Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody.
Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indium-labeled version of ABT-806, [(111)In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII-expressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity.


Removal of metals from aqueous solutions using natural chitinous materials.
Four naturally derived chitinous materials, commercial cryogenically milled carapace (CCMC), mechanically milled carapace (MMC), chitin and chitosan, were assessed for their ability to remove a range of alkali, alkaline earth, transition and heavy metals from aqueous media in flow-through column trials: The materials showed a poor affinity for the alkali metals and alkaline earth metals but significantly greater affinity for transition and heavy metals. In general, chitin was the least efficient material for removal of transition and heavy metals (approximately 35%) while chitosan was most effective (> 99%). CCMC and MMC both removed > 90% of transition and heavy metals tested from solution. Batch studies conducted using copper as a reference metal demonstrated that removal was dependent on a number of variables including pH, contact time, particle size, metal concentration, metal type and the physio-chemical characteristics of the materials. Detailed analysis of the results from these studies indicate that removal is a complex process and that metals can be sequestered from solution by a number of mechanisms including adsorption, absorption and precipitation.


Fast numerical integration of relaxation oscillator networks based on singular limit solutions.
Abstract-Relaxation oscillations exhibiting more than one time scale arise naturally from many physical systems. When relaxation oscillators are coupled in a way that resembles chemical synapses, we propose a fast method to numerically integrate such networks. The numerical technique, called the singular limit method, is derived from analysis of relaxation oscillations in the singular limit. In such limit, system evolution gives rise to time instants at which fast dynamics takes place and intervals between them during which slow dynamics takes place. A full description of the method is given for a locally excitatory globally inhibitory oscillator network (LEGION), where fast dynamics, characterized by jumping which leads to dramatic phase shifts, is captured in this method by iterative operation and slow dynamics is entirely solved. The singular limit method is evaluated by computer experiments, and it produces remarkable speedup compared to other methods of integrating these systems. The speedup makes it possible to simulate large-scale oscillator networks.


Progress in layered double hydroxides (LDHs): Synthesis and application in adsorption, catalysis and photoreduction.
Layered double hydroxides (LDHs), also known as anionic clays, have attracted significant attention in energy and environmental applications due to their exceptional physicochemical properties. These materials possess a unique structure with surface hydroxyl groups, tunable properties, and high stability, making them highly desirable. In this review, the synthesis and functionalization of LDHs have been explored including co-precipitation and hydrothermal methods. Furthermore, extensive research on LDH application in toxic pollutant removal has shown that modifying or functionalizing LDHs using materials such as activated carbon, polymers, and inorganics is crucial for achieving efficient pollutant adsorption, improved cyclic performance, as well as effective catalytic oxidation of organics and photoreduction of heavy metals. This study offers a comprehensive overview of the progress made in the field of LDHs and LDH-based composites for water and wastewater treatment. It critically discusses and explains both direct and indirect synthesis and modification techniques, highlighting their advantages and disadvantages. Additionally, this review critically discusses and explains the potential of LDH-based composites as absorbents. Importantly, it focuses on the capability of LDH and LDH-based composites in heterogeneous catalysis, including the Fenton reaction, Fenton-like reactions, photocatalysis, and photoreduction, for the removal of organic dyes, organic micropollutants, and heavy metals. The mechanisms involved in pollutant removal, such as adsorption, electrostatic interaction, complexation, and degradation, are thoroughly explained. Finally, this study outlines future research directions in the field.


The Southern Bluefin Tuna Mucosal Microbiome Is Influenced by Husbandry Method, Net Pen Location, and Anti-parasite Treatment.
Aquaculture is the fastest growing primary industry worldwide. Marine finfish culture in open ocean net pens, or pontoons, is one of the largest growth areas and is currently the only way to rear high value fish such as bluefin tuna. Ranching involves catching wild juveniles, stocking in floating net pens and fattening for 4 to 8 months. Tuna experience several parasite-induced disease challenges in culture that can be mitigated by application of praziquantel (PZQ) as a therapeutic. In this study, we characterized the microbiome of ranched southern Bluefin Tuna, Thunnus maccoyii, across four anatomic sites (gill, skin, digesta, and anterior kidney) and evaluated environmental and pathological factors that influence microbiome composition, including the impact of PZQ treatment on microbiome stability. Southern bluefin tuna gill, skin, and digesta microbiome communities are unique and potentially influenced by husbandry practices, location of pontoon growout pens, and treatment with the antiparasitic PZQ. There was no significant relationship between the fish mucosal microbiome and incidence or abundance of adult blood fluke in the heart or fluke egg density in the gill. An enhanced understanding of microbiome diversity and function in high-value farmed fish species such as bluefin tuna is needed to optimize fish health and improve aquaculture yield. Comparison of the bluefin tuna microbiome to other fish species, including Seriola lalandi (yellowtail kingfish), a common farmed species from Australia, and Scomber japonicus (Pacific mackerel), a wild caught Scombrid relative of tuna, showed the two Scombrids had more similar microbial communities compared to other families. The finding that mucosal microbial communities are more similar in phylogenetically related fish species exposes an opportunity to develop mackerel as a model for tuna microbiome and parasite research.


[The best approach to treat prolactinoma].
The prolactinoma is the most frequent pituitary tumor; the clinical presentation in women is characterized by menstrual disorders, amenorrhea, galactorrhea and/or sterility; neurological symptoms are present only when the tumor exceeds the sella turcica which is exceptional. Prolactin levels over 100 ng/mL are usually diagnostic of prolactinoma, as long as there are no pregnancy and/or hypothyroidism. The first therapeutical option is dopamine agonist drugs, thus surgery has been practically eliminated. Dopaminergic drugs suppress both synthesis and prolactin secretion, which in turn restores the ovarian function and induces tumor shrinkage. In conclusion, dopamine agonists constitute the prolactinoma treatment; in addition drug withdrawal is followed by remission of prolactinoma activity. In men, the size of the prolactinoma is larger, macroprolactinoma which usually presents extrasellar extension accompanied of neurological and visual symptoms; however the prolactinoma exhibits a favorable response with dopaminergic drugs.


The International Classification of Functioning, Disability and Health: a systematic review of observational studies.
To systematically review the use of the International Classification of Functioning, Disability and Health (ICF) in observational studies. This study is a systematic review of articles that use the ICF in observational studies. We took into account the observational design papers available in databases such as PubMed, Lilacs and SciELO, published in English and Portuguese from January 2001 to June 2011. We excluded those in which the samples did not comprise individuals, those about children and adolescents, and qualitative methodology articles. After reading the abstracts of 265 identified articles, 65 met the inclusion criteria. Of these, 18 were excluded. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) adapted Checklist, with 15 items needed for observational studies, was applied to the 47 remaining articles. Any paper that met 12 of these criteria was included in this systematic review. 29 articles were reviewed. Regarding the ICF application methodology, the checklist was used in 31% of the articles, the core set in 31% and the ICF categories in 31%. In the remaining 7%, it was not possible to define the applied methodology. In most papers (41%), qualifiers were used in their original format. As far as the area of knowledge is concerned, most of the studies were related to Rheumatology (24%) and Orthopedics (21%). Regarding the study design, 83% of the articles used cross-sectional studies. Results indicate a wide scientific production related to ICF over the past 10 years. Different areas of knowledge are involved in the debate on the improvement of information on morbidity. However, there are only a few quantitative epidemiological studies involving the use of ICF. Future studies are needed to improve data related to functioning and disability.


Cross-National Differences in Disability Among Elders: Transitions in Disability in Mexico and the United States.
Little is known about how exposure to a combination of infectious and chronic conditions throughout the lifecourse could impact disability in old age. This paper compares 2 cohorts of adults who have aged under very different country contexts by contrasting disability transitions among elders in Mexico with elders in the United States. Data comes from the Mexican Health and Aging Study (MHAS) and the U.S. Health and Retirement Study (HRS). Estimated probabilities of 2-year transitions among disability states and mortality are presented for adults aged 50 and older. The levels of disability prevalence and 2 year transitions are consistent with a higher rate of disability for the United States compared to Mexico. In 2-year transitions, the U.S. sample was more likely to transition to a disabled state or increase the number of disabilities than the Mexican counterparts, while Mexicans are more likely to move out of disability or reduce the number of disabilities reported. The findings suggest that the current rate of disability in old age is lower for a less developed country compared with a developed society. We discuss implications, possible explanations, and likely future scenarios.


Long-term trends in body mass index of children in Jena, Eastern Germany.
The body mass index (BMI) is widely used as an indicator of nutritional status of individuals and groups, changes in this measure reflecting changes in living conditions. The purpose of this paper is to present long-term BMI trends of schoolchildren from Jena/Eastern Germany over 125 years. The analysis is based on 10 anthropological investigations carried out between 1880 and 2005/2006 and belongs to the longest running, continuous investigation of schoolchildren in a single community worldwide. The average BMI of the 7- to 14-year-old probands generally increases between the first investigation in 1880 and the last study in 2005/2006 by 1.8 kg/m(2) in boys and by 2.1 kg/m(2) in girls. However, this long-term increase of the BMI does not occur continuously. The trend was interrupted for example by declining average BMI values between 1932 and 1944. In contrast, the time after German reunification is characterised by a marked increase in this measure. The changes in BMI of Jena schoolchildren are also analysed in relation to energy intake in different years. There is an association between changes in energy intake and changes in BMI, which weakens after 1985. This indicates that the recent dramatic increase in the prevalence of overweight and obesity is not only due to an increased energy intake but also reflects a more inactive lifestyle of children and adolescents. The continuing change in the BMI pattern of Jena children and adolescents is discussed in regard to programmes of prevention of overweight and obesity.


CD8+ T-cell response promotes evolution of hepatitis C virus nonstructural proteins.
Hepatitis C virus (HCV) acquires mutations that allow it to escape the CD8+ T-cell response, although the extent to which this process contributes to viral evolution at the population level is not clear. We studied viral adaptation using data from a large outbreak of HCV genotype 1b infection that occurred among women immunized with contaminated immunoglobulin from 1977 to 1978. The HCV nonstructural protein coding regions NS3-NS5B were sequenced from 78 patients, and mutations were mapped according to their location inside or outside previously described CD8+ T-cell epitopes. A statistical approach was developed to identify sites/regions under reproducible selection pressure associated with HLA class I. The frequency of nonsynonymous mutations was significantly higher inside previously described CD8+ T-cell epitopes than outside-particularly in NS3/4A and NS5B. We identified new regions that are under selection pressure, indicating that not all CD8+ T-cell epitopes have been identified; 6 new epitopes that interact with CD8+ T cells were identified and confirmed in vitro. In some CD8+ T-cell epitopes mutations were reproducibly identified in patients that shared the relevant HLA allele, indicating immune pressure at the population level. There was statistical support for selection of mutations in 18 individual epitopes. Interestingly, 14 of these were restricted by HLA-B allele. HLA class I-associated selection pressure on the nonstructural proteins and here predominantly on NS3/4A and NS5B promotes evolution of HCV. HLA-B alleles have a dominant effect in this selection process. Adaptation of HCV to the CD8+ T-cell response at the population level creates challenges for vaccine design.


Placental abnormalities differ in small for gestational age neonates in relation to their prenatal sonographic abdominal circumference measurements.
Antenatal detection of abdominal circumference (AC) <10th percentile, among small for gestational age (SGA) neonates, probably reflects the severity of their growth restriction. We aimed to study neonatal outcome and placental pathology among SGA neonates in correlation to their AC measurements. Maternal and neonatal computerized medical records and placental histopathology reports of all SGA neonates, (neonatal birth-weight ≤10th percentile), born between 24 and 42 weeks, during 2015-2018 were reviewed. Included cases with fetal biometric measurements conducted up to 7 days prior labor. Results were compared between cases with sonographic antenatal AC <10th percentile and neonates with sonographic antenatal AC ≥10th percentile. Placental lesions were classified according to "Amsterdam" Placental workshop criteria. The AC <10th percentile group (n = 148) was characterized by higher rate of nulliparity (p = .003), and induction of labor (p = .009), as compared to the AC ≥10th percentile group (n = 41). There were no between groups differences in the rate of maternal BMI (kg/m2), hypertensive disorders, diabetes or smoking. Neonatal hypoglycemia was more common in the AC <10th percentile group as compared to the AC ≥10th percentile group (p = .04). Placentas from the AC <10th percentile group were smaller (p < .001), with more MVM lesions (p = .02) and chronic villitis (p = .04). By multivariate regression analysis, AC <10th percentile and maternal hypertensive disorders, were found to be independently associated with placental MVM lesions, aOR = 2.43 (95% CI 1.04, 5.88) and aOR = 3.15 (95% CI 1.06, 9.31), respectively. Higher rate of placental maternal malperfusion lesions, chronic villitis, and more neonatal hypoglycemia characterize SGA neonates with AC <10th percentile, pointing to the importance of AC measurement as an indicator for placental insufficiency.


Internal and external workload in national and international netball competition.
Differences in workload exist between netball playing positions and competition levels, but no research has compared workloads experienced by the same elite players during national and international competitions. This study collected internal (heart rate) and external (PlayerLoad·min-1) workload data per match quarter from 44 players during a national competition and 12 players during an international competition. Nine players played in both competitions. Linear mixed models compared percentage of match quarter in each heart rate zone and PlayerLoad·min-1 between competitions for each playing position. Workloads against low- and high-ranked international opponents were also compared. Internal workloads were greater in national compared to international competition for GD and WD positions. PlayerLoad·min-1 was significantly higher by 8-13% in the national competition for positions WD and C, and by 5-8% in the international competition for GD and GA. Positional differences may indicate a role of the team's tactical style of play. Workloads were generally greater against higher- rather than lower-ranked international opponents. These results indicate that tactical factors in combination with playing position and opposition characteristics should be considered when preparing physically for matches.


Vacancy filling effect in thermoelectric NbO.
Using density functional theory, we have systematically explored the 1a and 1b vacancy filling in NbO (space group Pm-3m) with Nb and N, respectively, to design compounds with large Seebeck coefficients. The most dominating effect was identified for filling of 1b Wyckoff sites with N giving rise to a fivefold increase in the Seebeck coefficient. This may be understood based on the electronic structure. Nb d-nonmetal p hybridization induces quantum confinement and hence enables the enhancement of the Seebeck coefficient. This was validated by measuring the Seebeck coefficient of reactively sputtered thin films. At 800 °C these electrically conductive oxynitrides exhibit the Seebeck coefficient of -70 µV K(-1), which is the largest absolute value ever reported for these compounds.


Associations of Serum Folate and Holotranscobalamin with Cardiometabolic Risk Factors in Rural and Urban Cameroon.
A low intake of fruit and vegetables and a high intake of meat are associated with higher cardiometabolic disease risk; however much prior research has relied on subjective methods for dietary assessment and focused on Western populations. We aimed to investigate the association of blood folate as an objective marker of fruit and vegetable intake and holotranscobalamin (holoTC) as a marker of animal-sourced food intake with cardiometabolic risk factors. We conducted a population-based cross-sectional study on 578 adults (mean ± SD age = 38.2 ± 8.6 years; 64% women). The primary outcome was a continuous metabolic syndrome score. The median serum folate was 12.9 (IQR: 8.6-20.5) nmol/L and the mean holoTC was 75 (SD: 34.3) pmol/L. Rural residents demonstrated higher serum folate concentrations (15.9 (9.8-25.9) nmol/L) than urban residents (11.3 (7.9-15.8) nmol/L), but lower holoTC concentrations (rural: 69.8 (32.9) pmol/L; urban: 79.8 (34.9)) pmol/L, p < 0.001 for both comparisons. There was an inverse association between serum folate and metabolic syndrome score by -0.20 in the z-score (95% CI, -0.38 to -0.02) per 10.8 (1 SD) of folate) in a model adjusted for socio-demographic factors, smoking status, alcohol intake, BMI, and physical activity. HoloTC was positively associated with the metabolic syndrome score in unadjusted analysis (0.33 (95% CI, 0.10 to 0.56)) but became non-significant (0.17 (-0.05 to 0.39)) after adjusting for socio-demographic and behavioural characteristics. In conclusion, serum folate and holoTC were associated with the metabolic syndrome score in opposite directions. The positive association between serum holoTC and the metabolic syndrome score was partly dependent on sociodemographic characteristics. These findings suggest that, based on these biomarkers reflecting dietary intakes, public health approaches promoting a higher intake of fruit and vegetables may lower cardiometabolic risk factors in this population.


Tuning Protein Diffusivity with Membrane Tethers.
Diffusion is essential for biochemical processes because it dominates molecular movement on small scales. Enzymatic reactions, for example, require fast exchange of substrate and product molecules in the local environment of the enzyme to ensure efficient turnover. On larger spatial scales, diffusion of secreted signaling proteins is thought to limit the spatial extent of tissue differentiation during embryonic development. While it is possible to measure diffusion in vivo, specifically interfering with diffusion processes and testing diffusion models directly remains challenging. The development of genetically encoded nanobodies that bind specific proteins has provided the opportunity to alter protein localization and reduce protein mobility. Here, we extend the nanobody toolbox with a membrane-tethered low-affinity diffusion regulator that can be used to tune the effective diffusivity of extracellular molecules over an order of magnitude in living embryos. This opens new avenues for future applications to functionally interfere with diffusion-dependent processes.


Influence of Nitrite on Formation of Tobacco-Specific Nitrosamines in Electronic Cigarette Liquids and Aerosols.
Tobacco-specific nitrosamine (TSNA) formation occurred during aerosol generation from select commercial cig-a-like e-cigarette products. To understand the drivers behind the potential formation of TSNAs in electronic cigarette (e-cigarette) aerosols and e-liquids, model e-liquid systems were generated in the lab to demonstrate that nitrite can react with nicotine and minor alkaloids to form TSNAs in e-liquids. In the presence of nitrite and nicotine, TSNA levels in e-liquids increased over time and the process was accelerated by elevated temperature. Additionally, TSNAs formed during aerosol generation when nitrite was present in the corresponding e-liquids. The commercial e-cigarette products that showed higher levels and formation of TSNAs were observed to contain nitrite and minor alkaloid impurities in the corresponding e-liquids. This study provides valuable information about drivers for TSNA formation in e-liquids and e-cigarette aerosols that may be applied to the evaluation and quality assurance of e-cigarette products.


Cercarial density in the river of an endemic area of schistosomiasis haematobia in Kenya.
The cercarial density in natural water and number of infected Bulinus globosus were monitored over a one-year period to identify the transmission foci in an endemic area of schistosomiasis haematobia in Kenya. Overall prevalence and intensity of infection of the study community were 59.2% and 10.9 eggs/10 ml of urine. Cercariometry was carried out on 456 occasions at 20 study sites while snail sampling was done on 465 occasions at the same sites over a one-year period. Cercariometry was exclusively done at flowing water habitats. The results showed the focality and seasonality of transmission. Cercariae were detected on 44 occasions at 11 sites. The detections were made on seven occasions at two study sites, six occasions at one site, four occasions at four sites, three occasions at one site, two occasions at two sites, and one occasion at one site. Densities of 1-4 cercariae/100 liters of water were found on 31 occasions. Five to nine cercariae/100 liters of water were found on seven occasions, 10-19 cercariae/100 liters of water were found on two occasions, and high cercarial densities greater than 20 cercariae/100 liters of water were found on four occasions. The highest count was 52 cercariae/100 liters of water. The presence of cercariae in natural water was shown to depend on the water temperature, but the intensity and duration of sunlight did not affect the presence of cercariae in water. The monthly variability of cercarial density was proportional to the number of infected snails. Cercarial density was highest in March and April, in the middle of the rainy season, whereas no cercariae were detected in cool dry season. The snail population peaked late in March, the beginning of the long rainy season, remained high for two months, and decreased rapidly late in May when heavy rain occurred. The overall infection rate of snails was 7.3% and the majority of infected snails were collected from March to May. There was no definite correlation between the presence or absence of cercariae and infected snails. Cercariae were frequently found where infected snails were absent and cercariae were sometimes absent where infected snails were present. Cercariometry and snail sampling remain quite complementary in identifying the transmission foci of schistosomiasis.


Semantically Enhanced Online Configuration of Feedback Control Schemes.
Recent progress toward the realization of the "Internet of Things" has improved the ability of physical and soft/cyber entities to operate effectively within large-scale, heterogeneous systems. It is important that such capacity be accompanied by feedback control capabilities sufficient to ensure that the overall systems behave according to their specifications and meet their functional objectives. To achieve this, such systems require new architectures that facilitate the online deployment, composition, interoperability, and scalability of control system components. Most current control systems lack scalability and interoperability because their design is based on a fixed configuration of specific components, with knowledge of their individual characteristics only implicitly passed through the design. This paper addresses the need for flexibility when replacing components or installing new components, which might occur when an existing component is upgraded or when a new application requires a new component, without the need to readjust or redesign the overall system. A semantically enhanced feedback control architecture is introduced for a class of systems, aimed at accommodating new components into a closed-loop control framework by exploiting the semantic inference capabilities of an ontology-based knowledge model. This architecture supports continuous operation of the control system, a crucial property for large-scale systems for which interruptions have negative impact on key performance metrics that may include human comfort and welfare or economy costs. A case-study example from the smart buildings domain is used to illustrate the proposed architecture and semantic inference mechanisms.


Overexpression of a neuropeptide nociceptin/orphanin FQ precursor gene, N23K/N27K, induces neurite outgrowth in mouse NS20Y cells.
We recently discovered N23K and its splicing variant N27K as transcripts upregulated in mouse NS20Y cells after differentiation induced by dibutylyl cyclic AMP (dbcAMP) treatment. N23K and N27K encode precursor proteins for an opioid neuropeptide, nociceptin/orphanin FQ, but the transient expression of N23K and N27K suggests that it may be involved in neuronal differentiation. In the present study, we report that NS20Y cells transfected with N23K and/or N27K but not with vector alone formed neurites, with the expressed protein distributed in the perinuclear region and distal parts of the neurites. The granular staining of the N23K and N27K proteins was also colocalized with secretogranin I, indicating incorporation into large dense core vesicles. This cellular targeting of the N23K and/or N27K protein is similar to that of dbcAMP-induced processes in nontransfected NS20Y cells. In addition, the neurites of transfectants that expressed both N23K and N27K were longer than those of the transfectants that expressed N23K or N27K alone. Our results demonstrate that N23K and N27K participate in the regulation of neurite outgrowth.


Indirect questioning methods for sensitive survey questions: Modelling criminal behaviours among a prison population.
Information such as the prevalence and frequency of criminal behaviour is difficult to estimate using standard survey techniques because of the tendency of respondents to withhold or misrepresent information. Social desirability bias is a significant threat to the validity of self-reported data, especially when supplied by persons such as sexual offenders or those convicted of theft or substance abuse. The randomized response approach is an alternative to the standard interview method and offers great potential for researchers in the field of criminal justice. By means of a survey of 792 prison inmates, incorporating both indirect and direct response techniques, we investigate if the prison population also has problems recognizing their participation in criminal acts such as theft, illicit drug use, violence against property, reckless driving and arson. Our research findings suggest that self-reported criminal behaviour among a prison population is affected by social desirability bias and that the behaviour considered is significantly associated with the severity of obsessive-compulsive symptoms. The results also demonstrate the inadequacy of traditional, yet widely used, direct questioning methods, and the great potential for indirect questioning techniques to advance policy formation and evaluation in the field of criminal behaviour.


Shear stress in atherosclerotic plaque determination.
Atherosclerosis initiates at predictable focal sites near arterial branches and curves, where blood flow is disturbed and shear stress is complex. Endothelial shear stress is the tangential stress derived from the friction of the flowing blood on the endothelial surface of the arterial wall. It is a key factor in modulating endothelial cell gene expression and vascular development and remodeling. Increasing evidences suggest that shear stress patterns have a strong relationship with atherosclerotic features. Moreover, variations in the local artery geometry during atherogenesis further modify flow shear stress characteristics, which contribute to the rupture site at the plaque upstream. In this study, we summarize the mechanistic evidences that associate shear stress patterns with determined atherosclerotic plaque features. An enhanced understanding of the relationship and pathophysiological function of shear stress patterns in atherosclerotic plaque features is essential, which may provide early prediction of clinical risk and guide individualized treatment strategies. In the current review, we analyzed the function of shear stress on the determination of atherosclerotic lesion and provided an update on the mechanotransduction of shear stress, gene expression regulation, and atherosclerotic plaque development and rupture.


Antigenic and genomic diversity of human rotavirus VP4 in two consecutive epidemic seasons in Mexico.
In the present investigation we characterized the antigenic diversity of the VP4 and VP7 proteins in 309 and 261 human rotavirus strains isolated during two consecutive epidemic seasons, respectively, in three different regions of Mexico. G3 was found to be the prevalent VP7 serotype during the first year, being superseded by serotype G1 strains during the second season. To antigenically characterize the VP4 protein of the strains isolated, we used five neutralizing monoclonal antibodies (MAbs) which showed specificity for VP4 serotypes P1A, P1B, and P2 in earlier studies. Eight different patterns of reactivity with these MAbs were found, and the prevalence of three of these patterns varied from one season to the next. The P genotype of a subset of 52 samples was determined by PCR. Among the strains characterized as genotype P[4] and P[8] there were three and five different VP4 MAb reactivity patterns, respectively, indicating that the diversity of neutralization epitopes in VP4 is greater than that previously appreciated by the genomic typing methods.


Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice.
Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.


Transcriptional profiling identifies the metabolic phenotype of gonococcal biofilms.
Neisseria gonorrhoeae, the etiologic agent of gonorrhea, is frequently asymptomatic in women, often leading to chronic infections. One factor contributing to this may be biofilm formation. N. gonorrhoeae can form biofilms on glass and plastic surfaces. There is also evidence that biofilm formation may occur during natural cervical infection. To further study the mechanism of gonococcal biofilm formation, we compared transcriptional profiles of N. gonorrhoeae biofilms to planktonic profiles. Biofilm RNA was extracted from N. gonorrhoeae 1291 grown for 48 h in continuous-flow chambers over glass. Planktonic RNA was extracted from the biofilm runoff. In comparing biofilm with planktonic growth, 3.8% of the genome was differentially regulated. Genes that were highly upregulated in biofilms included aniA, norB, and ccp. These genes encode enzymes that are central to anaerobic respiratory metabolism and stress tolerance. Downregulated genes included members of the nuo gene cluster, which encodes the proton-translocating NADH dehydrogenase. Furthermore, it was observed that aniA, ccp, and norB insertional mutants were attenuated for biofilm formation on glass and transformed human cervical epithelial cells. These data suggest that biofilm formation by the gonococcus may represent a response that is linked to the control of nitric oxide steady-state levels during infection of cervical epithelial cells.


Obesity-hypoventilation syndrome: increased risk of death over sleep apnea syndrome.
To study whether mortality and cardiovascular morbidity differ in non-invasive ventilation (NIV)-treated patients with severe obesity-hypoventilation syndrome (OHS) as compared with CPAP-treated patients with obstructive sleep apnea syndrome (OSAS), and to identify independent predictors of mortality in OHS. Two retrospective cohorts of OHS and OSAS were matched 1:2 according to sex, age (± 10 year) and length of time since initiation of CPAP/NIV therapy (± 6 months). Three hundred and thirty subjects (110 patients with OHS and 220 patients with OSAS) were studied. Mean follow-up time was 7 ± 4 years. The five year mortality rates were 15.5% in OHS cohort and 4.5% in OSAS cohort (p< 0.05). Patients with OHS had a 2-fold increase (OR 2; 95% CI: 1.11-3.60) in the risk of mortality and 1.86 fold (OR 1.86; 95% CI: 1.14-3.04) increased risk of having a cardiovascular event. Diabetes, baseline diurnal SaO2 < 83%, EPAP < 7 cmH2O after titration and adherence to NIV < 4 hours independently predicted mortality in OHS. Mortality of severe OHS is high and substantially worse than that of OSAS. Severe OHS should be considered a systemic disease that encompasses respiratory, metabolic and cardiovascular components that require a multimodal therapeutic approach.


Teaching Magnetoelectric Sensing to Secondary School Students-Considerations for Educational STEM Outreach.
A major challenge in modern society is the need to increase awareness and excitement with regard to science, technology, engineering and mathematics (STEM) and related careers directly or among peers and parents in order to attract future generations of scientists and engineers. The numbers of students aiming for an engineering degree are low compared to the options available and the workforce needed. This may, in part, be due to a traditional lack of instruction in this area in secondary school curricula. In this regard, STEM outreach programs can complement formal learning settings and help to promote engineering as well as science to school students. In a long-term outreach collaboration with scientists and engineers, we developed an outreach program in the field of magnetoelectric sensing that includes an out-of-school project day and various accompanying teaching materials. In this article, we motivate the relevance of the topic for educational outreach, share the rationales, objectives and aims, models and implementation strategies of our program and provide practical advice for those interested in outreach in the field of magnetoelectric sensing.


The ICF-CY-based structural equation model of factors associated with participation in children with autism.
The aim of this study was to apply the International Classification of Functioning, Disability and Health - Child and Youth (ICF-CY) framework to identify the factors related to the participation of children with autism. A convenience sample included 162 preschool children with autism ages 36 to 72 months. The raters collected data using the ICF-CY-based questionnaire as an instrument to construct the structural equation modeling of factors associated with participation. The internal structure of the model was acceptable, indicating that the observed variables would suffice in accounting for latent variables. The structural model showed that the performance of participation in children with autism was influenced by body functions and personal factors. All the variables accounted for 77% of the explained variance for activities and for participation by 71% of the children with autism. These findings may provide critical information pertaining to predictive factors of participation for parents, educators, and professionals who work with children with autism.


Natural Voice Use in Patients With Voice Disorders and Vocally Healthy Speakers Based on 2 Days Voice Accumulator Information From a Database.
Information about how patients with voice disorders use their voices in natural communicative situations is scarce. Such long-term data have for the first time been uploaded to a central database from different hospitals in Sweden. The purpose was to investigate the potential use of a large set of long-term data for establishing reference values regarding voice use in natural situations. VoxLog (Sonvox AB, Umeå, Sweden) was tested for deployment in clinical practice by speech-language pathologists working at nine hospitals in Sweden. Files from 20 patients (16 females and 4 males) with functional, organic, or neurological voice disorders and 10 vocally healthy individuals (eight females and two males) were uploaded to a remote central database. All participants had vocally demanding occupations and had been monitored for more than 2 days. The total recording time was 681 hours and 50 minutes. Data on fundamental frequency (F0, Hz), phonation time (seconds and percentage), voice sound pressure level (SPL, dB), and background noise level (dB) were analyzed for each recorded day and compared between the 2 days. Variations across each day were measured using coefficients of variation. Average F0, voice SPL, and especially the level of background noise varied considerably for all participants across each day. Average F0 and voice SPL were considerably higher than reference values from laboratory recordings. The use of a remote central database and strict protocols can accelerate data collection from larger groups of participants and contribute to establishing reference values regarding voice use in natural situations and from patients with voice disorders. Information about activities and voice symptoms would supplement the objective data and is recommended in future studies.


Group I metabotropic glutamate receptors mediate an inward current in rat substantia nigra dopamine neurons that is independent from calcium mobilization.
Metabotropic glutamate receptors modulate neuronal excitability via a multitude of mechanisms, and they have been implicated in the pathogenesis of neurodegenerative processes. Here we investigated the responses mediated by group I metabotropic glutamate receptors (mGluRs) in dopamine neurons of the rat substantia nigra pars compacta, using whole cell patch-clamp recordings in combination with microfluorometric measurements of [Ca(2+)](i) and [Na(+)](i). The selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) was bath-applied (20 microM, 30 s to 2 min) or applied locally by means of short-lasting (2-4 s) pressure pulses, delivered through an agonist-containing pipette positioned close to the cell body of the neuron. 3,5-DHPG evoked an inward current characterized by a transient and a sustained component, the latter of which was uncovered only with long-lasting agonist applications. The fast component coincided with a transient elevation of [Ca(2+)](i), whereas the total current was associated with a rise in [Na(+)](i). These responses were not affected either by the superfusion of ionotropic excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D-2-amino-5-phosphono-pentanoic acid (D-APV), nor by the sodium channel blocker tetrodotoxin (TTX). (S)-alpha-methyl-4-carboxyphenylglycine (S-MCPG) and the more selective mGluR1 antagonist 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate (CPCCOEt) depressed both 3,5-DHPG-induced inward current components and, although less effectively, the associated [Ca(2+)](i) elevations. On repeated agonist applications the inward current and the calcium transients both desensitized. The time constant of recovery from desensitization differed significantly between these two responses, being 67.4+/-4.4 s for the inward current and 28.6+/-2.7 s for the calcium response. Bathing the tissue in a calcium-free/EGTA medium or adding thapsigargin (1 microM) to the extracellular medium prevented the generation of the [Ca(2+)](i) transient, but did not prevent the activation of the inward current. These electrophysiological and fluorometric results show that the 3, 5-DHPG-induced inward current and the [Ca(2+)](i) elevations are mediated by independent pathways downstream the activation of mGluR1.


cDNA suppression subtraction library for screening down-regulated genes in gastric carcinoma.
To establish cDNA suppression subtraction library with a high subtraction efficiency by counterpart normal gastric mucosa mixture mRNA subtracting gastric cancer cells mixture mRNA for screening down-regulated genes in gastric carcinoma. RNA of gastric cancer tissues and counterpart normal gastric mucosa were respectively isolated in five patients with gastric cancer, and their mRNA was purified. cDNA suppression subtraction library was established by counterpart normal gastric mucosa mixture mRNA (tester) subtracting gastric cancer tissues mixture mRNA (driver) of five patients with gastric carcinoma. The library plasmids were transformed into competent bacteria DH5a after ligation of the library cDNA fragments with T vectors. Library plasmids were extracted after picking colonies and shaking bacteria overnight. Its subtraction efficiency was confirmed by PCR and reverse hybridization of a nylon filter onto which the colonies of bacteria were transferred with probes of reverse transcription products cDNA of gastric cancer tissues mRNA and counterpart normal gastric mucosa mRNA labeled with alpha- (32)P dCTP. mRNA purified from total RNA of gastric cancer tissues and counterpart normal gastric mucosa in five patients with gastric carcinoma revealed a good quality. cDNA suppression subtraction library constructed for screening down-regulated genes in gastric carcinoma represented a high subtraction efficiency. 86 % of differential expression in down-regulated genes between counterpart normal gastric mucosa and gastric carcinoma was confirmed. cDNA suppression subtraction library with a high subtraction efficiency for screening down-regulated genes in gastric carcinoma is successfully established.


Advancements in sensor technology and decision support intelligent tools to assist smart livestock farming.
Remote monitoring, modern data collection through sensors, rapid data transfer, and vast data storage through the Internet of Things (IoT) have advanced precision livestock farming (PLF) in the last 20 yr. PLF is relevant to many fields of livestock production, including aerial- and satellite-based measurement of pasture's forage quantity and quality; body weight and composition and physiological assessments; on-animal devices to monitor location, activity, and behaviors in grazing and foraging environments; early detection of lameness and other diseases; milk yield and composition; reproductive measurements and calving diseases; and feed intake and greenhouse gas emissions, to name just a few. There are many possibilities to improve animal production through PLF, but the combination of PLF and computer modeling is necessary to facilitate on-farm applicability. Concept- or knowledge-driven (mechanistic) models are established on scientific knowledge, and they are based on the conceptualization of hypotheses about variable interrelationships. Artificial intelligence (AI), on the other hand, is a data-driven approach that can manipulate and represent the big data accumulated by sensors and IoT. Still, it cannot explicitly explain the underlying assumptions of the intrinsic relationships in the data core because it lacks the wisdom that confers understanding and principles. The lack of wisdom in AI is because everything revolves around numbers. The associations among the numbers are obtained through the "automatized" learning process of mathematical correlations and covariances, not through "human causation" and abstract conceptualization of physiological or production principles. AI starts with comparative analogies to establish concepts and provides memory for future comparisons. Then, the learning process evolves from seeking wisdom through the systematic use of reasoning. AI is a relatively novel concept in many science fields. It may well be "the missing link" to expedite the transition of the traditional maximizing output mentality to a more mindful purpose of optimizing production efficiency while alleviating resource allocation for production. The integration between concept- and data-driven modeling through parallel hybridization of mechanistic and AI models will yield a hybrid intelligent mechanistic model that, along with data collection through PLF, is paramount to transcend the current status of livestock production in achieving sustainability.


Mechanisms of transcriptional regulation of the human IL-3/GM-CSF locus by inducible tissue-specific promoters and enhancers.
The IL-3 and GM-CSF genes are closely linked in the genome and reside within a cluster of cytokine genes. IL-3 and GM-CSF are expressed in a highly inducible and tissue-specific pattern, and this review attempts to provide a comprehensive description of the key regulatory elements in this locus that control their expression. Although these genes are typically coexpressed in T cells, they are differentially regulated in many other cell types, whereby cells such as monocytes and endothelial cells express GM-CSF, but not IL-3. This suggests that they are likely to be regulated by distinct mechanisms. This view is reinforced by the identification of three inducible enhancers in the locus that have different specificities. These enhancers are embedded within arrays of tissue-specific DNaseI hypersensitive sites that most likely play additional roles in establishing distinct patterns of gene expression. This locus also represents a valuable model system for studying the role of chromatin remodeling in cytokine gene activation. NFAT is one inducible factor that appears to play a major role in the formation of DNaseI hypersensitive sites within enhancers, and which functions in a highly cooperative manner with other classes of transcription factors to direct specific patterns of cytokine gene expression.


Evaluation of transmission potential and pathobiological characteristics of mallard originated Avian orthoavulavirus 1 (sub-genotype VII.2) in commercial broilers.
Newcastle disease (ND), caused by Avian orthoavulavirus 1 (AOAV-1), affects multiple avian species around the globe. Frequent disease outbreaks are not uncommon even in vaccinates despite routine vaccination and, in this regards, viruses of diverse genotypes originating from natural reservoirs (migratory waterfowls) play an important role in a disease endemic setting. Though genomic characterization of waterfowl originated viruses has been well-elucidated previously, there is a paucity of data on clinico-pathological assessment of mallard-originated sub-genotype VII.2 in commercial chickens. Hence, the current study was designed to evaluate its transmission potential, tissue tropism and micro- and macroscopic lesions in commercial broilers. Based on complete genome and complete F gene, phylogenetic analysis clustered the study isolate within genotype VII and sub-genotype VII.2 in close association with those reported previously from multiple avian species worldwide. The study strain was found to be velogenic on the basis of typical residue pattern in the F-protein cleavage site (112R-RQ-K-R↓F117), sever disease induction in chicken, tissue tropism and subsequent clinico-pathological characteristics. Giving a clear evidence of horizontal transmission, a 100% mortality was observed by 4th and 6th day post infection (dpi) in chickens challenged with the virus and those kept with the challenged birds (contact birds), respectively. The observed clinical signs, particularly the greenish diarrhea, and macroscopic lesions such as pinpoint hemorrhages in proventriculus and caecal tonsils were typical of the infection caused by an AOAV-1 in chickens. The virus exhibited a broad tissue tropism where genomic RNA corresponding to study virus was detected in all of the tissues collected from recently mortile and necropsied birds. The study concludes that mallard-originated Avian orthoavulavirus 1 is highly velogenic to commercial chicken and therefore ascertain continuous disease monitoring and surveillance of migratory/aquatic fowls to better elucidate infection epidemiology and subsequent potential impacts on commercial poultry.


The evolutionary relationship between the duplicated copies of the zebrafish fabp11 gene and the tetrapod FABP4, FABP5, FABP8 and FABP9 genes.
We describe the structure of a fatty acid-binding protein 11 (fabp11b) gene and its tissue-specific expression in zebrafish. The 3.4 kb zebrafish fabp11b is the paralog of the previously described zebrafish fabp11a, with a deduced amino acid sequence for Fabp11B exhibiting 65% identity with that of Fabp11A. Whole mount in situ hybridization of a riboprobe to embryos and larvae showed that zebrafish fabp11b transcripts were restricted solely to the retina and were first detected at 24 h postfertilization. In situ hybridization revealed fabp11b transcripts along the spinal cord in adult zebrafish. However, the highly sensitive RT-PCR assay detected fabp11b transcripts in the brain, heart, ovary and eye in adult tissues. By contrast, fabp11a transcripts had been previously detected in the liver, brain, heart, testis, muscle, ovary and skin of adult zebrafish. Using the LN54 radiation hybrid panel, we assigned zebrafish fabp11b to linkage group 16. Phylogenetic analysis and conserved gene synteny with tetrapod genes indicated that the emergence of two copies of fabp11 in the zebrafish genome may have resulted from a fish-specific whole genome duplication event. Furthermore, we propose that the FABP4-FABP5-FABP8-FABP9 (PERF15) gene cluster on a single chromosome in the tetrapod genome and the fabp11 genes in the zebrafish genome originated from a common ancestral gene, which, following their divergence, gave rise to the fabp11 genes of zebrafish, and the progenitor of the FABP4, FABP5, FABP8 and FABP9 genes in tetrapods after the separation of the fish and tetrapod lineages.


Quantification of NADPH: cytochrome P-450 reductase in liver microsomes by a specific radioimmunoassay technique.
We have developed a specific radioimmunoassay to quantify NADPH: cytochrome P-450 reductase. The assay is based on the use of 125I-labelled NADPH: cytochrome P-450 reductase as the radiolabelled antigen and can detect quantities of this protein in amounts as low as 30 pg. The results of the radioimmunoassay demonstrates that the 2.7-fold increase in enzyme activity in rat liver microsomal membranes after phenobarbital treatment is due to increased amounts of the protein. beta-Naphthoflavone treatment, however, did not alter the activity or the quantity of this enzyme in microsomes. The quantification of NADPH: cytochrome P-450 reductase in the microsomes isolated from control and phenobarbital- and beta-naphthoflavone-treated animals permits the calculation of the ratio of this protein to that of total cytochromes P-450. A molar ratio of 15:1 (cytochromes P-450/NADPH: cytochrome P-450 reductase) was calculated for control and phenobarbital-treated animals. This ratio increased to 21:1 after beta-naphthoflavone treatment. Thus the molar ratio of these proteins in liver microsomes can vary with exposure of the animals to particular xenobiotics.


Is there an alternative to the full-leg radiograph for determining knee joint alignment in osteoarthritis?
To assess the concurrent validity of alternative measures of frontal plane knee alignment, namely the radiographic anatomic axis and 5 clinical measures, in medial compartment knee osteoarthritis (OA) as compared with the mechanical axis on radiograph. Forty individuals (mean +/- SD age 64.7 +/- 9.4 years) with symptomatic medial knee OA participated. Knee alignment was measured according to the following methods: lower-limb mechanical axis on radiograph, lower-limb anatomic axis on radiograph, visual observation, distance between medial knee joint lines or medial malleoli using a caliper, distance between a plumb line and medial knee joint line or malleolus using a caliper, tibial alignment using a gravity inclinometer, and lower-limb alignment using a goniometer. Data were analyzed using Pearson's correlation coefficient or Spearman's rho correlation coefficient and simple linear regression. The anatomic axis best correlated with the mechanical axis (r = 0.88), followed closely by the inclinometer method (r = 0.80). Other clinical measures of alignment that were significantly associated with the mechanical axis were the caliper method, the plumb-line method, and visual observation (r = 0.76, 0.71, and -0.52, respectively). However, the goniometer method failed to correlate. The anatomic axis on radiograph and the inclinometer method appear to be valid alternatives to the mechanical axis on full-leg radiograph for determining frontal plane knee alignment in medial knee OA. These alternative methods of measuring knee alignment may increase the assessment of this parameter by clinicians and researchers alike, given that malalignment is an important indicator of disease progression and treatment outcome.


Creating a wearable artificial kidney: where are we now?
A wearable and, ultimately, an implantable artificial kidney is a long-held aim in the treatment of patients with end-stage renal disease, provided that it would combine continuous blood purification, preventing the fluctuations in the internal environment associated with hemodialysis, while maintaining a high efficiency for removal of uremic toxins. Sorbent and enzyme technology, allowing for the regeneration of dialysis fluid, have played a vital role in the development of present prototypes, although the development of a low-weight regeneration module as well as safety and control issues still need to be solved. Whereas the first human trials with a wearable device have been successfully conducted, there are still many hurdles to overcome before wearable dialysis can be routinely implemented in dialysis practice. Important in this respect are the absence of a safe continuous blood access system and the risk balance between anticoagulation and clotting and regulatory aspects.


Brain: supratentorial central nuclei and tracts.
This article deals with numerous gray and white matter components of the forebrain, excluding the cerebral cortex. The basal ganglia, amygdalae, and basal forebrain structures are discussed including their groupings and subdivisions, as are the thalami, hypothalamus, and other derivatives of the diencephalon. The white matter structures considered include the capsules, optic and auditory radiations, and bundles ending or arising in the hypothalamus; all the major commissural tracts; and several major long association bundles that may be accurately located even if not discretely visualized.


[Leiomyosarcoma of the vagina: a rare case].
Vaginal leiomyosarcoma is unfrequent. We report on a case in a 50-year-old multipara patient who had presented a posterior vaginal swelling since 6 months. The tumor was discovered at the occasion of pains and non hemorragic discharge. The histological pattern of the tumor was well-differentiated spindle cell sarcoma with pleiomorphic areas. The immunohistochemistry confirmed the smooth myogenic differentiation. The treatment consisted of posterior pelvic exenteration extended to the vagina. The patient is alive and free of disease at 20 months of fellow-up.


Identification and partial purification of human double strand RNase activity. A novel terminating mechanism for oligoribonucleotide antisense drugs.
We have identified a double strand RNase (dsRNase) activity that can serve as a novel mechanism for chimeric antisense oligonucleotides comprised of 2'-methoxy 5' and 3' "wings" on either side of an oligoribonucleotide gap. Antisense molecules targeted to the point mutation in codon 12 of Harvey Ras (Ha-Ras) mRNA resulted in a dose-dependent reduction in Ha-Ras RNA. Reduction in Ha-Ras RNA was dependent on the oligoribonucleotide gap size with the minimum gap size being four nucleotides. An antisense oligonucleotide of the same composition, but containing four mismatches, was inactive. When chimeric antisense oligonucleotides were prehybridized with 17-mer oligoribonucleotides, extracts prepared from T24 cells, cytosol, and nuclei resulted in cleavage in the oligoribonucleotide gap. Both strands were cleaved. Neither mammalian nor Escherichia coli RNase HI cleaved the duplex, nor did single strand nucleases. The dsRNase activity resulted in cleavage products with 5'-phosphate and 3'-hydroxyl termini. Partial purification of dsRNase from rat liver cytosolic and nuclear fractions was effected. The cytosolic enzyme was purified approximately 165-fold. It has an approximate molecular weight of 50,000-65,000, a pH optimum of approximately 7.0, requires divalent cations, and is inactivated by approximately 300 mM NaCl. It is inactivated by heat, proteinase K, and also by a number of detergents and several organic solvents.


[Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy].
Gestational diabetes is considered as a carbohydrate intolerance, first diagnosed during pregnancy. A previous stage of carbohydrate impairement may precede its abnormality; therefore it may be convenient to establish some management in order to avoid the gestational diabetes. Six pregnant women who had moderate elevated level of blood glucose at fasting and postprandial were treated with acarbose, alpha-glucosidase inhibitor agent, given three times a day before meals. In all patients fasting and postprandial glucose levels were normalized; pregnancies went uneventful and the newborns were considered normal. Acarbose was associated with intestinal discomfort which persisted during the whole pregnancy.


Effects of pre-shipping marbofloxacin administration on fever and blood properties in healthy Thoroughbreds transported a long distance.
The present study evaluated the effects of single-dose marbofloxacin in protecting horses against fever associated with transportation using 48 healthy Thoroughbreds. All horses were premedicated with interferon-α (0.5 U/kg, sublingually, every 24 hr) for 2 days before transportation and on the day of transportation. Horses were randomly assigned to receive marbofloxacin (2 mg/kg, IV, once; MRFX group), enrofloxacin (5 mg/kg, IV, once; ERFX group) or saline (0.9% NaCl) solution (10 ml, IV, once; control group) ≤1 hr before being transportation. Each group contained 16 horses (8 males, 8 females). Horses were transported 1,210 km using commercial vans over the course of approximately 26 hr. Clinical examinations and hematologic analyses were performed on all horses both before and after transportation. Post-transportation neutrophil to lymphocyte ratios were significantly lower in horses in the MRFX group compared with the control horses. The serum amyloid A levels were significantly lower in horses in the MRFX group and ERFX group compared with the control horses. Regarding the post-transportation rectal temperatures, fever was detected in 0 horses and 1 horse in the MRFX and ERFX groups, respectively, whereas fevers exceeding 39.1°C were detected in 2 horses in the control group. Additionally, the number of essential post-transportation treatments provided by veterinarians was reduced 3-fold in the MRFX and ERFX groups compared with the saline group. MRFX provided ERFX-like protection against fever associated with long-distance transportation, yielding significantly better protection than saline. Administration of MRFX just before transportation deserves a further study for efficacy in preventing horse fever associated with transportation.


Hyperspectral imaging of atherosclerotic plaques in vitro.
Vulnerable plaques constitute a risk for serious heart problems, and are difficult to identify using existing methods. Hyperspectral imaging combines spectral- and spatial information, providing new possibilities for precise optical characterization of atherosclerotic lesions. Hyperspectral data were collected from excised aorta samples (n = 11) using both white-light and ultraviolet illumination. Single lesions (n = 42) were chosen for further investigation, and classified according to histological findings. The corresponding hyperspectral images were characterized using statistical image analysis tools (minimum noise fraction, K-means clustering, principal component analysis) and evaluation of reflectance/fluorescence spectra. Image analysis combined with histology revealed the complexity and heterogeneity of aortic plaques. Plaque features such as lipids and calcifications could be identified from the hyperspectral images. Most of the advanced lesions had a central region surrounded by an outer rim or shoulder-region of the plaque, which is considered a weak spot in vulnerable lesions. These features could be identified in both the white-light and fluorescence data. Hyperspectral imaging was shown to be a promising tool for detection and characterization of advanced atherosclerotic plaques in vitro. Hyperspectral imaging provides more diagnostic information about the heterogeneity of the lesions than conventional single point spectroscopic measurements.


Exudativory in the Bengal slow loris (Nycticebus bengalensis) in Trishna Wildlife Sanctuary, Tripura, northeast India.
In this study we estimated the extent of exudativory in Nycticebus bengalensis and examined whether exudates can be considered as fallback foods. This study was carried out in Trishna Wildlife Sanctuary, northeastern India, in winter (December-February) and summer (March and April). We estimated time-activity budget using instantaneous sampling and used continuous focal animal sampling to record all instances and durations of feeding, over a total of 177 hr. Feeding accounted for 22.3+/-2.2% of the activity budget, with no seasonal difference. Bengal slow lorises fed on exudates, nectar, fruit, bark, invertebrates and avian eggs. In addition to scraping they also obtained exudates by gouging holes into the bark of trees. In winter, lorises almost exclusively fed on exudates (94.3% of winter feeding time). In summer, exudates (67.3%) and nectar from one species (22.3%) dominated the diet. This study identifies the Bengal slow loris as the most exudativorous loris. Exudates rather than being a staple fallback food, seem to be a preferred, patchily distributed and common food in the diet of the Bengal slow loris. Exudativory in this species is characterized by high selectivity among species and seasonal variation, which may be related to variations in productivity of exudates and their chemical composition. An understanding of these factors is necessary for predicting the response of this species to human disturbance such as logging. This study also underscores the importance of protecting some of the common species such as Terminalia belerica on which the loris feeds during periods of scarcity.


Diagnosis and treatment of dermatofibrosarcoma protuberans. European consensus-based interdisciplinary guideline.
Dermatofibrosarcoma protuberans (DFSP) is a skin fibroblastic tumour that is locally aggressive, with a tendency for local recurrence, but rarely metastasizes. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on DFSP diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is suspected clinically and confirmed by pathology. Analysis by fluorescence in situ hybridisation (FISH) or multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) to detect specific chromosomal translocations and fusion gene transcripts is useful to confirm a difficult DFSP diagnosis. Treatment is mainly surgical, with the aim to achieve complete resection of the tumour. In order to reduce the recurrence rate, the treatment of choice of DFSP seems to be Mohs' micrographic surgery (MMS) and related variants. In hospitals where only standard histopathological procedures are available, standard excision with lateral safety margin of 3cm is advisable. Imatinib (Glivec®) is approved in Europe for the treatment of inoperable primary tumours, locally inoperable recurrent disease, and metastatic DFSP. Imatinib has also been given to patients with extensive, difficult-to-operate tumours for preoperative reduction of tumour size, but the usefulness of this attitude should be confirmed by clinical trials. Therapeutic decisions for patients with fibrosarcomatous DFSP should be primarily made by an interdisciplinary oncology team ('tumour board').


Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder.
Serotonergic antidepressants [selective serotonin reuptake inhibitor (SSRI)] are first-line treatments for generalised anxiety disorder (GAD); however, it is not known if synaptic serotonin (5-HT) availability is important for SSRI efficacy. The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion (ATD), would reverse the therapeutic effect of the SSRIs in GAD patients. Twelve patients (six males) with GAD, who showed sustained clinical improvement with SSRI treatment, underwent ATD in a double-blind, placebo-controlled, within-subjects design over 2 days, 1 week apart. At the peak time of depletion, the participants inhaled 7.5% CO2 and air in random order for at least 12 min each. Psychological responses were measured using the Spielberger State Anxiety Inventory (STAI-S) and GAD-symptom visual analogue scales (VASs; e.g., worry and tense) and Profile of Mood States. Free plasma tryptophan to large neutral amino acid (LNAA) ratio decreased by 92% on the depletion day and decreased by 2% on the control day. Irrespective of depletion condition, 7.5% CO(2) inhalation significantly increased STAI-S and GAD-related VAS scores (all p < 0.05) compared with air inhalation. ATD had no effect on any of these measures despite the substantial reduction in free tryptophan/LNAA ratio. Although SSRIs treat GAD effectively, the present results suggest that the mechanism of action is different to that seen in panic, social anxiety, and post-traumatic stress disorders. Successful SSRI treatment of GAD may involve long-term receptor changes or alterations in other neurotransmitter systems downstream of serotonin.


Diagnostic Performance of a Novel Noninvasive Workup in the Setting of Dry Eye Disease.
To evaluate the diagnostic performance of a novel noninvasive automated workup employed for the diagnosis of dry eye disease (DED). One hundred patients with mild to moderate DED and 100 matched control subjects were enrolled in this cross-sectional study. Ocular surface examinations were carried out by means of IDRA Plus (SBM Sistemi, Turin, Italy), which allows the automated evaluation of noninvasive breakup time (NIBUT), lipid layer thickness (LLT), tear meniscus height (TMH), infrared meibography for the measurement of meibomian gland loss (MGL), and blinking analysis. Continuous variables were compared between patients with DED and controls by using the Mann-Whitney U test. The area under the curve (AUC) of receiver operating characteristic curves was calculated. The correlations between ocular surface parameters were evaluated with Pearson correlation analysis. Patients with DED showed significantly lower values of NIBUT, LLT, and TMH compared to controls (6.9 ± 2.5 vs 10.4 ± 2.4 s, P < 0.001; 64.6 ± 20.3 vs 73.4 ± 21.9 nm, P = 0.003; 0.231 ± 0.115 vs 0.289 ± 0.164, P = 0.012, respectively). Conversely, no significant differences were observed for MGL and blinking analysis (both P > 0.05). NIBUT had the highest diagnostic power (AUC = 0.841, sensitivity = 0.89, and specificity = 0.69), followed by LLT (AUC = 0.621, sensitivity = 0.89, and specificity = 0.55), TMH (AUC = 0.606, sensitivity = 0.57, and specificity = 0.63), blink analysis (AUC = 0.533, sensitivity = 0.48, and specificity = 0.59), and MGL (AUC = 0.531, sensitivity = 0.54, and specificity = 0.48). In patients with DED, NIBUT showed a significant correlation with TMH (R = 0.347, P = 0.002) and blinking analysis (R = 0.356, P < 0.001), while blinking analysis was negatively correlated with MGL (R = -0.315, P = 0.008). The automated noninvasive workup validated in this study may be a useful tool for reaching a noninvasive diagnosis of DED with a good performance, especially for NIBUT.


Evaluation of Ad-BMP-2 for enhancing fracture healing in an infected defect fracture rabbit model.
The objective of this study was to evaluate the use of adenoviral transfer of the BMP-2 gene (Ad-BMP-2) for enhancing healing in an infected defect fracture model. A femoral defect stabilized with plates and screws was surgically created in sixty-four skeletally mature New Zealand white rabbits. Experimental groups were: (1) non-infected Ad-luciferase (Ad-LUC, NONLUC), (2) non-infected Ad-BMP-2 (NONBMP), (3) infected Ad-LUC (INFLUC), and (4) infected Ad-BMP-2 (INFBMP). A sclerosing agent was applied to the ends of the bone at surgery to facilitate the development of osteomyelitis. Fracture healing was evaluated radiographically and histologically. Data were analyzed using an ANOVA, with statistical significance set as p<0.05. Rabbits in the non-infected and infected groups that were treated with Ad-BMP-2 had earlier initial- and bridging-callus formation, and a higher overall external callus grade compared to rabbits in the Ad-LUC groups. Rabbits in the Ad-LUC groups had more defect ossification compared to rabbits in the Ad-BMP-2 groups. There was a trend for rabbits in the Ad-BMP-2 group that were euthanized at 2 and 4 weeks after surgery to have more bone and cartilage compared to rabbits in the Ad-LUC group. The results of this study suggest that Ad-BMP-2 enhances the early stages of healing in an infected defect fracture. The results of our study were not as favorable as those reported in previous studies because animals healed by a large bridging callus and not by defect ossification. This could have been a result of the sclerosing agent, which may have damaged the cells in the defect.


Carcinogenesis of the food mutagen PhIP in mice is independent of CYP1A2.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant of the heterocyclic amines found in cooked meat. Based on in vitro studies with rats and humans, CYP1A2 is believed to be the primary enzyme responsible for N(2)-hydroxylation, the initial step in the metabolic activation of PhIP. To determine whether CYP1A2 is the primary P450 responsible for metabolic activation of PhIP in mice that leads to tumor formation, neonatal Cyp1a2-null and wild-type mice were treated with approximately 11 (low dose) and approximately 22 (high dose) mg/kg PhIP at days 8 and 15, corresponding cumulatively to 600 and 1200 nmol PhIP, and analyzed at 19-21 months of age. Three major induced tumors were found; lymphomas and tumors in lung and liver. The incidence of lymphoma was higher in Cyp1a2-null females than wild-type females treated with low dose (600 nmol) PhIP whereas no significant differences were observed in other treatment groups of mice. Overall differences in incidences of lung adenoma/adenocarcinoma were in general not consistent among sexes, genotypes and PhIP doses used, although reduced incidences of lung tumors were found in Cyp1a2-null males with low dose (600 nmol) and null females with high dose (1200 nmol) PhIP. Higher incidences of hepatocellular adenoma were observed in Cyp1a2-null female and male mice as compared with wild-type mice. In vitro studies using Cyp1a2-null and wild-type mouse liver microsomes revealed that CYP1A2 is the major enzyme required for PhIP N2-hydroxylation in mouse, the initial metabolic activation of PhIP that is thought to lead to tumor formation. These in vivo and in vitro results suggest that although the metabolic activation of PhIP is carried out primarily by CYP1A2, an unknown pathway unrelated to CYP1A2 appears to be responsible for PhIP carcinogenesis in mouse when examined in the neonatal bioassay. In fact, CYP1A2 may even be protective against all transformation, especially in females.


Luminal lipid regulates CD36 levels and downstream signaling to stimulate chylomicron synthesis.
The membrane glycoprotein CD36 binds nanomolar concentrations of long chain fatty acids (LCFA) and is highly expressed on the luminal surface of enterocytes. CD36 deficiency reduces chylomicron production through unknown mechanisms. In this report, we provide novel insights into some of the underlying mechanisms. Our in vivo data demonstrate that CD36 gene deletion in mice does not affect LCFA uptake and subsequent esterification into triglycerides by the intestinal mucosa exposed to the micellar LCFA concentrations prevailing in the intestine. In rodents, the CD36 protein disappears early from the luminal side of intestinal villi during the postprandial period, but only when the diet contains lipids. This drop is significant 1 h after a lipid supply and associates with ubiquitination of CD36. Using CHO cells expressing CD36, it is shown that the digestion products LCFA and diglycerides trigger CD36 ubiquitination. In vivo treatment with the proteasome inhibitor MG132 prevents the lipid-mediated degradation of CD36. In vivo and ex vivo, CD36 is shown to be required for lipid activation of ERK1/2, which associates with an increase of the key chylomicron synthesis proteins, apolipoprotein B48 and microsomal triglyceride transfer protein. Therefore, intestinal CD36, possibly through ERK1/2-mediated signaling, is involved in the adaptation of enterocyte metabolism to the postprandial lipid challenge by promoting the production of large triglyceride-rich lipoproteins that are rapidly cleared in the blood. This suggests that CD36 may be a therapeutic target for reducing the postprandial hypertriglyceridemia and associated cardiovascular risks.


Circadian rhythmicity of the activity of hydroxyindole-O-methyl transferase (HIOMT) in the formation of melatonin and 5-methoxytryptophol in the pineal, retina, and harderian gland of the golden hamster.
The day and night rhythms in the activity of HIOMT in the formation of melatonin of 5-methoxytryptophol have been determined in the pineal, retina and Harderian gland of the adult male golden hamster. In all hamsters used there was no detectable HIOMT activity in the deep pineal. In the superficial pineal HIOMT activity, involved in the synthesis of melatonin (Mel), was observed to be high at the end of the dark period and at the middle of the light period. Considering the HIOMT activity involved in the production of 5-methoxytryptophol (5-MTL), an increase in 5-MTL synthesis was observed only during the light period. Comparing the peak of Mel-production with that of 5-MTL it appears that during the light period the pineal produces more 5-MTL than Mel. In the Harderian glands, the circadian course of HIOMT activity involved in the synthesis of Mel seems to run parallel to that of the enzyme implicated in 5-MTL synthesis, both being stimulated at the end of the dark period. The activity of HIOMT in 5-MTL production is, however, always approximately 2 times higher than for Mel synthesis. In the retina the synthesis of Mel and 5-MTL is not significantly higher during the dark period than during the light period. However, the production of 5-MTL is larger than that of Mel. It appears that (1) with the exception of the end of the dark period, the extra-pineal synthesis of Mel and 5-MTL is always higher than that in the pineal; (2) the carcadian synthesis of 5-methoxyindoles is different in each organ, and (3) in the pineal the carcadian activity of HIOMT involved in 5-MTL formation is different from that of the same enzyme involved in the formation of Mel. The results are discussed.


Liquid biopsy using the nanotube-CTC-chip: capture of invasive CTCs with high purity using preferential adherence in breast cancer patients.
In this paper, we report the development of the nanotube-CTC-chip for isolation of tumor-derived epithelial cells (circulating tumor cells, CTCs) from peripheral blood, with high purity, by exploiting the physical mechanisms of preferential adherence of CTCs on a nanotube surface. The nanotube-CTC-chip is a new 76-element microarray technology that combines carbon nanotube surfaces with microarray batch manufacturing techniques for the capture and isolation of tumor-derived epithelial cells. Using a combination of red blood cell (RBC) lysis and preferential adherence, we demonstrate the capture and enrichment of CTCs with a 5-log reduction of contaminating WBCs. EpCAM negative MDA-MB-231/luciferase-2A-green fluorescent protein (GFP) cells were spiked in the blood of wild mice and enriched using an RBC lysis protocol. The enriched samples were then processed using the nanotube-CTC-chip for preferential CTC adherence on the nanosurface and counting the GFP cells yielded anywhere from 89% to 100% capture from the droplets. Electron microscopy (EM) studies showed focal adhesion with filaments from the cell body to the nanotube surface. We compared the nanotube preferential adherence to collagen adhesion matrix (CAM) scaffolding, reported as a viable strategy for CTC capture in patients. The CAM scaffolding on the device surface yielded 50% adherence with 100% tracking of cancer cells (adhered vs. non-adhered) versus carbon nanotubes with >90% adherence and 100% tracking for the same protocol. The nanotube-CTC-chip successfully captured CTCs in the peripheral blood of breast cancer patients (stage 1-4) with a range of 4-238 CTCs per 8.5 ml blood or 0.5-28 CTCs per ml. CTCs (based on CK8/18, Her2, EGFR) were successfully identified in 7/7 breast cancer patients, and no CTCs were captured in healthy controls (n = 2). CTC enumeration based on multiple markers using the nanotube-CTC-chip enables dynamic views of metastatic progression and could potentially have predictive capabilities for diagnosis and treatment response.


Calcitonin levels in washout samples vs. cytology in the detection of malignant lymph node metastasis in recurrent medullary thyroid cancer
Calcitonin level in fine-needle aspirate washout fluid (Ct-FNA) was extensively studied for thyroid nodules and lymph nodes (LN). However, the data was scarce for neck recurrences/metastases of medullary thyroid cancer (MTC). Thus, the diagnostic accuracy of Ct-FNA and cytology in the detection of neck LN metastases of recurrent MTC cases were assessed. The database of MTC patients between 2010 and 2021 was retrospectively reviewed. A total of 32 patients with recurrent MTC and suspicious LN who underwent FNA and Ct measurement from washout samples were included in this study. Preoperative serum Ct (sCt), Ct-FNA, Ct-FNA/sCt ratio, cytology data were recorded for all participants. Median sCt of 32 patients and Ct-FNA washout fluid levels of operated suspicious 44 LNs were 723 (54–9000) pg/mL and 1800 (151–9500) pg/mL, respectively. The diagnostic accuracy of Ct-FNA washout fluid was greater than cytology (95.4% vs. 86%, respectively). Using a cut-off level of >638.5 pg/mL, the Ct-FNA predicted the diagnosis of LN metastasis of recurrent MTC with a sensitivity of 80% and specificity of 94.9%. Furthermore, using a cut-off level of >1.16, the Ct-FNA/sCt ratio well predicted the diagnosis of LN metastasis of recurrent MTC with a sensitivity of 92.3% and specificity of 100%. As Ct-FNA has greater diagnostic accuracy in our study, it would be complementary to cytology results to localize metastatic LNs in recurrent MTC. Furthermore, for the first time, we demonstrated that the Ct-FNA/sCt ratio was a better predictor of metastatic LNs in recurrent MTC than a particular cut-off for Ct-FNA alone.


In situ labeling of DNA reveals interindividual variation in nuclear DNA breakdown in hair and may be useful to predict success of forensic genotyping of hair.
Hair fibers are formed by keratinocytes of the hair follicle in a process that involves the breakdown of the nucleus including DNA. Accordingly, DNA can be isolated with high yield from the hair bulb which contains living keratinocytes, whereas it is difficult to prepare from the distal portions of hair fibers and from shed hair. Nevertheless, forensic investigations are successful in a fraction of shed hair samples found at crime scenes. Here, we report that interindividual differences in the completeness of DNA removal from hair corneocytes are major determinants of DNA content and success rates of forensic investigations of hair. Distal hair samples were permeabilized with ammonia and incubated with the DNA-specific dye Hoechst 33258 to label DNA in situ. Residual nuclear DNA was visualized under the fluorescence microscope. Hair from some donors did not contain any stainable nuclei, whereas hair of other donors contained a variable number of DNA-positive nuclear remnants. The number of DNA-containing nuclear remnants per millimeter of hair correlated with the amount of DNA that could be extracted and amplified by quantitative PCR. When individual hairs were investigated, only hairs in which DNA could be labeled in situ gave positive results in short tandem repeat typing. This study reveals that the completeness of DNA degradation during cornification of the hair is a polymorphic trait. Furthermore, our results suggest that in situ labeling of DNA in hair may be useful for predicting the probability of success of forensic analysis of nuclear DNA in shed hair.


Alteration of the cortisol-cortisone shuttle in leprosy type 1 reactions in leprosy patients in Hyderabad, India.
Regulation of inflammation in leprosy may be influenced by local concentrations of active cortisol and inactive cortisone, whose concentrations are regulated by enzymes in the cortisol-cortisone shuttle. We investigated the cortisol-cortisone shuttle enzymes in the skin of leprosy patients with type 1 reactions (T1R), which are characterised by skin and nerve inflammation. Gene expression of the shuttle enzymes were quantified in skin biopsies from 15 leprosy patients with new T1R before and during prednisolone treatment and compared with levels in skin biopsies from 10 borderline leprosy patients without reactions. Gene expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which converts cortisol to cortisone, is down-regulated in skin from T1R lesions. However expression levels of 11beta-HSD type 1, which converts cortisone to cortisol, were similar in skin with and without reactions and did not change during anti-leprosy drug treatment. Prednisolone treatment of patients with reactions is associated with an upregulation of 11beta-HSD2 expression in skin. The down regulation of 11beta-HSD2 at the beginning of a reaction may be caused by pro-inflammatory cytokines in the leprosy reactional lesion and may be a local attempt to down-regulate inflammation. However in leprosy reactions this local response is insufficient and exogenous steroids are required to control inflammation.


Agonist-mediated regulation of alpha 1- and beta 2-adrenergic receptors in cloned MDCK cells.
Chronic exposure of cells to neurotransmitters and hormones can result in a decrease in receptor number (down-regulation). We asked whether two different types of receptors on the same cell that can both respond to a particular hormone are identically regulated. For this study we used MDCK-D-1, a cloned renal epithelial cell line that coexpresses alpha 1- and beta 2-adrenergic receptors, as a model system in which to examine the effects of an adrenergic agonist on the expression and function of these receptors. MDCK-D-1 cells retain differentiated features of renal tubular epithelium with respect to morphology and hormonal responsiveness. When MDCK-D-1 cells were incubated for 21 h with 100 microM epinephrine, alpha 1- and beta 2-receptor numbers decreased by 81 and 90%, respectively. The down-regulation of beta 2-receptors proceeded more rapidly than that of alpha 1-receptors. Down-regulated cells showed a greater than 80% loss of both alpha 1- and beta 2-adrenergic responses (alpha 1: stimulation of prostaglandin E2 release; beta 2: elevation of adenosine 3',5'-cyclic monophosphate levels). We conclude that in renal epithelial cells chronic exposure to a catecholamine agonist can result in a profound decrease in the number of alpha 1- and beta 2-receptors, this down-regulation is accompanied by a loss of adrenergic response, and the kinetics of receptor loss are different for alpha 1- and beta 2-receptors.


The use of a systemic therapy checklist improves the quality of data acquisition and recording in multicentre trials. A study of the EORTC Soft Tissue and Bone Sarcoma Group.
The aim of this study was to verify whether the introduction of a systemic therapy checklist in the performance of multinational multicentre studies improves the quality of data acquisition and recording. We retrospectively analysed the results obtained through the use of this checklist in a study of the EORTC Soft Tissue and Bone Sarcoma Group. During the clinical trial, data were recorded in the hospital record with optional use of a predesigned EORTC Systemic Therapy Checklist. After completion of the study, 11 centres were monitored for the use of this checklist. Monitors were highly experienced medical oncologists. Items checked included all aspects of patient eligibility, drug administration, biochemical and haematological values, variables related to toxicities of treatment and response parameters. Data of 183 cycles given to 51 patients were checked. A total of 8983 items were checked. 91% of the data was reported correctly, 1% was missing and 6% was reported on the case record from (CRF) but could not be retrieved in the hospital record file. Compared with data obtained before the introduction of the checklist (68% correct, 4% incorrect, 0.1% missing and 28% on CRF but not in hospital files), these results show marked improvement generally. In centres where no Systemic Therapy Checklist was used, 85.9% of data were correct 2.8% incorrect, 0.7% missing and 10.6% only on CRF, which compares unfavourably with those where the Systemic Checklist was completely used (97.7% correct, 0.7% incorrect, 1% missing, 0.6% only on CRF). In addition the time required for data checking largely decreased by the use of the checklist-without this, a median of 3.5 cycles could be checked per hour, whilst if the checklist was used, this number increased to 6.5 cycles per hour. The use of a Systemic Therapy Checklist as an integral part of the hospital file for data recording in multicentre multinational trials is highly recommended and leads to a major improvement in data quality.


Effect of feeding rolled flaxseed on milk fatty acid profiles and reproductive performance of dairy cows.
The objectives were to study the effects of feeding rolled flaxseed (FLX) to early-lactation dairy cows on milk yield, milk components, and milk fatty acid profiles as well as on measures of cow reproduction. Lactating Holstein cows, on 3 commercial dairies, were fed either an early-lactation ration (CON) or a ration that was similar in protein, energy, and fat content but that included FLX (0.85 kg of DM/cow per day). Within each dairy, cows were allocated alternately to breeding pens upon leaving the fresh pen (approximately 10 ± 5 d postpartum). Pens (n = 4 to 5 pens/dairy) were randomized to treatment (n = 2 to 3 pens/treatment per dairy). Pen (CON, n = 6; FLX, n = 7) was considered the experimental unit and data were analyzed as a split plot with pen as the whole-plot error term. Cows fed FLX had greater (P ≤ 0.06) proportions of cis-9, trans-11 C18:2, C18:3n-3, and C20:0 fatty acids in milk fat and a lesser (P = 0.03) proportion of C20:3n-6 fatty acid when compared with cows fed the CON diet. Treatment did not affect (P ≥ 0.24) milk yield, milk protein, protein yield, milk fat, or milk fat yield. No interactions (P ≥ 0.52) were found between treatment and season of the year or parity, or between treatment and days open, pregnancies per AI at first or second service, or pregnancy loss. In conclusion, feeding FLX at 0.85 kg/cow per day (DM basis) altered the fatty acid profile of milk, but milk yield, milk composition, and reproductive performance of dairy cows were not affected.


Risk factors at pretreatment predicting treatment-induced nausea and vomiting in Australian cancer patients: a prospective, longitudinal, observational study.
Despite significant advances in antiemetic management, almost 50% of cancer patients still experience nausea and vomiting during treatment. The goal of antiemetic therapy is complete prevention of treatment-induced nausea and/or vomiting (TINV); however, realisation of this goal remains elusive, thus supplementary strategies identifying patients at high risk must be employed in the interim. Consequently, we examined TINV incidence and its risk factors, including patient, clinical and pretreatment quality of life (QOL)/psychological factors. Two hundred newly diagnosed cancer patients beginning combined treatment participated in this prospective, longitudinal, observational study. QOL (including TINV), psychological adjustment, and patient/clinical characteristics were examined at pretreatment, on-treatment (8 weeks ± 1 week) and post-treatment. Overall, 62% of patients experienced TINV, with TIN incidence (60%) doubling that of TIV (27%). Eight independent risk factors predicted 73% of TIN incidence: high premorbid/anticipatory NV, moderately/highly emetogenic chemotherapy (M/HEC), longer treatment (>3 months), female gender, surgery prior to adjuvant chemotherapy ± radiotherapy, private health insurance and low emotional functioning (pretreatment). Six independent risk factors predicted 77% of TIV incidence: premorbid/anticipatory vomiting, M/HEC, female gender, cancer resection and low role functioning (pretreatment). TINV still represents a very major concern for patients. Several pretreatment risk factors for the development of TIN and TIV, respectively, were identified. Patients about to undergo cancer treatment, particularly combined treatment involving emetogenic chemotherapy and surgery, should be screened for these factors with a view to modifying standard pretreatment/maintenance antiemetic therapy. Furthermore, and consistent with recent research, it is recommended that more comprehensive interventions combining antiemetics with other effective pharmacological (e.g. anxiolytics) and non-pharmacological approaches (e.g. acupuncture, relaxation techniques) be considered by clinicians in attempts to improve control of TIN and TIV (and overall QOL) for their patients. In this way, optimal holistic care will be ensured for cancer patients by clinicians providing conventional oncology treatment.


Residential Water Meters as Edge Computing Nodes: Disaggregating End Uses and Creating Actionable Information at the Edge.
We present a new, open source, computationally capable datalogger for collecting and analyzing high temporal resolution residential water use data. Using this device, execution of water end use disaggregation algorithms or other data analytics can be performed directly on existing, analog residential water meters without disrupting their operation, effectively transforming existing water meters into smart, edge computing devices. Computation of water use summaries and classified water end use events directly on the meter minimizes data transmission requirements, reduces requirements for centralized data storage and processing, and reduces latency between data collection and generation of decision-relevant information. The datalogger couples an Arduino microcontroller board for data acquisition with a Raspberry Pi computer that serves as a computational resource. The computational node was developed and calibrated at the Utah Water Research Laboratory (UWRL) and was deployed for testing on the water meter for a single-family residential home in Providence City, UT, USA. Results from field deployments are presented to demonstrate the data collection accuracy, computational functionality, power requirements, communication capabilities, and applicability of the system. The computational node's hardware design and software are open source, available for potential reuse, and can be adapted to specific research needs.