Effect of oxidation catalysts on diesel soot particles.
The effect of a conventional oxidation catalyst and a novel particle oxidation catalyst (POC) on diesel particles is studied using identical methodology. Regulated particulate matter emission measurement is followed by analyzing soluble organic fraction. In addition, size distributions are measured using a partial flow sampling system with a thermodenuder as an option. A parallel ELPI-SMPS method is used to study the particle effective density and, further, the mass. Tests are conducted using a heavy duty diesel engine with a very low sulfur fuel. A decrease in particle mass was observed when using a catalyst. When using a conventional catalyst the decrease was attributed to the decrease of soluble organic fraction, while using POC the nonsoluble fraction was also found to decrease, by 8-38%. This observation is confirmed by particle number measurement, and POC was found to decrease the dry particle number concentration measured downstream of a thermodenuder by 13-28%. Further particle structure analysis indicated lower density values when using conventional catalyst or POC. The physical size of the particles was not changed noticeably over either catalyst--implying the soluble organic fraction was condensed onto the soot, filling the voids in the porous structure of soot agglomerates, when no catalyst is used.


Are light traps baited with kairomones effective in the capture of Lutzomyia longipalpis and Lutzomyia intermedia? An evaluation of synthetic human odor as an attractant for phlebotomine sand flies (Diptera: Psychodidae: Phlebotominae).
Phlebotomine sand flies are often captured with human bait and/or light traps, either with or without an animal bait. More recently, synthetic attractants have been used as bait in traps to improve the capture of phlebotomine sand flies as well as other insects of medical and veterinary importance. The aim of the present study was to evaluate the effects of the kairomone 1-octen-3-ol (octenol) and the synthetic human odor BG-Mesh Lure (BGML--lactic acid, caproic acid and ammonia) baited in modified CDC light traps on the capture of phlebotomine sand flies. The experiments followed the 5x5 Latin square design. Among the species caught, Lutzomyia intermedia apparently presented a dose-dependent response to octenol. The response obtained with the BGML, alone or in combination with octenol (5 mg/h), indicated some degree of attractiveness of these baits to different phlebotomine sand fly species. Octenol seems to be more attractive to L. intermedia than to Lutzomyia longipalpis, while the BGML presented a higher success in capturing L. longipalpis. When the components of the BGML were used separately, there was no increase in catching the female of L. intermedia. Apparently, there was no synergistic effect between the octenol and the BGML. In conclusion, the octenol and the BGML were demonstrated to be possible baits to attract some phlebotomine sand fly species.


Energy absorption as a measure of intestinal failure in the short bowel syndrome.
Energy absorption from a liquid test meal, intestinal transit rate and water and sodium output over a six hour period were measured in five patients with an ileostomy and 12 patients with the short bowel syndrome, five of whom were on longterm parenteral nutrition. The proportion of total energy absorbed was greatest in the ileostomists (median 87%, range 82-92%), less in short bowel patients not on parenteral nutrition (median 67%, range 59-78%, p less than 0.01) and least in the short bowel group who needed it (median 27%, range 2-63%, p less than 0.01). Transit rate was more rapid in the short bowel patients compared with the ileostomists. A close correlation was observed between percentage energy absorption and the dry weight of the stools/stoma effluent collected during the six hour test period (r = -0.99, p less than 0.001). This simple non-invasive test quantitates the degree of intestinal failure and may be of practical help in management.


Quality of urban runoff in wet and dry seasons: a case study in a semi-arid zone.
Urban runoff (UR) is a promising new resource that may alleviate growing tensions in numerous arid and semi-arid regions of the world. However, it is precisely in these zones that the available UR quality characteristics are scarcer. This work aims to evaluate a wide set of parameters to establish a detailed approach to both the quality of UR in a midsized city in Central Mexico and the feasibility of using UR to recharge aquifers. UR from an institutional land use site was sampled during wet and dry seasons and assessed for suspended solids, organic matter, nutrients, microorganisms, metals, and persistent organic chemicals (i.e., polycyclic aromatic hydrocarbons, PAH). The results were analyzed using multivariate statistical methods to identify relationships among the variables, the sampling sites and the seasons. The soil erosion and the leaching of materials due to the water flow through vegetated areas were identified as the most influencing factor on the quality of the site runoff in both dry and wet seasons. Additionally, data were more heterogeneous during the dry season, and higher pollutant concentrations were found both during the dry season and in more pervious zones. We consider UR a promising water source for recharging aquifers in arid and semi-arid zones if a program is implemented that can integrate an adequate runoff treatment system, soil protection, and other non-structural measures.


[Imaging techniques for studying functional recovery following a stroke: I. Methodological aspects].
Many patients that survive stroke have to face serious functional disabilities for the rest of their lives, which is a personal drama for themselves and their relatives, and an elevated charge for society. Thus functional recovery following stroke should be a key objective for the development of new therapeutic approaches. In this series of two works we review the strategies and tools available nowadays for the evaluation of multiple aspects related to brain function (both in humans and research animals), and how they are helping neuroscientist to better understand the processes of restoration and reorganization of brain function that are triggered following stroke. We have mainly focused on magnetic resonance applications, probably the most versatile neuroimaging technique available nowadays, and that everyday surprises us with new and exciting applications. But we tackle other alternative and complementary techniques, since a multidisciplinary approach allows a wider perspective over the underlying mechanisms behind tissue repair, plastic reorganization of the brain and compensatory mechanisms that are triggered after stroke. The first of the works of this series is focused on methodological aspects that will help us to understand how it is possible to assess brain function based on different physical and physiological principles. In the second work we will focus on different practical issues related to the application of the techniques here discussed.


Mutation of FOP/FGFR1OP in mice recapitulates human short rib-polydactyly ciliopathy.
Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. A total of 436 skeletal dysplasias are listed in the 2015 revised version of the nosology and classification of genetic skeletal disorders, of which nearly 20% are still genetically and molecularly uncharacterized. We report the clinical and molecular characterization of a lethal skeletal dysplasia of the short-rib group caused by mutation of the mouse Fop gene. Fop encodes a centrosomal and centriolar satellite (CS) protein. We show that Fop mutation perturbs ciliogenesis in vivo and that this leads to the alteration of the Hedgehog signaling pathway. Fop mutation reduces CSs movements and affects pericentriolar material composition, which probably participates to the ciliogenesis defect. This study highlights the role of a centrosome and CSs protein producing phenotypes in mice that recapitulate a short rib-polydactyly syndrome when mutated.


Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8.
Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/β-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.


The adenoid: Its history and a cautionary tale.
The existence of the adenoid first appears to have been noted by Conrad Victor Schneider in 1661. James Yearsley reported in 1842 one case in which he improved hearing by removal of a mucus membrane from behind the uvula, which indicates some appreciation of a relationship of the nasopharynx to ear disease. Hans Wilhelm Meyer, in 1868, was the first to demonstrate the relationship of the adenoid to ear disease and to develop an effective, although somewhat difficult, surgical operation to remove the adenoid. Removal of the adenoid became rapidly accepted worldwide as a treatment for many morbidities, including otitis, speech problems, cognitive problems, and sleep apnea. Until the 1920s, adenoidectomy often was performed as a staged procedure and without general anesthesia. Early tools and techniques included use of the bare fingernail, a finger ring knife, a curette, and electrical desiccation. From the mid-1930s to the early 1960s, radiation therapy of the adenoid was in extensive use, both for children and in caring for army aviators and navy submarine crews during WWII. The effectiveness of surgical adenoidectomy for hearing loss led to a belief that radiation, which had been found to ablate lymphoid tissue, would be equally effective, and led to the wide-spread use of radiation. Ultimately, 500 thousand to 2.5 million children and adults were estimated to have been treated with radiation, and follow-up studies found increased risk for cancer. Furthermore, a follow-up study by Stacey R. Guild (1890-1966), published in 1950, on a very large sample of children who previously were reported to have had their hearing loss diminished through radiation, found that irradiation had produced no effect on high-tone loss. Thus, irradiation was both useless and harmful. Acceptance of authority, which can lurk within medical culture, led to the development of a tragically misguided management of adenoid disease. Laryngoscope, 127:S13-S28, 2017.


CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions.
Better understanding of tolerance and autoimmunity toward melanocyte-specific Ags is needed to develop effective treatment for vitiligo and malignant melanoma; yet, a systematic assessment of these mechanisms has been hampered by the difficulty in tracking autoreactive T cells. To address this issue, we have generated transgenic mice that express hen egg lysozyme as a melanocyte-specific neoantigen. By crossing these animals to a hen egg lysozyme-specific CD4 TCR transgenic line we have been able to track autoreactive CD4+ T cells from their development in the thymus to their involvement in spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris and Vogt-Koyanagi-Harada syndrome. Our findings show that CD4-dependent destruction of melanocytes is partially inhibited by blocking Fas-Fas ligand interactions and also highlights the importance of local control of autoimmunity, as vitiligo remains patchy and never proceeds to confluence even when Ag and autoreactive CD4+ T cells are abundant. Immune therapy to enhance or suppress melanocyte-specific T cells can be directed at a series of semiredundant pathways involving tolerance and cell death.


An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects.
We have developed an in vitro muscle preparation suitable for metabolic studies with human muscle tissue and have investigated the effects of obesity and non-insulin-dependent diabetes mellitus (NIDDM) on glucose transport. Transport of 3-O-methylglucose and 2-deoxyglucose was stimulated approximately twofold by insulin in muscle from normal nonobese subjects and stimulation occurred in the normal physiological range of insulin concentrations. In contrast to insulin stimulation of 3-O-methylglucose and 2-deoxyglucose transport in muscle from normal, nonobese subjects, tissue from morbidly obese subjects, with or without NIDDM, were not responsive to insulin. Maximal 3-O-methylglucose transport was lower in muscle of obese than nonobese subjects. Morbidly obese patients, with or without NIDDM, have a severe state of insulin resistance in glucose transport. The novel in vitro human skeletal muscle preparation herein described should be useful in investigating the mechanism of this insulin resistance.


Adaptive functioning following pediatric traumatic brain injury: Relationship to executive function and processing speed.
Pediatric traumatic brain injury (TBI) may affect children's ability to perform everyday tasks (i.e., adaptive functioning). Guided by the American Association for Intellectual and Developmental Disabilities (AAIDD) model, we explored the association between TBI and adaptive functioning at increasing levels of specificity (global, AAIDD domains, and subscales). We also examined the contributions of executive function and processing speed as mediators of TBI's effects on adaptive functioning. Children (ages 8-13) with severe TBI (STBI; n = 19), mild-moderate TBI (MTBI; n = 50), or orthopedic injury (OI; n = 60) completed measures of executive function (TEA-Ch) and processing speed (WISC-IV) an average of 2.7 years postinjury (SD = 1.2; range: 1-5.3). Parents rated children's adaptive functioning (ABAS-II, BASC-2, CASP). STBI had lower global adaptive functioning (η2 = .04-.08) than the MTBI and OI groups, which typically did not differ. Deficits in the STBI group were particularly evident in the social domain, with specific deficits in social participation, leisure, and social adjustment (η2 = .06-.09). Jointly, executive function and processing speed were mediators of STBI's effects on global adaptive functioning and in conceptual and social domains. In the STBI group, executive function mediated social functioning, and processing speed mediated social participation. Children with STBI experience deficits in adaptive functioning, particularly in social adjustment, with less pronounced deficits in conceptual and practical skills. Executive function and processing speed may mediate the effects of STBI on adaptive functioning. Targeting adaptive functioning and associated cognitive deficits for intervention may enhance quality of life for pediatric TBI survivors. (PsycINFO Database Record


Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis.
Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.


DSM-IV substance use disorder criteria for adolescents: a critical examination based on a statewide school survey.
The DSM-IV criteria for substance use disorders were incorporated into the 1995 Minnesota Student Survey in order to estimate the need for alcohol/drug treatment among adolescents in the state. This study used data from the survey to examine the utility of individual diagnostic criterion items, diagnostic categories, and diagnostic thresholds in a general adolescent population. The survey was administered to ninth- and 12th-grade public school students. Participation was voluntary, and survey questionnaires were anonymous. The survey included questions about the use of substances during the past year and the presence of DSM-IV criterion symptoms for substance abuse and dependence. This study was based on responses from 74,008 students who answered these questions. Of the students who reported any substance use in the past 12 months, 13.8% of the ninth graders and 22.7% of the 12th graders met the criteria for a substance abuse diagnosis, and 8.2% of the ninth graders and 10.5% of the 12th graders met the criteria for dependence. The presence of multiple criterion symptoms was strongly associated with the use of multiple drugs. Analyses of positive and negative predictive value, sensitivity, and specificity did not support the diagnostic distinction between dependence criteria and abuse criteria. A combined set of criteria, with empirically derived diagnostic threshold categories based on total number of symptoms, may be more suitable for estimates of substance use disorders and need for treatment among adolescents.


How little do we actually know? On the size of gene regulatory networks.
The National Center for Biotechnology Information (NCBI) recently announced the availability of whole genome sequences for more than 1,000 species. And the number of sequenced individual organisms is growing. Ongoing improvement of DNA sequencing technology will further contribute to this, enabling large-scale evolution and population genetics studies. However, the availability of sequence information is only the first step in understanding how cells survive, reproduce, and adjust their behavior. The genetic control behind organized development and adaptation of complex organisms still remains widely undetermined. One major molecular control mechanism is transcriptional gene regulation. The direct juxtaposition of the total number of sequenced species to the handful of model organisms with known regulations is surprising. Here, we investigate how little we even know about these model organisms. We aim to predict the sizes of the whole-organism regulatory networks of seven species. In particular, we provide statistical lower bounds for the expected number of regulations. For Escherichia coli we estimate at most 37 percent of the expected gene regulatory interactions to be already discovered, 24 percent for Bacillus subtilis, and <3% human, respectively. We conclude that even for our best researched model organisms we still lack substantial understanding of fundamental molecular control mechanisms, at least on a large scale.


Reconstitution of CD4 T cells in bronchoalveolar lavage fluid after initiation of highly active antiretroviral therapy.
The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells.


Temporal heterogeneity of myocardial blood flow in anesthetized dogs.
Temporal variation in perfusion to small segments of the myocardium was studied in 19 opened-chest dogs. In six control dogs, three or four differently labeled 7-10 mu microspheres were injected simultaneously into the left atrium to assess the variability in measured myocardial perfusion due to the microsphere technique. In 13 other dogs, microspheres were injected four times at 5 minute intervals while various hemodynamics parameters (mean aortic pressure, peak systolic pressure, heart rate, left ventricular end-diastolic pressure, and Vmax) were stable (less than 10% variation in any one parameter). The left ventricles were divided into 96 segments, the mean weight+/- SD of each segment was 0.95+/-0.17 grams. The flow to each segment was expressed as a percent of the mean flow of the three or four measured flows to that segment, and the difference between the largest and the smallest percent of each segment was taken as a measure of the variability of flow to that segment. The average variability of segmental flow (mean +/-SD) when the three to four differently labeled microspheres were injected was 14.0+/-4.7; and the variability when differently labeled microspheres injected sequentially was 31.0+/-10.8% (P less than 0.001). Furthermore, in the sequentially injected animals the magnitude of temporal variation was similar in various subdivisions of the ventricle (layers, walls, apex to base). The mean and standard deviation of the variability of flow to the endo, mid, and epicardial layers were 28.7+/-10.2, 30.0+/-11.3 and 34.5+/-12.4%, respectively. These changes may reflect either spontaneous or local autoregulatory changes in precapillary sphincters or arterioles.


Up-down asymmetry of cerebellar activation during vertical pursuit eye movements.
Animal experiments have demonstrated that the vast majority of vertical gaze-velocity Purkinje cells in the cerebellar floccular lobe, whose firing rate is modulated during vertical smooth pursuit eye movements, show a preference for downward pursuit. Here we validate the functional vertical asymmetry of the cerebellar flocculus in humans using functional magnetic resonance imaging by demonstrating a significantly higher activation of the floccular lobe for downward than for upward pursuit. The findings corroborate our recent hypothesis on the pathogenesis of cerebellar downbeat nystagmus.


Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children's Oncology Group.
Purpose Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting. Patients and Methods Eligible participants were 1 to 30 years, with planned cisplatin-containing treatment. Hearing evaluations were conducted at baseline, before each cisplatin cycle, and at the end of therapy. Audiologic results were assessed and graded by the testing audiologist and by two central review audiologists using the American Speech-Language-Hearing Association Ototoxicity Criteria (ASHA), Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE), and Brock Ototoxicity Grades (Brock). One central reviewer also used the International Society of Pediatric Oncology Ototoxicity Scale (SIOP). Results At the end of treatment, the prevalence of any degree of ototoxicity ranged from 40% to 56%, and severe ototoxicity ranged from 7% to 22%. Compared with CTCAE, SIOP detected significantly more ototoxicity ( P = .004), whereas Brock criteria detected significantly fewer patients with any or severe ototoxicity ( P < .001 for both). SIOP detected ototoxicity earlier than did the other scales. Agreement between the central reviewers and the institutional audiologist was almost perfect for ASHA and Brock, whereas the poorest agreement occurred with CTCAE. Conclusion The SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin. Future studies should evaluate inter-rater reliability of the SIOP scale.


Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts.
The occurrence of phenotypic differences between monozygotic (MZ) twins is commonly attributed to environmental factors, assuming that MZ twins have a complete identical genetic make-up. Yet, recently several lines of evidence showed that both genetic and epigenetic factors could have a role in phenotypic discordance after all. A high occurrence of copy number variation (CNV) differences was observed within MZ twin pairs discordant for Parkinson's disease, thereby stressing on the importance of post-zygotic mutations as disease-predisposing events. In this study, the prevalence of discrepant CNVs was analyzed in discordant MZ twins of the Esophageal Atresia (EA) and Congenital Diaphragmatic Hernia (CDH) cohort in the Netherlands. Blood-derived DNA from 11 pairs (7 EA and 4 CDH) was screened using high-resolution SNP arrays. Results showed an identical copy number profile in each twin pair. Mosaic chromosome gain or losses could not be detected either with a detection threshold of 20%. Some of the germ-line structural events demonstrated in five out of eleven twin pairs could function as a susceptible genetic background. For example, the 177-Kb loss of chromosome 10q26 in CDH pair-3 harbors the TCF7L2 gene (Tcf4 protein), which is implicated in the regulation of muscle fiber type development and maturation. In conclusion, discrepant CNVs are not a common cause of twin discordancy in these investigated congenital anomaly cohorts.


Oxytocin is present in islets and plays a role in beta-cell function and survival.
Oxytocin is associated mainly with modulating reproductive function. However, studies suggest that oxytocin also plays a role in endocrine pancreatic function. In the present study, islet expression of oxytocin and its related receptor was confirmed in mouse islets as well as cultured rodent and human beta-cells. Oxytocin significantly stimulated glucose-induced insulin secretion from isolated mouse islets. Similar insulinotropic actions were also observed in rodent BRIN BD11 and human 1.1B4 beta-cells. Positive effects of oxytocin on insulin secretion were almost fully annulled by the oxytocin receptor antagonist, atosiban. In terms of mechanism of insulin secretory action, oxytocin had no effect on beta-cell membrane potential or cAMP generation, but did augment intracellular calcium concentrations. In vivo administration of oxytocin to mice significantly reduced overall blood glucose levels and increased plasma insulin concentrations in response to a glucose challenge. Oxytocin also had a modest, but significant, appetite suppressive effect. As expected, streptozotocin diabetic mice had marked loss of beta-cell area accompanied by increases in alpha-cell area, whilst hydrocortisone treatment increased beta-cell and overall islet areas. Both mouse models of diabetes presented with dramatically decreased percentage islet oxytocin co-localisation with insulin and increased co-localisation with glucagon. More detailed studies in cultured beta-cell lines revealed direct positive effects of oxytocin on beta-cell proliferation and protection against apoptosis. Together, these data highlight a potentially important role of islet-derived oxytocin and related receptor signalling pathways on the modulation of beta-cell function and survival.


The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation.
TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA recognition motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mRNA may be critical to maintain the solubility of TDP-43 in the nucleus and the miscibility of TDP-43 in cytoplasmic stress granules. We anticipate that the knowledge of a higher order assembly of TDP-43 on mRNA may clarify its role in intron processing and provide a means of interfering with the cytoplasmic aggregation of TDP-43.


Final report of the safety assessment of methylisothiazolinone.
Methylisothiazolinone (MIT) is a heterocyclic organic compound used as a preservative in cosmetics and personal care products in concentrations up to 0.01%. MIT is a colorless, clear liquid with a mild odor that is completely soluble in water; mostly soluble in acetonitrile, methanol, and hexane; and slightly soluble in xylene. Consistent with its solubility, dermal penetration is low. The Cosmetic Ingredient Review Expert Panel noted the in vitro evidence of neurotoxicity but concluded that the absence of any neurotoxicity findings in the many in vivo studies, including subchronic, chronic, and reproductive and developmental animal studies, suggests that MIT would not be neurotoxic as used in cosmetics. Although recognizing that MIT was a sensitizer in both animal and human studies, the panel concluded that there is a threshold dose response and that cosmetic products formulated to contain concentrations of MIT at 100 ppm (0.01%) or less would not be expected to pose a sensitization risk. Accordingly, MIT may be safely used as a preservative in cosmetics up to that concentration.


Facile and Fast Transformation of Nonluminescent to Highly Luminescent Metal-Organic Frameworks: Acetone Sensing for Diabetes Diagnosis and Lead Capture from Polluted Water.
Metal-organic frameworks (MOFs) stand as one of the most promising materials for the development of advanced technologies owing to their unique combination of properties. The conventional synthesis of MOFs involves a direct reaction of the organic linkers and metal salts; however, their postsynthetic modification is a sophisticated route to produce new materials or to confer novel properties that cannot be attained through the traditional methods. This work describes the postsynthetic MOF-to-MOF transformation of a nonluminescent MOF (Zn-based Oxford University-1 material [Zn-BDC, where BDC = 1,4-benzene dicarboxylate] (OX-1)) into a highly luminescent framework (Ag-based Oxford University-2 material [Ag-BDC] (OX-2)) by a simple immersion of the former in a silver salt solution. The conversion mechanism exploits the uncoordinated oxygen atoms of terephthalate linkers found in OX-1, instead of the unsaturated metal sites commonly employed, making the reaction much faster. The materials derived from the OX-1 to OX-2 transformation are highly luminescent and exhibit a selective response to acetone, turning them into a promising candidate for manufacturing fluorometric sensors for the diagnosis and monitoring of diabetes mellitus. Our methodology can be extended to other metals such as lead (Pb). The fabrication of a polymer mixed-matrix membrane containing OX-1 is used as a proof-of-concept for capturing Pb ions (as pollutants) from water. This research instigates the exploration of alternative methodologies to confer MOFs with special aptitudes for photochemical sensing or for environmental applications such as water purification.


Does the quality of chest compressions deteriorate when the chest compression rate is above 120/min?
The quality of chest compressions along with defibrillation is the cornerstone of cardiopulmonary resuscitation (CPR), which is known to improve the outcome of cardiac arrest. We aimed to investigate the relationship between the compression rate and other CPR quality parameters including compression depth and recoil. A conventional CPR training for lay rescuers was performed 2 weeks before the 'CPR contest'. CPR anytime training kits were distributed to respective participants for self-training on their own in their own time. The participants were tested for two-person CPR in pairs. The quantitative and qualitative data regarding the quality of CPR were collected from a standardised check list and SkillReporter, and compared by the compression rate. A total of 161 teams consisting of 322 students, which includes 116 men and 206 women, participated in the CPR contest. The mean depth and rate for chest compression were 49.0±8.2 mm and 110.2±10.2/min. Significantly deeper chest compression depths were noted at rates over 120/min than those at any other rates (47.0±7.4, 48.8±8.4, 52.3±6.7, p=0.008). Chest compression depth was proportional to chest compression rate (r=0.206, p<0.001), but there were significantly more incomplete chest recoils at the rate of over 120/min than at any other rates (9.8%, 6.3%, 25.6%, p=0.011). The study showed conflicting results in the quality of chest compression including chest compression depth and chest recoil by chest compression rate. Further evaluation regarding the upper limit of the chest compression rate is needed to ensure complete full chest wall recoil while maintaining an adequate chest compression depth.


Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653,180) as therapy for experimental recurrent genital herpes.
Herpes simplex virus (HSV)-coded thymidine kinase (TK) is important in efficient reactivation of latent infection. These studies were designed to investigate whether treatment of latently infected animals with a TK inhibitor altered the natural history of recurrent HSV disease. 9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) is a potent and selective nonsubstrate inhibitor of HSV TK which can suppress or delay reactivation of HSV-1 from latently infected cells in vitro without affecting viral replication. In an initial study, six female Hartley guinea pigs were treated with L-653,180 in their diet (25 mg/30 g of food) and water (300 mg/liter) for 7 days. Blood, urine, kidney, liver, spinal cord, and cerebral cortex specimens were collected. L-653,180 was detected in all specimens at concentrations which, although low, were higher than the in vitro 50% inhibitory concentration of the drug against HSV TK. In the second study, 20 female Hartley guinea pigs were randomized into two groups following recovery from primary genital HSV-2 infection. One group received L-653,180 in diet and water for 4 weeks beginning 21 days postinoculation. Animals were examined daily for recurrent lesions for 10 weeks. Treated animals experienced fewer recurrences during the treatment period but the results were not significantly different from results with controls. During the first 2-week posttreatment period, L-653,180-treated animals had significantly fewer recurrences than control animals (P = 0.02). Over the entire 10-week observation period, treated animals experienced fewer recurrences (P = 0.06). These results suggest that inhibitors of viral TK may be useful in limiting reactivation of latent virus and thus recurrent infections. In these experiments, the amount of drug that could be administered to the animals was limited by its poor solubility. Further studies with more potent and soluble inhibitors of HSV TK appear to be warranted.


Identification of novel inhibitors of nonreplicating Mycobacterium tuberculosis using a carbon starvation model.
During Mycobacterium tuberculosis infection, a population of bacteria is thought to exist in a nonreplicating state, refractory to antibiotics, which may contribute to the need for prolonged antibiotic therapy. The identification of inhibitors of the nonreplicating state provides tools that can be used to probe this hypothesis and the physiology of this state. The development of such inhibitors also has the potential to shorten the duration of antibiotic therapy required. Here we describe the development of a novel nonreplicating assay amenable to high-throughput chemical screening coupled with secondary assays that use carbon starvation as the in vitro model. Together these assays identify compounds with activity against replicating and nonreplicating M. tuberculosis as well as compounds that inhibit the transition from nonreplicating to replicating stages of growth. Using these assays we successfully screened over 300,000 compounds and identified 786 inhibitors of nonreplicating M. tuberculosis In order to understand the relationship among different nonreplicating models, we tested 52 of these molecules in a hypoxia model, and four different chemical scaffolds in a stochastic persister model, and a streptomycin-dependent model. We found that compounds display varying levels of activity in different models for the nonreplicating state, suggesting important differences in bacterial physiology between models. Therefore, chemical tools identified in this assay may be useful for determining the relevance of different nonreplicating in vitro models to in vivo M. tuberculosis infection. Given our current limited understanding, molecules that are active across multiple models may represent more promising candidates for further development.


Molecular cloning of two partial serotonin 5-HT1D receptor sequences in mouse and one in guinea pig.
The G protein coupled serotonin (5-HT) receptors, with seven membrane spanning domains, form a multigene family of which several members have been cloned and sequenced. The presence of 5-HT1D binding sites to our knowledge has not yet been reported in mouse. Here we describe the cloning and sequencing by the polymerase chain reaction (PCR) method of two 5-HT1D receptor sequences of the third cytoplasmic loop in mouse, strongly suggesting the existence of two 5-HT1D receptor genes, located on chromosome 4. A homologous sequence to one of them was cloned in guinea pig.


Reminder design and childhood vaccination coverage.
A major policy concern across public vaccination programs is non-compliance. Exploiting Danish population data and three national reforms in regression discontinuity designs, we document the effects of reminders for childhood vaccination coverage. Retrospective reminders are primarily effective for families with small children and when sent out close to the recommended vaccination age. Digital and postal reminders are equally effective. Prospective reminders increase timely vaccinations in later childhood and help reaching high coverage for new vaccines in increasingly complex vaccination programs. While reminders prompt additional preventive care for focal children, we find no spillovers to other health behaviors or relatives.


Discovery of anti-Formin-like 1 protein (FMNL1) antibodies in membranous nephropathy and other glomerular diseases.
Evidence has shown that podocyte-directed autoantibodies can cause membranous nephropathy (MN). In the present work we investigated sera of MN patients using a high-density peptide array covering the whole coding sequences of the human genome encompassing 7,499,126 tiled peptides. A panel of 21 proteins reactive to MN sera were identified. We focused our attention on Formin-like 1 (FMNL1), a protein expressed by macrophages in MN patients tissues. High levels of anti-FMNL1 IgG4 were demonstrated in sera of MN patients with an orthogonal methodology (ELISA) contemporary demonstrating FMNL1 positive cells in kidney co-staining with CD68 in glomeruli. High levels of circulating anti-FMNL1 IgG4 were associated with lack of remission of proteinuria, potentially indicating that autoantibodies directed against cells other than podocytes, involved in tissue repair, might play a role in MN disease progression. High serum levels of anti-FMNL1 IgGs were also observed in other non-autoimmune glomerolonephrites, i.e. idiopathic and genetic FSGS, IgAGN. These findings are suggestive of a broader role of those autoantibodies in other glomerular disease conditions.


Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (rituximab) therapy in type 1 diabetes.
Type 1 diabetes mellitus is believed to be due to the autoimmune destruction of β-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte Ab, can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease-associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease-associated target Ags, and C-peptide levels of participants who did (responders) or did not (nonresponders) show signs of β-cell preservation 1 y after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after four weekly doses of mAb. T cell proliferative responses to diabetes-associated Ags were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 mo (58%), the proliferative responses to diabetes-associated total (p = 0.032), islet-specific (p = 0.048), and neuronal autoantigens (p = 0.005) increased over the 12-mo observation period. This relationship was not seen in placebo-treated patients. We conclude that in patients with type 1 diabetes mellitus, anti-B cell mAb causes increased proliferative responses to diabetes Ags and attenuated β-cell loss. The way in which these responses affect the disease course remains unknown.


Nootropic drugs and brain cholinergic mechanisms.
1. This review has two aims: first, to marshal and discuss evidences demonstrating an interaction between nootropic drugs and brain cholinergic mechanisms; second, to define the relationship between the effects on cholinergic mechanisms and the cognitive process. 2. Direct or indirect evidences indicating an activation of cholinergic mechanisms exist for pyrrolidinone derivatives including piracetam, oxiracetam, aniracetam, pyroglutamic acid, tenilsetam and pramiracetam and for miscellaneous chemical structures such as vinpocetine, naloxone, ebiratide and phosphatidylserine. All these drugs prevent or revert scopolamine-induced disruption of several learning and memory paradigms in animal and man. 3. Some of the pyrrolidinone derivatives also prevent amnesia associated with inhibition of acetylcholine synthesis brought about by hemicholinium. Oxiracetam prevents the decrease in brain acetylcholine and amnesia caused by electroconvulsive shock. Oxiracetam, aniracetam and pyroglutamic acid prevent brain acetylcholine decrease and amnesia induced by scopolamine. Comparable bell-shaped dose-effect relationships result for both actions. Phosphatidylserine restores acetylcholine synthesis and conditioned responses in aging rats. 4. The mechanisms through which the action on cholinergic systems might take place, including stimulation of the high affinity choline uptake, are discussed. The information available are not yet sufficient to define at which steps of the cognitive process the action on cholinergic system plays a role and which are the influences of the changes in cholinergic function on other neurochemical mechanisms of learning and memory.


Inhibitory Effects of Tangeretin, A Citrus Peel-Derived Flavonoid, on Breast Cancer Stem Cell Formation through Suppression of Stat3 Signaling.
Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified compound was identified as tangeretin by using nuclear magnetic resonance (NMR). Tangeretin inhibited cell proliferation, CSC formation and tumor growth, and modestly induced apoptosis in CSCs. The frequency of a subpopulation with a CSC phenotype (CD44+/CD24-) was reduced by tangeretin. Tangeretin reduced the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3). Our results in this study show that tangeretin inhibits the Stat3 signaling pathway and induces CSC death, indicating that tangeretin may be a potential natural compound that targets breast cancer cells and CSCs.


The long-term psychosocial impact of cancer: the views of young adult survivors of childhood cancer.
It is rare for studies to approach psychosocial outcomes of childhood cancer in a holistic and explanatory way. Doing so would enable a greater understanding of why and in what way a young person's life may be affected by cancer. This qualitative study aimed to explore the views of childhood cancer survivors (CCS) regarding how they perceive their illness to have influenced them and their subsequent lives. Twelve CCS with a median age of 23 years old took part in either a focus group or a telephone interview. Data were analysed using thematic analysis. The main themes were altered life perspectives, perceptions of self and lasting effects on relationships. Through these themes, the survivors gave insight into how their experience had influenced their views and how this had impacted on different areas of their lives. Although positive aspects were discussed, enduring issues were reported by some. Findings suggest that despite high levels of achievement, some survivors may still benefit from further information and support especially in relation to relationships and fertility. This study will inform the development of a questionnaire aiming to collect important information on the many factors which may influence long-term psychosocial outcomes in CCS.


Lipids increase after solitary pancreas transplantation.
The aims of this study were to determine 1) changes in lipids after solitary pancreas transplantation (SPTX) in patients with type 1 diabetes and 2) factors that influence those changes. Lipids were evaluated prospectively in 24 patients who underwent SPTX. Three were excluded because of early graft failure. The remaining patients (n = 21; 13 men, 8 women) were studied for changes in lipids over time (pre-SPTX, 0-2, 3-6, 7-12, and > 12 months). Glycohemoglobin, serum creatinine, BMI, and medications were also analyzed for their effects on lipid changes. Cholesterol, HDL, and LDL decreased in the immediate postoperative period (0-2 months), whereas triglycerides (TGs) increased (P < 0.05). At 3-6 months, cholesterol, HDL, and TG were higher than before the SPTX, whereas LDL returned to pre-SPTX levels. After 12 months, HDL and TG remained higher than their pre-SPTX levels (P < 0.05). During the study, systolic and diastolic blood pressure increased, renal function decreased, glyco-hemoglobin improved, and weight was unchanged. Changes in cholesterol/HDL ratio, HDL, and TG correlated with changes in prednisone dose (P < 0.05), and changes in TG correlated with changes in creatinine (P < 0.05). The same pattern of lipids occurred in patients prescribed or not prescribed hypolipidemic agents. Lipids do not improve within the 1st year after SPTX, despite improved glycemic control and blood pressure control, and renal function is worse. These results are in contrast to those reported for combined kidney-pancreas transplantation, where lipids, blood pressure, and renal function improved immediately after transplant. Further studies are needed to determine whether lipids continue to change with time after SPTX. The impact of these changes after SPTX on overall cardiovascular risk is unknown.


Psychological Factors Associated with Delayed Symptom Resolution in Children with Concussion.
To characterize the psychological factors associated with persistent symptoms after pediatric concussion. Longitudinal cohort study of 179 children with concussion 8-18 years old evaluated in a pediatric emergency department. Participants were followed for 1 month for delayed symptom resolution, defined as ≥3 symptoms that were new/worse than preinjury symptoms measured by the use of graded symptom inventory. Preinjury psychological traits were measured by parental report on subscales of the Personality Inventory for Children-2 (maladjustment, cognitive abilities, somatization). Child report of postinjury anxiety and injury perception were measured with the State-Trait Anxiety Inventory for Children and Children's Illness Perception Questionnaire. Psychological instrument scores were compared between those with and without delayed symptom resolution via a Kruskal-Wallis test. Associations between psychological traits and delayed symptom resolution were investigated by the use of logistic regression. Delayed symptom resolution occurred in 21% of participants. Score distributions were significantly worse on the State-Trait Anxiety Inventory for Children (38 [IQR 33-40] vs 35 [IQR 31-39]; P = .04) and somatization subscale (1 [IQR 0-3] vs 1 [IQR 0-1]; P = .01) among children with delayed symptom resolution compared with children with early symptom resolution. Somatization was associated with delayed symptom resolution (aOR 1.35, 95% CI 1.08-1.69). The proportion of children with abnormal somatization scores was significantly greater in the delayed symptom resolution group (34.2%) than the early symptom resolution group (12.8%; P < .01). Other psychological measures were not different between groups. Somatization is associated with delayed symptom resolution in this cohort of children with concussion. Postconcussive symptoms lasting at least 1 month may warrant referral to a neuropsychologist familiar with postconcussion care.


Side effects of phenobarbital in epilepsy: a systematic review.
In recent years, phenobarbital, as an antiepileptic drug, has become less popular based on adverse events, especially cognitive and behavioural side effects. Despite the development of better tolerated new generation AEDs, phenobarbital is still widely used particularly in developing countries because of its low cost. The purpose of this review was to: (i) investigate whether phenobarbital can be safely used as an antiepileptic drug and (ii) determine the questions which need to be addressed in order to comprehensively and adequately evaluate the safety of phenobarbital for the treatment of epilepsy. The literature was searched using the Cochrane Central Register of randomised controlled trials (1800-2009), Medline (1966-2009), Embase (1966-2009) and three Chinese databases. Twenty studies were finally included in this systematic review. The determination of adverse effects of combined antiepileptic drugs (AEDs) from different studies was complicated by numerous factors including study design, different descriptions of adverse events and a lack of standardised data collection. These factors may also have been responsible for the heterogeneity present in the meta-analysis. The data did not demonstrate any evidence of association between phenobarbital and a higher risk of adverse events. However, phenobarbital appeared to be associated with a higher rate of adverse drug reaction related withdrawal (ADR-related withdraw), compared to carbamazepine, valproic acid and phenytoin. This may have been due to a concern for possible adverse effects of phenobarbital. Phenobarbital was associated with a higher rate of drug withdrawal although there was no evidence to suggest that phenobarbital caused more adverse events compared to carbamazepine, valproic acid or phenytoin. However, in the case of pregnant women, it is important for clinicians to evaluate the benefits and risks of phenobarbital administration before making a final recommendation. Furthermore, unified scales for the assessment of cognitive function should be applied for future studies particularly in children.


Fr-PPIChem: An Academic Compound Library Dedicated to Protein-Protein Interactions.
Protein-protein interactions (PPIs) mediate nearly every cellular process and represent attractive targets for modulating disease states but are challenging to target with small molecules. Despite this, several PPI inhibitors (iPPIs) have entered clinical trials, and a growing number of PPIs have become validated drug targets. However, high-throughput screening efforts still endure low hit rates mainly because of the use of unsuitable screening libraries. Here, we describe the collective effort of a French consortium to build, select, and store in plates a unique chemical library dedicated to the inhibition of PPIs. Using two independent predictive models and two updated databases of experimentally confirmed PPI inhibitors developed by members of the consortium, we built models based on different training sets, molecular descriptors, and machine learning methods. Independent statistical models were used to select putative PPI inhibitors from large commercial compound collections showing great complementarity. Medicinal chemistry filters were applied to remove undesirable structures from this set (such as PAINS, frequent hitters, and toxic compounds) and to improve drug likeness. The remaining compounds were subjected to a clustering procedure to reduce the final size of the library while maintaining its chemical diversity. In practice, the library showed a 46-fold activity rate enhancement when compared to a non-iPPI-enriched diversity library in high-throughput screening against the CD47-SIRPα PPI. The Fr-PPIChem library is plated in 384-well plates and will be distributed on demand to the scientific community as a powerful tool for discovering new chemical probes and early hits for the development of potential therapeutic drugs.


Protein arginine methylation: a prominent modification and its demethylation.
Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases.


"You have to change your whole life": A qualitative study of the dynamics of treatment adherence among adults with tuberculosis in the United Kingdom.
Maintaining adherence to treatment for tuberculosis (TB) is essential if the disease is to be eliminated. As part of formative research to develop an intervention to improve adherence, we documented the lived experiences of adults receiving anti-TB treatment (ATT) in three UK cities and examined how personal, social, and structural circumstances interacted to impact on individuals' adherence to treatment. Using a topic guide that explored social circumstances and experiences of TB care, we conducted in-depth interviews with 18 adults (six women) who were being or had been treated for TB (patients) and four adults (all women) who were caring for a friend, relative, or partner being treated for TB (caregivers). We analysed transcripts using an adapted framework method that classified factors affecting adherence as personal, social, structural, health systems, or treatment-related. Eleven of 18 patients were born outside the UK (in South, Central, and East Asia, and Eastern and Southern Africa); among the seven who were UK-born, four were Black, Asian, or Minority Ethnic and three were White British. TB and its treatment were often disruptive: in addition to debilitating symptoms and side effects of ATT, participants faced job insecurity, unstable housing, stigma, social isolation, worsening mental health, and damaged relationships. Those who had a strong support network, stable employment, a routine that could easily be adapted, a trusting relationship with their TB team, and clear understanding of the need for treatment reported finding it easier to adhere to ATT. Changes in circumstances sometimes had dramatic effects on an individual's ability to take ATT; participants described how the impact of certain acute events (e.g., the onset of side effects or fatigue, episodes of stigmatisation, loss of income) were amplified by their timing or through their interaction with other elements of the individual's life. We suggest that the dynamic and fluctuating nature of these factors necessitates comprehensive and regular review of needs and potential problems, conducted before and during ATT; this, coupled with supportive measures that consider (and seek to mitigate) the influence of social and structural factors, may help improve adherence.


Hedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy.
The effectiveness of single-drug antiviral interventions to reduce morbidity and mortality during the next influenza pandemic will be substantially weakened if transmissible strains emerge which are resistant to the stockpiled antiviral drugs. We developed a mathematical model to test the hypothesis that a small stockpile of a secondary antiviral drug could be used to mitigate the adverse consequences of the emergence of resistant strains. We used a multistrain stochastic transmission model of influenza to show that the spread of antiviral resistance can be significantly reduced by deploying a small stockpile (1% population coverage) of a secondary drug during the early phase of local epidemics. We considered two strategies for the use of the secondary stockpile: early combination chemotherapy (ECC; individuals are treated with both drugs in combination while both are available); and sequential multidrug chemotherapy (SMC; individuals are treated only with the secondary drug until it is exhausted, then treated with the primary drug). We investigated all potentially important regions of unknown parameter space and found that both ECC and SMC reduced the cumulative attack rate (AR) and the resistant attack rate (RAR) unless the probability of emergence of resistance to the primary drug p(A) was so low (less than 1 in 10,000) that resistance was unlikely to be a problem or so high (more than 1 in 20) that resistance emerged as soon as primary drug monotherapy began. For example, when the basic reproductive number was 1.8 and 40% of symptomatic individuals were treated with antivirals, AR and RAR were 67% and 38% under monotherapy if p(A) = 0.01. If the probability of resistance emergence for the secondary drug was also 0.01, then SMC reduced AR and RAR to 57% and 2%. The effectiveness of ECC was similar if combination chemotherapy reduced the probabilities of resistance emergence by at least ten times. We extended our model using travel data between 105 large cities to investigate the robustness of these resistance-limiting strategies at a global scale. We found that as long as populations that were the main source of resistant strains employed these strategies (SMC or ECC), then those same strategies were also effective for populations far from the source even when some intermediate populations failed to control resistance. In essence, through the existence of many wild-type epidemics, the interconnectedness of the global network dampened the international spread of resistant strains. Our results indicate that the augmentation of existing stockpiles of a single anti-influenza drug with smaller stockpiles of a second drug could be an effective and inexpensive epidemiological hedge against antiviral resistance if either SMC or ECC were used. Choosing between these strategies will require additional empirical studies. Specifically, the choice will depend on the safety of combination therapy and the synergistic effect of one antiviral in suppressing the emergence of resistance to the other antiviral when both are taken in combination.


Brain-wide glymphatic enhancement and clearance in humans assessed with MRI.
To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.


Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes.
Type I diabetes [insulin-dependent diabetes mellitus (IDDM)] is an autoimmune disease associated with the destruction of pancreatic beta cells. Serum from patients with IDDM increased L-type calcium channel activity of insulin-producing cells and of GH3 cells derived from a pituitary tumor. The subsequent increase in the concentration of free cytoplasmic Ca2+ ([Ca2+]i) was associated with DNA fragmentation typical of programmed cell death or apoptosis. These effects of the serum were prevented by adding a blocker of voltage-activated L-type Ca2+ channels. When the serum was depleted of immunoglobulin M (IgM), it no longer affected [Ca2+]i. An IgM-mediated increase in Ca2+ influx may thus be part of the autoimmune reaction associated with IDDM and contribute to the destruction of beta cells in vivo.


Causes of death among persons of all ages within the Kilifi Health and Demographic Surveillance System, Kenya, determined from verbal autopsies interpreted using the InterVA-4 model.
The vast majority of deaths in the Kilifi study area are not recorded through official systems of vital registration. As a result, few data are available regarding causes of death in this population. To describe the causes of death (CODs) among residents of all ages within the Kilifi Health and Demographic Surveillance System (KHDSS) on the coast of Kenya. Verbal autopsies (VAs) were conducted using the 2007 World Health Organization (WHO) standard VA questionnaires, and VA data further transformed to align with the 2012 WHO VA instrument. CODs were then determined using the InterVA-4 computer-based probabilistic model. Five thousand one hundred and eighty seven deaths were recorded between January 2008 and December 2011. VA interviews were completed for 4,460 (86%) deaths. Neonatal pneumonia and birth asphyxia were the main CODs in neonates; pneumonia and malaria were the main CODs among infants and children aged 1-4, respectively, while HIV/AIDS was the main COD for adult women of reproductive age. Road traffic accidents were more commonly observed among men than women. Stroke and neoplasms were common CODs among the elderly over the age of 65. We have established the main CODs among people of all ages within the area served by the KHDSS on the coast of Kenya using the 2007 WHO VA questionnaire coded using InterVA-4. We hope that our data will allow local health planners to estimate the burden of various diseases and to allocate their limited resources more appropriately.


COMETARY SCIENCE. Properties of the 67P/Churyumov-Gerasimenko interior revealed by CONSERT radar.
The Philae lander provides a unique opportunity to investigate the internal structure of a comet nucleus, providing information about its formation and evolution in the early solar system. We present Comet Nucleus Sounding Experiment by Radiowave Transmission (CONSERT) measurements of the interior of Comet 67P/Churyumov-Gerasimenko. From the propagation time and form of the signals, the upper part of the "head" of 67P is fairly homogeneous on a spatial scale of tens of meters. CONSERT also reduced the size of the uncertainty of Philae's final landing site down to approximately 21 by 34 square meters. The average permittivity is about 1.27, suggesting that this region has a volumetric dust/ice ratio of 0.4 to 2.6 and a porosity of 75 to 85%. The dust component may be comparable to that of carbonaceous chondrites.


Dual Gate Black Phosphorus Field Effect Transistors on Glass for NOR Logic and Organic Light Emitting Diode Switching.
We have fabricated dual gate field effect transistors (FETs) with 12 nm-thin black phosphorus (BP) channel on glass substrate, where our BP FETs have a patterned-gate architecture with 30 nm-thick Al2O3 dielectrics on top and bottom of a BP channel. Top gate dielectric has simultaneously been used as device encapsulation layer, controlling the threshold voltage of FETs as well when FETs mainly operate under bottom gate bias. Bottom, top, and dual gate-controlling mobilities were estimated to be 277, 92, and 213 cm(2)/V s, respectively. Maximum ON-current was measured to be ∼5 μA at a drain voltage of -0.1 V but to be as high as ∼50 μA at -1 V, while ON/OFF current ratio appeared to be 3.6 × 10(3) V. As a result, our dual gate BP FETs demonstrate organic light emitting diode (OLED) switching for green and blue OLEDs, also demonstrating NOR logic functions by separately using top- and bottom-input.


Electroencephalographic differences between WAG/Rij and GAERS rat models of absence epilepsy.
The inbred Wistar Albino Glaxo Rats from Rijswijk (WAG/Rij) and the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are well-validated genetic models of absence epilepsy. Although they share similar characteristics including the spike-and-wave discharges (SWDs) in the EEG, some differences have been reported between both strains. This study aimed a systematic and detailed comparison of the SWD patterns of both strains in terms of the intensity, frequency and waveform morphology of the discharges by using exactly the same measurement and analysis techniques. The number, cumulative total duration and mean duration of SWDs were significantly higher in GAERS compared to WAG/Rij, while the discharge frequency was higher in the WAG/Rij. Furthermore, SWDs spectra and average SWD waveforms indicated that a single cycle of the SWD contains more energy in faster components such as spike and late positive transient in the GAERS. Additionally, WAG/Rij exhibited a significantly higher power between 8 and 14 Hz during the pre-SWD period. These clear phenomenological differences in the EEGs of both animal models suggest that these variables may represent basic phenotypic features of SWDs that should be sought after in the future studies that explore the genetic and molecular basis of absence epilepsy.


Endometriosis.
Endometriosis is a common mysterious and fascinating gynaecological condition with diverse clinical manifestations, highly variable and unpredictable clinical course with decreased quality of life. Despite extensive research, endometriosis is fraught with controversies. Review of pertinent literature on endometriosis, selected references, internet services through gynaecological search which have been critical in the understanding of this puzzling gynaecologic condition were included in the review. Endometriosis most commonly afflict women in there late 20s and 30s. The classic symptom complex include dysmenorrhoea, dyspareunia, menorrhagia and infertility. About 30% of the patients are asymptomatic. The incidence of infertility amongst women suffering from endometriosis ranges from 30%-40%. The factors implicated in causing endometriosis-associated infertility are multiple and its management is shrouded in controversy, complex and imperfectly understood. Inspite of diverse clinical manifestations, variable and unpredictable clinical course, there is a chance to improve pregnancy rates with improvement in assisted reproductive technology.


Teaching epidemiology in the digital age: considerations for academicians and their students.
The way in which we prepare future public health professionals is changing because of the digital age. Online education is expanding the accessibility of public health training to students and practitioners with diverse backgrounds. Online courses offer many advantages for students, including flexible schedules, elimination of commuting time, and fostering interactions among students and the instructor. A few disadvantages of online courses for the student can include a feeling of isolation, difficulty adjusting to the time-intensive nature, and the required self-discipline to regularly tend to online course materials that immature and working students can find challenging. For faculty who are faced with teaching epidemiology in these changing times of the traditional face-to-face classroom and the virtual classroom, the core teaching principles of this science of public health remain unchanged, yet how they are delivered in the online environment adds a layer of complexity not previously encountered. This paper presents practical considerations for faculty who will be teaching online and their students who will be learning online. In addition, a framework for an online epidemiology course is presented as a model by which faculty interested in teaching epidemiology online can modify the course structure, content, and assessment tools to fit their needs.


A prospective study of nutritional factors and hypertension among US men.
An effect of diet in determining blood pressure is suggested by epidemiological studies, but the role of specific nutrients is still unsettled. The relation of various nutritional factors with hypertension was examined prospectively among 30,681 predominantly white US male health professionals, 40-75 years old, without diagnosed hypertension. During 4 years of follow-up, 1,248 men reported a diagnosis of hypertension. Age, relative weight, and alcohol consumption were the strongest predictors for the development of hypertension. Dietary fiber, potassium, and magnesium were each significantly associated with lower risk of hypertension when considered individually and after adjustment for age, relative weight, alcohol consumption, and energy intake. When these nutrients were considered simultaneously, only dietary fiber had an independent inverse association with hypertension. For men with a fiber intake of < 12 g/day, the relative risk of hypertension was 1.57 (95% confidence interval, 1.20-2.05) compared with an intake of > 24 g/day. Calcium was significantly associated with lower risk of hypertension only in lean men. Dietary fiber, potassium, and magnesium were also inversely related to baseline systolic and diastolic blood pressure and to change in blood pressure during the follow-up among men who did not develop hypertension. Calcium was inversely associated with baseline blood pressure but not with change in blood pressure. No significant associations with hypertension were observed for sodium, total fat, or saturated, transunsaturated, and polyunsaturated fatty acids. Fruit fiber but not vegetable or cereal fiber was inversely associated with incidence of hypertension. These results support hypotheses that an increased intake of fiber and magnesium may contribute to the prevention of hypertension.


Structure and alignment of the membrane-associated peptaibols ampullosporin A and alamethicin by oriented 15N and 31P solid-state NMR spectroscopy.
Ampullosporin A and alamethicin are two members of the peptaibol family of antimicrobial peptides. These compounds are produced by fungi and are characterized by a high content of hydrophobic amino acids, and in particular the alpha-tetrasubstituted amino acid residue ?-aminoisobutyric acid. Here ampullosporin A and alamethicin were uniformly labeled with (15)N, purified and reconstituted into oriented phophatidylcholine lipid bilayers and investigated by proton-decoupled (15)N and (31)P solid-state NMR spectroscopy. Whereas alamethicin (20 amino acid residues) adopts transmembrane alignments in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membranes the much shorter ampullosporin A (15 residues) exhibits comparable configurations only in thin membranes. In contrast the latter compound is oriented parallel to the membrane surface in 1,2-dimyristoleoyl-sn-glycero-3-phosphocholine and POPC bilayers indicating that hydrophobic mismatch has a decisive effect on the membrane topology of these peptides. Two-dimensional (15)N chemical shift -(1)H-(15)N dipolar coupling solid-state NMR correlation spectroscopy suggests that in their transmembrane configuration both peptides adopt mixed alpha-/3(10)-helical structures which can be explained by the restraints imposed by the membranes and the bulky alpha-aminoisobutyric acid residues. The (15)N solid-state NMR spectra also provide detailed information on the helical tilt angles. The results are discussed with regard to the antimicrobial activities of the peptides.


Synergy, redundancy, and independence in population codes.
A key issue in understanding the neural code for an ensemble of neurons is the nature and strength of correlations between neurons and how these correlations are related to the stimulus. The issue is complicated by the fact that there is not a single notion of independence or lack of correlation. We distinguish three kinds: (1) activity independence; (2) conditional independence; and (3) information independence. Each notion is related to an information measure: the information between cells, the information between cells given the stimulus, and the synergy of cells about the stimulus, respectively. We show that these measures form an interrelated framework for evaluating contributions of signal and noise correlations to the joint information conveyed about the stimulus and that at least two of the three measures must be calculated to characterize a population code. This framework is compared with others recently proposed in the literature. In addition, we distinguish questions about how information is encoded by a population of neurons from how that information can be decoded. Although information theory is natural and powerful for questions of encoding, it is not sufficient for characterizing the process of decoding. Decoding fundamentally requires an error measure that quantifies the importance of the deviations of estimated stimuli from actual stimuli. Because there is no a priori choice of error measure, questions about decoding cannot be put on the same level of generality as for encoding.


Screening for sexual orientation in psychiatric emergency departments.
Our goal was to explore whether emergency department (ED) patients would disclose their sexual orientation in a research evaluation and to examine demographic and clinical characteristics of patients by self-identified sexual orientation. Participants (n=177) presented for psychiatric treatment at three urban EDs in New York City, Rochester, NY, and Philadelphia, PA. Participants were interviewed in the context of a larger study of a standardized suicide risk assessment. We assessed participants' willingness to answer questions regarding sexual orientation along three dimensions: a self-description of sexual orientation, a self-description of sexual attraction, and the gender of any prior sexual partners. No participants (0/177) refused to respond to the categorical question about sexual orientation, 168/177 (94.9%) agreed to provide information about prior sexual partners, and 100/109 (91.7%) provided information about current sexual attraction toward either gender. Of all 177 participants, 154 (87.0%) self-identified as heterosexual, 11 (6.2%) as bisexual, 10 (5.6%) as gay or lesbian, and 2 (1.1%) indicated they were not sure. As compared with heterosexual patients, lesbian, gay and bisexual (LGB) patients were significantly younger and more likely to be non-white, but did not differ significantly in terms of education, income, employment, or religious affiliation or participation. Further, LGB participants did not differ from self-identified heterosexual participants for lifetime suicide attempt rate or lifetime history of any mood, substance-related, psychotic spectrum, or other Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) Axis I disorder. Of self-identified heterosexual participants 5.6% (5/89) reported sexual attraction as other than 'only opposite sex,' and 10.3% (15/142) of sexually active 'heterosexual' participants reported previous same-gender sexual partners. Assessing patients' sexual orientation in the ED by a three-question approach appeared feasible in the ED and acceptable to ED patients. However, since many patients have sexual experiences not suggested by simple labels, self-report of sexual identity alone may not inform clinicians of health risks inherent in same or opposite gender sexual contact.


A Point Mutation Creating a 3' Splice Site in C8A Is a Predominant Cause of C8α-γ Deficiency in African Americans.
C8α-γ deficiency was examined in four unrelated African Americans. Two individuals were compound heterozygotes for a previously reported point mutation in exon 9. mRNA from the remaining six C8A alleles contained a 10 nt insertion between nt 992 and 993 corresponding to the junction between exons 6 and 7. This suggested that C8α-γ deficiency in these individuals was caused by a splicing defect. Genomic sequencing revealed a G→A point mutation in intron 6, upstream of the exon 7 acceptor site. This mutation converts a GG to an AG, generates a consensus 3' splice site that shifts the reading frame, and creates a premature stop codon downstream. To verify that the point mutation caused a splicing defect, we tested wild-type and mutant mRNA substrates, containing 333 nt of the C8α intron 6/exon 7 boundary, in an in vitro splicing assay. This assay generated spliced RNA containing the 10 bp insertion observed in the C8α mRNA of affected patients. In addition, in mutant RNA substrates, the new 3' splice site was preferentially recognized compared with wild-type. Preferential selection of the mutant splice site likely reflects its positioning adjacent to a polypyrimidine tract that is stronger than that adjacent to the wild-type site. In summary, we have identified a G→A mutation in intron 6 of C8A as a predominant cause of C8α-γ deficiency in African Americans. This mutation creates a new and preferred 3' splice site, results in a 10 nt insertion in mRNA, shifts the reading frame, and produces a premature stop codon downstream.


In vivo time-lapse microscopy reveals no loss of murine myonuclei during weeks of muscle atrophy.
Numerous studies have suggested that muscle atrophy is accompanied by apoptotic loss of myonuclei and therefore recovery would require replenishment by muscle stem cells. We used in vivo time-lapse microscopy to observe the loss and replenishment of myonuclei in murine muscle fibers following induced muscle atrophy. To our surprise, imaging of single fibers for up to 28 days did not support the concept of nuclear loss during atrophy. Muscles were inactivated by denervation, nerve impulse block, or mechanical unloading. Nuclei were stained in vivo either acutely by intracellular injection of fluorescent oligonucleotides or in time-lapse studies after transfection with a plasmid encoding GFP with a nuclear localization signal. We observed no loss of myonuclei in fast- or slow-twitch muscle fibers despite a greater than 50% reduction in fiber cross-sectional area. TUNEL labeling of fragmented DNA on histological sections revealed high levels of apoptotic nuclei in inactive muscles. However, when costained for laminin and dystrophin, virtually none of the TUNEL-positive nuclei could be classified as myonuclei; apoptosis was confined to stromal and satellite cells. We conclude that disuse atrophy is not a degenerative process, but is rather a change in the balance between protein synthesis and proteolysis in a permanent cell syncytium.


Effect of regional versus general anaesthesia on postoperative delirium in elderly patients undergoing surgery for hip fracture: a systematic review.
Older patients with hip fractures who are undergoing surgery are at high risk of significant mortality and morbidity including postoperative delirium. It is unclear whether different types of anaesthesia may reduce the incidence of postoperative delirium. This systematic review will investigate the impact of anaesthetic technique on postoperative delirium. Other outcomes included mortality, length of stay, complications and functional outcomes. Systematic review of randomised controlled trials and non-randomised controlled studies. Bibliographic databases were searched from inception to June 2018. Web of Science and ZETOC databases were searched for conference proceedings. Reference lists of relevant articles were checked, and clinical trial registers were searched to identify ongoing trials. Studies were eligible if general and regional anaesthesia were compared in patients (aged 60 and over) undergoing hip fracture surgery, reporting primary outcome of postoperative delirium and secondary outcomes of mortality, length of hospital stay, adverse events, functional outcomes, discharge location and quality of life. Exclusion criteria were anaesthetic technique or drug not considered current standard practice; patients undergoing hip fracture surgery alongside other surgery and uncontrolled studies. One hundred and four studies were included. There was no evidence to suggest that anaesthesia type influences postoperative delirium or mortality. Some studies suggested a small reduction in length of hospital stay with regional anaesthesia. There was some evidence to suggest that respiratory complications and intraoperative hypotension were more common with general anaesthesia. Heterogeneity precluded meta-analysis. All findings were described narratively and data were presented where possible in forest plots for illustrative purposes. While there was no evidence to suggest that anaesthesia types influence postoperative delirium, the evidence base is lacking. There is a need to ascertain the impact of type of anaesthesia on outcomes with an adequately powered, methodologically rigorous study. CRD42015020166.


Virus-like particle expression and assembly in plants: hepatitis B and Norwalk viruses.
Expression of vaccine antigens in plants and delivery via ingestion of transgenic plant material has shown promise in numerous pre-clinical animal studies and in a few clinical trials. A number of different viral antigens have been tested, and among the most promising are those that can assemble virus-like particles (VLP), which mimic the form of authentic virions and display neutralizing antibody epitopes. We have extensively studied plant expression, VLP assembly, and immunogenicity of hepatitis B surface antigen (HBsAg) and Norwalk virus capsid protein (NVCP). The HBsAg small protein (S protein) was found by TEM to assemble tubular membrane complexes derived from endoplasmic reticulum in suspension cultured cells of tobacco and soybean, and in potato leaf and tuber tissues. The potato material was immunogenic in mice upon delivery by ingestion. Here we describe the plant expression and immunogenicity of HBsAg middle protein (M protein or pre-S2 + S) which contains additional 55 amino acid pre-S2 region at N-terminus of the S protein. Plant-derived recombinant M protein provoked stronger serum antibody responses against HBsAg than did S protein when injected systemically in mice. We discuss implications for use of fusion proteins for enhanced immunogenicity and mucosal targeting of HBsAg, as well as delivery of heterologous fused antigens. NVCP expressed in plants assembled 38 nm virion-size icosahedral (T = 3) VLP, similar to those produced in insect cells. The VLP stimulated serum IgG and IgA responses in mice and humans when they were delivered by ingestion of fresh potato tuber. Here we show that freeze-drying of transgenic NVCP tomato fruit yielded stable preparations that stimulated excellent IgG and IgA responses against NVCP when fed to mice. However, the predominant VLP form in tomato fruit was the small 23 nm particle also observed in insect cell-derived NVCP.


Activation of a microRNA response in trans reveals a new role for poly(A) in translational repression.
Here, we report that the untreated rabbit reticulocyte lysate contains over 300 different endogenous microRNAs together with the major components of the RNA-induced silencing complex and thus can be used as a model in vitro system to study the effects of microRNAs on gene expression. By using this system, we were able to show that microRNA hybridization to its target resulted in a very rapid and strong inhibition of expression that was exerted exclusively at the level of translation initiation with no involvement of transcript degradation or deadenylation. Moreover, we demonstrate that the magnitude of microRNA-induced repression can only be recapitulated in the context of a competitive translating environment. By using a wide spectrum of competitor cellular and viral RNAs, we could further show that competition was not exerted at the level of general components of the translational machinery, but relied exclusively on the presence of the poly(A) tail with virtually no involvement of the cap structure.


Histogenesis of Kaposi's sarcoma in patients with and without acquired immune deficiency syndrome (AIDS).
Immunohistochemical studies were performed in thirty skin biopsies from patients with Kaposi's sarcoma, who did and did not have the acquired immune deficiency syndrome (AIDS). Tumour histogenesis was rigorously tested using a battery of endothelial cell markers, which included two new monoclonal antibodies, EN4 and PAL E. These are both specific for endothelial cells and can be visualised in appropriately fixed paraffin embedded tissue. Whereas EN4 labels all endothelial cells, PAL E is negative in endothelium of lymphatic derivation. Lectin binding with Ulex europaeus agglutinin 1 (UEA-1) and the presence of factor VIII related antigen (FVIIIRA) and laminin were also examined. In nodular lesions of Kaposi's sarcoma the spindle cell areas were positive with EN4 and UEA-1, negative with PAL E, and showed focal staining for FVIIIRA and laminin. These results confirm that the tumour is of endothelial cell origin. Six patch stage lesions showed a network of angulated spaces, lined by cells that were positive with EN4 and UEA-1, negative with PAL E and anti-FVIIIRA, and showed only weak staining for laminin. This pattern was observed in both AIDS and non-AIDS related cases and strongly favours a lymphatic derivation for the tumour. This has important implications as it suggests that lymphatic endothelium may have special characteristics that lead to neoplastic transformation in patients with retrovirus infection.


pH-Dependent absorption spectrum of a protein: a minimal electrostatic model of Anabaena sensory rhodopsin.
A minimal electrostatic model is introduced which aims at reproducing and analyzing the visible-light absorption energy shift of a protein with pH. It relies on the existence of a protein structure, the prediction of titratable amino-acid pKa values and a very limited set of parameters. Applied to the case of the photochromic Anabaena sensory rhodopsin protein, the model succeeds in reproducing qualitatively the reported experimental data, confirming the importance of aspartic acid 217 in the observed blue shift in the λmax of ASR at neutral pH. It also suggests for the first time the role of two other amino acids, glutamic acid 36 at basic pH and aspartic acid 120 at acidic pH.


[Active surveillance is a useful strategy in the management of patients with low-risk prostate cancer].
Radical prostatectomy has in randomised settings failed to demonstrate a survival difference in patients with low-risk prostate cancer when tested against an observational strategy. Active surveillance has been introduced in order to reduce overtreatment by distinguishing between cancers with a biological potential, and truly indolent cancers best left untreated. Preliminary results from large prospective active surveillance cohorts are promising; however, uncertainties persist concerning optimal patient selection and follow-up, as well as the long-term safety.


Exchanging and using research evidence in health policy networks: a statistical network analysis.
Evidence-informed health policymaking is a goal of equitable and effective health systems but occurs infrequently in reality. Past research points to the facilitating role of interpersonal relationships between policy-makers and researchers, imploring the adoption of a social network lens. This study aims to identify network-level factors associated with the exchange and use of research evidence in policymaking. Data on social networks and research use were collected from seventy policy actors across three health policy cases in Burkina Faso (child health, malaria, and HIV). Networks were graphed for actors' interactions, their provision of, and request for research evidence. Exponential random graph models estimated the probability of evidence provision and request between actors, controlling for network- and individual-level covariates. Logistic regression models estimated actors' use of research evidence to inform policy. Network structure explained more than half of the evidence exchanges (ties) observed in these networks. Across all cases, a pair of actors was more likely to form a provision tie if they already had a request tie between them and visa versa (θ=6.16, p<0.05; θ=2.87, p<0.05; θ=2.31, p<0.05). The child health network displayed clustering tendencies, meaning that actors were more likely to form ties if they shared an acquaintance (θ=2.36, p<0.05). Actors' use of research evidence was positively associated with their centrality (i.e., connectedness). The exchange and use of research evidence in policymaking can be partly explained by the structure of actors' networks of relationships. Efforts to support knowledge translation and evidence-informed policymaking should consider network factors.


Risk assessment of down-the-drain chemicals at large spatial scales: Model development and application to contaminants originating from urban areas in the Saint Lawrence River Basin.
Chemicals released into freshwater systems threaten ecological functioning and may put aquatic life and the health of humans at risk. We developed a new contaminant fate model (CFM) that follows simple, well-established methodologies and is unique in its cross-border, seamless hydrological and geospatial framework, including lake routing, a critical component in northern environments. We validated the model using the pharmaceutical Carbamazepine and predicted eco-toxicological risk for 15 pharmaceuticals in the Saint-Lawrence River Basin, Canada. The results indicated negligible to low environmental risk for the majority of tested chemicals, while two pharmaceuticals showed elevated risk in up to 13% of rivers affected by municipal effluents. As an integrated model, our CFM is designed for application at very large scales with the primary goal of detecting high risk zones. In regulatory frameworks, it can help screen existing or new chemicals entering the market regarding their potential impact on human and environmental health. Due to its high geospatial resolution, our CFM can also facilitate the prioritization of actions, such as identifying regions where reducing contamination sources or upgrading treatment plants is most pertinent to achieve targeted pollutant removal or to protect drinking water resources.


Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults.
Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: (A) days 0, 14; (B) days 0 and 28; (C) days 0, 14, and 28; or (D) 0.25 mL at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. Almost all subjects developed some local reactions with 46-64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥ 4 fold antibody rise in more subjects on days 21, 28, and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages.