Multiple paths extraction in images using a constrained expanded trellis.
Single shortest path extraction algorithms have been used in a number of areas such as network flow and image analysis. In image analysis, shortest path techniques can be used for object boundary detection, crack detection, or stereo disparity estimation. Sometimes one needs to find multiple paths as opposed to a single path in a network or an image where the paths must satisfy certain constraints. In this paper, we propose a new algorithm to extract multiple paths simultaneously within an image using a constrained expanded trellis (CET) for feature extraction and object segmentation. We also give a number of application examples for our multiple paths extraction algorithm.


Axially chiral racemic half-sandwich nickel(ii) complexes by ring-closing metathesis.
A remarkable nickelacycle has been synthesised via olefin metathesis of the α,ω-diene complex [Ni(η5-C5H4R)(Br)(NHC)] (R = C(CH3)2CH2CH[double bond, length as m-dash]CH2, NHC = 1-(6-hexenyl)-3-(2,4,6-trimethylphenyl)-imidazol-2-ylidene). Single-crystal X-ray analysis reveals a helical shape of the molecule and stretching of some interatomic distances in the Ni(ii) coordination sphere. The Cp-NHC tethered complex shows catalytic activity resembling that of the parent complexes.


Bee Venom Phospholipase A2 Alleviate House Dust Mite-Induced Atopic Dermatitis-Like Skin Lesions by the CD206 Mannose Receptor.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic, erythematous, and eczematous skin plaques. We previously reported that phospholipase A2 (PLA2) derived from bee venom alleviates AD-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) in a murine model. However, the underlying mechanisms of PLA2 action in actopic dermatitis remain unclear. In this study, we showed that PLA2 treatment inhibited epidermal thickness, serum immunoglobulin E (IgE) and cytokine levels, macrophage and mast cell infiltration in the ear of an AD model induced by DFE and DNCB. In contrast, these effects were abrogated in CD206 mannose receptor-deficient mice exposed to DFE and DNCB in the ear. These data suggest that bvPLA2 alleviates atopic skin inflammation via interaction with CD206.


Epstein-Barr virus and persistent graft dysfunction after liver transplantation.
Epstein-Barr virus infection has been associated with a broad spectrum of clinical manifestations, depending on the immune status of the host. In this report, we describe two liver transplant patients who received hepatic allografts from donors serologically positive for Epstein-Barr virus and who experienced primary infection with Epstein-Barr virus associated with prolonged liver graft dysfunction. In both patients, Epstein-Barr serologies converted within 3 mo of liver transplantation, and hepatic histological study revealed mononuclear infiltration of the sinusoids evolving to pronounced immunoblastic features suggestive of evolving lymphoma. In both cases, in situ hybridization studies confirmed the presence of Epstein-Barr virus genome in the liver. Furthermore, polymerase chain reaction analysis suggested that high levels of Epstein-Barr virus DNA were present in biopsy specimens obtained during the episode of acute hepatitis that followed Epstein-Barr virus seroconversion. The degree of Epstein-Barr virus DNA estimated by polymerase chain reaction appeared to increase in parallel with the progression of parenchymal lymphocytic infiltrates. In one patient, a biopsy sample from a cervical node also revealed high levels of Epstein-Barr virus DNA estimated using the polymerase chain reaction technique. Furthermore, in these patients, Epstein-Barr virus DNA levels appeared to decrease dramatically after discontinuing azathioprine administration and beginning treatment with acyclovir. These two cases illustrate the dynamics of Epstein-Barr virus immune regulation and confirm chronic hepatic allograft dysfunction related to Epstein-Barr viral infection.


Electrically controlled nonlinear generation of light with plasmonics.
Plasmonics provides a route to develop ultracompact optical devices on a chip by using extreme light concentration and the ability to perform simultaneous electrical and optical functions. These properties also make plasmonics an ideal candidate for dynamically controlling nonlinear optical interactions at the nanoscale. We demonstrate electrically tunable harmonic generation of light from a plasmonic nanocavity filled with a nonlinear medium. The metals that define the cavity also serve as electrodes that can generate high direct current electric fields across the nonlinear material. A fundamental wave at 1.56 micrometers was frequency doubled and modulated in intensity by applying a moderate external voltage to the electrodes, yielding a voltage-dependent nonlinear generation with a normalized magnitude of ~7% per volt.


Population-based trend analysis of 2813 patients undergoing laparoscopic sigmoid resection.
The use of laparoscopic sigmoid resection for diverticular disease has become increasingly popular. The objective of this trend analysis was to assess whether clinical outcomes following laparoscopic sigmoid resection for diverticular disease have improved over the past 10 years. The analysis was based on the prospective database of the Swiss Association of Laparoscopic and Thoracoscopic Surgery. Some 2813 patients undergoing elective laparoscopic sigmoid resection for diverticular disease from 1995 to 2006 were included. Unadjusted and risk-adjusted analyses were performed. Over time, there was a significant reduction in the conversion rate (from 27.3 to 8.6 per cent; P(trend) < 0.001), local postoperative complication rate (23.6 to 6.2 per cent; P(trend) = 0.004), general postoperative complication rate (14.6 to 4.9 per cent; P(trend) = 0.024) and reoperation rate (5.5 to 0.6 per cent; P(trend) = 0.015). Postoperative median length of hospital stay significantly decreased from 11 to 7 days (P(trend) < 0.001). This first trend analysis in the literature of clinical outcomes after laparoscopic sigmoid resection, based on almost 3000 patients, has provided compelling evidence that rates of postoperative complications, conversion and reoperation, and length of hospital stay have decreased significantly over the past 10 years.


Neutrophil Count Is Associated With Reduced Gray Matter and Enlarged Ventricles in First-Episode Psychosis.
Although there is recent evidence that cells from the peripheral immune system can gain access to the central nervous system in certain conditions such as multiple sclerosis, their role has not been assessed in psychosis. Here, we aimed to explore whether blood cell count was associated with brain volume and/or clinical symptomatology. A total of 218 participants (137 first-episode psychosis patients [FEP] and 81 healthy controls [HC]) were included in the study. For each participant, a T1 structural image was acquired, from which brain tissue volumes were calculated. We found that, in FEP, neutrophil count was associated with reduced gray matter (GM) volume (β = -0.117, P < .001) and increased cerebrospinal fluid volume (β = 0.191, P = .007). No associations were observed in HC. GM reduction was generalized but more prominent in certain regions, notably the thalamus, the anterior insula, and the left Heschl's gyrus, among many others. Neutrophil count was also associated with the total PANSS score (β = 0.173, P = .038), including those items assessing hallucinations (β = 0.182, P = .028) and avolition (β = 0.197, P = .018). Several confounders, such as antipsychotic medication, body mass index, and smoking, were controlled for. Overall, the present study may represent the first indirect evidence of brain tissue loss associated with neutrophils in psychosis, and lends support to the hypothesis of a dysregulated immune system. Higher neutrophil count was also associated with more severe clinical symptomatology, which renders it a promising indicator of schizophrenia severity and could even give rise to new therapies.


Overserving and Allowed Entry of Obviously Alcohol-Intoxicated Spectators at Sporting Events.
Alcohol intoxication among spectators at sporting events and related problems, such as violence, are of great concern in many countries around the world. However, knowledge is scarce about whether or not alcohol is served to obviously intoxicated spectators at licensed premises inside and outside the sporting arenas, and if obviously intoxicated spectators are allowed entrance to these events. The objective of this study was therefore to examine the occurrences of overserving at licensed premises inside and outside arenas, and of allowed entry of obviously intoxicated spectators into arenas. An observational study assessing the rate of denied alcohol service and denied entry to arenas of trained professional actors portraying a standardized scene of obvious alcohol intoxication (i.e., pseudo-patrons) was conducted. The scene was developed by an expert panel, and each attempt was monitored by an observer. The settings were 2 arenas hosting matches in the Swedish Premier Football League in the largest city in Sweden and 1 arena in the second largest city, including entrances and licensed premises inside and outside the arenas. The rates of denied alcohol service were 66.9% at licensed premises outside the arenas (n = 151) and 24.9% at premises inside the arenas (n = 237). The rate of denied entry to the arenas (n = 102) was 10.8%. Overserving and allowed entry of obviously alcohol-intoxicated spectators are problematic at sporting events in Sweden and may contribute to high overall intoxication levels among spectators. The differences in server intervention rates indicate that serving staff at licensed premises inside the arenas and entrance staff are not likely to have been trained in responsible beverage service. This result underscores the need for server training among staff at the arenas.


Protocol of the impact of alternative social assistance disbursement on drug-related harm (TASA) study: a randomized controlled trial to evaluate changes to payment timing and frequency among people who use illicit drugs.
Government social assistance payments seek to alleviate poverty and address survival needs, but their monthly disbursement may cue increases in illicit drug use. This cue may be magnified when assistance is disbursed simultaneously across the population. Synchronized payments have been linked to escalations in drug use and unintended but severe drug-related harms, including overdose, as well as spikes in demand for health, social, financial and police services. The TASA study examines whether changing payment timing and frequency can mitigate drug-related harm associated with synchronized social assistance disbursement. The study is a parallel arm multi-group randomized controlled trial in which 273 participants are randomly allocated for six assistance cycles to a control or one of two intervention arms on a 1:1:1 basis. Intervention arm participants receive their payments: (1) monthly; or (2) semi-monthly, in each case on days that are not during the week when cheques are normally issued. The study partners with a community-based credit union that has developed a system to vary social assistance payment timing. The primary outcome is a 40 % increase in drug use during the 3 days beginning with cheque issue day compared to other days of the month. Bi-weekly follow-up interviews collect participant information on this and secondary outcomes of interest, including drug-related harm (e.g. non-fatal overdose), exposure to violence and health service utilization. Self-reported data will be supplemented with participant information from health, financial, police and government administrative databases. A longitudinal, nested, qualitative parallel process evaluation explores participant experiences, and a cost-effectiveness evaluation of different disbursement scenarios will be undertaken. Outcomes will be compared between control and intervention arms to identify the impacts of alternative disbursement schedules on drug-related harm resulting from synchronized income assistance. This structural RCT benefits from strong community partnerships, highly detailed outcome measurement, robust methods of randomization and data triangulation with third party administrative databases. The study will provide evidence regarding the potential importance of social assistance program design as a lever to support population health outcomes and service provision for populations with a high prevalence of substance use. NCT02457949 Registered 13 May 2015.


Rapid isolation and susceptibility testing of Leptospira spp. using a new solid medium, LVW agar.
Pathogenic Leptospira spp., the causative agents of leptospirosis, are slow-growing Gram-negative spirochetes. Isolation of Leptospira from clinical samples and testing of antimicrobial susceptibility are difficult and time-consuming. Here, we describe the development of a new solid medium that facilitates more-rapid growth of Leptospira spp. and the use of this medium to evaluate the Etest's performance in determining antimicrobial MICs to drugs in common use for leptospirosis. The medium was developed by evaluating the effects of numerous factors on the growth rate of Leptospira interrogans strain NR-20157. These included the type of base agar, the concentration of rabbit serum (RS), and the concentration and duration of CO(2) incubation during the initial period of culture. The highest growth rate of NR-20157 was achieved using a Noble agar base supplemented with 10% RS (named LVW agar), with an initial incubation at 30°C in 5% CO(2) for 2 days prior to continuous culture in air at 30°C. These conditions were used to develop the Etest for three species, L. interrogans (NR-20161), L. kirschnerii (NR-20327), and L. borgpetersenii (NR-20151). The MICs were read on day 7 for all samples. The Etest was then performed on 109 isolates of pathogenic Leptospira spp. The MIC(90) values for penicillin G, doxycycline, cefotaxime, ceftriaxone, and chloramphenicol were 0.64 units/ml and 0.19, 0.047, 0.5, and 2 μg/ml, respectively. The use of LVW agar, which enables rapid growth, isolation of single colonies, and simple antimicrobial susceptibility testing for Leptospira spp., provides an opportunity for new areas of fundamental and applied research.


Visual performance in patients with neovascular age-related macular degeneration undergoing treatment with intravitreal ranibizumab.
Purpose. To assess visual function and its response to serial intravitreal ranibizumab (Lucentis, Genentech) in patients with neovascular age-related macular degeneration (nv-AMD). Methods. Forty-seven eyes of 47 patients with nv-AMD, and corrected distance visual acuity (CDVA) logMAR 0.7 or better, undergoing intravitreal injections of ranibizumab, were enrolled into this prospective study. Visual function was assessed using a range of psychophysical tests, while mean foveal thickness (MFT) was determined by optical coherence tomography (OCT). Results. Group mean (±sd) MFT reduced significantly from baseline (233 (±59)) to exit (205 (±40)) (P = 0.001). CDVA exhibited no change between baseline and exit visits (P = 0.48 and P = 0.31, resp.). Measures of visual function that did exhibit statistically significant improvements (P < 0.05 for all) included reading acuity, reading speed, mesopic and photopic contrast sensitivity (CS), mesopic and photopic glare disability (GD), and retinotopic ocular sensitivity (ROS) at all eccentricities. Conclusion. Eyes with nv-AMD undergoing intravitreal ranibizumab injections exhibit improvements in many parameters of visual function. Outcome measures other than CDVA, such as CS, GD, and ROS, should not only be considered in the design of studies investigating nv-AMD, but also in treatment and retreatment strategies for patients with the condition.


A supramolecular radical cation: folding-enhanced electrostatic effect for promoting radical-mediated oxidation.
We report a supramolecular strategy to promote radical-mediated Fenton oxidation by the rational design of a folded host-guest complex based on cucurbit[8]uril (CB[8]). In the supramolecular complex between CB[8] and a derivative of 1,4-diketopyrrolo[3,4-c]pyrrole (DPP), the carbonyl groups of CB[8] and the DPP moiety are brought together through the formation of a folded conformation. In this way, the electrostatic effect of the carbonyl groups of CB[8] is fully applied to highly improve the reactivity of the DPP radical cation, which is the key intermediate of Fenton oxidation. As a result, the Fenton oxidation is extraordinarily accelerated by over 100 times. It is anticipated that this strategy could be applied to other radical reactions and enrich the field of supramolecular radical chemistry in radical polymerization, photocatalysis, and organic radical battery and holds potential in supramolecular catalysis and biocatalysis.


Cleavage/polyadenylation factor IA associates with the carboxyl-terminal domain of RNA polymerase II in Saccharomyces cerevisiae.
The carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II plays an important role in transcription and processing of the nascent transcript by interacting with both transcription and RNA processing factors. We show here that the cleavage/polyadenylation factor IA of Saccharomyces cerevisiae directly contacts CTD. First by affinity chromatography experiments with yeast extracts we demonstrate that the Rna15p, Rna14p, and Pcf11p subunits of this complex are associated with phosphorylated CTD. This interaction is confirmed for Rna15p by yeast two-hybrid analysis. Second, Pcf11p, but not Rna15p, is shown to directly contact phosphorylated CTD based on in vitro binding studies with recombinant proteins. These findings establish a direct interaction of cleavage/polyadenylation factor IA with the CTD. Furthermore, a quantitative analysis of transcription run-on performed on temperature-sensitive mutant strains reveals that the lack of either functional Rna14p or Pcf11p affects transcription termination more severely than the absence of a functional Rna15p. Moreover, these data reinforce the concept that CTD phosphorylation acts as a regulatory mechanism in the maturation of the primary transcript.


Latent Cytomegalovirus Infection in Rheumatoid Arthritis and Increased Frequencies of Cytolytic LIR-1+CD8+ T Cells.
Leukocyte immunoglobulin-like receptor 1 (LIR-1) is up-regulated by cytomegalovirus (CMV), which in turn, has been associated with premature aging and more severe joint disease in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the expression and functional significance of LIR-1 in CMV-positive RA patients. We determined the phenotype, cytolytic potential, CMV-specific proliferation, and HLA-G-triggered, LIR-1-mediated inhibition of interferon-γ secretion of LIR-1+ T cells in RA patients and healthy controls. We found increased frequencies of CD8+ T cells with CMV pp65-specific T cell receptors in CMV-positive RA patients as compared to CMV-positive healthy controls. CMV-specific CD8+ T cells in these patients were preferentially LIR-1+ and exhibited a terminally differentiated polyfunctional phenotype. The numbers of LIR-1+CD8+ T cells increased with age and disease activity, and showed high levels of reactivity to CMV antigens. Ligation of LIR-1 with soluble HLA-G molecules in vitro confirmed an inhibitory role of the molecule when expressed on CD8+ T cells in RA patients. We propose that latent CMV infection in the context of a chronic autoimmune response induces the recently described "chronic infection phenotype" in CD8+ T cells, which retains anti-infectious effector features while exhibiting autoreactive cytolytic potential. This response is likely dampened by LIR-1 to avoid overwhelming immunopathologic changes in the setting of the autoimmune disease RA. The known deficiency of soluble HLA-G in RA and the observed association of LIR-1 expression with disease activity suggest, however, that LIR-1+ T cells are insufficiently controlled in RA and are still likely to be involved in the pathogenesis of the disease.


Effect of bivalent cations on rat liver cytosol casein (glycogen synthase) kinases 1 and 2. Influence of the protein substrate.
Rat liver cytosol casein kinases 1 and 2 were stimulated by free Mg2+, but the optimal concentration of cation varied with both the casein kinase and the protein substrate used. Mn2+, but neither Ca2+ nor Zn2+, could efficiently substitute for Mg2+ in forming the bivalent-cation-ATP complex used as substrate, but free Mn2+ was inhibitory. The magnitude of these effects depended on the type of casein kinase and the protein substrate used. These results support the idea that, besides the effects of Mg2+ as a component of the Mg-ATP complex, or through interaction with the protein substrate, free Mg2+ is an allosteric effector of both casein kinases.


The Psychometric Properties and the Development of the Indicators of Quality Nursing Work Environments in Taiwan.
The nursing shortage in medical institutions in Taiwan averaged 9% in 2012, considerably higher than the 5% indicated in the literature. As a result, many hospitals have been forced to close wards or reduce beds. Despite the acute need, the percentage of registered nurses who are employed as nurses in Taiwan (60.4%) is considerably lower than those in Canada or the United States. This low rate may be because of the poor working environment for nurses in Taiwan. This study aimed to develop a set of nursing work environment quality indicators for Taiwan and to test the reliability and validity of the resulting survey tool. Multiple methods were used in this study. In Phase 1, we organized an expert panel, reviewed the literature, and conducted seven rounds of expert panel discussion and six focus group discussions with nursing directors. The goal was to draft indicators representing a quality nursing work environment to fit current conditions in Taiwan. In Phase 2, we conducted an expert review for content validity, held three public hearings, and conducted a survey. Four hundred twenty-seven questionnaires were sent out, with 381 returned. The goal was to test the content validity, construct validity, and internal consistency reliability. The study produced a set of indicators of a quality nursing work environment with eight dimensions and 65 items. The content validity index for importance and suitability dimensions were 1.0, whereas the internal consistency was 0.91. The eight dimensions were safe practice environment (16 items), quality and quantity of staff (four items), salary and welfare (seven items), professional specialization and teamwork (seven items), work simplification (five items), informatics (five items), career development (nine items), and support and caring (12 items). The overall load for the indicators was 77.57%. The developed indicators may be used to evaluate the quality of nursing work environments. Furthermore, the indicators may be used in hospital surveys to establish baseline conditions and for outcome research that measures improvement in nursing work environments after interventions.


Comparative efficacy of two treatment modalities for dentinal hypersensitivity: a clinical trial.
Dentin hypersensitivity is a recurrent condition causing discomfort and sometimes pain to the patient, which also deters him from maintaining adequate oral hygiene. Home care and office measures are used for treatment of this malady. To evaluate and compare the efficacy of 2 treatment modalities for dentinal hypersensitivity, iontophoresis with acidulated phosphate gel (APF) gel, and dentin-bonding agent application. This split mouth randomized clinical study recruited subjects with a history of hypersensitivity with at least 2 teeth, verified by a light stroke with a dental explorer along the cervical third of the teeth. The patients were subjected to a 1-s air blast and cold water stimuli and their responses were recorded on a verbal rating scale. A total of 30 sites from 15 patients were divided into Group A-1.23% APF gel iontophoresis; and Group B-aqueous solution of hydroxyl-ethyl-methacrylate and glutaraldehyde. The teeth were evaluated immediately after the treatment and at the end of 2 weeks. In case of failure, the tooth was retreated with the same agent as before. The results were statistically analyzed using Kruskal-Wallis analysis of variance and Mann-Whitney U tests. There was no statistically significant difference between the groups at the end of 2 weeks. However, Group A was more effective clinically, with fewer number of failures compared with Group B. Both the agents showed a statistically significant reduction in sensitivity compared with baseline; however, APF gel iontophoresis was more effective in reducing hypersensitivity over a longer time period.


Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction.
Ischemic injury in the heart induces an inflammatory cascade that both repairs damage and exacerbates scar tissue formation. Cardiosphere-derived cells (CDCs) are a stem-like population that is derived ex vivo from cardiac biopsies; they confer both cardioprotection and regeneration in acute myocardial infarction (MI). While the regenerative effects of CDCs in chronic settings have been studied extensively, little is known about how CDCs confer the cardioprotective process known as cellular postconditioning. Here, we used an in vivo rat model of ischemia/reperfusion (IR) injury-induced MI and in vitro coculture assays to investigate how CDCs protect stressed cardiomyocytes. Compared with control animals, animals that received CDCs 20 minutes after IR had reduced infarct size when measured at 48 hours. CDCs modified the myocardial leukocyte population after ischemic injury. Specifically, introduction of CDCs reduced the number of CD68+ macrophages, and these CDCs secreted factors that polarized macrophages toward a distinctive cardioprotective phenotype that was not M1 or M2. Systemic depletion of macrophages with clodronate abolished CDC-mediated cardioprotection. Using both in vitro coculture assays and a rat model of adoptive transfer after IR, we determined that CDC-conditioned macrophages attenuated cardiomyocyte apoptosis and reduced infarct size, thereby recapitulating the beneficial effects of CDC therapy. Together, our data indicate that CDCs limit acute injury by polarizing an effector macrophage population within the heart.


Long-term resilience of late holocene coastal subsistence system in Southeastern South america.
Isotopic and molecular analysis on human, fauna and pottery remains can provide valuable new insights into the diets and subsistence practices of prehistoric populations. These are crucial to elucidate the resilience of social-ecological systems to cultural and environmental change. Bulk collagen carbon and nitrogen isotopic analysis of 82 human individuals from mid to late Holocene Brazilian archaeological sites (∼6,700 to ∼1,000 cal BP) reveal an adequate protein incorporation and, on the coast, the continuation in subsistence strategies based on the exploitation of aquatic resources despite the introduction of pottery and domesticated plant foods. These results are supported by carbon isotope analysis of single amino acid extracted from bone collagen. Chemical and isotopic analysis also shows that pottery technology was used to process marine foods and therefore assimilated into the existing subsistence strategy. Our multidisciplinary results demonstrate the resilient character of the coastal economy to cultural change during the late Holocene in southern Brazil.


A microworld in Triassic amber.
Amber provides an effective medium for conservation of soft-bodied microorganisms, but finds older than 135 million years are very rare and have not so far contained any microbial inclusions. Here we describe 220-million-year-old droplets of amber containing bacteria, fungi, algae and protozoans that are assignable to extant genera. These inclusions provide insight into the evolution and palaeoecology of Lower Mesozoic microorganisms: it seems that the basal levels of food webs of terrestrial communities (biocoenoses) have undergone little or no morphological change from the Triassic to the Recent.


Combination of Methoprene and Controlled Aeration to Manage Insects in Stored Wheat.
A commercial formulation of the insect growth regulator methoprene was applied to wheat stored in small bins either alone or in combination with controlled aeration of the bins, to lower grain temperature for insect pest management of stored wheat. Grain temperatures were monitored and modified by a computer-controlled thermocouple system that also activated the aeration system at programmed set-points to move cool ambient air through the grain mass to lower grain temperature. Results from sampling insect populations in experimental storage bins along with laboratory mortality bioassays of insects placed on wheat taken from the bins over the course of the storage period showed that methoprene was very effective in controlling infestation by the externally-feeding stored grain insects Plodia interpunctella (Hübner), the Indian meal moth Tribolium castaneum (Herbst), the red flour beetle, Cryptolestes ferrugineus (Stephens), the rusty grain beetle, and also for the internal-feeding pest Rhyzopertha dominica( Fauvel), the lesser grain borer. Methoprene did not give good control of the internal-feeding pest Sitophilus oryzae (L.), the rice weevil. Aeration alone was somewhat effective in suppressing insect population development, while methoprene alone or when combined with aeration greatly enhanced insect control. Commercial grain grading for industry quality standards at the end of the storage period confirmed the impact of insect suppression on maintaining high quality of the stored wheat. This field experiment shows that methoprene combined with aeration to cool grain can be effective for pest management of stored wheat in the southern plains of the United States of America.


Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.
Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. To characterise genetic and clinical findings in individuals with SHH mutations. Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.


On the effect of populations in evolutionary multi-objective optimisation.
Multi-objective evolutionary algorithms (MOEAs) have become increasingly popular as multi-objective problem solving techniques. An important open problem is to understand the role of populations in MOEAs. We present two simple bi-objective problems which emphasise when populations are needed. Rigorous runtime analysis points out an exponential runtime gap between the population-based algorithm simple evolutionary multi-objective optimiser (SEMO) and several single individual-based algorithms on this problem. This means that among the algorithms considered, only the population-based MOEA is successful and all other algorithms fail.


Gestational diabetes mellitus--guidelines.
The Diabetes In Pregnancy Study group India (DIPSI) is reporting practice guidelines for GDM in the Indian environment. Due to high prevalence, screening is essential for all Indian pregnant women. DIPSI recommends that as a pregnant woman walks into the antenatal clinic in the fasting state, she has to be given a 75g oral glucose load and at 2 hrs a venous blood sample is collected for estimating plasma glucose. This one step procedure of challenging women with 75 gm glucose and diagnosing GDM is simple, economical and feasible. Screening is recommended between 24 and 28 weeks of gestation and the diagnostic criteria of ADA are applicable. A team approach is ideal for managing women with GDM. The team would usually comprise an obstetrician, diabetes physician, a diabetes educator, dietitian, midwife and pediatrician. Intensive monitoring, diet and insulin is the corner stone of GDM management. Oral agents or analogues though used are still controversial. Until there is evidence to absolutely prove that ignoring maternal hyperglycemia when the fetal growth patterns appear normal on the ultrasonogram, it is prudent to achieve and maintain normoglycemia in every pregnancy complicated by gestational diabetes. The maternal health and fetal outcome depends upon the care by the committed team of diabetologists, obstetricians and neonatologists. A short term intensive care gives a long term pay off in the primary prevention of obesity, IGT and diabetes in the offspring, as the preventive medicine starts before birth.


Invertebrate models of Alzheimer's disease.
A majority of the genes linked to human disease belong to evolutionarily conserved pathways found in simpler organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The genes and pathways of these simple organisms can be genetically and pharmacologically manipulated to better understand the function of their orthologs in vivo, and how these genes are involved in the pathogenesis of different diseases. Often these manipulations can be performed much more rapidly in flies and worms than in mammals, and can generate high quality in vivo data that is translatable to mammalian systems. Other qualities also make these organisms particularly well suited to the study of human disease. For example, developing in vivo disease models can help illuminate the basic mechanisms underlying disease, as in vitro studies do not always provide the natural physiological complexity associated with many diseases. Invertebrate models are relatively inexpensive, easy to work with, have short lifespans, and often have very well characterized and stereotypical development and behavior. This is particularly true for the two invertebrate model organisms that this review will focus on: Caenorhabditis elegans and Drosophila melanogaster. In this review, we will first describe an overview of modeling Alzheimer's disease in flies and worms, and will then highlight some of the more recent advances that these "simple" animals have contributed to our understanding of Alzheimer's disease in recent years.


Comparison of CAT Item Selection Criteria for Polytomous Items.
Item selection is a core component in computerized adaptive testing (CAT). Several studies have evaluated new and classical selection methods; however, the few that have applied such methods to the use of polytomous items have reported conflicting results. To clarify these discrepancies and further investigate selection method properties, six different selection methods are compared systematically. The results showed no clear benefit from more sophisticated selection criteria and showed one method previously believed to be superior-the maximum expected posterior weighted information (MEPWI)-to be mathematically equivalent to a simpler method, the maximum posterior weighted information (MPWI).


PCR-based detection of Plasmodium falciparum in saliva using mitochondrial cox3 and varATS primers.
Sampling of saliva for diagnosing Plasmodium falciparum infections is a safe, non-invasive alternative to sampling of blood. However, the use of saliva presents a challenge because lower concentrations of parasite DNA are present in saliva compared to peripheral blood. Therefore, a sensitive method is needed for detection of parasite DNA in saliva. This study utilized two recently reported "ultra-sensitive" PCR assays based on detection of the P. falciparum mitochondrial cox3 gene and the multi-copy nuclear varATS gene. The ultra-sensitive assays have an advantage over standard 18S rRNA gene-based PCR assay as they target genes with higher copy numbers per parasite genome. Stored saliva DNA samples from 60 Cameroonian individuals with infections previously confirmed by 18S rRNA gene PCR in peripheral blood were tested with assays targeting the cox3 and varATS genes. Overall, the standard 18S rRNA gene-based PCR assay detected P. falciparum DNA in 62% of the stored saliva DNA samples, whereas 77 and 68% of the samples were positive with assays that target the cox3 and varATS genes, respectively. Interestingly, the ultra-sensitive assays detected more P. falciparum infections in stored saliva samples than were originally detected by thick-film microscopy (41/60 = 68%). When stratified by number of parasites in the blood, the cox3 assay successfully detected more than 90% of infections using saliva when individuals had > 1000 parasites/μl of peripheral blood, but sensitivity was reduced at submicroscopic parasitemia levels. Bands on electrophoresis gels were distinct for the cox3 assay, whereas faint or non-specific bands were sometimes observed for varATS and 18S rRNA that made interpretation of results difficult. Assays could be completed in 3.5 and 3 h for the cox3 and varATS assays, respectively, whereas the 18S rRNA gene assays required at least 7 h. This study demonstrates that a PCR assay targeting the cox3 gene detected P. falciparum DNA in more saliva samples than primers for the 18S rRNA gene. Non-invasive collection of saliva in combination with the proposed cox3 primer-based PCR assay could potentially enhance routine testing of P. falciparum during disease surveillance, monitoring, and evaluation of interventions for malaria elimination.


Dietary mechanism behind the costs associated with resistance to Bacillus thuringiensis in the cabbage looper, Trichoplusia ni.
Beneficial alleles that spread rapidly as an adaptation to a new environment are often associated with costs that reduce the fitness of the population in the original environment. Several species of insect pests have evolved resistance to Bacillus thuringiensis (Bt) toxins in the field, jeopardizing its future use. This has most commonly occurred through the alteration of insect midgut binding sites specific for Bt toxins. While fitness costs related to Bt resistance alleles have often been recorded, the mechanisms behind them have remained obscure. We asked whether evolved resistance to Bt alters dietary nutrient intake, and if reduced efficiency of converting ingested nutrients to body growth are associated with fitness costs and variation in susceptibility to Bt. We fed the cabbage looper Trichoplusia ni artificial diets differing in levels of dietary imbalance in two major macronutrients, protein and digestible carbohydrate. By comparing a Bt-resistant T. ni strain with a susceptible strain we found that the mechanism behind reduced pupal weights and growth rates associated with Bt-resistance in T. ni was reduced consumption rather than impaired conversion of ingested nutrients to growth. In fact, Bt-resistant T. ni showed more efficient conversion of nutrients than the susceptible strain under certain dietary conditions. Although increasing levels of dietary protein prior to Bt challenge had a positive effect on larval survival, the LC50 of the resistant strain decreased when fed high levels of excess protein, whereas the LC50 of the susceptible strain continued to rise. Our study demonstrates that examining the nutritional basis of fitness costs may help elucidate the mechanisms underpinning them.


Accelerated obstructive pulmonary disease in HIV infected patients with bronchiectasis.
Human immunodeficiency virus (HIV) infection has been associated with a wide spectrum of pulmonary disease. We report three HIV-seropositive patients with rapidly worsening airway obstruction associated with bronchiectasis. All subjects (age range 33-39 yrs) were cigarette smokers. Two had previously used intravenous drugs. The CD4 lymphocyte count ranged 40-250 cells x mm(-3). All individuals had complained of increasing dyspnoea for 3-6 months. Within 1 yr, they all developed severe airway obstruction with a decrease in both forced expiratory volume in one second (FEV1) and ratio of FEV1 to forced vital capacity (FEV1/FVC) to less than 60% of predicted value, and a decrease in mean forced expiratory flow at 25-75% of the forced vital capacity (FEF25-75) to less than 35% of predicted value. Computed tomography of the chest disclosed bilateral dilated and thickened bronchi. No classical causes of genetic or acquired bronchiectasis were identified in our patients. Recurrent bacterial bronchitis occurred in the follow-up period of the three patients. In conclusion, unusually rapid airway obstruction associated with bronchiectasis should be added to the wide spectrum of respiratory complications of human immunodeficiency virus infection.


Subdividing the Common Intertidal Hermit Crab Pagurus minutus Hess, 1865 (Decapoda: Anomura: Paguridae) Based on Molecular, Morphological and Coloration Analyses.
Jibom Jung, Jongwoo Jung, and Won Kim (2018) A phylogenetic study was conducted to investigate whether distinct genetic groups are present within the East Asian Pagurus minutus. In this study, 167 individuals of P. minutus were collected along the coasts of South Korea, east coast of Honshu, west coast of Kyushu, Okinawa Islands of Japan, and Taiwan. The collection of P. minutus was divided into three groups based on the differences in cytochrome c oxidase subunit I (COI) sequences and morphological and color characters: Major Group (MAG), Minor Group (MIG), and Taiwan-Okinawa Group (TOG). MAG commonly inhabits the entire coast of South Korea (except for the northeast coast), east coast of Honshu, and west coast of Kyushu in Japan. MIG predominantly inhabits the northeast coast of South Korea, while a small proportion inhabits the west coast of South Korea and west coast of Kyushu in Japan. TOG is restricted to Taiwan and the Okinawa Islands of Japan. The COI divergence among MAG, MIG, and TOG was larger than the minimum interspecific divergence of the other Pagurus species. Little ingroup COI divergences exist in the MAG and MIG, but distinct ingroup COI divergence is present between the two subgroups of TOG inhabiting Taiwan and Okinawa Islands. MAG, MIG, and TOG show minor differences among morphological characters. Each specimen of these three groups has distinguishing color patterns. These differences in molecular, morphological and color characters suggest that P. minutus are separated into three groups at the species level, and this subdivision of P. minutus shows that additional phylogenetic studies of other hermit crabs and common marine decapod species in East Asia are needed.


Public health research and lay knowledge.
Social science research into the social patterning of health and illness is extensive. One important aspect of this has been work on lay knowledge about health and illness. In this paper we develop three main arguments. First, we suggest that recent developments in social science understanding of the nature and significance of lay knowledge should be more widely recognized within the social sciences themselves. Second, we argue that if public health research, whatever the disciplinary perspective, is to provide an understanding of contemporary health problems that is simultaneously more robust and more holistic, it must incorporate and develop the theoretical and conceptual insights offered by this recent work on lay knowledge and with lay people. Finally, we argue that in order to accomplish this it will be necessary to construct research questions in such a way that the conventional distinctions between science and non-science, and the methodological wrangles associated with this distinction, become marginal to the research process. This will inevitably involve conflicts between members of different professional groups. These conflicts provide the opportunity for open debate on the science and politics of public health research and represent a challenge for the many disciplines involved in this field.


The effect of high intensity focused ultrasound treatment on metastases in a murine melanoma model.
This study aims to assess the risk of high intensity focused ultrasound (HIFU) therapy on the incidence of distant metastases and to investigate its association with HIFU-elicited anti-tumor immunity in a murine melanoma (B16-F10) model. Tumor-bearing legs were amputated immediately after or 2 days following HIFU treatment to differentiate the contribution of the elicited anti-tumor immunity. In mice undergoing amputation immediately after mechanical, thermal, or no HIFU treatment, metastasis rates were comparable (18.8%, 13.3%, and 12.5%). In contrast, with a 2-day delay in amputation, the corresponding metastasis rates were 6.7%, 11.8%, and 40%, respectively. Animal survival rate was higher and CTL activity was enhanced in the HIFU treatment groups. Altogether, our results suggest that HIFU treatment does not increase the risk of distant metastasis. Instead, HIFU treatment can elicit an anti-tumor immune response that may be harnessed to improve the overall effectiveness and quality of cancer therapy.


Modification of an OSCE format to enhance patient continuity in a high-stakes assessment of clinical performance.
Traditional Objective Structured Clinical Examinations (OSCEs) are psychometrically sound but have the limitation of fragmenting complex clinical cases into brief stations. We describe a pilot study of a modified OSCE that attempts to balance a typical OSCE format with a semblance of a continuous, complex, patient case. Two OSCE scenarios were developed. Each scenario involved a single standardized patient and was subdivided into three sequential 10 minute sections that assessed separate content areas and competencies. Twenty Canadian PGY-4 internal medicine trainees were assessed by trained examiner pairs during each OSCE scenario. Paired examiners rated participant performance independent of each other, on each section of each scenario using a validated global rating scale. Inter-rater reliabilities and Pearson correlations between ratings of the 3 sections of each scenario were calculated. A generalizability study was conducted. Participant and examiner satisfaction was surveyed. There was no main effect of section or scenario. Inter-rater reliability was acceptable. The g-coefficient was 0.68; four scenarios would achieve 0.80. Moderate correlations between sections of a scenario suggest a possible halo effect. The majority of examiners and participants felt that the modified OSCE provided a sense of patient continuity. The modified OSCE provides another approach to the assessment of clinical performance. It attempts to balance the advantages of a traditional OSCE with a sense of patient continuity.


No significant effect on bone mineral density by high doses of vitamin D3 given to overweight subjects for one year.
In meta-analyses supplementation with vitamin D appears to reduce incidence of fractures, and in cross-sectional studies there is a positive association between serum 25-hydroxyvitamin D (25(OH)D) levels and bone mineral density (BMD). However, the effect of supplementation with high doses of vitamin D on BMD is more uncertain and could in theory have both positive and negative effects. The study was a one year, double blind placebo-controlled intervention trial performed at the University Hospital of North Norway. 421 subjects, 21 - 70 years old, were included and 312 completed the study. The subjects were randomized to vitamin D3 40.000 IU per week (DD group), vitamin D3 20.000 IU per week (DP group), or placebo (PP group). All subjects were given 500 mg calcium daily. Serum 25(OH)D, osteoprotegrin (OPG), receptoractivator of nuclear factor-kappaB ligand (RANKL), and BMD at the lumbar spine and the hip were measured before and at the end of the study. At baseline the mean serum 25(OH)D levels were 58 nmol/L (all subjects) and increased to 141 and 100 nmol/L in the DD and DP groups, respectively. After one year, no significant differences were found between the three groups regarding change in BMD, serum OPG or RANKL. Supplementation with high doses of vitamin D for one year does not appear to have a negative effect on BMD in healthy subjects. In order to disclose a positive effect, subjects with low BMD and/or low serum 25(OH)D levels need to be studied. The trial was registered at ClinicalTrials.gov (NCT00243256).


Inter-individual, inter-city, and temporal trends of per- and polyfluoroalkyl substances in human milk from Swedish mothers between 1972 and 2016.
Inter-individual, inter-city, and temporal trends of 19 per- and polyfluoroalkyl substances (PFASs) were investigated in human milk collected in Stockholm (1972-2016) and Gothenburg (2007-2015), Sweden. The concentrations of perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), and perfluorotridecanoate (PFTrDA) in human milk from Stockholm increased significantly over the entire monitoring periods, whereas branched (Br) and linear (L) isomers of perfluorooctane sulfonamide (FOSA) decreased. In human milk from Gothenburg, significant downward trends were detected for perfluorododecanoate (PFDoDA), PFHxS and Br-perfluorooctane sulfonate (Br-PFOS) over the last decade. This declining trend was also observed for perfluorohexanoate (PFHxA), PFHxS, perfluorooctanoate (PFOA) and Br-PFOS in Stockholm over the same time period. No significant differences were observed in concentrations or relative PFAS profiles between Stockholm and Gothenburg. However, a comparison of the PFAS profile in Stockholm milk revealed distinct profiles for the time periods 1972-1996, 2000-2012, and 2013-2016, reflecting a shift in exposure over time. The lower bound estimated daily intake (EDI) for ∑PFAS concentrations in infants ranged from 7.1-40 ng per kg body weight per day (ng/kg bw/d) in Stockholm and from 5.2-25 ng/kg bw/d in Gothenburg over the studied time period, consistent with other European countries. Overall these data indicate that exposure to some legacy PFASs via breastmilk is declining, presumably as a result of regulation and phase-out initiatives. However, increasing concentrations for other PFASs and a shift in the overall PFAS profile in recent years may pose an ongoing health risk to infants.


The impact of behavioural interventions on young people's attitudes toward tobacco use.
The objective of the present study was to study the ability to influence young at-risk patients' attitudes toward tobacco use through two intervention methods that were performed by dental health professionals. Two interventions, a brief individual motivational interview and an adapted school lecture, were studied, and both were compared with a control group. Before and after interventions, a questionnaire was used. Patients born in 1989 and 1992 who were judged by the dental personnel as potentially at risk for dental diseases, a total of 301 individuals, were included. Both before and after interventions, the results showed a generally negative attitude towards tobacco use. A majority of the participants were positive towards measures that were taken to control the spread of tobacco use, younger participants (born 1992) to a greater extent (73%) than the older participants (born 1989) (54%). Important factors that kept the participants away from tobacco use were the harmful effects and the approaches of parents and friends. The older participants believed to a greater extent that they would try smoking as adults. No change in tobacco use was registered after intervention, although the participants reported an increased use among friends. The two pedagogical methods that were used in the present study influenced the young people's attitudes towards tobacco use only to a small extent. However, the period between 12 and 15 years old seems to provide a good opportunity to influence attitudes towards tobacco. The adolescents' demand for interactive learning and their development of attitudes and tobacco use habits in relation to family and friends provide opportunities to use new pedagogical models.


The sitting position during neurosurgical procedures does not influence serum biomarkers of pulmonary parenchymal injury.
The sitting position during neurosurgical operations predisposes to air penetration through veins and the movement of the air through the pulmonary circulation. Contact of an air bubble with the endothelium can lead to acute lung injury. The presence of specific pulmonary proteins in the plasma such as surfactant protein D (SP-D) and Clara cell protein (CC16) is a biomarker of damaging processes at the air-blood barrier. The aim of our study was to examine the hypothesis that the level of investigated pulmonary biomarkers in plasma is higher in patients operated on in the sitting position. The study included patients undergoing planned neurosurgical operations, who were divided into two groups: the sitting group (40 patients, operated on in the sitting position) and the supine group (24 patients, operated in the supine position). After the operation blood samples were drawn, centrifuged, frozen and stored until analyses were conducted. The determination of the SP-D and CC16 levels was performed using an ELISA test. Air embolism (VAE) was defined as a sudden drop in etCO2 of more than 2 mmHg and the presence of air bubbles in the aspirated blood from the central cannula. In all patients, the number of hospitalization days in the postoperative period was calculated. There were no differences in the average levels of SP-D between the groups (the mean in the sitting group was 95.56 ng/mL and the mean in the supine group was 101.21 ng/mL). The average levels of CC16 were similar in both groups as well (6.56 ng/mL in the sitting group and 6.79 ng/mL in the supine group). There was a statistically significant positive correlation between SP-D and CC16 values in both groups. VAE was diagnosed clinically in 12.5% of cases in the sitting group without a significant increase in SP-D and CC16 levels. On average, patients in both groups were discharged from the hospital within 9 days of surgery. The sitting position and intraoperative VAE during neurosurgical procedures do not affect the concentration of plasma biomarkers of pulmonary parenchymal injury such as SP-D and CC16.


Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity.
Accumulation of visceral adipose tissue correlates with elevated inflammation and increased risk of metabolic diseases. However, little is known about the molecular mechanisms that control its pathological expansion. Transcription factor interferon regulatory factor 5 (IRF5) has been implicated in polarizing macrophages towards an inflammatory phenotype. Here we demonstrate that mice lacking Irf5, when placed on a high-fat diet, show no difference in the growth of their epididymal white adipose tissue (epiWAT) but they show expansion of their subcutaneous white adipose tissue, as compared to wild-type (WT) mice on the same diet. EpiWAT from Irf5-deficient mice is marked by accumulation of alternatively activated macrophages, higher collagen deposition that restricts adipocyte size, and enhanced insulin sensitivity compared to epiWAT from WT mice. In obese individuals, IRF5 expression is negatively associated with insulin sensitivity and collagen deposition in visceral adipose tissue. Genome-wide analysis of gene expression in adipose tissue macrophages highlights the transforming growth factor β1 (TGFB1) gene itself as a direct target of IRF5-mediated inhibition. This study uncovers a new function for IRF5 in controlling the relative mass of different adipose tissue depots and thus insulin sensitivity in obesity, and it suggests that inhibition of IRF5 may promote a healthy metabolic state during this condition.


Nanostructured gradient index microaxicons made by a modified stack and draw method.
We report the design and fabrication of nanostructured gradient index microaxicons suitable for integration with optical fibers. A structure with the effective refractive index decreasing linearly from the center to the edges (i.e., an axicon) was designed using a combination of a simulated annealing method and the effective medium theory. The design was verified numerically with beam propagation method simulations. The axicons were made by the modified stack and draw method and integrated with optical fibers. The optical properties of the fabricated elements were measured and showed good agreement with the numerical simulations. The fabricated axicons produced an extended line focus at a distance from about 70 to 160 μm from the lens facet with a minimum FWHM diameter of 8 μm at 90 μm. At smaller distances, an interference pattern is observed both in the experiment and in simulations, which is attributed to the uneven effective refractive index profile at the structure.


Outcome study of surgical treatment for axial neck pain.
We reviewed our surgical treatment of chronic axial cervical pain over a 4-year period to determine whether surgery in selected cases was associated with favorable outcomes. We retrospectively studied 27 consecutive cases (20 patients with follow-up) of longstanding axial cervical spine pain treated surgically by a single surgeon from June 1994 through August 1998. Diagnostic workup included the following when appropriate: Minnesota Multiphasic Personality Inventory (MMPI) with interview, provocative diskography (with a nonpainful control level), single photon emission computed tomography (SPECT), and diagnostic facet injection. Twenty patients (74%) responded to a postoperative telephone survey. For general outcome measures, 85% of patients reported satisfaction with pain relief and surgical result. Ninety-five percent stated they would repeat the procedure; 85% manifested improvement in Prolo score. Surgical treatment of chronic axial neck pain, when preceded by thorough evaluation, can yield excellent clinical results.


Optimal control of transient dynamics in balanced networks supports generation of complex movements.
Populations of neurons in motor cortex engage in complex transient dynamics of large amplitude during the execution of limb movements. Traditional network models with stochastically assigned synapses cannot reproduce this behavior. Here we introduce a class of cortical architectures with strong and random excitatory recurrence that is stabilized by intricate, fine-tuned inhibition, optimized from a control theory perspective. Such networks transiently amplify specific activity states and can be used to reliably execute multidimensional movement patterns. Similar to the experimental observations, these transients must be preceded by a steady-state initialization phase from which the network relaxes back into the background state by way of complex internal dynamics. In our networks, excitation and inhibition are as tightly balanced as recently reported in experiments across several brain areas, suggesting inhibitory control of complex excitatory recurrence as a generic organizational principle in cortex.


Neuronal activity in the substantia nigra in the anaesthetized rat has fractal characteristics. Evidence for firing-code patterns in the basal ganglia.
Current models of the basal ganglia assume a firing-rate code for information processing. We have applied five complementary computing methods to assess firing patterns in 188 cells of the substantia nigra in the anaesthetized rat. Fractal firing activity was found in 100% of nigral cells projecting to the superior colliculus, in 51% of cells projecting to the thalamus and in 33% of cells projecting to the pedunculopontine nucleus, but was practically absent in dopaminergic nigrostriatal neurons (3%). The finding of fractal firing patterns may lead to a better understanding of the normal operational mode and pathological manifestations of the basal ganglia.


Cleaning Efficacy of Manual Toothbrushes Around Brackets - A Pilot Randomised Control Trial.
To test the cleaning efficacy of different manual toothbrushes in orthodontic patients in a single-blind randomised clinical trial. The brushes tested were selected based on previous in vitro tests. Thirty-five regular orthodontic patients with a minimum of six bonded brackets on the maxillary anterior teeth were randomly assigned to three experimental groups: staged (2-level) (Candida Parodin, 12 patients) and V-shaped (Oral-B Ortho, 12 patients) toothbrush head designs were compared in a two-phase study to planar control brushes (Paro M 43, 11 patients). First, all participants were advised to brush their teeth twice daily for 2 min for 3 weeks. Prior to the start and at the end of the study, the gingival index was assessed to evaluate the level of oral hygiene. Afterwards, cleaning efficacy was assessed planimetrically by disclosing the respective teeth after two days of not performing any oral hygiene measures. Of the initial 35 participants, two did not attend after 3 weeks and had to be excluded. After 3 weeks, the control (5 out of 180 sites or -2.8% with GI ≥ 2) and staged groups (16 out of 216 sites or 7.5% with GI ≥ 2) showed minor improvement in the oral hygiene level. In contrast, the V-shaped group (29 out of 198 sites or 14.6 % with GI ≥ 2) showed a statistically significant improvement of the oral hygiene level. Planimetric evaluation, however, showed no superior cleaning efficacy of any of the tested head designs. The use of V-shaped and staged toothbrush head designs might be beneficial in patients with inadequate oral hygiene undergoing orthodontic treatment with a fixed appliance. Further large-scale investigations are, however, necessary to validate the presented results.


Trabectedin: the evidence for its place in therapy in the treatment of soft tissue sarcoma.
Soft tissue sarcoma accounts for less than 1% of all malignant neoplasms and is comprised of a very heterogeneous group of tumors with over 50 different subtypes. Due to its diversity and rarity, developing new therapeutics has been difficult, at best. The standard of care in the treatment of advanced and metastatic disease over the last 30 years has been doxorubicin and ifosfamide, either alone or in combination. There has been significant focus on developing new therapeutics to treat primary and metastatic disease. Trabectedin (ecteinascidin-743) is a tetrahydroiso-quinoline alkaloid which has been evaluated in the treatment of metastatic soft tissue sarcoma. To review the current evidence for the therapeutic use of trabectedin in patients with soft tissue sarcoma. Five phase I studies in patients with solid tumors, all of which include sarcoma patients, evaluating the dosing and toxicity of trabectedin were performed with efficacy being evaluated as a secondary endpoint. Additionally, there are four phase I trials evaluating trabectedin in combination with frontline therapeutic drugs in soft tissue sarcoma. Four phase II studies were performed in soft-tissue sarcoma patients with objective response rates ranging from 3.7% to 17.1%. Additionally, in two compassionate use trials, objective response rates between 14% and 51% were seen, the largest response resulting from a study specifically focusing on liposarcoma. Trabectedin is a potential therapeutic option for the management of soft-tissue sarcoma. It appears to have specific activity in a select group of histologies, most notably myxoid/round cell liposarcoma. Although it would be helpful to study the use of trabectedin in a randomized, controlled fashion, the relative rarity of soft-tissue sarcoma, and heterogeneity of the histologic subtypes, makes phase III trials a difficult prospect.


Validation of walkway tribometers: establishing a reference standard.
Tribometers are mechanical devices used to measure walkway coefficient of friction (COF) for the purpose of assessing slip risk. The purpose of this study was to define a tribometer reference standard and use it to assess the performance of various tribometers. Eighty subjects were randomly assigned to walk across one of four wet walkway surfaces (polished black granite, porcelain, vinyl composition tile, and ceramic tile) to establish the relative slipperiness of each surface. Eleven tribometers were subsequently used to measure and rank the COF of all four surfaces. Our results revealed that only four of the 11 tribometers (Wessex pendulum, Sigler pendulum, Mark II, and Mark III) met our compliance criteria by both correctly ranking all four surfaces and differentiating between surfaces of varying degrees of slipperiness. Our protocol demonstrates that human gait-based measures of slipperiness can be used to create reference standards against which tribometer measurements can be validated.


Continuity and discontinuity of behavioral inhibition and exuberance: psychophysiological and behavioral influences across the first four years of life.
Four-month-old infants were screened (N = 433) for temperamental patterns thought to predict behavioral inhibition, including motor reactivity and the expression of negative affect. Those selected (N = 153) were assessed at multiple age points across the first 4 years of life for behavioral signs of inhibition as well as psychophysiological markers of frontal electroencephalogram (EEG) asymmetry. Four-month temperament was modestly predictive of behavioral inhibition over the first 2 years of life and of behavioral reticence at age 4. Those infants who remained continuously inhibited displayed right frontal EEG asymmetry as early as 9 months of age while those who changed from inhibited to noninhibited did not. Change in behavioral inhibition was related to experience of nonparental care. A second group of infants, selected at 4 months of age for patterns of behavior thought to predict temperamental exuberance, displayed a high degree of continuity over time in these behaviors.


Hydrogelation and self-assembly of Fmoc-tripeptides: unexpected influence of sequence on self-assembled fibril structure, and hydrogel modulus and anisotropy.
The self-assembly and hydrogelation properties of two Fmoc-tripeptides [Fmoc = N-(fluorenyl-9-methoxycarbonyl)] are investigated, in borate buffer and other basic solutions. A remarkable difference in self-assembly properties is observed comparing Fmoc-VLK(Boc) with Fmoc-K(Boc)LV, both containing K protected by N(epsilon)-tert-butyloxycarbonate (Boc). In borate buffer, the former peptide forms highly anisotropic fibrils which show local alignment, and the hydrogels show flow-aligning properties. In contrast, Fmoc-K(Boc)LV forms highly branched fibrils that produce isotropic hydrogels with a much higher modulus (G' > 10(4) Pa), and lower concentration for hydrogel formation. The distinct self-assembled structures are ascribed to conformational differences, as revealed by secondary structure probes (CD, FTIR, Raman spectroscopy) and X-ray diffraction. Fmoc-VLK(Boc) forms well-defined beta-sheets with a cross-beta X-ray diffraction pattern, whereas Fmoc-KLV(Boc) forms unoriented assemblies with multiple stacked sheets. Interchange of the K and V residues when inverting the tripeptide sequence thus leads to substantial differences in self-assembled structures, suggesting a promising approach to control hydrogel properties.


Motor vehicle crash deaths in metropolitan areas--United States, 2009.
Although rates have declined in recent years, motor vehicle crashes (MVCs) remain a leading cause of injury death in the United States. In 2009, a total of 34,485 MVC deaths were reported among U.S. residents, and 22% of those who died were aged 15-24 years. MVCs were the leading cause of death for that age group, which represents approximately 14% of the total U.S. population. To assess patterns in MVC death rates for persons of all ages and for those aged 15-24 years, in recognition of the elevated risk for this age group, CDC used data from the National Vital Statistics System (NVSS) and the U.S. Census Bureau for 2009 representing the 50 most populous U.S. metropolitan statistical areas (MSAs). The overall MVC death rate (age-adjusted) for all 50 MSAs combined was 8.2 per 100,000 residents, compared with a national rate of 11.1; among MSAs, rates ranged from 4.4 to 17.8. For persons aged 15-24 years, the MVC death rate was 13.0 per 100,000 residents for all MSAs combined (range: 7.3-25.8), compared with a national rate of 17.3. Although rates for the MSAs generally were lower than the rate for the nation as a whole, higher rates for persons aged 15-24 years were observed both in the MSAs and nationally. The wide variation in rates among MSAs suggests a need to better understand how urban development patterns might relate to MVC deaths and to identify and implement effective strategies to reduce the number of such deaths.


Rpo26p, a subunit common to yeast RNA polymerases, is essential for the assembly of RNA polymerases I and II and for the stability of the largest subunits of these enzymes.
Eukaryotic nuclear RNA polymerases (RNAPs) are composed of two large subunits and a number of small polypeptides, some of which are common among these enzymes. To understand the function of Rpo26p, one of the five subunits common to yeast RNAPs, 34 different mutations have been isolated in RP026 that cause cell death in a strain carrying a temperature-sensitive (ts) mutation in the gene (RP021) encoding the largest subunit of RNAPII. These mutant alleles were grouped into three phenotypic classes (null, ts, and neutral) on the basis of the phenotype they imposed in combination with wild-type RP021. The function of Rpo26p was addressed by biochemical analysis of the ts rpo26-31 allele. The steady-state level of rpo26-31p was reduced at high temperature; this was accompanied by a decrease in the level of at least two other subunits, the largest subunits of RNAPI (A190p) and RNAPII (Rpo21p). Pulse-chase metabolic labeling and immunoprecipitation of RNAPII showed that at high temperature, rpo26-31 did not lead to dissociation of Rpo26p from the polymerase but prevented the assembly of RNAPII. Overexpression of rpo26-31 partially suppressed the ts phenotype and led to accumulation of the mutant subunit. However, overexpression only marginally suppressed the assembly defect of RNAPII. Furthermore, A190p and Rpo21p continued to accumulate at low levels under these conditions. We suggest that Rpo26p is essential for the assembly of RNAPI and RNAPII and for the stability of the largest subunits of these enzymes.


Understanding the factors influencing the removal of heavy metals in urban stormwater runoff.
In this research, an infiltration trench equipped with an extensive pretreatment and filter bed consisting of woodchip, sand and gravel was utilized as a low impact development technique to manage stormwater runoff from a highly impervious road with particular emphasis on heavy metal removal. Findings revealed that the major factors influencing the removal of heavy metals were the concentration of the particulate matters and heavy metals in runoff, runoff volume and flow rates. The reduction of heavy metals was enhanced by sedimentation of particulates through pretreatment. Fine particles (<2 mm) had the most significant amount of heavy metals, thus, enhanced adsorption and filtration using various filter media were important design considerations. Sediment was most highly attached on the surface area of woodchip than to other filter media like sand, gravel and geotextile. It is suggested that maintenance must be performed after the end of the winter season wherein high sediment rate was observed to maintain the efficiency of the treatment system.


Ethical and public policy aspects of childhood obesity: opinions of scientists working on an intervention study.
Scientists working on an obesity intervention project were asked questions, via questionnaire and interviews, relating to ethical and public-policy aspects of tackling childhood obesity. The main areas of enquiry concerned elements responsible for the rise in childhood obesity, key ethical areas of obesity interventions, helpfulness and effectiveness of policy measures, socioeconomic factors, and media coverage and political debate. Key results from this indicate that: there is disagreement about the amount of information about the causes of obesity that is needed before implementing interventions; an improvement in health and nutrition education of both children and adults through positive messages is seen as highly desirable; scientists regard environment, rather than genetics, as playing the major role in rising obesity levels; the level of individual responsibility being placed on parents and children may be unfair and unhelpful; whole-system, long-term and sensitive policy actions are needed rather than relying on quick fixes such as miracle pills; and there are country-specific issues related to rising obesity levels that need to be considered, though the respondents tended to have a great deal of faith in EU-wide interventions.


JARID1B Expression Plays a Critical Role in Chemoresistance and Stem Cell-Like Phenotype of Neuroblastoma Cells.
Neuroblastoma (NB) is a common neural crest-derived extracranial solid cancer in children. Among all childhood cancers, NB causes devastating loss of young lives as it accounts for 15% of childhood cancer mortality. Neuroblastoma, especially high-risk stage 4 NB with MYCN amplification has limited treatment options and associated with poor prognosis. This necessitates the need for novel effective therapeutic strategy. JARID1B, also known as KDM5B, is a histone lysine demethylase, identified as an oncogene in many cancer types. Clinical data obtained from freely-accessible databases show a negative correlation between JARID1B expression and survival rates. Here, we demonstrated for the first time the role of JARID1B in the enhancement of stem cell-like activities and drug resistance in NB cells. We showed that JARID1B may be overexpressed in either MYCN amplification (SK-N-BE(2)) or MYCN-non-amplified (SK-N-SH and SK-N-FI) cell lines. JARID1B expression was found enriched in tumor spheres of SK-N-BE(2) and SK-N-DZ. Moreover, SK-N-BE(2) spheroids were more resistant to chemotherapeutics as compared to parental cells. In addition, we demonstrated that JARID1B-silenced cells acquired a decreased propensity for tumor invasion and tumorsphere formation, but increased sensitivity to cisplatin treatment. Mechanistically, reduced JARID1B expression led to the downregulation of Notch/Jagged signaling. Collectively, we provided evidence that JARID1B via modulation of stemness-related signaling is a putative novel therapeutic target for treating malignant NB.


Source of Social Support and Caregiving Self-Efficacy on Caregiver Burden and Patient's Quality of Life: A Path Analysis on Patients with Palliative Care Needs and Their Caregivers.
Few studies have explored the inter-relationships of sources of social support and caregiving self-efficacy with caregiver burden and patient's quality of life among patients with palliative care needs and their caregivers. This study tested the associations of two sources of social support (family and friends) and the mediating role of caregiving self-efficacy on caregiver burden and patient's quality of life. A convenience sample of 225 patient-caregiver dyads recruited between September 2016 and May 2017 from three hospitals in Hong Kong was included in the current analysis. Results showed that the final model provided a satisfactory fit (SRMR = 0.070, R-RMSEA = 0.055 and R-CFI = 0.926) with the data, as good as the hypothesized model did (p = 0.326). Significant associations were detected. Family support had a significant negative indirect effect on caregiver burden and a significant positive indirect effect on patient's quality of life through caregiving self-efficacy, whereas friend support had a significant positive direct effect on caregiver burden but a minimal effect, if any, on patient's quality of life. These findings emphasized (1) the importance of caregiving self-efficacy in improving caregiver burden and patient's quality of life and that (2) sources of social support may be an important dimension moderating the associations of caregiving self-efficacy with caregiver burden and patient's quality of life.


Prolonged Outbreak of Mycobacterium chimaera Infection After Open-Chest Heart Surgery.
Invasive Mycobacterium chimaera infections were diagnosed in 2012 in 2 heart surgery patients on extracorporeal circulation. We launched an outbreak investigation to identify the source and extent of the potential outbreak and to implement preventive measures. We collected water samples from operating theaters, intensive care units, and wards, including air samples from operating theaters. Mycobacterium chimaera strains were characterized by randomly amplified polymorphic DNA polymerase chain reaction (RAPD-PCR). Case detection was performed based on archived histopathology samples and M. chimaera isolates since 2006, and the patient population at risk was prospectively surveyed. We identified 6 male patients aged between 49 and 64 years with prosthetic valve endocarditis or vascular graft infection due to M. chimaera, which became clinically manifest with a latency of between 1.5 and 3.6 years after surgery. Mycobacterium chimaera was isolated from cardiac tissue specimens, blood cultures, or other biopsy specimens. We were able also to culture M. chimaera from water circuits of heater-cooler units connected to the cardiopulmonary bypass, and air samples collected when the units were in use. RAPD-PCR demonstrated identical patterns among M. chimaera strains from heater-cooler unit water circuits and air samples, and strains in 2 patient clusters. The epidemiological and microbiological features of this prolonged outbreak provided evidence for the airborne transmission of M. chimaera from contaminated heater-cooler unit water tanks to patients during open-heart surgery.


Absorption as a selective mechanism in surface plasmon resonance fiber optic sensors.
A new concept of surface plasmon resonance fiber optic sensor is presented. By tuning the plasmon resonance to a wavelength for which the outer medium is absorptive, a significant variation of the spectral transmittance of the device is produced as a function of the concentration of the analyte. With this mechanism, selectivity can be achieved without the need of any functionalization of the surfaces or the use of recognizing elements, which is a very interesting feature for any kind of chemical sensor or biosensor. Doubly deposited uniform-waist tapered fibers are well suited for the development of these new sensors. Multiple surface plasmon resonance, obtainable in those structures, can be used for the development of microspectrometers based on this principle.


Functional and molecular imaging in cancer drug development.
Imaging biomarkers have a potential to identify key metabolic pathways that are up-regulated in cancer cells compared to normal cells. In early drug development, they can provide valuable information on the dissemination of the drug and estimate whether the drug reaches the target and, consequently, to determine the appropriate clinical benefit. The use of imaging as an early surrogate biomarker of response is also appealing, since it allows to tailor treatment regimens in individual patients. The aim of this review is to describe various imaging biomarkers covering most important cancer hallmarks such as cell death, proliferation, metabolism, vascularity, and hypoxia. We highlight the current status of using molecular imaging such as fluorodeoxyglucose (FDG), fluorothymidine (FLT), fluoromisonidazole (FMISO), and fluoroazomycin arabinoside (FAZA) positron emission tomography (PET) as well as advanced magnetic resonance imaging (MRI) techniques such as dynamic contrast enhancing (DCE) and diffusion weighted (DW)-MRI, and their potential roles in cancer drug development.


Chemoprevention of lung carcinogenesis by cacao liquor proanthocyanidins in a male rat multi-organ carcinogenesis model.
The effects of cacao liquor proanthocyanidins (CLPr) on tumorigenesis were investigated using a multi-organ carcinogenesis model in male F344 rats receiving combined treatment with a single i.p. injection of diethylnitrosamine (100 mg/kg body wt), four i.p. injections of N-methylnitrosourea (20 mg/kg body wt), four s.c. injections of dimethylhydrazine (40 mg/kg body wt), along with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine and then 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine, both in the drinking water, for 2 weeks each, during the initial 4-week period (DMBDD treatment). Starting 1 week thereafter, rats were administered CLPr at a dose of 0.025% or 0.25% and the experiment was terminated at week 36. The final survival rate for the DMBDD+0.25% CLPr group was significantly greater than for the DMBDD alone group. In the lung, significant reduction in the incidence and multiplicity of carcinomas was also observed, and in the thyroid, quantitative values for adenomas also tended to decrease in a CLPr dose-dependent manner. No significant modification in the small intestine, colon or kidney was evident. These results indicate that CLPr exerts chemopreventive effects in the lung without any promoting influence in other major organs.


Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer.
The eukaryotic translation initiation factor complex 4E (eIF4E) is downstream in the mammalian target of rapamycin (mTOR) pathway. This study explored expression of eIF4E and its relationship with the PTEN/AKT and RAS/MEK/ERK pathways in non-small cell lung carcinoma (NSCLC). The status of phosphorylated eIF4E (p-eIF4E), phosphorylated AKT (p-AKT), PTEN, phosphorylated tuberin (p-TSC2), phosphorylated mTOR (p-mTOR), phosphorylated S6 (p-S6), and phosphorylated Erk1/2 (p-Erk1/2) was studied using immunohistochemical analysis applied to a tissue microarray containing 300 NSCLCs. Staining results for each antibody were compared with clinical and pathologic features, and the relationship between staining results was explored. Overexpression of p-eIF4E, p-AKT, p-TSC2, p-mTOR, p-S6, and p-Erk1/2 in NSCLC was found in 39.9%, 78.8%, 5.1%, 46.7%, 27.1%, and 16.6% of tumors, respectively. The phenotype of p-eIF4E correlated positively with that of p-AKT, p-TSC2, and p-S6 (P < 0.001). Overall survival in NSCLC patients was significantly shorter in cases with overexpression of p-eIF4E and p-AKT alone and in combination (log-rank P < 0.001, each). Cases with underexpression of PTEN were limited (6.4%), and this phenotype did not correlate with any clinical variable. In cluster analysis, the p-AKT/p-mTOR/p-eIF4E/p-S6-positive group had significantly shorter survival compared with the survival of all cases (P < 0.001). Multivariate analysis showed that p-eIF4E overexpression is an independent prognostic factor for NSCLC (P = 0.004). This study shows that p-eIF4E expression in addition to p-AKT predicts poor prognosis in NSCLC. Moreover, the correlation between expression of p-eIF4E with p-AKT, as well as p-TSC2 and p-S6, indicates that eIF4E activation through the AKT pathway plays an important role in the progression of NSCLC.


Association of cognitive impairment with combinations of vitamin B₁₂-related parameters.
Low vitamin B₁₂ concentrations have been associated with higher risks of cognitive impairment, but whether these associations are causal is uncertain. The associations of cognitive impairment with combinations of vitamin B₁₂, holotranscobalamin, methylmalonic acid, and total homocysteine, and with the vitamin B₁₂ transport proteins transcobalamin and haptocorrin, have not been previously studied. We performed a population-based cross-sectional study of 839 people 75 years old or older. We examined the association of cognitive function as measured by mini-mental state examination scores, with markers of vitamin B₁₂ status. Spearman correlations as well as multivariate-adjusted odds ratios and 95% CIs for cognitive impairment were calculated for extreme thirds of serum concentrations of vitamin B₁₂, holotranscobalamin, methylmalonic acid, total homocysteine, combination of these markers in a wellness score, heaptocorrin, and transcobalamin for all data and with B₁₂ analogs in a nested case-control study. Cognitive impairment was significantly associated with low vitamin B₁₂ [odds ratio 2.3 (95% CI 1.2-4.5)]; low holotranscobalamin [4.1 (2.0-8.7)], high methylmalonic acid [3.5 (1.8-7.1)], high homocysteine [4.8 (2.3-10.0)] and low wellness score [5.1 (2.61-10.46)]. After correction for relevant covariates, cognitive impairment remained significantly associated with high homocysteine [4.85 (2.24-10.53)] and with a low wellness score [5.60 (2.61-12.01)] but not with transcobalamin, haptocorrin, or analogs on haptocorrin. Cognitive impairment was associated with the combined effects of the 4 biomarkers of vitamin B₁₂ deficiency when included in a wellness score but was not associated with binding proteins or analogs on haptocorrin.


Breath of Life: The Respiratory Vagal Stimulation Model of Contemplative Activity.
Contemplative practices, such as meditation and yoga, are increasingly popular among the general public and as topics of research. Beneficial effects associated with these practices have been found on physical health, mental health and cognitive performance. However, studies and theories that clarify the underlying mechanisms are lacking or scarce. This theoretical review aims to address and compensate this scarcity. We will show that various contemplative activities have in common that breathing is regulated or attentively guided. This respiratory discipline in turn could parsimoniously explain the physical and mental benefits of contemplative activities through changes in autonomic balance. We propose a neurophysiological model that explains how these specific respiration styles could operate, by phasically and tonically stimulating the vagal nerve: respiratory vagal nerve stimulation (rVNS). The vagal nerve, as a proponent of the parasympathetic nervous system (PNS), is the prime candidate in explaining the effects of contemplative practices on health, mental health and cognition. We will discuss implications and limitations of our model.


Cross-organizational collaboration supported by Augmented Reality.
This paper presents a study where Augmented Reality (AR) technology has been used as a tool for supporting collaboration between the rescue services, the police and military personnel in a crisis management scenario. There are few studies on how AR systems should be designed to improve cooperation between actors from different organizations while at the same time supporting individual needs. In the present study, an AR system was utilized for supporting joint planning tasks by providing organization specific views of a shared map. The study involved a simulated emergency event conducted in close to real settings with representatives from the organizations for which the system is developed. As a baseline, a series of trials without the AR system was carried out. Results show that the users were positive toward the AR system and would like to use it in real work. They also experience some performance benefits of using the AR system compared to their traditional tools. Finally, the problem of designing for collaborative work as well as the benefits of using an iterative design processes is discussed.


Diagnostics of primary immunodeficiency diseases: a sequencing capture approach.
Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of "next generation" sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.


The effects of eticlopride and naltrexone on responding maintained by food, cocaine, heroin and cocaine/heroin combinations in rats.
In the first experiment, responding was maintained for food under a fixed ratio (FR) 10 with a 6-min timeout reinforcement schedule. Eticlopride (0.1-1.0 mg/kg i.p.) dose-dependently decreased the number of food pellets obtained, whereas naltrexone (3-30 mg/kg i.p.) did not significantly alter responding. In the second experiment, intravenous self-administration of cocaine (vehicle, 125, 250 and 500 micrograms/infusion), heroin (vehicle, 5.4, 9 and 18 micrograms/infusion) and cocaine/heroin combinations were maintained under a FR10 reinforcement schedule. Cocaine/heroin combinations included the aforementioned cocaine doses combined with 5.4 micrograms/infusion heroin (CH5.4) or 18 micrograms/infusion heroin (CH18). Cocaine/heroin combinations dose-dependently decreased the number of infusions compared with cocaine alone. Eticlopride (0.03-0.3 mg/kg i.p.) decreased self-administration of 125 micrograms/infusion cocaine and increased self-administration of 500 micrograms/infusion cocaine. Self-administration of 250 micrograms/infusion cocaine was increased after 0.03 and 0.1 mg/kg and decreased after 0.3 mg/kg eticlopride. Eticlopride decreased heroin self-administration, an effect which may be attributable to its rate-decreasing effects. Eticlopride partially reversed the downward shift of the CH5.4 group but did not reverse the effect in the CH18 group. Naltrexone (1.0-10.0 mg/kg i.p.) decreased self-administration of 5.4 micrograms/infusion heroin and increased self-administration of 18 micrograms/infusion heroin. Self-administration of 9 micrograms/infusion heroin was increased by 1.0 mg/kg, not affected by 3.0 mg/kg and decreased by 10.0 mg/kg naltrexone. For the CH5.4 and CH18 groups, naltrexone dose-dependently shifted the dose-effect curves toward the cocaine dose-effect curve. Therefore, self-administration of cocaine/heroine combinations can be maintained in the rat and downward shifts in the cocaine dose-effect curve after combination with heroin are mediated through a naltrexone-sensitive mechanism.


Miniplate removal in operated cases of maxillofacial region in a dental institute in Rajasthan, India.
The long term management of miniplate fixation osteosynthesis remains debatable and controversial with few authors advocating routine removal of the miniplates after 3-6 months of placement, while others recommend retention of the miniplates unless their removal is clinically indicated. The aim was to study the incidence, indications, time gap, role of metallic composition and site of removal of miniplates in operated cases of maxillofacial region over a two-year period. Patients undergoing removal of miniplates over 2-year period were studied and evaluated regarding the number of miniplates removed, time gap present between fixation and removal of miniplates, indications for removal, metallic composition of miniplates removed, sites of removal and complications. Correlations between indications for miniplate removal based upon time gap, metallic composition, age group and number of miniplates present were determined using Chi-square test. Correlation between metallic composition of miniplate and time gap was also determined using Chi-square test. The miniplates were removed in 20 patients (16 males and 4 females). Most common indication for removal was infection (45%). Forty-five percent of the patients underwent miniplate removal within 1 year of placement. Thirty-four miniplates and 118 screws were removed. The correlation between indications for miniplate removal and time gap was found to be statistically significant (P = 0.04). Most of the hardware removal is performed subsequent to complications associated with hardware and local factors play more important role than metallic composition. Routine asymptomatic miniplates do not require removal and is not recommended.


Use of paracetamol (acetaminophen) for suicide and nonfatal poisoning: worldwide patterns of use and misuse.
Paracetamol (acetaminophen) is one of the most frequently used drugs in intentional overdoses. We have investigated associations between its availability and its use for overdose and suicide around the world by means of a postal questionnaire and literature review. Countries that limit the quantity of paracetamol available in a single purchase generally report lower rates of paracetamol-related morbidity and mortality. National policy decisions regarding restrictions on its availability need to weigh the inconvenience caused to the many who use the drug safely against those of the few in whom overdose may be fatal. We recommend restricting the quantity of drug available as a single purchase as the most pragmatic means of reducing paracetamol-related suicide and liver failure.


Microfluidic-enabled quantitative measurements of insulin release dynamics from single islets of Langerhans in response to 5-palmitic acid hydroxy stearic acid.
Proper release of insulin from pancreatic islets of Langerhans is essential for maintaining glucose homeostasis. For full efficacy, both the pattern and the amount of hormone release are critical. It is therefore important to understand how insulin levels are secreted from single islets in both a quantitative fashion and in a manner that resolves temporal dynamics. In this study, we describe a microfluidic analytical system that can both quantitatively monitor insulin secretion from single islets while simultaneously maintaining high temporal sampling to resolve dynamics of release. We have applied this system to determine the acute and chronic effects of a recently-identified lipid, 5-palmitic acid hydroxy stearic acid (5-PAHSA), which is a member of the fatty acid hydroxy fatty acid class of lipids that are upregulated in healthy individuals. Chronic incubation (48 h) with 5-PAHSA significantly increased glucose-stimulated insulin secretion (GSIS) in murine islets compared to chronic incubation without the lipid or in the presence of palmitic acid (PA). The studies were continued in human islets from both healthy donors and donors diagnosed with type 2 diabetes mellitus (T2DM). Total amounts of GSIS were not only augmented in islets that were chronically incubated with 5-PAHSA, but the dynamic insulin release profiles also improved as noted by more pronounced insulin oscillations. With this quantitative microfluidic system, we have corroborated the anti-diabetic effects of 5-PAHSA by demonstrating improved islet function after chronic incubation with this lipid via improved oscillatory dynamics along with higher basal and peak release rates.


Novel approaches for stability improvement in natural medicines.
Natural product market has seen tremendous growth in the last few years. It results in the formulation of a number of proprietary herbal products, majority of them being multi-component formulations. With the advancement of herbal drug treatments, it has now been observed that many of the constituents present in the drug may react with each other, raising the serious concern about the stability of such formulations which is an important issue in the field of phytochemistry and natural medicines. Natural products are often prone to deterioration, especially during storage, leading to loss of active component, production of metabolites with no activity and, in extreme cases, production of toxic metabolites. This area needs to be addressed in order to determine the efficacy of the formulation. Understanding the problems related to natural product stability can give the idea of dealing with the stability issues. Modifications of the conventional herbal formulations can deal with the stability problems to a large extent. This article deals with the stability problems and is aimed to provide some tools and techniques to increase stability of natural medicines and herbal formulations.