingested food (ECI) and digested food (ECD) at the same dose (219.88 mg/l) showed that there was maximum reduction in the ECI (49.90%) and ECD (62.21%) index of larvae fed diets incorporated with piperine. Larvae that were fed diets incorporated with different black pepper extracts experienced increases in the expression of detoxification genes (glutathione S-transferase and cytochrome P450), and this upregulation in detoxification genes (glutathione S-transferase, cytochrome P450 and esterase) was tremendously high in larvae fed diets incorporated with piperine. Results suggest that piperine is a promising bio-pesticide agent for the control of R. ferrugineus Olivier.


Long-term effects of educational and peer discussion group interventions on adjustment to breast cancer.
The authors report a 3-year follow-up of the effects of 8-week support group interventions on the quality of life of women with early stage breast cancer. Shortly after diagnosis, women were randomly assigned to 1 of 4 conditions: control, education, peer discussion, and education plus peer discussion. The education group intervention focused on providing information to enhance control over the illness experience, whereas the peer discussion group intervention focused on providing emotional support through the expression of feelings. Consistent with the results that emerged 6 months after the interventions (V. S. Helgeson, S. Cohen, R. Schulz, & J. Yasko, 1999), the authors found that the benefits of the education intervention were maintained over a 3-year period (N=252), although effects dissipated with time. The authors continued to find no benefits of the peer discussion intervention, either alone or in combination with education.


Training of peritoneal dialysis patients--Taiwan's experiences.
In Taiwan, peritoneal dialysis (PD) was launched in 1984. Since then, the Taiwan Society of Nephrology (TSN) has taken the responsibility for supervising PD programs. All PD programs are required to pass evaluations from the TSN before inception. Every new PD patient receives individual training from a qualified PD nurse. The training, accompanied by a review test, is usually provided in the hospital during the week right after catheter implantation. To evaluate the effect of the patient training program on PD outcomes, we designed a retrospective observation study and reviewed the post-training tests of 100 new PD patients. The post-training test has 10 parts: anatomy and physiology, overview of chronic kidney disease, overview of PD, complications of peritonitis and exit-site infection, diet control, cardiovascular complications, PD skills and procedures, aseptic techniques, management of peritonitis, and routine tasks. The relationship between the post-training test scores and peritonitis was analyzed. Results showed that risk of peritonitis is not related to the post-training test score. However, based on our experiences, we believe that PD patient training should be lengthened and repeated periodically as suggested by the International Survey of Peritoneal Dialysis Training Programs. Training on certain issues such as the signs and symptoms of peritonitis should be especially enhanced.


Investigating the relationship between fetal growth and academic attainment: secondary analysis of the Born in Bradford (BiB) cohort.
The relationship between ultrasongraphically derived estimates of fetal growth and educational attainment in the postnatal period is unknown. Results from previous studies focusing on cognitive ability, however, suggest there may be gestation-specific associations. Our objective was to model growth in fetal weight (EFW) and head circumference (HC) and identify whether growth variation in different periods was related to academic attainment in middle childhood. Data come from the Born in Bradford (BiB) cohort study, which has performed data linkage to both routine antenatal scans and national academic attainment tests at age 6-7 years. Multilevel linear spline models were used to model EFW and HC. Random effects from these were related to Key Stage 1 (KS1) results in reading, writing, mathematics, science and a composite of all four (age 6-7 years), using ordinal logistic and logistic regression. Associations were adjusted for potential confounders, facilitated by directed acyclic graphs. Missing covariate data were imputed using multiple imputation. In all, 6995 and 8438 children had complete KS1, and EFW and HC data, respectively. Positive associations were observed between both fetal weight in early pregnancy (14 weeks) and EFW growth in mid-pregnancy (14-26 weeks) and the individual KS1 outcomes. Furthermore, after adjustment for previous size and confounders, a 1-z score increase in growth in mid-pregnancy was associated with an 8% increased odds of achieving the expected standard for all KS1 outcomes [odds ratio (OR): 1.08, 95% confidence interval (CI): 1.02; 1.13]. Similar results were observed for HC, with generally larger effect sizes. Smaller associations were observed with growth in the early-third trimester, with no associations observed with growth in the later-third trimester. We observed consistent positive associations between fetal size and growth in early and mid-gestation and academic attainment in childhood. The smaller and null associations with growth in the early-third and later-third trimester, respectively, suggests that early-mid gestation may be a sensitive period for future cognitive development.


Diversity in striatal synaptic circuits arises from distinct embryonic progenitor pools in the ventral telencephalon.
Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here, we explore how distinct embryonic neural progenitor pools in the lateral ganglionic eminence contribute to neuronal diversity and synaptic circuit connectivity in the mouse striatum. In utero labeling of Tα1-expressing apical intermediate progenitors (aIP), as well as other progenitors (OP), reveals that both progenitors generate direct and indirect pathway spiny projection neurons (SPNs) with similar electrophysiological and anatomical properties and are intermingled in medial striatum. Subsequent optogenetic circuit-mapping experiments demonstrate that progenitor origin significantly impacts long-range excitatory input strength, with medial prefrontal cortex preferentially driving aIP-derived SPNs and visual cortex preferentially driving OP-derived SPNs. In contrast, the strength of local inhibitory inputs among SPNs is controlled by birthdate rather than progenitor origin. Combined, these results demonstrate distinct roles for embryonic progenitor origin in shaping neuronal and circuit properties of the postnatal striatum.


IFN-gamma negatively modulates self-renewal of repopulating human hemopoietic stem cells.
Whereas multiple growth-promoting cytokines have been demonstrated to be involved in regulation of the hemopoietic stem cell (HSC) pool, the potential role of negative regulators is less clear. However, IFN-gamma, if overexpressed, can mediate bone marrow suppression and has been directly implicated in a number of bone marrow failure syndromes, including graft-vs-host disease. Whether IFN-gamma might directly affect the function of repopulating HSCs has, however, not been investigated. In the present study, we used in vitro conditions promoting self-renewing divisions of human HSCs to investigate the effect of IFN-gamma on HSC maintenance and function. Although purified cord blood CD34(+)CD38(-) cells underwent cell divisions in the presence of IFN-gamma, cycling HSCs exposed to IFN-gamma in vitro were severely compromised in their ability to reconstitute long-term cultures in vitro and multilineage engraft NOD-SCID mice in vivo (>90% reduced activity in both HSC assays). In vitro studies suggested that IFN-gamma accelerated differentiation of targeted human stem and progenitor cells. These results demonstrate that IFN-gamma can negatively affect human HSC self-renewal.


Intentional partial coil occlusion followed by delayed clip application to wide-necked middle cerebral artery aneurysms in patients presenting with severe vasospasm. Report of two cases.
The treatment of ruptured cerebral aneurysms in patients presenting with vasospasm remains a particular challenge. The authors treated two patients harboring Hunt and Hess Grade 1 subarachnoid hemorrhages from middle cerebral artery (MCA) aneurysms associated with severe local angiographically demonstrated yet asymptomatic vasospasm on presentation. Because both aneurysms had wide necks and were located at the MCA bifurcation, they were believed to be anatomically suitable for microsurgical clip application. Severe M, vasospasm was believed to be a relative contraindication to open surgery, however. An intentionally staged endovascular and microsurgical treatment strategy was planned in each patient. Partial coil occlusion of the aneurysmal dome was performed to prevent the lesion from rebleeding and was followed by balloon angioplasty of the spastic vessel. Early treatment of the severe spasm appeared to prevent significant delayed neurological ischemic deficit. Following resolution of the vasospasm, definitive clipping of the aneurysms was performed on Day 13 post embolization. One patient had a good clinical recovery and was discharged without neurological deficit. The other patient's hospital course was complicated by the occurrence of a postoperative posterior temporal infarct requiring partial temporal lobectomy, although she eventually had a good recovery with only a small visual field deficit. Based on data obtained in these two patients, one can infer that ruptured wide-necked MCA aneurysms associated with severe local vasospasm may best be treated using a staged combined treatment plan. Delayed clip application might be performed more safely 4 to 6 weeks postocclusion, or later, than at 2 weeks.


Target specificity of mammalian DNA methylation and demethylation machinery.
DNA methylation is an essential epigenetic modification for mammalian embryonic development and biology. The DNA methylation pattern across the genome, together with other epigenetic signals, is responsible for the transcriptional profile of a cell and thus preservation of the cell's identity. Equally, the family of TET enzymes which triggers the initiation of the DNA demethylation cycle plays a vital role in the early embryonic development and a lack of these enzymes at later stages leads to a diseased state and dysregulation of the epigenome. DNA methylation has long been considered a very stable modification; however, it has become increasingly clear that for the establishment and maintenance of the methylation pattern, both generation of DNA methylation and its removal are important, and that a delicate balance of ongoing DNA methylation and demethylation shapes the final epigenetic methylation pattern of the cell. Although this epigenetic mark has been investigated in great detail, it still remains to be fully understood how specific DNA methylation imprints are precisely generated, maintained, read or erased in the genome. Here, we provide a biochemist's view on how both DNA methyltransferases and TET enzymes are recruited to specific genomic loci, and how their chromatin interactions, as well as their intrinsic sequence specificities and molecular mechanisms, contribute to the methylation pattern of the cell.


Chlorine disinfection promotes the exchange of antibiotic resistance genes across bacterial genera by natural transformation.
Chlorine disinfection to drinking water plays an important role in preventing and controlling waterborne disease outbreaks globally. Nevertheless, little is known about why it enriches the antibiotic resistance genes (ARGs) in bacteria after chlorination. Here, ARGs released from killed antibiotic-resistant bacteria (ARB), and culturable chlorine-injured bacteria produced in the chlorination process as the recipient, were investigated to determine their contribution to the horizontal transfer of ARGs during disinfection treatment. We discovered Escherichia coli, Salmonella aberdeen, Pseudomonas aeruginosa and Enterococcus faecalis showed diverse resistance to sodium hypochlorite, and transferable RP4 could be released from killed sensitive donor consistently. Meanwhile, the survival of chlorine-tolerant injured bacteria with enhanced cell membrane permeabilisation and a strong oxidative stress-response demonstrated that a physiologically competent cell could be transferred by RP4 with an improved transformation frequency of up to 550 times compared with the corresponding untreated bacteria. Furthermore, the water quality factors involving chemical oxygen demand (CODMn), ammonium nitrogen and metal ions (Ca2+ and K+) could significantly promote above transformation frequency of released RP4 into injured E. faecalis. Our findings demonstrated that the chlorination process promoted the horizontal transfer of plasmids by natural transformation, which resulted in the exchange of ARGs across bacterial genera and the emergence of new ARB, as well as the transfer of chlorine-injured opportunistic pathogen from non-ARB to ARB. Considering that the transfer elements were quite resistant to degradation through disinfection, this situation poses a potential risk to public health.


Compensation for systematic cross-contribution improves normalization of mass spectrometry based metabolomics data.
Most mass spectrometry based metabolomics studies are semiquantitative and depend on efficient normalization techniques to suppress systematic error. A common approach is to include isotope-labeled internal standards (ISs) and then express the estimated metabolite abundances relative to the IS. Because of problems such as insufficient chromatographic resolution, however, the analytes may directly influence estimates of the IS, a phenomenon known as cross-contribution (CC). Normalization using ISs that suffer from CC effects will cause significant loss of information if the interfering analytes are associated with the studied factors. We present a novel normalization algorithm, which compensates for systematic CC effects that can be traced back to a linear association with the experimental design. The proposed method was found to be superior at purifying the signal of interest compared to current normalization methods when applied to two biological data sets and a multicomponent dilution mixture. Our method is applicable to data from randomized and designed experiments that use ISs to monitor the systematic error.


A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway.
The JAK/STAT pathway exerts pleiotropic effects on a wide range of developmental processes in Drosophila. Four key components have been identified: Unpaired, a secreted ligand; Domeless, a cytokine-like receptor; Hopscotch, a JAK kinase; and Stat92E, a STAT transcription factor. The identification of additional components and regulators of this pathway remains an important issue. To this end, we have generated a transgenic line where we misexpress the upd ligand in the developing Drosophila eye. GMR-upd transgenic animals have dramatically enlarged eye-imaginal discs and compound eyes that are normally patterned. We demonstrate that the enlarged-eye phenotype is a result of an increase in cell number, and not cell volume, and arises from additional mitoses in larval eye discs. Thus, the GMR-upd line represents a system in which the proliferation and differentiation of eye precursor cells are separable. Removal of one copy of stat92E substantially reduces the enlarged-eye phenotype. We performed an F1 deficiency screen to identify dominant modifiers of the GMR-upd phenotype. We have identified 9 regions that enhance this eye phenotype and two specific enhancers: C-terminal binding protein and Daughters against dpp. We also identified 20 regions that suppress GMR-upd and 13 specific suppressors: zeste-white 13, pineapple eye, Dichaete, histone 2A variant, headcase, plexus, kohtalo, crumbs, hedgehog, decapentaplegic, thickveins, saxophone, and Mothers against dpp.


Liver cirrhosis, other liver diseases, pancreatitis and subsequent cancer: record linkage study.
To determine the risk of cancer in cohorts of patients with alcoholic cirrhosis, other alcoholic liver diseases, other and unspecified cirrhosis, primary biliary cirrhosis, viral hepatitis, acute pancreatitis and chronic pancreatitis compared with the risk in a control cohort. Analysis of statistical database of linked hospital and mortality data in an area in southern England. Compared with the control cohort, rate ratios were elevated for cancer overall and were particularly high for liver cancer in patients with alcoholic cirrhosis (rate ratio for cancer overall 2.4, 95% confidence interval 2.0-3.0 and 27.8, 17.7-41.7 for liver cancer); with other and unspecified cirrhosis (3.1, 2.7-3.6 and 35.1, 25.4-47.6); with other alcoholic liver diseases (2.3, 2.0-2.7 and 17.7, 11.5-26.0); with primary biliary cirrhosis (1.4, 0.9-2.0 and 19.6, 8.4-39.1) and with viral hepatitis (1.5, 1.2-1.9 and 18.6, 9.8-32.2). Pancreatic cancer risk was significantly and substantially elevated in all cohorts except that with primary biliary cirrhosis. Lung cancer risk was significantly high in all cohorts except those with primary biliary cirrhosis and viral hepatitis. Oral cavity cancers were elevated in alcoholic cirrhosis cohort (8.6; 3.1-18.9) and the other alcoholic liver diseases cohort (10.1; 5.9-16.2), as was colon cancer (2.8; 1.4-5.0 and 2.0; 1.2-3.3, respectively). Non-Hodgkin's lymphoma was significantly elevated in the group of 'other and unspecified cirrhosis' (11.4; 7.2-17.3). All seven conditions carry an increased risk of cancer, but each condition has a somewhat different profile of cancer risk associated with it.


A comprehensive comparison of tools for differential ChIP-seq analysis.
ChIP-seq has become a widely adopted genomic assay in recent years to determine binding sites for transcription factors or enrichments for specific histone modifications. Beside detection of enriched or bound regions, an important question is to determine differences between conditions. While this is a common analysis for gene expression, for which a large number of computational approaches have been validated, the same question for ChIP-seq is particularly challenging owing to the complexity of ChIP-seq data in terms of noisiness and variability. Many different tools have been developed and published in recent years. However, a comprehensive comparison and review of these tools is still missing. Here, we have reviewed 14 tools, which have been developed to determine differential enrichment between two conditions. They differ in their algorithmic setups, and also in the range of applicability. Hence, we have benchmarked these tools on real data sets for transcription factors and histone modifications, as well as on simulated data sets to quantitatively evaluate their performance. Overall, there is a great variety in the type of signal detected by these tools with a surprisingly low level of agreement. Depending on the type of analysis performed, the choice of method will crucially impact the outcome.


The importance of strategic space.
Does anyone own exclusive space in the journey to create a community-based primary healthcare system? What is the role of public health in this important work? This response to the lead paper explores the unique contribution that public health professionals make in transforming our primary healthcare system, focusing on some of the excellent work that is currently happening in Nova Scotia as examples of how public health and primary healthcare are collaborating and each contributing to this exciting journey. Public health does not need to wait to be invited to the party! It has a responsibility to fulfill the mandate that has been given to it and, in doing so, is contributing greatly to positively impacting on the determinants of health.


Analysis of multidrug resistance-associated protein (MRP) messenger RNA in normal and malignant hematopoietic cells.
The multidrug resistance-associated protein (MRP) gene is a member of the ATP-binding cassette transporter gene superfamily and may be partially responsible for clinical drug resistance. Reverse transcriptase-polymerase chain reaction was used to measure MRP mRNA in normal hematopoietic cells from bone marrow and peripheral blood as well as patients with high risk acute myelocytic leukemia and multiple myeloma. All normal peripheral blood cells, regardless of cell lineage (CD4, CD8, CD14, CD15, CD19, CD56), expressed a similar basal level of MRP mRNA. Specimens from bone marrow containing mixed lineages also expressed a similar basal level of MRP expression. In patients with acute myelocytic leukemia, 10 of 12 (83%) of the specimens had detectable MRP mRNA, but the level of expression was similar to that of normal blood cells and low compared to a cell line known to overexpress MRP (H69/AR). All myeloma patients (12 of 12) had detectable MRP mRNA expression at levels comparable to normal peripheral blood and bone marrow cells. We conclude that MRP is commonly expressed in normal hematopoietic cells as well as certain hematopoietic malignancies. The therapeutic relevance of MRP expression is unknown, but these studies emphasize the importance of measuring MRP expression in normal cells as a point of reference and comparison for detection in malignant cells. We also recommend obtaining sequential specimens from patients, which may reveal an increased expression of MRP from baseline as the disease progresses and becomes resistant.


Principles of orthodontic mechanics in orthognathic surgery cases.
In orthognathic surgery cases the treatment objectives, extraction patterns, and types of mechanics used are frequently the reverse of those used in conventional orthodontics. Thus, starting cases orthodontically and then, if unsuccessful, referring them for surgery often produces compromised results. Presurgical intra-arch objectives include positioning of the incisors in "ideal" positions, establishment of correct torque, and elimination of tooth-size discrepancies so as to permit the establishment of Class I canine and molar relationships after surgery. Presurgical objectives in the sagittal plane focus on removal of dental compensations. This may require the use of Class III elastics in Class II cases (and vice versa), thus allowing for maximal surgical correction of the underlying skeletal deformity. In the transverse plane, differentiation of skeletal from dental problems as well as identification of relative and absolute discrepancies should be carried out presurgically. Lateral corticotomies or segmental maxillary procedures should be used, depending on individual circumstances. Presurgical objectives in the vertical plane include maximizing the amount of presurgical orthodontic treatment carried out in open bites and minimizing the presurgical mechanics in deep bites. Encouragement of opening mandibular rotation at surgery while avoiding an increase in posterior face height contributes to stability. Orthodontic mechanics should not always include presurgical leveling of the curve of Spee and should actively avoid movements that may cause relapse tendencies. Careful attention to the use of surgical arch wires and splints during surgery and fixation, along with controlled elastic therapy and exercise programs after fixation, can greatly facilitate treatment.


Graveyards on the move: the spatio-temporal distribution of dead ophiocordyceps-infected ants.
Parasites are likely to play an important role in structuring host populations. Many adaptively manipulate host behaviour, so that the extended phenotypes of these parasites and their distributions in space and time are potentially important ecological variables. The fungus Ophiocordyceps unilateralis, which is pan-tropical in distribution, causes infected worker ants to leave their nest and die under leaves in the understory of tropical rainforests. Working in a forest dynamic plot in Southern Thailand we mapped the occurrence of these dead ants by examining every leaf in 1,360 m(2) of primary rainforest. We established that high density aggregations exist (up to 26 dead ants/m(2)), which we coined graveyards. We further established that graveyards are patchily distributed in a landscape with no or very few O. unilateralis-killed ants. At some, but not all, spatial scales of analysis the density of dead ants correlated with temperature, humidity and vegetation cover. Remarkably, having found 2243 dead ants inside graveyards we only found 2 live ants of the principal host, ant Camponotus leonardi, suggesting that foraging host ants actively avoid graveyards. We discovered that the principal host ant builds nests in high canopy and its trails only occasionally descend to the forest floor where infection occurs. We advance the hypothesis that rare descents may be a function of limited canopy access to tree crowns and that resource profitability of such trees is potentially traded off against the risk of losing workers due to infection when forest floor trails are the only access routes. Our work underscores the need for an integrative approach that recognises multiple facets of parasitism, such as their extended phenotypes.


Proton coupled electron transfer from the excited state of a ruthenium(II) pyridylimidazole complex.
Proton coupled electron transfer (PCET) from the excited state of [Ru(bpy)2pyimH](2+) (bpy = 2,2'-bipyridine; pyimH = 2-(2'-pyridyl)imidazole) to N-methyl-4,4'-bipyridinium (monoquat, MQ(+)) was studied. While this complex has been investigated previously, our study is the first to show that the formal bond dissociation free energy (BDFE) of the imidazole-N-H bond decreases from (91 ± 1) kcal mol(-1) in the electronic ground state to (43 ± 5) kcal mol(-1) in the lowest-energetic (3)MLCT excited state. This makes the [Ru(bpy)2pyimH](2+) complex a very strong (formal) hydrogen atom donor even when compared to metal hydride complexes, and this is interesting for light-driven (formal) hydrogen atom transfer (HAT) reactions with a variety of different substrates. Mechanistically, formal HAT between (3)MLCT excited [Ru(bpy)2pyimH](2+) and monoquat in buffered 1 : 1 (v : v) CH3CN/H2O was found to occur via a sequence of reaction steps involving electron transfer from Ru(ii) to MQ(+) coupled to release of the N-H proton to buffer base, followed by protonation of reduced MQ(+) by buffer acid. Our study is relevant in the larger contexts of photoredox catalysis and light-to-chemical energy conversion.


Comparative Efficacy of Amoxicillin/Clavulanic Acid and Levofloxacin in the Reduction of Postsurgical Sequelae After Third Molar Surgery: A Randomized, Double-Blind, Clinical Trial in a Nigerian University Teaching Hospital.
The most common sequelae after surgical removal of mandibular third molar are pain, trismus, swelling, and dysphagia. However, these symptoms can also signal the onset of surgical site infection and alveoli osteitis. The aim of this study was to evaluate the efficacy of prophylactic amoxicillin/clavulanic acid and levofloxacin and preemptive therapy of amoxicillin/clavulanic acid in the reduction of postinflammatory complications, surgical site infection, and alveolar osteitis following the third molar surgery. A total of 135 patients were randomized into three equal groups: Group A (preemptive therapy of amoxicillin/clavulanic acid) with preoperative dose of 875/125 mg amoxicillin/clavulanic acid followed by 500/125 mg amoxicillin/clavulanic acid 12 hourly for 5 days, Group B (amoxicillin/clavulanic acid prophylaxis) with a single preoperative dose of amoxicillin/clavulanic acid 875/125 mg tablets, and Group C (levofloxacin prophylaxis) with a single preoperative dose of levofloxacin 1000 mg tablets. All patients had ostectomy using surgical handpiece and burs and received same analgesics (tabs ibuprofen 400 mg 8 hourly for 3 days). No case of surgical site infection or alveoli osteitis was recorded in the study groups. There were no statistically significant differences between the treatment groups with regard to pain, mouth opening, postoperative facial dimension, and body temperature. Amoxicillin/clavulanic acid as a single preoperative bolus should be adequate for the prevention of postoperative wound infection and alveoli osteitis following the third molar extraction as there is no need for an extension of the antibiotic. Moreover, levofloxacin can be utilized as prophylaxis in patients undergoing mandibular third molar extraction if such patients are allergic to penicillins.


Sensory cortex is optimized for prediction of future input.
Neurons in sensory cortex are tuned to diverse features in natural scenes. But what determines which features neurons become selective to? Here we explore the idea that neuronal selectivity is optimized to represent features in the recent sensory past that best predict immediate future inputs. We tested this hypothesis using simple feedforward neural networks, which were trained to predict the next few moments of video or audio in clips of natural scenes. The networks developed receptive fields that closely matched those of real cortical neurons in different mammalian species, including the oriented spatial tuning of primary visual cortex, the frequency selectivity of primary auditory cortex and, most notably, their temporal tuning properties. Furthermore, the better a network predicted future inputs the more closely its receptive fields resembled those in the brain. This suggests that sensory processing is optimized to extract those features with the most capacity to predict future input.


Interferon resistance of hepatitis C virus replicon-harbouring cells is caused by functional disruption of type I interferon receptors.
Hepatitis C virus (HCV) replicon-harbouring cell lines possessing interferon (IFN)-resistant phenotypes have recently been established. These were divided into two classes: partially IFN resistant and highly IFN resistant. Here, the viral and cellular factors contributing to the IFN resistance of HCV replicon-harbouring cells were evaluated. The results revealed that cellular factors rather than viral factors contributed to a highly IFN-resistant phenotype. The possibility of genetic abnormality of the factors involved in IFN signalling was investigated. As a result, nonsense mutations and deletions in type I IFN receptor genes (IFNAR1 and IFNAR2c) were found in replicon-harbouring cells showing a highly IFN-resistant phenotype, but rarely appeared in cells showing a partially IFN-resistant phenotype. Furthermore, similar genetic alterations were also found in IFN-resistant phenotype, replicon-harbouring cell lines obtained additionally by IFN-beta treatment. Moreover, it was shown that ectopic expression of wild-type IFNAR1 in IFN-resistant phenotype, replicon-harbouring cells possessing the IFNAR1 mutant restored type I IFN signalling.


Low Copeptin Levels in Patients With Intradialytic Hypotension.
Intradialytic hypotension (IDH) is related to high morbidity and mortality. There is evidence that arginine-vasopressin (AVP) responses could play a role. Copeptin is a reliable biomarker of AVP. In this study, copeptin, aldosterone, epinephrine, and norepinephrine levels in patients with IDH were evaluated throughout a hemodialysis (HD) session and compared with the control group. The study includes 15 patients who were normotensive during HD and 15 patients with IDH with a minimum HD vintage of 1 year. Blood samples were collected before the initiation of an HD session (T0 ), in the mid-session for control group, 30 min after mean arterial pressure drop for IDH patients (T1 ), and at the end of the session (T2 ). Groups had similar demographic features and health parameters, interdialytic weight gains, and ultrafiltration amounts. The IDH group had a mean arterial pressure decline of 39.9 (±6.4) mm Hg. Copeptin levels of the control group increased an average of 79.9 (±97.5) pmol/L at T1 and an additional 24.8 (±33.9) pmol/L at T2 . In the IDH group, copeptin level increases at T1 and T2 were 3.2 (±5.5) pmol/L and 34 (±44.6) pmol/L, respectively. Copeptin levels of the IDH group were significantly lower at T1 (P < 0.001) and at the T0 -T2 interval than control group (P = 0.05). In the control group, aldosterone levels distinctly decreased, and in the IDH group, aldosterone levels were elevated (P < 0.001). Small changes were detected in epinephrine and norepinephrine levels for both groups but did not reach significance (P = 0.6 and P = 0.3, respectively). Lower copeptin level alterations suggest inadequate AVP responses in patients with IDH.


Anti-Proliferative Properties and Proapoptotic Function of New CB2 Selective Cannabinoid Receptor Agonist in Jurkat Leukemia Cells.
Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results. Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist.


Association Between Neighborhood Supermarket Presence and Glycated Hemoglobin Levels Among Patients With Type 2 Diabetes Mellitus.
We estimated associations between neighborhood supermarket gain or loss and glycemic control (assessed by glycated hemoglobin (HbA1c) values) in patients from the Kaiser Permanente Northern California Diabetes Registry (n = 434,806 person-years; 2007-2010). Annual clinical measures were linked to metrics from a geographic information system for each patient's address of longest residence. We estimated the association between change in supermarket presence (gain, loss, or no change) and change in HbA1c value, adjusting for individual- and area-level attributes and according to baseline glycemic control (near normal, <6.5%; good, 6.5%-7.9%; moderate, 8.0%-8.9%; and poor, ≥9.0%). Supermarket loss was associated with worse HbA1c trajectories for those with good, moderate, and poor glycemic control at baseline, while supermarket gain was associated with marginally better HbA1c outcomes only among patients with near normal HbA1c values at baseline. Patients with the poorest baseline HbA1c values (≥9.0%) had the worst associated changes in glycemic control following either supermarket loss or gain. Differences were not clinically meaningful relative to no change in supermarket presence. For patients with type 2 diabetes mellitus, gaining neighborhood supermarket presence did not benefit glycemic control in a substantive way. The significance of supermarket changes on health depends on a complex interaction of resident, neighborhood, and store characteristics.


Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions, decreased factor IX consumption and lower bleeding rates.
In the phase 3 B-LONG [Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Subjects with Haemophilia B] study, rFIXFc dosed every 1-2 weeks was safe and efficacious in previously treated subjects with haemophilia B. To date, there are no evaluations of transitioning from conventional to long-acting factor IX (FIX) prophylaxis. This post-hoc analysis of B-LONG subjects compared prophylaxis with other FIX products and rFIXFc. Pre- and on-study data were analysed to assess dosing regimen, weekly FIX consumption and annualized bleeding rates (ABRs). Population pharmacokinetics models were used to generate FIX activity profiles with rFIXFc and recombinant FIX prophylaxis. Thirty-nine subjects, previously treated prophylactically, were evaluated. Prior to study, most subjects (69·2%) received twice-weekly FIX infusions; on study, subjects infused rFIXFc once every 1-2 weeks with c. 30-50% reductions in weekly consumption. On-study estimated mean ABRs were lower than pre-study estimated mean ABRs. Models predicted that rFIXFc administered 50 iu/kg weekly and 100 iu/kg every 10 d would maintain steady-state FIX trough levels ≥1 iu/dl in 95·4% and 89·2% of subjects, respectively. These results indicate that patients receiving rFIXFc prophylaxis can markedly reduce infusion frequency and FIX consumption, have a greater likelihood of maintaining FIX activity >1 iu/dl and experience fewer bleeding episodes compared with prior FIX prophylaxis.


Evaluation of Continuous Renal Replacement Therapy and Therapeutic Plasma Exchange, in Severe Sepsis or Septic Shock in Critically Ill Children.
Background and objective: Severe sepsis and septic shock are life-threatening organ dysfunctions and causes of death in critically ill patients. The therapeutic goal of the management of sepsis is restoring balance to the immune system and fluid balance. Continuous renal replacement therapy (CRRT) is recommended in septic patients, and it may improve outcomes in patients with severe sepsis or septic shock. Therapeutic plasma exchange (TPE) is another extracorporeal procedure that can improve organ function by decreasing inflammatory and anti-fibrinolytic mediators and correcting haemostasis by replenishing anticoagulant proteins. However, research about sepsis and CRRT and TPE in children has been insufficient and incomplete. Therefore, we investigated the reliability and efficacy of extracorporeal therapies in paediatric patients with severe sepsis or septic shock. Materials and methods: We performed a multicentre retrospective study using data from all patients aged <18 years who were admitted to two paediatric intensive care units. Demographic data and reason for hospitalization were recorded. In addition, vital signs, haemogram parameters, and biochemistry results were recorded at 0 h and after 24 h of CRRT. Patients were compared according to whether they underwent CRRT or TPE; mortality between the two treatment groups was also compared. Results: Between January 2014 and April 2019, 168 septic patients were enrolled in the present study. Of them, 47 (27.9%) patients underwent CRRT and 24 underwent TPE. In patients with severe sepsis, the requirement for CRRT was statistically associated with mortality (p < 0.001). In contrast, the requirement for TPE was not associated with mortality (p = 0.124). Conclusion: Our findings revealed that the requirement for CRRT in patients with severe sepsis is predictive of increased mortality. CRRT and TPE can be useful techniques in critically ill children with severe sepsis. However, our results did not show a decrease of mortality with CRRT and TPE.


A mixed methods evaluation of Advanced Life Support in Obstetrics (ALSO) and Basic Life Support in Obstetrics (BLSO) in a resource-limited setting on the Thailand-Myanmar border.
Background: Short emergency obstetric care (EmOC) courses have demonstrated improved provider confidence, knowledge and skills but impact on indicators such as maternal mortality and stillbirth is less substantial. This manuscript evaluates Advanced Life Support in Obstetrics (ALSO) and Basic Life Support (BLSO) as an adult education tool, in a protracted, post-conflict and resource-limited setting. Methods: A mixed methods evaluation was used. Basic characteristics of ALSO and BLSO participants and their course results were summarized. Kirkpatrick's framework for assessment of education effectiveness included: qualitative data on participants' reactions to training (level 1); and quantitative health indicator data on change in the availability and quality of EmOC and in maternal and/or neonatal health outcomes (level 4), by evaluation of the post-partum haemorrhage (PPH) related maternal mortality ratio (MMR) and stillbirth rate in the eight years prior and following implementation of ALSO and BLSO. Results: 561 Thailand-Myanmar border health workers participated in ALSO (n=355) and BLSO (n=206) courses 2008-2020. Pass rates on skills exceeded 90% for both courses while 50% passed the written ALSO test. Perceived confidence significantly improved for all items assessed. In the eight-year block preceding the implementation of ALSO and BLSO (2000-07) the PPH related MMR per 100,000 live births was 57.0 (95%CI 30.06-108.3)(9/15797) compared to 25.4 (95%CI 11.6-55.4)(6/23620) eight years following (2009-16), p=0.109. After adjustment, PPH related maternal mortality was associated with birth before ALSO/BLSO implementation aOR 3.825 (95%CI 1.1233-11.870), migrant (not refugee) status aOR 3.814 (95%CI 1.241-11.718) and attending ≤four antenatal consultations aOR 3.648 (95%CI 1.189-11.191). Stillbirth rate per 1,000 total births was 18.2 (95%CI 16.2-20.4)(291/16016) before the courses, and 11.1 (95%CI 9.8-12.5)(264/23884) after, p=0.038. Birth before ALSO/ BLSO implementation was associated with stillbirth aoR 1.235 (95%CI 1.018-1.500). Conclusions: This evaluation suggests ALSO and BLSO are sustainable, beneficial, EmOC trainings for adult education in protracted, post-conflict, resource-limited settings.


The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease.
The goals of this study were to define the natural history and growth pattern of hemangioblastomas of the central nervous system (CNS) that are associated with von Hippel-Lindau (VHL) disease and to correlate features of hemangioblastomas that are associated with the development of symptoms and the need for treatment. The authors reviewed serial magnetic resonance images and clinical histories of 160 consecutive patients with VHL disease who harbored CNS hemangioblastomas and serially measured the volumes of tumors and associated cysts Six hundred fifty-five hemangioblastomas were identified in the cerebellum (250 tumors), brainstem (64 tumors, all of which were located in the posterior medulla oblongata), spinal cord (331 tumors, 96% of which were located in the posterior half of spinal cord), and the supratentorial brain (10 tumors). The symptoms were related to a mass effect. A serial increase in hemangioblastoma size was observed in cerebellar, brainstem, and spinal cord tumors as patients progressed from being asymptomatic to symptomatic and requiring surgery (p < 0.0001). Twenty-one (72%) of 29 symptom-producing cerebellar tumors had an associated cyst, whereas only 28 (13%) of 221 nonsymptomatic cerebellar tumors had tumor-associated cysts (p < 0.0001). Nine (75%) of 12 symptomatic brainstem tumors had associated cysts, compared with only four (8%) of 52 nonsymptomatic brainstem lesions (p < 0.0001). By the time the symptoms appeared and surgery was required, the cyst was larger than the causative tumor; cerebellar and brainstem cysts measured 34 and 19 times the size of their associated tumors at surgery, respectively. Ninety-five percent of symptom-producing spinal hemangioblastomas were associated with syringomyelia. The clinical circumstance was dynamic. Among the 88 patients who had undergone serial imaging for 6 months or longer (median 32 months), 164 (44%) of 373 hemangioblastomas and 37 (67%) of 55 tumor-associated cysts enlarged. No tumors or cysts spontaneously diminished in size. Symptomatic cerebellar and brainstem tumors grew at rates six and nine times greater, respectively, than asymptomatic tumors in the same regions. Cysts enlarged seven (cerebellum) and 15 (brainstem) times faster than the hemangioblastomas causing them. Hemangioblastomas frequently demonstrated a pattern of growth in which they would enlarge for a period of time (growth phase) and then stabilize in a period of arrested growth (quiescent phase). Of 69 patients with documented tumor growth, 18 (26%) harbored tumors with at least two growth phases. Of 160 patients with hemangioblastomas, 34 patients (median follow up 51 months) were found to have 115 new hemangioblastomas and 15 patients new tumor-associated cysts. In this study the authors define the natural history of CNS hemangioblastomas associated with VHL disease. Not only were cysts commonly associated with cerebellar, brainstem, and spinal hemangioblastomas, the pace of enlargement was much faster for cysts than for hemangioblastomas. By the time symptoms appeared, the majority of mass effect-producing symptoms derived from the cyst, rather than from the tumor causing the cyst. These tumors often have multiple periods of tumor growth separated by periods of arrested growth, and many untreated tumors may remain the same size for several years. These characteristics must be considered when determining the optimal timing of screening for individual patients and for evaluating the timing and results of treatment.


Fantasized recipient-donor relationships following lung transplantations: a qualitative case analysis based on patient narratives.
The present study examines the relationships between lung transplant recipients and their unknown, deceased donors. Out of 20 semi-structured interviews, eight narratives, by three female and three male recipients respectively, were identified in which the figure of the donor played a role. These narratives were examined using JAKOB, a qualitative research tool that analyses relational configurations and diagnoses psychodynamic conflicts. Analysis revealed a broad range of varying themes and relationships with equally varying wish and fear themes. All the narrators dealt either explicitly or implicitly with whether and how they are connected to their donors. In five narratives, specific personality traits were attributed to the figure of the donor; in four narratives, latent feelings of guilt concerning the donor's death were expressed. Indeed, the figure of the donor was not always perceived as an independent person, separate from the narrator's self: in two cases, the donor appears as part of the recipient's self, while in another case, the donor is presented as a transitional object for the recipient. The findings of the narrative analysis are discussed within a theoretical model of psychical organ integration.


[Clinical efficiency of cytokines in prophylactics and treatment of infectious and inflammatory complications after oral surgery procedures].
The study presents the results of prevention and treatment of infectious and inflammatory complications after oral surgery procedures. Combined therapy with antibiotics and superlimf promotes a more rapid reduction in the duration of clinical symptoms and duration of treatment than monotherapy with antibiotics. Results of the study substantiate the feasibility of using superlimf in outpatient oral surgical procedures for infectious and inflammatory complications treatment.


A new procedure for determining the genetic basis of a physiological process in a non-model species, illustrated by cold induced angiogenesis in the carp.
Physiological processes occur in many species for which there is yet no sequenced genome and for which we would like to identify the genetic basis. For example, some species increase their vascular network to minimise the effects of reduced oxygen diffusion and increased blood viscosity associated with low temperatures. Since many angiogenic and endothelial genes have been discovered in man, functional homolog relationships between carp, zebrafish and human were used to predict the genetic basis of cold-induced angiogenesis in Cyprinus Carpio (carp). In this work, carp sequences were collected and built into contigs. Human-carp functional homolog relationships were derived via zebrafish using a new Conditional Stepped Reciprocal Best Hit (CSRBH) protocol. Data sources including publications, Gene Ontology and cDNA libraries were then used to predict the identity of known or potential angiogenic genes. Finally, re-analyses of cold carp microarray data identified carp genes up-regulated in response to low temperatures in heart and muscle. The CSRBH approach outperformed all other methods and attained 8,726 carp to human functional homolog relationships for 16,650 contiguous sequences. This represented 3,762 non-redundant genes and 908 of them were predicted to have a role in angiogenesis. The total number of up-regulated differentially expressed genes was 698 and 171 of them were putatively angiogenic. Of these, 5 genes representing the functional homologs NCL, RHOA, MMP9, GRN and MAPK1 are angiogenesis-related genes expressed in response to low temperature. We show that CSRBH functional homologs relationships and re-analyses of gene expression data can be combined in a non-model species to predict genes of biological interest before a genome sequence is fully available. Programs to run these analyses locally are available from http://www.cbrg.ox.ac.uk/~jherbert/.


MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia.
A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL.


Evaluation of the magnitude of hip joint deformation in subjects with avascular necrosis of the hip joint during walking with and without Scottish Rite orthosis.
The femoral head in subjects with leg calve perthes disease (LCPD) is generally considerably deformed. It is debatable whether this deformation is due to an increase in applied loads, a decrease in bone mineral density or a change in containment of articular surfaces. The aim of this study was to determine the influence of these factors on deformation of the femoral head. Two subjects with LCPD participated in this study. Subject motion and the forces applied on the affected leg were recorded using a motion analysis system (QualsisTM) and a Kistler force plate. OpenSim software was used to determine joint contact force of the hip joint whilst walking with and without a Scottish Rite orthosis. 3D Models of hip joints of both subjects were produced by Mimics software. The deformation of femoral bone was determined by Abaqus. Mean values of the force applied on the leg increased while walking with the orthosis. There was no difference between bone mineral density (BMD) of the femoral bone of normal and LCPD sides (p-value>0.05) and no difference between hip joint contact force of normal and LCPD sides. Hip joint containment appeared to decrease follow the use of the orthosis. It can be concluded that the deformation of femoral head in LCPD may not be due to change in BMD or applied load. Although the Scottish Rite orthosis is used mostly to increase hip joint containment, it appears to reduce hip joint contact area. It is recommended that a similar study is conducted using a higher number of subjects.


Outcomes of acute phase cognitive therapy in outpatients with anxious versus nonanxious depression.
Compared to nonanxious depressed patients, anxious depressed patients respond less to pharmacotherapy, prompting consideration of alternate treatments. Based on the transdiagnostic principles of cognitive therapy (CT), we predicted that anxious depressed patients would respond as well to CT as nonanxious depressed patients. Adults (n = 523) with recurrent major depressive disorder received 12-14 weeks of CT as part of the Continuation Phase Cognitive Therapy Relapse Prevention Trial. Anxious depressed patients (n = 264; 50.4%) were compared to nonanxious depressed patients (n = 259; 49.6%) on demographic variables, initial severity, attrition, and rates and patterns of response and remission. Anxious depressed patients presented with greater illness severity and had significantly lower response (55.3 vs. 68.3%) and remission rates (26.9 vs. 40.2%) based on clinician-administered measures. By contrast, smaller between-group differences for attrition, and for response (59.1 vs. 64.9%) and remission (41.7 vs. 48.7%) rates on self-report measures were not significant. Further, anxious depressed patients had greater speed of improvement on self-reported anxiety symptom severity and clinician-rated depressive and anxiety symptom severity measures. Consistent with prior reports, anxious depressed patients presented with greater severity and, following CT, had lower response and remission rates on clinician-administered scales. However, anxious depressed patients improved more rapidly and response and remission rates on self-report measures were not significantly different from nonanxious depressed patients. Our findings suggest that anxious depressed patients may simply need additional time or more CT sessions to reach outcomes fully comparable to those of less anxious patients.


The effects of aging on information-processing channels in the sense of touch: II. Temporal summation in the P channel.
Thresholds for detecting 250-Hz vibrotactile signals of variable duration applied to the thenar eminence of the hand were measured in 16 subjects ranging in age from 19 to 81 years. Detection thresholds were higher in older than in younger subjects. Correlation coefficients for the relation between threshold and age ranged from 0.94 to 0.96, depending on signal duration. In addition, the amount of temporal summation was negatively correlated with age. Both the elevated detection thresholds and the reduced amount of temporal summation in elderly subjects may be partially due to the decrease in the number of Pacinian corpuscles in the hand that occurs with aging. Another factor that could be responsible for reduced temporal summation in older as compared to younger subjects is impairment of the temporal integrator.


Multiple domains of MCIP1 contribute to inhibition of calcineurin activity.
Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes such as T-cell activation, apoptosis, skeletal myocyte differentiation, and cardiac hypertrophy. Calcineurin-dependent signals are transduced to the nucleus by nuclear factor of activated T-cells (NFAT) transcription factors that undergo nuclear translocation upon dephosphorylation and promote transcriptional activation of target genes. Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. Peptides corresponding to the substrate domain competitively inhibit calcineurin activity in vitro. However, a detailed structure/function analysis of MCIP1 reveals that either of two additional domains of MCIP1 is sufficient for binding to calcineurin in vitro and for inhibition of calcineurin activity in vivo. We conclude that MCIP1 inhibits calcineurin through mechanisms that include, but are not limited to, competition with other substrates such as nuclear factor of activated T-cells.


Universal Subsidized Continuous Glucose Monitoring Funding for Young People With Type 1 Diabetes: Uptake and Outcomes Over 2 Years, a Population-Based Study.
Continuous glucose monitoring (CGM) is increasingly used in type 1 diabetes management; however, funding models vary. This study determined the uptake rate and glycemic outcomes following a change in national health policy to introduce universal subsidized CGM funding for people with type 1 diabetes aged <21 years. Longitudinal data from 12 months before the subsidy until 24 months after were analyzed. Measures and outcomes included age, diabetes duration, HbA1c, episodes of diabetic ketoacidosis and severe hypoglycemia, insulin regimen, CGM uptake, and percentage CGM use. Two data sources were used: the Australasian Diabetes Database Network (ADDN) registry (a prospective diabetes database) and the National Diabetes Service Scheme (NDSS) registry that includes almost all individuals with type 1 diabetes nationally. CGM uptake increased from 5% presubsidy to 79% after 2 years. After CGM introduction, the odds ratio (OR) of achieving the HbA1c target of <7.0% improved at 12 months (OR 2.5, P < 0.001) and was maintained at 24 months (OR 2.3, P < 0.001). The OR for suboptimal glycemic control (HbA1c ≥9.0%) decreased to 0.34 (P < 0.001) at 24 months. Of CGM users, 65% used CGM >75% of time, and had a lower HbA1c at 24 months compared with those with usage <25% (7.8 ± 1.3% vs. 8.6 ± 1.8%, respectively, P < 0.001). Diabetic ketoacidosis was also reduced in this group (incidence rate ratio 0.49, 95% CI 0.33-0.74, P < 0.001). Following the national subsidy, CGM use was high and associated with sustained improvement in glycemic control. This information will inform economic analyses and future policy and serve as a model of evaluation diabetes technologies.


Formal education and back-related disability. In search of an explanation.
The present study is a 2-year prospective study with repeated measurements. To examine the association of education with back-related disability along with four sets of variables that might explain this relationship: clinical, behavioral, and environmental factors; occupational variables; health care use; and interactions between stressful events and coping strategies. Although education has been found to be associated with back-related disability in previous reports, this relationship remains to be explained. Examination of this association may yield a better understanding of the causes and natural history of disability resulting from back pain. Subjects were 1213 enrollees of a Health Maintenance Organization (HMO) who consulted a primary care physician for back pain in 1989-1990, completed a baseline telephone interview, and had a follow-up evaluation after 1 and 2 years, using a modified version of the Roland-Morris Scale to measure disability. Subjects who completed 13 years or more of schooling had less disability and a greater decline in their disability over time than those who completed less schooling. Occupational characteristics and somatization were among the strongest explanatory factors. Cigarette smoking contributed to the explanation of the cross-sectional association. Education is associated cross-sectionally and longitudinally with disability resulting from back pain. A wide range of variables may mediate the education-back-related disability association, including a propensity to report diffuse physical symptoms (somatization), lifestyle (e.g., cigarette smoking), and occupational factors.


Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.
Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.


Time smear effects in spatial frequency multiplexed holography.
Spurious background fringes have been observed in time-resolved holograms recorded with a pulsed laser source and a rapidly deflected reference beam. These fringes were determined to be a time smear effect due to the small change in the angle of incidence of the reference beam during the exposure time. By analyzing the phenomenon theoretically, equations were derived that could be used to describe the observed fringe formation. A numerical solution was obtained for a realistic laser pulse time profile and an analytical solution was obtained using a simple mathematical model of the pulse profile. These solutions allow an a priori determination of bounds of the exposure parameters that would reduce the time smear effects to acceptable levels.


The biological effects of magnetic stimulation in epileptic patients.
The magnetoencephalogram (MEG) is the magnetic activity emitted by the brain, which can be measured using a superconductive quantum interference device (SQUID). This is a totally non-invasive method for localizing functional healthy, epileptic and other CNS brain disorders. Using the MEG brain activity recorded from epileptic patients we were able to obtain a mapping technique characterized by the ISO-spectral amplitude of scalp distribution of the MEG Fourier power spectrum. In addition, by utilizing the above recorded MEG activity we energize an electronic device, which emits back to the abnormal brain points of the epileptic patients magnetic fields with proper frequencies and intensities. Using this method we present here in more detail three randomly selected epileptic patients in which application of external magnetic fields of low intensities and frequencies produced a substantial attenuation of their abnormal brain activity. Furthermore, we present a statistical analysis of 50 randomly selected epileptic patients who underwent magnetic stimulation for the treatment of their seizures and we found that the anticonvulsant response to magnetic stimulation was statistically significant (chi 2 = 6.55, df = 1, p < 0.02). Our findings indicate that the use of low external magnetic fields produce substantial attenuation in seizure activity in epileptic patients and therefore it may open new ways in the future for management of epileptic activity.


The roles of acidosis and lactate in the behavioral hypothermia of exhausted lizards.
We conducted this study to determine whether two of the physiological changes associated with non-sustainable exercise, elevated blood lactate levels and decreased arterial pH, contribute to the behavioral hypothermia exhibited by exhausted lizards. Dipsosaurus dorsalis were placed in a thermal gradient and their body temperatures were recorded from 08:00 to 14:00 h. At 14:00 h, animals were subjected to different experimental regimens. In the exercise (E) regimen, animals at 40 degrees C were forced to exercise maximally for 5 min on a treadmill. In the lactate (L) regimen, animals were infused with 11.5 ml kg-1 of 250-500 mmol l-1 sodium lactate. In the osmolarity control (O) regimen, animals were injected with 11.5 ml kg-1 of 500 mmol l-1 NaCl, and in the injection control (I) regimen, animals were injected with 11.5 ml kg-1 of 150 mmol l-1 NaCl. In the hypercapnia (H) regimen, the thermal gradient was flushed with a gas mixture containing 10 % CO2, 21 % O2 and 69 % N2, a treatment that lowers the arterial pH of D. dorsalis to a value comparable with that imposed by exhaustive exercise. A group of control (C) animals was left undisturbed in the thermal gradient for 24 h. Animals in all experimental groups were returned to the thermal gradient, and their cloacal temperatures were monitored until 08:00 h the following morning. The mean cloacal temperature of E animals underwent a significant decrease of 4-7 degrees C, relative to control animals, which persisted for 7 h. The mean cloacal temperatures of animals subjected to 2 h of regimen H also decreased by 3.5-9 degrees C and remained depressed for 12 h following the beginning of the treatment. L, O and I animals did not undergo a significant change in body temperature following treatment, and their mean body temperatures did not differ from those of C animals at any time during the experiment. The results of this study suggest that the metabolic acidosis, but not the elevated blood lactate level, that follows exhausting exercise might play a role in the behavioral hypothermia that follows exhausting exercise in D. dorsalis.


Controlled human blood stage malaria infection: current status and potential applications.
Controlled human malaria infection by blood stage parasite (BSP) inoculation is an alternative to the well-established model of infection with Plasmodium falciparum sporozoites delivered by mosquito bites. The BSP model has been utilized less frequently, but its use is increasing. Advantages of BSP challenge include greater ease of administration, better standardization of the infecting dose per volunteer, and good inter-study reproducibility of in vivo parasite dynamics. Recently, a surprising reduction in clinical symptoms at microscopic patency in the BSP model has been identified, which has an undefined and intriguing pathophysiologic basis, but may make this approach more acceptable to volunteers. We summarize clinical, parasitologic, and immunologic data from all BSP challenges to date, explore differences between the BSP and sporozoite models, and propose future applications for BSP challenge.


Lagrangian based methods for coherent structure detection.
There has been a proliferation in the development of Lagrangian analytical methods for detecting coherent structures in fluid flow transport, yielding a variety of qualitatively different approaches. We present a review of four approaches and demonstrate the utility of these methods via their application to the same sample analytic model, the canonical double-gyre flow, highlighting the pros and cons of each approach. Two of the methods, the geometric and probabilistic approaches, are well established and require velocity field data over the time interval of interest to identify particularly important material lines and surfaces, and influential regions, respectively. The other two approaches, implementing tools from cluster and braid theory, seek coherent structures based on limited trajectory data, attempting to partition the flow transport into distinct regions. All four of these approaches share the common trait that they are objective methods, meaning that their results do not depend on the frame of reference used. For each method, we also present a number of example applications ranging from blood flow and chemical reactions to ocean and atmospheric flows.


Selection for tameness, a key behavioral trait of domestication, increases adult hippocampal neurogenesis in foxes.
Work on laboratory and wild rodents suggests that domestication may impact on the extent of adult hippocampal neurogenesis and its responsiveness to regulatory factors. There is, however, no model of laboratory rodents and their nondomesticated conspecifics that would allow a controlled comparison of the effect of domestication. Here, we present a controlled within-species comparison of adult hippocampal neurogenesis in farm-bred foxes (Vulpes vulpes) that differ in their genetically determined degree of tameness. Quantitative comparisons of cell proliferation (Ki67) and differentiating cells of neuronal lineage (doublecortin, DCX) in the hippocampus of foxes were performed as a proxy for neurogenesis. Higher neurogenesis was observed in tameness-selected foxes, notably in an extended subgranular zone of the middle and temporal compartments of the hippocampus. Increased neurogenesis is negatively associated with aggressive behavior. Across all animals, strong septotemporal gradients were found, with higher numbers of proliferating cells and young neurons relative to resident granule cells in the temporal than in the septal hippocampus. The opposite gradient was found for the ratio of DCX/Ki67- positive cells. When tameness-selected and unselected foxes are compared with rodents and primates, proliferation is similar, while the number of young neurons is higher. The difference may be mediated by an extended period of differentiation or higher rate of survival. On the background of this species-specific neurogenic pattern, selection of foxes for a single behavioral trait key to domestication, i.e., genetic tameness, is accompanied by global and region-specific increases in neurogenesis.


Using the VA LV VFQ-48 and LV VFQ-20 in low vision rehabilitation.
This study was conducted to demonstrate use of a simple scoring algorithm for the 48-item Veterans Affairs Low Vision Visual Functioning Questionnaire (VA LV VFQ-48) that approximates the measure of persons' visual ability that would be calculated with Rasch analysis and to provide a short form version of the questionnaire for clinical practice and outcomes research. Items were eliminated from the VA LV VFQ-48 to reduce redundancy and shorten the instrument. The approximation of persons' visual ability calculated with the scoring algorithm for vision function questionnaires developed by Massof was compared with the person measure estimated from Rasch analysis for a sample of 126 subjects entering a low vision rehabilitation program. The approximation captures 98% of the variability in the Rasch measure estimate of persons' visual ability and 97% of the variability in the change score estimate. The relationship does not hold in circumstances where patients with high visual ability find most items to be easy. A 20-item short form of the instrument was constructed for use in low vision service delivery. The scoring algorithm can be used with the VA LV VFQ-48 or short form versions of the questionnaire. Clinicians can use the algorithm to score the VA LV VFQ from examination of individual patients or as an outcome measure for their low vision rehabilitation programs. Research investigators can use the scoring algorithm with small samples when Rasch analysis is not reliable or in studies where Rasch analysis is not practical. Rasch analysis is still recommended for research studies that require more accurate assessments.


The thin blue line of health: Police contact and wellbeing in Europe.
Increasing evidence suggests that even minor forms of contact with the criminal justice system-such as being stopped by police-may be implicated in poor health. Police use of force can increase the risk of physical injury, whereas interactions accompanied by abusive rhetoric or threats can lead to psychological and emotional harm. Police contact may also have no health consequences for individuals or even be linked to good health because of an increased sense of public safety and confidence in law enforcement. This is the first study that explores whether contact with law enforcement is related to health and wellbeing in Europe. We estimated multilevel models with data from 26 countries that participated in the 2010 round of the European Social Survey. Across all outcomes-self-rated health, functional limitations, happiness, loneliness, and emotional wellbeing-having been approached, stopped or contacted by police was associated with worse health and wellbeing, especially when police treatment was perceived as unsatisfactory.


Network effects on scientific collaborations.
The analysis of co-authorship network aims at exploring the impact of network structure on the outcome of scientific collaborations and research publications. However, little is known about what network properties are associated with authors who have increased number of joint publications and are being cited highly. Measures of social network analysis, for example network centrality and tie strength, have been utilized extensively in current co-authorship literature to explore different behavioural patterns of co-authorship networks. Using three SNA measures (i.e., degree centrality, closeness centrality and betweenness centrality), we explore scientific collaboration networks to understand factors influencing performance (i.e., citation count) and formation (tie strength between authors) of such networks. A citation count is the number of times an article is cited by other articles. We use co-authorship dataset of the research field of 'steel structure' for the year 2005 to 2009. To measure the strength of scientific collaboration between two authors, we consider the number of articles co-authored by them. In this study, we examine how citation count of a scientific publication is influenced by different centrality measures of its co-author(s) in a co-authorship network. We further analyze the impact of the network positions of authors on the strength of their scientific collaborations. We use both correlation and regression methods for data analysis leading to statistical validation. We identify that citation count of a research article is positively correlated with the degree centrality and betweenness centrality values of its co-author(s). Also, we reveal that degree centrality and betweenness centrality values of authors in a co-authorship network are positively correlated with the strength of their scientific collaborations. Authors' network positions in co-authorship networks influence the performance (i.e., citation count) and formation (i.e., tie strength) of scientific collaborations.


Multimodal imaging-based therapeutic fingerprints for optimizing personalized interventions: Application to neurodegeneration.
Personalized Medicine (PM) seeks to assist the patients according to their specific treatment needs and potential intervention responses. However, in the neurological context, this approach is limited by crucial methodological challenges, such as the requirement for an understanding of the causal disease mechanisms and the inability to predict the brain's response to therapeutic interventions. Here, we introduce and validate the concept of the personalized Therapeutic Intervention Fingerprint (pTIF), which predicts the effectiveness of potential interventions for controlling a patient's disease evolution. Each subject's pTIF can be inferred from multimodal longitudinal imaging (e.g. amyloid-β, metabolic and tau PET; vascular, functional and structural MRI). We studied an aging population (N = 331) comprising cognitively normal and neurodegenerative patients, longitudinally scanned using six different neuroimaging modalities. We found that the resulting pTIF vastly outperforms cognitive and clinical evaluations on predicting individual variability in gene expression (GE) profiles. Furthermore, after regrouping the patients according to their predicted primary single-target interventions, we observed that these pTIF-based subgroups present distinctively altered molecular pathway signatures, supporting the across-population identification of dissimilar pathological stages, in active correspondence with different therapeutic needs. The results further evidence the imprecision of using broad clinical categories for understanding individual molecular alterations and selecting appropriate therapeutic needs. To our knowledge, this is the first study highlighting the direct link between multifactorial brain dynamics, predicted treatment responses, and molecular alterations at the patient level. Inspired by the principles of PM, the proposed pTIF framework is a promising step towards biomarker-driven assisted therapeutic interventions, with additional important implications for selective enrollment of patients in clinical trials.


Relationship of plcR-regulated factors to Bacillus endophthalmitis virulence.
The explosive, destructive course of Bacillus endophthalmitis has been attributed to the production of toxins during infection. In this study we analyzed the contribution of toxins controlled by the global regulator plcR to the pathogenesis of experimental Bacillus endophthalmitis. Isogenic plcR-deficient mutants of Bacillus cereus and Bacillus thuringiensis were constructed by insertional inactivation of plcR by the kanamycin resistance cassette, aphA3. Rabbit eyes were injected intravitreally with approximately 100 CFU of wild-type B. cereus or B. thuringiensis or a plcR-deficient mutant. The evolution of endophthalmitis resulting from each plcR-deficient mutant was considerably slower than that caused by each wild-type strain. Retinal function was not eliminated until 42 h postinfection in rabbits with endophthalmitis caused by the plcR-deficient mutants, whereas wild-type infections resulted in a complete loss of retinal function within 18 h. The intraocular inflammatory cell influx and retinal destruction in plcR-deficient endophthalmitis approached the severity observed in wild-ype infections, but not until 36 h postinfection. Gross and histological examinations of eyes infected with plcR mutants demonstrated that the anterior and posterior segment changes were muted compared to the changes observed in eyes infected with the wild types. The loss of plcR-regulated factors significantly attenuated the severity of Bacillus endophthalmitis. The results therefore suggest that plcR may represent a target for which adjunct therapies could be designed for the prevention of blindness during Bacillus endophthalmitis.


Effect of hyperglycaemia on glucose concentration of human nasal secretions.
Glucose is not detectable in airways secretions of normoglycaemic volunteers, but is present at 1-9 mmol x l(-1) in airways secretions from people with hyperglycaemia. These observations suggest the existence of a blood glucose threshold at which glucose appears in airways secretions, similar to that seen in renal and salivary epithelia. In the present study we determined the blood glucose threshold at which glucose appears in nasal secretions. Blood glucose concentrations were raised in healthy human volunteers by 20% dextrose intravenous infusion or 75 g oral glucose load. Nasal glucose concentrations were measured using modified glucose oxidase sticks as blood glucose concentrations were raised. Glucose appeared rapidly in nasal secretions once blood glucose was clamped at approx. 12 mmol x l(-1) ( n =6). On removal of the clamp, nasal glucose fell to baseline levels in parallel with blood glucose concentrations. An airway glucose threshold of 6.7-9.7 mmol x l(-1) was identified ( n =12). In six subjects with normal glucose tolerance, blood glucose concentrations rose above the airways threshold and nasal glucose became detectable following an oral glucose load. The presence of an airway glucose threshold suggests that active glucose transport by airway epithelial cells normally maintains low glucose concentrations in airways secretions. Blood glucose exceeds the airway threshold after a glucose load even in people with normal glucose tolerance, so it is likely that people with diabetes or hyperglycaemia spend a significant proportion of each day with glucose in their airways secretions.