Cognitive-motivational deficits in ADHD: development of a classification system.
The classification systems developed so far to detect attention deficit/hyperactivity disorder (ADHD) do not have high sensitivity and specificity. We have developed a classification system based on several neuropsychological tests that measure cognitive-motivational functions that are specifically impaired in ADHD children. A total of 240 (120 ADHD children and 120 healthy controls) children in the age range of 6-9 years and 32 Oppositional Defiant Disorder (ODD) children (aged 9 years) participated in the study. Stop-Signal, Task-Switching, Attentional Network, and Choice Delay tests were administered to all the participants. Receiver operating characteristic (ROC) analysis indicated that percentage choice of long-delay reward best classified the ADHD children from healthy controls. Single parameters were not helpful in making a differential classification of ADHD with ODD. Multinominal logistic regression (MLR) was performed with multiple parameters (data fusion) that produced improved overall classification accuracy. A combination of stop-signal reaction time, posterror-slowing, mean delay, switch cost, and percentage choice of long-delay reward produced an overall classification accuracy of 97.8%; with internal validation, the overall accuracy was 92.2%. Combining parameters from different tests of control functions not only enabled us to accurately classify ADHD children from healthy controls but also in making a differential classification with ODD. These results have implications for the theories of ADHD.


Interface Adhesion and Structural Characterization of Rolled-up GaAs/In0.2Ga0.8As Multilayer Tubes by Coherent Phonon Spectroscopy.
We present a detailed experimental and theoretical study of the acoustic phonon modes in rolled-up multilayers with thickness of the layers in the nanometre and diameters in the micrometre range. We compare our results to planar, unrolled multilayers grown by molecular beam epitaxy. For the planar multilayers the experimentally obtained acoustic modes exhibit properties of a superlattice and match well to calculations obtained by the Rytov model. The rolled-up superlattice tubes show intriguing differences compared to the planar structures which can be attributed to the imperfect adhesion between individual tube windings. A transfer matrix method including a massless spring accounting for the imperfect adhesion between the layers yields good agreement between experiment and calculations for up to five windings. Areas with sufficient mechanical coupling between all windings can be distinguished by their acoustic mode spectrum from areas where individual windings are only partially in contact. This allows the spatially resolved characterization of individual tubes with micrometre spatial resolution where areas with varying interface adhesion can be identified.


The efficacy of transbronchial indocyanine green instillation for fluorescent-guided wedge resection.
The purpose of this study was to investigate the feasibility of lung wedge resection by combining 3-dimensional (3D) image analysis with transbronchial indocyanine green (ICG) instillation, in order to delineate the intended area for resection. From December 2017 to July 2020, 28 patients undergoing wedge resection (17 primary lung cancers, 11 metastatic lung tumours) were enrolled, and fluorescence-guided wedge resection was attempted. Virtual sublobar resections were created preoperatively for each patient using a 3D Image Analyzer. Surgical margins were measured in each sublobar resection simulation in order to select the most optimal surgical resection area. After transbronchial instillation of ICG, near-infrared thoracoscopic visualization allowed matching of the intended area for resection to the virtual sublobar resection area. To investigate the effectiveness of ICG instillation, the clarity of the ICG-florescent border was evaluated, and the distance from the true tumour to the surgical margins was compared to that of simulation. Mean tumour diameter was 12.4 ± 4.3 mm. The entire targeted tumour was included in resected specimens of all patients (100% success rate). The shortest distances to the surgical margin via 3D simulation and by actual measurement of the specimen were11.4 ± 5.4 and 12.2 ± 4.1 mm, respectively (P = 0.285) and were well correlated (R2 = 0.437). While all specimens had negative malignant cells at the surgical margins, one loco-regional recurrence was observed secondary to the dissemination of neuroendocrine carcinoma. ICG-guided lung wedge resection after transbronchial ICG instillation and preoperative 3D image analysis allow for adequate negative surgical margins, providing decreased risk of local recurrence.


A microfluidic chip for controlled release of drugs from microcapsules.
A new microfluidic device with liquid-droplet merging and droplet storage functions for the controlled release of drugs from microcapsules is reported. A switching channel is designed and integrated within the microfluidic device, facilitating the generation and capturing of uniform droplets by the storage chambers. The drug model is the MnCO3 microparticle, which is encapsulated by a microcapsule and fabricated using a simple layer-by-layer nanoassembly process. The merging function is used for dynamically adding the control solution into the droplets, which contain drugs within the microcapsules (DWμCs) and water. The storage chambers are used for collecting DWμCs-laden droplets so that the controlled-drug release in specific droplets can be monitored for an extended period of time, which has been experimentally implemented successfully. This technology could offer a promising technical platform for the long-term observation and studies of drug effects on specific cells in a controlled manner, which is especially useful for single cell analysis.


Application of Fluorescence In Situ Hybridization (FISH) Technique for the Detection of Genetic Aberration in Medical Science.
Fluorescence in situ hybridization (FISH) is a macromolecule recognition technique, which is considered as a new advent in the field of cytology. Initially, it was developed as a physical mapping tool to delineate genes within chromosomes. The accuracy and versatility of FISH were subsequently capitalized upon in biological and medical research. This visually appealing technique provides an intermediate degree of resolution between DNA analysis and chromosomal investigations. FISH consists of a hybridizing DNA probe, which can be labeled directly or indirectly. In the case of direct labeling, fluorescent nucleotides are used, while indirect labeling is incorporated with reporter molecules that are subsequently detected by fluorescent antibodies or other affinity molecules. FISH is applied to detect genetic abnormalities that include different characteristic gene fusions or the presence of an abnormal number of chromosomes in a cell or loss of a chromosomal region or a whole chromosome. It is also applied in different research applications, such as gene mapping or the identification of novel oncogenes. This article reviews the concept of FISH, its application, and its advantages in medical science.


An extinction scale-expansion unit for the Beckman DK2 spectrophotometer.
The paper describes a simple but accurate unit for the Beckman DK2 recording spectrophotometer, whereby any 0.1 section of the extinction (;absorbance') scale may be expanded tenfold, while preserving complete linearity in extinction.


Acute basilar artery occlusion: Endovascular Interventions versus Standard Medical Treatment (BEST) Trial-Design and protocol for a randomized, controlled, multicenter study.
Rationale Endovascular treatment plus standard medical therapy is superior to standard medical therapy alone for acute anterior proximal intracranial large artery occlusion strokes. The benefit of endovascular treatment in acute ischemic stroke caused by basilar artery occlusion remains unproven. Aim This study compares the safety and efficacy of endovascular treatment plus standard medical therapy versus standard medical therapy alone in acute ischemic stroke due to basilar artery occlusion. Design The study is a multicenter randomized control trial with blinded outcome assessment. A projected total 344 subjects with acute basilar arterial occlusion within 8 h of estimated occlusion time will be enrolled over three years in China. Patients will be assigned to endovascular treatment plus standard medical therapy and standard medical therapy alone group in 1:1 ratio for study centers. Study outcomes The primary outcome measure is a favorable functional outcome, defined as a modified Rankin Score of 0-3 at 90 days. The primary safety measure is mortality at 90 days. Trial registration ClinicalTrials.gov (NCT 02441556). Summary The BEST trial will provide valuable insights into the safety and efficacy of endovascular treatment for acute ischemic stroke patients with basilar artery occlusion.


Genetic structure and diversity of cultivated soybean (Glycine max (L.) Merr.) landraces in China.
The Chinese genebank contains 23,587 soybean landraces collected from 29 provinces. In this study, a representative collection of 1,863 landraces were assessed for genetic diversity and genetic differentiation in order to provide useful information for effective management and utilization. A total of 1,160 SSR alleles at 59 SSR loci were detected including 97 unique and 485 low-frequency alleles, which indicated great richness and uniqueness of genetic variation in this core collection. Seven clusters were inferred by STRUCTURE analysis, which is in good agreement with a neighbor-joining tree. The cluster subdivision was also supported by highly significant pairwise Fst values and was generally in accordance with differences in planting area and sowing season. The cluster HSuM, which contains accessions collected from the region between 32.0 and 40.5 degrees N, 105.4 and 122.2 degrees E along the central and downstream parts of the Yellow River, was the most genetically diverse of the seven clusters. This provides the first molecular evidence for the hypotheses that the origin of cultivated soybean is the Yellow River region. A high proportion (95.1%) of pairs of alleles from different loci was in LD in the complete dataset. This was mostly due to overall population structure, since the number of locus pairs in LD was reduced sharply within each of the clusters compared to the complete dataset. This shows that population structure needs to be accounted for in association studies conducted within this collection. The low value of LD within the clusters can be seen as evidence that much of the recombination events in the past have been maintained in soybean, fixed in homozygous self-fertilizing landraces.


Evaluation of survival extrapolation in immuno-oncology using multiple pre-planned data cuts: learnings to aid in model selection.
Due to limited duration of follow up in clinical trials of cancer treatments, estimates of lifetime survival benefits are typically derived using statistical extrapolation methods. To justify the method used, a range of approaches have been proposed including statistical goodness-of-fit tests and comparing estimates against a previous data cut (i.e. interim data collected). In this study, we extend these approaches by presenting a range of extrapolations fitted to four pre-planned data cuts from the JAVELIN Merkel 200 (JM200) trial. By comparing different estimates of survival and goodness-of-fit as JM200 data mature, we undertook an iterative process of fitting and re-fitting survival models to retrospectively identify early indications of likely long-term survival. Standard and spline-based parametric models were fitted to overall survival data from each JM200 data cut. Goodness-of-fit was determined using an assessment of the estimated hazard function, information theory-based methods and objective comparisons of estimation accuracy. Best-fitting extrapolations were compared to establish which one provided the most accurate estimation, and how statistical goodness-of-fit differed. Spline-based models provided the closest fit to the final JM200 data cut, though all extrapolation methods based on the earliest data cut underestimated the 'true' long-term survival (difference in restricted mean survival time [RMST] at 36 months: - 1.1 to - 0.5 months). Goodness-of-fit scores illustrated that an increasingly flexible model was favored as data matured. Given an early data cut, a more flexible model better aligned with clinical expectations could be reasonably justified using a range of metrics, including RMST and goodness-of-fit scores (which were typically within a 2-point range of the statistically 'best-fitting' model). Survival estimates from the spline-based models are more aligned with clinical expectation and provided a better fit to the JM200 data, despite not exhibiting the definitively 'best' statistical goodness-of-fit. Longer-term data are required to further validate extrapolations, though this study illustrates the importance of clinical plausibility when selecting the most appropriate model. In addition, hazard-based plots and goodness-of-fit tests from multiple data cuts present useful approaches to identify when a more flexible model may be advantageous. JAVELIN Merkel 200 was registered with ClinicalTrials.gov as NCT02155647 on June 4, 2014.


[Treatment results of treatment for congenital, unilateral microcoria and pupil displacement--case report].
The purpose of this report was to present rarely occurring developmental anomaly of congenital unilateral microcoria and pupil displacement. We present a case of a boy, who underwent a plastic surgery of pupil at age of 3 year. Despite of relatively tardy onset of treatment and existing profound amblyopia (light perception with projection), a full vision recovery was achieved after 4 years of occlusion therapy.


Lateralization of weight in the presence of structural short leg: a preliminary report.
Previous research has reported upon the use of a radiographic method to determine the presence of structural short leg using full spine radiography. In the current study, ninety-two (92) freshman students at the National College of Chiropractic in Lombard, Illinois were first measured for the presence of structural short leg and then placed on a modified Janse-Illi four quadrant weight scale. Measurements of weight were taken at fifteen, thirty, forty-five and sixty seconds. Precise placement of the feet were used. The data collected in kilograms of weight was then converted to total force in Newtons, and the data was normalized as percentage of total body weight. This was then compared to the side of structural short leg. Certain trends have tended to appear. Those subjects with small leg length differential had a greater tendency to bear weight upon the homolateral side of short leg, while those with greater degree of short leg (six millimeters or more) tended to bear weight upon the contralateral leg. It is felt that this is so due to a compensatory mechanism involving the gluteus medius muscle in its use as a "tie-rod" for pelvic function. The greater the degree of short leg, the more the gluteus medius is needed to level the pelvis, and thus the greater shift of body weight to the contralateral side. With a small leg length differential the compensatory mechanism is believed not to be activated, and thus weight bearing will occur on the homolateral side.(ABSTRACT TRUNCATED AT 250 WORDS)


Application value of joint STOP-Bang questionnaire and Epworth Sleepiness Scale in screening for obstructive sleep apnea.
This paper evaluates the application value of the STOP-Bang questionnaire combined with the Epworth Sleepiness Scale (ESS) in screening for obstructive sleep apnea (OSA) in the population. Thousand-six hundred seventy-one patients with suspected OSA who visited the Sleep Medicine Center of the First Affiliated Hospital of Guangzhou Medical University from August 2017 to August 2020 were monitored by overnight polysomnography (PSG) after completing the ESS scale and STOP-Bang questionnaire. The sensitivity, specificity, positive predictive value, negative predictive value and receiver operating characteristic (ROC) curves of the two scales were calculated, and the accuracy in predicting OSA of the STOP-Bang questionnaire combined with ESS was analyzed. With Apnea Hypopnea Index (AHI) cutoffs of ≥5, ≥15 and ≥30 events/h, the areas under the ROC curve scored by STOP-Bang were 0.724, 0.703 and 0.712, and those of ESS were 0.632, 0.634 and 0.695; the diagnostic odds ratio (DOR) values of STOP-Bang for OSA, moderate to severe OSA, and severe OSA were 3.349, 2.651 and 3.189, and those of ESS were 2.665, 2.279 and 3.289. The STOP-Bang score of three was used as the cut-off point for OSA diagnosis with higher sensitivity and lower specificity, while ESS had higher specificity. STOP-Bang (≥3) combined with ESS significantly improved its specificity for predicting OSA. The STOP-Bang questionnaire is a simple and effective new tool for screening patients for OSA, while a STOP-Bang score of ≥3 combined with ESS can further improve its specificity. Thus, we suggest further screening with ESS after a STOP-Bang score of ≥3 in suspected patients.


A class III myosin expressed in the retina is a potential candidate for Bardet-Biedl syndrome.
Class III myosins are actin-based motors with amino-terminal kinase domains. Expression of these motors is highly enhanced in retinal photoreceptors. As mutations in the gene encoding NINAC, a Drosophila melanogaster class III myosin, cause retinal degeneration, human homologs of this gene are potential candidates for human retinal disease. We have recently reported the cloning of MYO3A, a human myosin III expressed predominantly in the retina and retinal pigmented epithelium [1]. The map locus of MYO3A is close to, but does not overlap, that of human Usher's 1F [2]. Here we introduce a shorter class III myosin isoform, MYO3B, which is expressed in the retina, kidney, and testis. We describe the cDNA sequence, genomic organization, and splice variants of MYO3B expressed in the human retina. A product of 36 exons, MYO3B has several splice variants containing either one or two calmodulin binding (IQ) motifs in the neck domain and one of three predominant tail variations: a short tail ending just past the second IQ motif, or two alternatively spliced longer tails. MYO3B maps to 2q31.1-q31.2, a region that overlaps the locus for a Bardet-Biedl syndrome (BBS5) linked to markers at 2q31 [3].


Spatial analysis of soil organic carbon in Zhifanggou catchment of the Loess Plateau.
Soil organic carbon (SOC) reflects soil quality and plays a critical role in soil protection, food safety, and global climate changes. This study involved grid sampling at different depths (6 layers) between 0 and 100 cm in a catchment. A total of 1282 soil samples were collected from 215 plots over 8.27 km(2). A combination of conventional analytical methods and geostatistical methods were used to analyze the data for spatial variability and soil carbon content patterns. The mean SOC content in the 1282 samples from the study field was 3.08 g · kg(-1). The SOC content of each layer decreased with increasing soil depth by a power function relationship. The SOC content of each layer was moderately variable and followed a lognormal distribution. The semi-variograms of the SOC contents of the six different layers were fit with the following models: exponential, spherical, exponential, Gaussian, exponential, and exponential, respectively. A moderate spatial dependence was observed in the 0-10 and 10-20 cm layers, which resulted from stochastic and structural factors. The spatial distribution of SOC content in the four layers between 20 and 100 cm exhibit were mainly restricted by structural factors. Correlations within each layer were observed between 234 and 562 m. A classical Kriging interpolation was used to directly visualize the spatial distribution of SOC in the catchment. The variability in spatial distribution was related to topography, land use type, and human activity. Finally, the vertical distribution of SOC decreased. Our results suggest that the ordinary Kriging interpolation can directly reveal the spatial distribution of SOC and the sample distance about this study is sufficient for interpolation or plotting. More research is needed, however, to clarify the spatial variability on the bigger scale and better understand the factors controlling spatial variability of soil carbon in the Loess Plateau region.


Outcomes of Pain Management Training for the Fourth- and Fifth-Year Medical Students.
Pain management is a major medical issue. However, current medical education in Japan is inadequate with regard to training students to properly assess patients with acute and chronic pain and plan their treatment. Therefore, starting in 2019, Hyogo Medical University established a multidisciplinary educational system to better train medical students to provide pain care. The course, called clinical pain study, is offered to fourth- and fifth-year medical students. Fourth-year students learn the scientific aspects of pain through clinical practice. In this study, we assessed students' understanding of pain management based on the results of pretests and posttests performed before and after their practicum. These tests were administered from November 2019 to April 2022 to 263 fourth- and fifth-year medical students who took the clinical pain study class. The test results were compared in terms of the percentage of correct answers and the total score for each question using McNemar's chi-square test and paired t-tests, respectively. The results showed a significant improvement in the mean of the total score, confirming the improvement in medical students' knowledge (6.43 vs. 7.35 points; p < 0.001). Based on the results, overall, pain education at the university has had positive outcomes and will therefore be continued in the future.


Trends in Gastric Cancer Incidence According to the Clinicopathological Characteristics in Korea, 1999-2014.
The aim of this study was to evaluate recent trends in gastric cancer incidence according to the age, sex, and tumor location in the Korean population. Using data from the Korea Central Cancer Registry between 1999 and 2014, gastric cancer incidence, annual percent changes, and male-to-female incidence rate ratios (IRRs) according to tumorlocationwere determined. The distribution of disease extent according to the tumor location and its changes between 2006 and 2014 were also analyzed. Incidence of gastric cancer was stable until 2011 and decreased between 2011 and 2014. The age-standardized incidence rate of gastric cancer was 43.6 (per 100,000) in 1999 and 35.8 in 2014. The proportion of cardia/fundus cancer remained stable (5.9% to 7.1%), and that of body cancer increased (35.3% to 43.2%). The male-to-female IRR decreased in most age groups, except for those in their 60s. In the distribution of disease extent, the proportion of localized disease increased, and regional and distant disease decreased in all tumor locations (53.9% to 66.0%, 31.4% to 22.5%, and 14.8% to 11.5%, respectively; p < 0.001). For histological type, the proportion of carcinoid tumor and non-epithelial tumor increased (0.3% to 1.0%, and 0.8% to 1.4%, respectively). In the 15 years from 1999 through 2014, age-standardized incidence of gastric cancer started to decrease from 2012, and the proportion of cardia/fundus cancer remained unchanged. The trend of increasing localized cancer was observed in all tumor locations.


Symplectic Gaussian process regression of maps in Hamiltonian systems.
We present an approach to construct structure-preserving emulators for Hamiltonian flow maps and Poincaré maps based directly on orbit data. Intended applications are in moderate-dimensional systems, in particular, long-term tracing of fast charged particles in accelerators and magnetic plasma confinement configurations. The method is based on multi-output Gaussian process (GP) regression on scattered training data. To obtain long-term stability, the symplectic property is enforced via the choice of the matrix-valued covariance function. Based on earlier work on spline interpolation, we observe derivatives of the generating function of a canonical transformation. A product kernel produces an accurate implicit method, whereas a sum kernel results in a fast explicit method from this approach. Both are related to symplectic Euler methods in terms of numerical integration but fulfill a complementary purpose. The developed methods are first tested on the pendulum and the Hénon-Heiles system and results compared to spectral regression of the flow map with orthogonal polynomials. Chaotic behavior is studied on the standard map. Finally, the application to magnetic field line tracing in a perturbed tokamak configuration is demonstrated. As an additional feature, in the limit of small mapping times, the Hamiltonian function can be identified with a part of the generating function and thereby learned from observed time-series data of the system's evolution. For implicit GP methods, we demonstrate regression performance comparable to spectral bases and artificial neural networks for symplectic flow maps, applicability to Poincaré maps, and correct representation of chaotic diffusion as well as a substantial increase in performance for learning the Hamiltonian function compared to existing approaches.


Computing autocatalytic sets to unravel inconsistencies in metabolic network reconstructions.
Genome-scale metabolic network reconstructions have been established as a powerful tool for the prediction of cellular phenotypes and metabolic capabilities of organisms. In recent years, the number of network reconstructions has been constantly increasing, mostly because of the availability of novel (semi-)automated procedures, which enabled the reconstruction of metabolic models based on individual genomes and their annotation. The resulting models are widely used in numerous applications. However, the accuracy and predictive power of network reconstructions are commonly limited by inherent inconsistencies and gaps. Here we present a novel method to validate metabolic network reconstructions based on the concept of autocatalytic sets. Autocatalytic sets correspond to collections of metabolites that, besides enzymes and a growth medium, are required to produce all biomass components in a metabolic model. These autocatalytic sets are well-conserved across all domains of life, and their identification in specific genome-scale reconstructions allows us to draw conclusions about potential inconsistencies in these models. The method is capable of detecting inconsistencies, which are neglected by other gap-finding methods. We tested our method on the Model SEED, which is the largest repository for automatically generated genome-scale network reconstructions. In this way, we were able to identify a significant number of missing pathways in several of these reconstructions. Hence, the method we report represents a powerful tool to identify inconsistencies in large-scale metabolic networks. The method is available as source code on http://users.minet.uni-jena.de/∼m3kach/ASBIG/ASBIG.zip. email@example.com Supplementary data are available at Bioinformatics online.


[Lifestyle, nutrition and oral health].
Diet and nutrition play a fundamental role in general health and oral health in children and adults. Dietary guidelines have been developed to provide evidence-based recommendations for populations promoting a diet that meets the best nutritional requirements and prevents diet-related diseases such as overweight, obesity, diabetes and dental caries. Lifestyle and dietary habits are strongly influenced by the (social) media and the products on offer in the supermarkets. Knowledge of the field of the development of foodstuffs and lifestyle trends contributes to effective, appropriate and individualised advice for a healthy mouth in children. Sugar-free flavoured waters with aroma are a good alternative to fizzy drinks, they are tooth friendly and promote a healthy weight.


Never in neutral: a systems biology and evolutionary perspective on how aneuploidy contributes to human diseases.
Whereas germline-inherited whole-chromosome aneuploidy has long been known to cause miscarriages and developmental abnormalities, somatically acquired aneuploidies have been observed in cancer cells and more recently also in cells of the normal liver and brain. Furthermore, aneuploidy is being increasingly reported in clinical isolates of pathogenic microbes such as fungi and parasites. Whereas many efforts have been devoted to the dissection of the molecular mechanisms that lead to aneuploidy, we have only recently started to investigate how aneuploidy alters the phenotypic makeup of a cell. Here we review recent evidence supporting the idea that aneuploidy is a large-effect mutation that introduces large changes in the cellular phenome. From a systems biology perspective, this can be explained by the extensive changes that aneuploidy brings about in both the transcriptome and the proteome of a cell. We further provide an evolutionary perspective on how aneuploidy-induced phenotypic variation may contribute to the exacerbation of human pathologies such as cancer and infectious diseases, by conferring selectable traits such as increased virulence and drug resistance.


Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction.
Age-related macular degeneration is the most common form of legal blindness in westernized societies, and polymorphisms in the gene encoding complement factor H (CFH) are associated with susceptibility to age-related macular degeneration in more than half of affected individuals. To investigate the relationship between complement factor H (CFH) and retinal disease, we performed functional and anatomical analysis in 2-year-old CFH-deficient (cfh(-/-)) mice. cfh(-/-) animals exhibited significantly reduced visual acuity and rod response amplitudes on electroretinography compared with age-matched controls. Retinal imaging by confocal scanning laser ophthalmoscopy revealed an increase in autofluorescent subretinal deposits in the cfh(-/-) mice, whereas the fundus and vasculature appeared normal. Examination of tissue sections showed an accumulation of complement C3 in the neural retina of the cfh(-/-) mice, together with a decrease in electron-dense material, thinning of Bruch's membrane, changes in the cellular distribution of retinal pigment epithelial cell organelles, and disorganization of rod photoreceptor outer segments. Collectively, these data show that, in the absence of any specific exogenous challenge to the innate immune system, CFH is critically required for the long-term functional health of the retina.


Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: a multicentre cohort study.
Prevalence estimates for monoclonal gammopathy of undetermined significance (MGUS) are based on predominantly White study populations screened by serum protein electrophoresis supplemented with immunofixation electrophoresis. A prevalence of 3% is reported for MGUS in the general population of European ancestry aged 50 years or older. MGUS prevalence is two times higher in individuals of African descent or with a family history of conditions related to multiple myeloma. We aimed to evaluate the prevalence and clinical implications of monoclonal gammopathies in a high-risk US population screened by quantitative mass spectrometry. We used quantitative matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry and EXENT-iQ software to screen for and quantify monoclonal gammopathies in serum from 7622 individuals who consented to the PROMISE screening study between Feb 26, 2019, and Nov 4, 2021, and the Mass General Brigham Biobank (MGBB) between July 28, 2010, and July 1, 2021. M-protein concentrations at the monoclonal gammopathy of indeterminate potential (MGIP) level were confirmed by liquid chromatography mass spectrometry testing. 6305 (83%; 2211 from PROMISE, 4094 from MGBB) of 7622 participants in the cohorts were at high risk for developing a monoclonal gammopathy on the basis of Black race or a family history of haematological malignancies and fell within the eligible high-risk age range (30 years or older for PROMISE cohort and 18 years or older for MGBB cohort); those over 18 years were also eligible if they had two or more family members with a blood cancer (PROMISE cohort). Participants with a plasma cell malignancy diagnosed before screening were excluded. Longitudinal clinical data were available for MGBB participants with a median follow-up time from serum sample screening of 4·5 years (IQR 2·4-6·7). The PROMISE study is registered with ClinicalTrials.gov, NCT03689595. The median age at time of screening was 56·0 years (IQR 46·8-64·1). 5013 (66%) of 7622 participants were female, 2570 (34%) male, and 39 (<1%) unknown. 2439 (32%) self-identified as Black, 4986 (65%) as White, 119 (2%) as other, and 78 (1%) unknown. Using serum protein electrophoresis with immunofixation electrophoresis, the MGUS prevalence was 6% (101 of 1714) in high-risk individuals aged 50 years or older. Using mass spectrometry, we observed a total prevalence of monoclonal gammopathies of 43% (1788 of 4207) in this group. We termed monoclonal gammopathies below the clinical immunofixation electrophoresis detection level (<0·2 g/L) MGIPs, to differentiate them from those with higher concentrations, termed mass-spectrometry MGUS, which had a 13% (592 of 4207) prevalence by mass spectrometry in high-risk individuals aged 50 years or older. MGIP was predominantly of immunoglobulin M isotype, and its prevalence increased with age (19% [488 of 2564] for individuals aged <50 years, 29% [1464 of 5058] for those aged ≥50 years, and 37% [347 of 946] for those aged ≥70 years). Mass-spectrometry MGUS prevalence increased with age (5% [127 of 2564] for individuals aged <50 years, 13% [678 of 5058] for those aged ≥50 years, and 18% [173 of 946] for those aged ≥70 years) and was higher in men (314 [12%] of 2570) compared with women (485 [10%] 5013; p=0·0002), whereas MGIP prevalence did not differ significantly by gender. In those aged 50 years or older, the prevalence of mass spectrometry was significantly higher in Black participants (224 [17%] of 1356) compared with the controls (p=0·0012) but not in those with family history (368 [13%] of 2851) compared with the controls (p=0·1008). Screen-detected monoclonal gammopathies correlated with increased all-cause mortality in MGBB participants (hazard ratio 1·55, 95% CI 1·16-2·08; p=0·0035). All monoclonal gammopathies were associated with an increased likelihood of comorbidities, including myocardial infarction (odds ratio 1·60, 95% CI 1·26-2·02; p=0·00016 for MGIP-high and 1·39, 1·07-1·80; p=0·015 for mass-spectrometry MGUS). We detected a high prevalence of monoclonal gammopathies, including age-associated MGIP, and made more precise estimates of mass-spectrometry MGUS compared with conventional gel-based methods. The use of mass spectrometry also highlighted the potential hidden clinical significance of MGIP. Our study suggests the association of monoclonal gammopathies with a variety of clinical phenotypes and decreased overall survival. Stand Up To Cancer Dream Team, the Multiple Myeloma Research Foundation, and National Institutes of Health.


Towards microalgal triglycerides in the commodity markets.
Microalgal triglycerides (TAGs) hold great promise as sustainable feedstock for commodity industries. However, to determine research priorities and support business decisions, solid techno-economic studies are essential. Here, we present a techno-economic analysis of two-step TAG production (growth reactors are operated in continuous mode such that multiple batch-operated stress reactors are inoculated and harvested sequentially) for a 100-ha plant in southern Spain using vertically stacked tubular photobioreactors. The base case is established with outdoor pilot-scale data and based on current process technology. For the base case, production costs of 6.7 € per kg of biomass containing 24% TAG (w/w) were found. Several scenarios with reduced production costs were then presented based on the latest biological and technological advances. For instance, much effort should focus on increasing the photosynthetic efficiency during the stress and growth phases, as this is the most influential parameter on production costs (30 and 14% cost reduction from base case). Next, biological and technological solutions should be implemented for a reduction in cooling requirements (10 and 4.5% cost reduction from base case when active cooling is avoided and cooling setpoint is increased, respectively). When implementing all the suggested improvements, production costs can be decreased to 3.3 € per kg of biomass containing 60% TAG (w/w) within the next 8 years. With our techno-economic analysis, we indicated a roadmap for a substantial cost reduction. However, microalgal TAGs are not yet cost efficient when compared to their present market value. Cost-competiveness strictly relies on the valorization of the whole biomass components and on cheaper PBR designs (e.g. plastic film flat panels). In particular, further research should focus on the development and commercialization of PBRs where active cooling is avoided and stable operating temperatures are maintained by the water basin in which the reactor is placed.


The genomic basis of the Williams-Beuren syndrome.
The Williams-Beuren syndrome is a genomic disorder (prevalence: 1/7,500 to 1/20,000), caused by a hemizygous contiguous gene deletion on chromosome 7q11.23. Typical symptoms comprise supravalvular aortic stenosis, mental retardation, overfriendliness and visuospatial impairment. The common deletion sizes range of 1.5-1.8 mega base pairs (Mb), encompassing app. 28 genes. For a few genes, a genotype-phenotype correlation has been established. The best-explored gene within this region is the elastin gene; its haploinsufficiency causes arterial stenosis. The region of the Williams-Beuren syndrome consists of a single copy gene region (approximately 1.2 Mb) flanked by repetitive sequences--Low Copy Repeats (LCR). The deletions arise as a consequence of misalignment of these repetitive sequences during meiosis and a following unequal crossing over due to high similarity of LCRs. This review presents an overview of the Williams-Beuren syndrome region considering the genomic assembly, chromosomal rearrangements and their mechanisms (i.e. deletions, duplications, inversions) and evolutionary and historical aspects.


Oppression of the bereaved: a critical analysis of grief in Western society.
Bereaved individuals often experience profound social pressure to conform to societal norms that constrict the experience of grief rather than support it. This article explores grief in Western society through an analysis of the underlying structures and values that are a part of this social system, utilizing the lens of critical theory. Critical theory examines social norms and conditions in order to identify and expose oppression in various contexts. This article examines the social rules that govern the expression of grief, the role of attachment, social pain, and shame as potent forces that promote compliance with social rules, and the ways that the underlying assumptions and values in Western society shape how bereaved individuals are expected to react. Implications for clinicians who work with terminally ill or bereaved individuals are then reviewed.


Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth?
Several studies have found positive associations between birth weight and breast cancer risk at premenopausal ages. The mechanisms underlying this association are not known, but it is possible that it may be mediated through childhood growth. We examined data from a British cohort of 2176 women born in 1946 and for whom there were prospective measurements of birth weight and of body size throughout life. In all, 59 breast cancer cases occurred during follow-up, 21 of whom were known to be premenopausal. Women who weighed at least 4 kg at birth were five times (relative risk (RR)=5.03; 95% confidence interval=1.13, 22.5) more likely to develop premenopausal breast cancer than those who weighed less than 3 kg (P-value for linear trend=0.03). This corresponded to an RR of 2.31 (0.95, 5.64) per 1 kg increase in birth weight. Birth weight was also a predictor of postnatal growth, that is, women who were heavy at birth remained taller and heavier throughout their childhood and young adulthood. However, the effect of birth weight on premenopausal breast cancer risk was only reduced slightly after simultaneous adjustment for height and body mass index (BMI) at age 2 years and height and BMI velocities throughout childhood and adolescence (adjusted RR=1.94 (0.74, 5.14) per 1 kg increase in birth weight). The pathways through which birth weight is associated with premenopausal breast cancer risk seem to be largely independent of those underlying the relation of postnatal growth to risk.


The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K).
The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders as they are key components in regulating cell signalling pathways. In an effort to make probe molecules available for further exploring these targets, we have previously reported PI5P4Kα-selective and PI5P4Kγ-selective ligands. Herein we report the rational design of PI5P4Kα/γ dual inhibitors, using knowledge gained during the development of selective inhibitors for these proteins. ARUK2007145 (39) is disclosed as a potent, cell-active probe molecule with ADMET properties amenable to conducting experiments in cells.


Nature and progression of pericardial effusion in patients with a first myocardial infarction: relationship to age and free wall rupture.
Left ventricular free wall rupture (FWR) usually develops within the first days of acute myocardial infarction (AMI) without warning, but it is uncertain whether a mild pericardial effusion might herald this complication. A 2-dimensional echocardiogram (2DE) was performed in patients with first AMI with (1149) or without (324) ST-segment elevation within 2 days. A second 2DE was performed 2 to 4 days later in 300 patients, 100 with and 200 without an initial mild PE (3-9 mm), and in those with initial moderate-severe PE (> or =10 mm) (MSPE) or who developed hypotension or died. The first 2DE showed mild PE in 177 patients and MSPE in 51 patients, whereas a late (>2 days) MSPE occurred in 27 with a second routine 2DE, 15 (15%) with and 12 (6%) without initial mild PE (P =.01). Fourteen additional patients, 5 of 77 (6%) with and 9 of 1045 (1%) without initial PE, presented with hypotension and late MSPE (P <.002). Of 92 patients with MSPE, 90 had ST-segment elevation (98%), 60 had tamponade (65%), and 38 died of FWR or were operated on (41%). Results of pericardiocentesis performed in 64 patients were positive in 58, with hemopericardium in 57 (98%). Multivariant analysis showed mild PE on first 2DE and age of >60 years as the only independent predictors of late MSPE or late tamponade. Mild PE within the first 2 days in patients aged >60 years with a first ST-segment elevation AMI is associated with an increased risk of late MSPE. Moreover, in this setting MSPE is most frequently associated with hemopericardium, and two thirds of these patients may develop tamponade/FWR.


Peer learning in the UNSW Medicine program.
The UNSW Australia Medicine program explicitly structures peer learning in program wide mixing of students where students from two adjoining cohorts complete the same course together, including all learning activities and assessment. The purpose of this evaluation is to explore the student experience of peer learning and determine benefits and concerns for junior and senior students. All medical students at UNSW Australia in 2012 (n = 1608) were invited to complete the Peer Learning Questionnaire consisting of 26 fixed-response items and 2 open-ended items exploring vertical integration and near-peer teaching. Assessment data from vertically integrated and non-vertically integrated courses were compared for the period 2011-2013. We received valid responses from 20 % of medical students (n = 328). Eighty percent of respondents were positive about their experience of vertical integration. Year 1 students reported that second year students provided guidance and reassurance (87.8 %), whilst year 2 students reported that the senior role helped them to improve their own understanding, communication and confidence (84 %). Vertical integration had little effect on examination performance and failure rates. This evaluation demonstrates that vertical integration of students who are one year apart and completing the same course leads to positive outcomes for the student experience of learning. Students benefit through deeper learning and the development of leadership qualities within teams. These results are relevant not only for medical education, but also for other professional higher education programs.


[Diagnostic value of bone scintigraphy in otorhinolaryngology].
18 patients with inflammatory or neoplastic diseases of the skull underwent bone scintigraphy; the scintigraphic and radiologic findings were compared with the extent of the lesion found at surgery. Possible errors and the diagnostic value of this method are discussed.


Selenoprotein K is required for palmitoylation of CD36 in macrophages: implications in foam cell formation and atherogenesis.
Selk is an ER transmembrane protein important for calcium flux and macrophage activation, but its role in foam cell formation and atherosclerosis has not been evaluated. BMDMs from Selk(-/-) mice exhibited decreased uptake of modLDL and foam cell formation compared with WT controls, and the differences were eliminated with anti-CD36 blocking antibody. CD36 expression was decreased in TNF-α-stimulated Selk(-/-) BMDMs compared with WT controls. Fluorescence microscopy revealed TNF-α-induced clustering of CD36 in WT BMDMs indicative of lipid raft localization, which was absent in Selk(-/-) BMDMs. Fractionation revealed lower levels of CD36 reaching lipid rafts in TNF-α-stimulated Selk(-/-) BMDMs. Immunoprecipitation showed that Selk(-/-) BMDMs have decreased CD36 palmitoylation, which occurs at the ER membrane and is crucial for stabilizing CD36 expression and directing its localization to lipid rafts. To assess if this phenomenon had a role in atherogenesis, a HFD was fed to irradiated Ldlr(-/-) mice reconstituted with BM from Selk(-/-) or WT mice. Selk was detected in aortic plaques of controls, particularly in macrophages. Selk(-/-) in immune cells led to reduction in atherosclerotic lesion formation without affecting leukocyte migration into the arterial wall. These findings suggest that Selk is important for stable, localized expression of CD36 in macrophages during inflammation, thereby contributing to foam cell formation and atherogenesis.


Differences in lymphocyte subpopulation count and function in cord, maternal and adult blood.
Phenotypical characterization and functional activity of lymphocytes and natural killer (NK) cells in cord blood (CB) were investigated, and maternal peripheral blood (MPB) values were compared to those of adult peripheral blood (APB) (control). To determine cytotoxic activity target cells (K562) were labeled with carboxyfluorescein diacetate (CFDA) or fluorescein isothiocyanate (FITC), and propidium iodide (PI) was used to label dead cells. Cell surface expression in CB, APB, and MPB cells were analyzed using flow cytometry. CB and MPB mononuclear cells had similar CD45, CD34, CD4, and surface molecule for T helper cell expression, but had low-level expression of total T-lymphocyte surface molecules CD3 and CD8. CD19 and HLA-DR expression was higher in CB than in MPB. The same high-level of expression for CD19 and HLA-DR was observed in APB, as compared to MPB. All other cell surface expressions were similar in APB and MPB samples. NK (CD16+ and CD56+) cells in CB was similar to that in MPB and APB, and the level of inhibitory KIR receptors in NK cells was higher in venous CB than in MPB and APB. The only difference between MPB and APB was that the CD158a level was higher in MPB. No difference was observed in NK cells in CB and MPB, in terms of cytotoxicity. The present results show that there was numerical and proportional variability of lymphocytes and their subgroups in CB and APB, but no cytological difference.


Hypothyroidism and Hyponatremia: Rather Coincidence Than Causality.
Hypothyroidism is referred to be a rare but possible cause of hyponatremia. However, there is only poor evidence supporting this association. Since hyponatremia and hypothyroidism are both common conditions themselves, co-occurrence does not have to be causal. To address a potential relationship, a retrospective analysis of data from the Division of Endocrinology of the Medical University of Vienna from April 2004 to February 2016 was performed. A total of 8053 hypothyroid patients (48 ± 18 years of age; 71% female) with thyrotropin >4.0 μIU/mL and available blood tests for free thyroxine and sodium (Na+) within maximal ± seven days were included and screened for hyponatremia. Patients' records were searched for concomitant disease and medication when Na+ concentration was <135 mmol/L. Hyponatremia was present in 448/8053 (5.56%) patients. Analysis of medical history revealed potential alternative causes of hyponatremia in 442/448 (98.88%) patients (i.e., side effects of medication, concomitant underlying disease, or other endocrine disorders). This distribution did not differ between patients suffering from clinical or subclinical hypothyroidism. No case of clinically relevant hyponatremia (Na+ < 130 mmol/L), present in 111/448 (24.78%) patients could be attributed only to hypothyroidism. There was a very weak but statistically significant trend toward a positive association between thyroid function and serum Na+ levels (Na+/thyrotropin: R = 0.022, p = 0.046; Na+/free thyroxine: R = -0.047, p < 0.001). The results suggest that hypothyroid patients with moderate to severe hyponatremia often have other potential explanations for their low serum Na+ concentrations in routine care.


Selenium in the prevention and treatment of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed.


New onset diabetes after nivolumab treatment.
The authors describe a case of a life-threatening diabetic emergency 25 days after initiation of nivolumab (3 mg/kg) for stage 4 lung adenocarcinoma. She was admitted to the emergency department, with hyperglycaemia-related signs and symptoms, such as polyuria, polydipsia, weight loss, confusion, asthenia, dehydration, hypotension and Kussmaul respiratory pattern. Her body mass index was 21.9 kg/m2 and she did not show acanthosis nigricans. Arterial blood gas determination revealed high anion gap metabolic acidaemia and blood tests showed hyperglycaemia (1060 mg/dL), hyperketonaemia (beta-hydroxybutyrate: 6.6 mmol/dL), elevated total serum osmolality (389 mOsm/kg), low serum and urinary C-peptide and positive antiglutamic acid decarboxylase antibodies. Since nivolumab was initiated a few days before, and due to its known immune-mediated endocrine adverse events, we assumed the diagnosis of new onset immune-mediated type 1 diabetes mellitus. After prompt and adequate treatment of diabetic ketoacidosis/hyperosmolar hyperglycaemic state, she was discharged improved on multiple daily injections of insulin.


Association of passive smoking with cognitive impairment in nonsmoking older adults: a systematic literature review and a new study of Chinese cohort.
Association of passive smoking with cognitive impairment in older adults is unclear. We carried out a systematic literature review and a new study to determine the association. There were 3 cross-sectional studies published, showing a significant association of passive smoking with cognitive impairment (a relative risk (RR) of about 1.30-1.90). In the new cohort study, we interviewed 1081 never-smoking participants aged ≥ 65 years in China using a standard method of the Geriatric Mental State-Automated Geriatric Examination for Computer Assisted Taxonomy and found a significant association with dose response; multivariate adjusted RR was 1.02 (95% confidence interval 0.67-1.55) in > 0 to 49 exposure level years of passive smoking, 1.57 (1.00-2.47) in 50 to 99, and 2.12 (1.24-3.63) in ≥ 100, trend P = .008. The relationship seems not to be a reverse causality of the effect. Passive smoking could be considered an important risk factor for cognitive impairment in older adults. Avoiding exposure to passive smoking would help to preserve cognitive decline in later life.


Shh promotes direct interactions between epidermal cells and osteoblast progenitors to shape regenerated zebrafish bone.
Zebrafish innately regenerate amputated fins by mechanisms that expand and precisely position injury-induced progenitor cells to re-form tissue of the original size and pattern. For example, cell signaling networks direct osteoblast progenitors (pObs) to rebuild thin cylindrical bony rays with a stereotypical branched morphology. Hedgehog/Smoothened (Hh/Smo) signaling has been variably proposed to stimulate overall fin regenerative outgrowth or promote ray branching. Using a photoconvertible patched2 reporter, we resolve active Hh/Smo output to a narrow distal regenerate zone comprising pObs and adjacent motile basal epidermal cells. This Hh/Smo activity is driven by epidermal Sonic hedgehog a (Shha) rather than Ob-derived Indian hedgehog a (Ihha), which nevertheless functions atypically to support bone maturation. Using BMS-833923, a uniquely effective Smo inhibitor, and high-resolution imaging, we show that Shha/Smo is functionally dedicated to ray branching during fin regeneration. Hh/Smo activation enables transiently divided clusters of Shha-expressing epidermis to escort pObs into similarly split groups. This co-movement likely depends on epidermal cellular protrusions that directly contact pObs only where an otherwise occluding basement membrane remains incompletely assembled. Progressively separated pObs pools then continue regenerating independently to collectively re-form a now branched skeletal structure.


[Glucocorticoids and osteoporosis].
Treatment with glucocorticoids (GC) has no alternative in many medical disciplines for their anti-inflammatory and immunosuppressive effect. However, osteoporosis and the related fractures are a serious complication brought about by long-term GC therapy. The risk of fractures, especially of the vertebras and the ribs, becomes higher as early as in the first months of oral GC therapy. It grows in proportion to the daily dose of GC, and is present even if low doses are administered (2.5-7.5 mg of prednisone per day). Decreasing bone density (BMD) is not accountable for the higher risk of fractures in GC therapy and fractures occur with higher values of BMD than in primary osteoporosis. There is still no tool that we could use to quantify the changes in the bone quality and the increased risk of fracture in clinical practice. The principal mechanism by which GC induces osteoporosis is inhibition of bone formation caused by the suppression of osteoblastogenesis as well as the activity of functional osteoblasts, with accelerated osteocyte and osteoblast apoptosis. There are significant differences between individuals in terms of GC sensitivity, the reasons of which have not yet been explained. Prior to planned long-term GC therapy (> 3 months) with daily doses higher than 2.5 mg of prednisone p.o. (or higher doses of inhaled GC), it is recommended to perform a densitometry exam using dual-energy X-ray absorptiometry (DXA) in the lumbar region of the spine and femoral collum to evaluate additional risk factors of osteoporosis and fractures for a more precise estimate of the risk of fracture in the specific patient. Sufficient intake of calcium (1,000-1,500 mg of elementary calcium per day) and of the vitamin D (800 IU per day) should be assured in all patients treated by GC. Endogenous production of sexagens should be evaluated and possible substitution therapy should be considered in premenopausal women and younger men. Today, bisphosphonates can be given to patients with a high risk of fracture, the effects of which in preventing the decrease of BMD and vertebral fractures have been documented in randomised clinical studies, even though the evaluation of the risk of fractures was not the primary endpoint of those studies. However, in view of the antiremodelling effect of bisphosphonates, it is clear that this therapy does not eliminate the cause of GC induced osteoporosis and drugs with stimulating effect on osteoblasts will certainly be preferred in the future. Very promising are the first clinical studies of injection parathormone (PTH 1-34) which stimulated bone formation in a continuing GC treatment.


[Whipple's disease, a non-rheumatoid cause of seronegative arthritis].
In 15-25% of patients with rheumatoid arthritis, the presence of pathognomonic autoantibodies (anti-citrullinated protein (aCCP) or rheumafactor (RF) is lacking. In these cases of seronegative rheumatoid arthritis, diagnosis is based on clinical presentation. However, some of the patients with seronegative rheumatoid arthritis are misdiagnosed. Here we discuss a case of a 64 year old female, with a diagnoses of seronegative rheumatoid arthritis for 18 years. Although extensively treated with immunosuppressive medication, she did not reach remission. After second opinion in our hospital we diagnosed Whipple's disease. This case report illustrates the importance of a broad differential diagnosis of seronegative arthritis as well as the importance of re-assessment of patients diagnosed with seronegative rheumatoid arthritis, who do not reach remission upon immunosuppressive treatment.


Use of a CO2 electrode to monitor fermentations that use xenobiotic compounds as source of carbon.
Bacterial strains were isolated from contaminated waters, mud or soils. They are capable of growing in mineral medium with different chemicals as carbon source, such as aliphatic or aromatic hydrocarbons and polychlorinated biphenyls (PCBs). Most of these strains tolerate high concentrations (up to 30% v/v) of the xenobiotic substrates. This is particularly important for the development of fermenting processes to treat effluents or residues with a high content of contaminating compounds. An ion-specific potentiometric electrode (CO2) has been developed to measure CO2 production continuously. When the different strains were incubated in a mineral medium and in the presence of the corresponding substrate, a parallel between growth, substrate consumption and CO2 production was found. The developed system is suggested as an efficient and economical alternative to evaluate the potential of biodegradation by different microorganisms.


Increasing dominance of large lianas in Amazonian forests.
Ecological orthodoxy suggests that old-growth forests should be close to dynamic equilibrium, but this view has been challenged by recent findings that neotropical forests are accumulating carbon and biomass, possibly in response to the increasing atmospheric concentrations of carbon dioxide. However, it is unclear whether the recent increase in tree biomass has been accompanied by a shift in community composition. Such changes could reduce or enhance the carbon storage potential of old-growth forests in the long term. Here we show that non-fragmented Amazon forests are experiencing a concerted increase in the density, basal area and mean size of woody climbing plants (lianas). Over the last two decades of the twentieth century the dominance of large lianas relative to trees has increased by 1.7-4.6% a year. Lianas enhance tree mortality and suppress tree growth, so their rapid increase implies that the tropical terrestrial carbon sink may shut down sooner than current models suggest. Predictions of future tropical carbon fluxes will need to account for the changing composition and dynamics of supposedly undisturbed forests.


Controlled immobilization of His-tagged proteins for protein-ligand interaction experiments using Ni²⁺-NTA layer on glass surfaces.
Gold surfaces functionalized with nickel-nitrilotriacetic acid (Ni²⁺-NTA) as self-assembled monolayers (SAM) to immobilize histidine (His)-tagged biomolecules are broadly reported in the literature. However, the increasing demand of using microfluidic systems and biosensors takes more and more advantage on silicon technology which provides dedicated glass surfaces and substantially allows cost and resource savings. Here we present a novel method for the controlled oriented immobilization of His-tagged proteins on glass surfaces functionalized with a Ni²⁺-NTA layer. Exemplarily, the protein pattern morphology after immobilization on the Ni²⁺-NTA layer of His6-tagged soluble receptor for advanced glycation endproducts (sRAGE) was investigated and compared to non-oriented immobilization of sRAGE on amino SAM by using scanning electron microscopy (SEM). Moreover, we demonstrated interaction of immobilized sRAGE with three structurally different ligands, S100A12, S100A4, and glycated low density lipoproteins (glycLDL), by means of peak-force tapping atomic force microscopy (PF-AFM). We showed a clear discrimination of different protein-ligand orientations by differential height measurements.


In vitro confirmation of chloroquine-resistant Plasmodium falciparum malaria in KwaZulu.
In May 1987 and January 1988 the chloroquine sensitivity of Plasmodium falciparum in the Ubombo and Ingwavuma districts of KwaZulu was determined by a modified in vitro microtest in which the patients' plasma was replaced with non-immune human AB serum and the test plates were incubated in an atmosphere of 3% oxygen, 4% carbon dioxide and 93% nitrogen. A success rate of 74% was achieved using this technique. All of 23 successfully tested isolates from malaria patients reporting to clinics and a hospital in these areas were found to be resistant to chloroquine, schizogony being inhibited at 32 pmol per well in the majority of tests. Seventy-five per cent of the isolates obtained through active surveillance in the Ubombo district were found to be resistant in varying degrees. Malarial parasites collected from clinics and a hospital in the endemic area did not change markedly in their in vitro response to chloroquine during the 8-month period May 1987-January 1988.


A new simplified method for laser sinus node modification without electrophysiological technique.
As the treatment of inappropriate sinus tachycardia, beta-adrenoreceptor blockade therapy is the most common method for pharmacological heart rate control, but it is occasionally limited by side effects of the drugs, especially in patients with cardiac dysfunction. On the other hand, cryoablation or surgical exclusion of the sinus node have not been accepted generally for their necessity of permanent pacemaker implantation. Modification of the sinus node function is a new method of nonpharmacological treatments, although the skillfull and troublesome technique is required. In this study, the efficacy and safety of laser sinus node modification without electrophysiological technique were investigated as a new simplified method. In six mongrel dogs, the laser-tissue interactions by epicardial Nd-YAG laser irradiation were investigated by measuring the diameter and the depth of the irradiated lesions. Laser irradiations were performed from the head to the tail on the sinus node areas directed only by terminal groove for the visual landmark without electrophysiological technique until about 25% decrease in heart rate occurred in other six open-chest dogs.


Interaction of miltefosine with intercellular membranes of stratum corneum and biomimetic lipid vesicles.
Miltefosine (MT) is an alkylphospholipid approved for breast cancer metastasis and visceral leishmaniasis treatments, although the respective action mechanisms at the molecular level remain poorly understood. In this work, the interaction of miltefosine with the lipid component of stratum corneum (SC), the uppermost skin layer, was studied by electron paramagnetic resonance (EPR) spectroscopy of several fatty acid spin-labels. In addition, the effect of miltefosine on (i) spherical lipid vesicles of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and (ii) lipids extracted from SC was also investigated, by EPR and time-resolved polarized fluorescence methods. In SC of neonatal Wistar rats, 4% (w/w) miltefosine give rise to a large increase of the fluidity of the intercellular membranes, in the temperature range from 6 to about 50°C. This effect becomes negligible at temperatures higher that ca. 60°C. In large unilamelar vesicles of DPPC no significant changes could be observed with a miltefosine concentration 25% molar, in close analogy with the behavior of biomimetic vesicles prepared with bovine brain ceramide, behenic acid and cholesterol. In these last samples, a 25 mol% molar concentration of miltefosine produced only a modest decrease in the bilayer fluidity. Although miltefosine is not a feasible skin permeation enhancer due to its toxicity, the information provided in this work could be of utility in the development of a MT topical treatment of cutaneous leishmaniasis.


Low temperature Fourier transform infrared spectra and hydrogen bonding in polycrystalline uracil and thymine.
The FTIR spectra of pure NH and isotopically diluted (NH/ND and ND/NH) polycrystalline uracil and thymine were measured in the range 4000-400 cm(-1) at temperatures from 300 to 10K. For the first time, the essentially narrow bands corresponding to the uncoupled stretching (nu(1)) and out of plane bending (nu(4)) NH proton modes of uracil and thymine were observed in the solid phase. It was found that in the nu(4) region the spectra reveal more details on the H-bond interactions present in both solids than in the nu(1) range. The frequencies of the various bands observed in both spectral regions were used for estimation of the H-bond energy, using empirical correlations between this property and both the red shift of nu(1) and the blue shift of nu(4) that occur upon crystallization due to the establishment of the H-bonds. The results are compared with known thermodynamic, structural and theoretical data. The IR data also suggest that the H-bond networks of both crystals contain, besides the two NH...O=C bonds revealed by X-ray experiments, additional types of H-bonds, which do not show long range periodicity and, thus, cannot be detected by the conventional structural methods. The assignment of some other bands in the spectra of both substances was also reviewed.


Predictors of pituitary tumour behaviour: an analysis from long-term follow-up in 2 tertiary centres.
To determine the clinical utility of assessment of tumour invasion, markers of proliferation, and the French clinicopathological classification in pituitary tumour prognostication. This is a retrospective evaluation of adult patients undergoing pituitary surgery at Oxford University and St Vincent's Hospitals, between 1989 and 2016, with at least 12 months of clinical data. Invasion was assessed radiologically, proliferative markers (Ki67, mitotic count, p53) by immunohistochemistry. Tumours were graded according to the clinicopathological classification. Intra- and interlaboratory variability of histopathology reporting was evaluated. (1) Tumour recurrence (radiological or reintervention ≥12 months postoperatively) and/or (2) "aggressive behaviour" (≥4 interventions and/or invasive tumour with recurrence/reintervention between 12 and 24 months postoperatively). A total of 386 patients were included, age at surgery was 56 (interquartile range [IQR] 41-67) years, 54% were male, and median follow-up was 90 months (range 44-126). Tumours were predominantly clinically nonfunctioning (252, 65%), with overall 53% invasive, and 10% that demonstrated ≥2 proliferative marker positivity. Recurrence was predicted by invasiveness (hazards ratio [HR] 1.6 [1.10-2.37], P .02), elevated mitotic count (HR 2.17 [1.21-3.89], P .01), grade (2b vs 1a HR 2.32 [1.06-5.03], P .03), and absence of gross total resection (HR 3.70 [1.72-8.00], P .01). Clinically defined aggressiveness was associated with elevated Ki67, mitotic count, and invasiveness. Ki67 reporting methodologies showed moderate correlation across laboratories (Phi 0.620), whereas p53 reporting reproducibility was poor (Phi 0.146). Proliferative markers, including Ki67 and mitotic count, but not p53, are important in predicting the development of aggressive pituitary tumour behaviour.


Are duplicated genes responsible for anthracnose resistance in common bean?
The race 65 of Colletotrichum lindemuthianum, etiologic agent of anthracnose in common bean, is distributed worldwide, having great importance in breeding programs for anthracnose resistance. Several resistance alleles have been identified promoting resistance to this race. However, the variability that has been detected within race has made it difficult to obtain cultivars with durable resistance, because cultivars may have different reactions to each strain of race 65. Thus, this work aimed at studying the resistance inheritance of common bean lines to different strains of C. lindemuthianum, race 65. We used six C. lindemuthianum strains previously characterized as belonging to the race 65 through the international set of differential cultivars of anthracnose and nine commercial cultivars, adapted to the Brazilian growing conditions and with potential ability to discriminate the variability within this race. To obtain information on the resistance inheritance related to nine commercial cultivars to six strains of race 65, these cultivars were crossed two by two in all possible combinations, resulting in 36 hybrids. Segregation in the F2 generations revealed that the resistance to each strain is conditioned by two independent genes with the same function, suggesting that they are duplicated genes, where the dominant allele promotes resistance. These results indicate that the specificity between host resistance genes and pathogen avirulence genes is not limited to races, it also occurs within strains of the same race. Further research may be carried out in order to establish if the alleles identified in these cultivars are different from those described in the literature.


CLINICAL AND GENETIC PECULIARITIES OF VASCULAR MANIFESTATIONS OF ANTIPHOSPHOLIPID SYNDROME (CASE REPORT).
Pathogenetic mechanisms of the development of antiphospholipid syndrome (APS) are considered in the article, which is the basis for the development of clinical manifestations and laboratory markers of APS. The modern literature data are analyzed, according to which the presence of antiphospholipid antibodies is a hypercoagulable background, and the formation of thrombi occurs under the influence of other allowing procoagulation factors. The classification of the main types of hereditary thrombophilia is given, which is the primary disorder, against the background of which an autoimmune thrombosis APS develops. A clinical observation of a young age patient is given, whose heterozygous carriage of mutations in the genes responsible for blood coagulation (F7, PAI-1 and ITGB3-β-integrin), as well as homozygous carriage of a mutation in the MTRR gene associated with a violation of homocysteine methylation, APS was developed, which led to the processes of thrombosis. Timely diagnosis and individually developed pathogenetic therapy allow avoiding life-threatening complications of APS and improving the patients' quality of life. A conclusion about the need for APS and hereditary thrombophilias' examination to all patients of young age with unprovoked thrombosis of deep veins of lower extremities and PE was made.


The effect of polypeptide-lipid interactions on the ultraviolet spectrum of the olefinic bonds of the lipid.
The effect of associating acidic and basic polypeptides with dilute suspensions of vesicles composed of various unsaturated phospholipids was assessed with regard to optical density and ultraviolet absorption. Associating basic polypeptides with phosphatidylserine, phosphatidylethanolamine, and phosphatidylglycerol vesicles, or acidic polypeptide with phosphatidylcholine vesicles, caused an increase in the optical density of the preparations, with no measurable effect on the intensity of the ultraviolet spectrum of the olefinic bonds of the lipid. Associating basic polypeptides with phosphatidylcholine vesicles, in addition to causing similar increases in optical density, resulted in a large decrease in the intensity of ultraviolet absorption by the olefinic bonds. This implies that the interaction between the basic polypeptides and phosphatidylcholine vesicles results in major alterations in the microenvironment of the olefinic bonds, which would require intimate association of the polypeptide with the ninth carbon region of the acyl chains. These observations support the conclusion, drawn from our earlier studies, that the association of basic polypeptides and liquid crystalline phase phosphatidylcholine vesicles is peculiar in that it involves a major hydrophobic component.


Gas-Phase Reactions of Atomic Gold Cations with Linear Alkanes (C2-C9).
To develop proper ionization methods for alkanes, the reactivity of bare or ligated transition metal ions toward alkanes has attracted increasing interests. In this study, the reactions of the gold cations with linear alkanes from ethane up to nonane (CnH2n+2, n = 2-9) under mild conditions have been characterized by mass spectrometry and density functional theory calculations. When reacting with Au(+), small alkanes (n = 2-6) were confirmed to follow specific reaction channels of dehydrogenation for ethane and hydride transfer for others to generate product ions characteristic of the original alkanes, which indicates that Au(+) can act as a reagent ion to ionize alkanes from ethane to n-hexane. Strong dependence of the chain length of alkanes was observed for the rate constants and reaction efficiencies. Extensive fragmentation took place for larger alkanes (n > 6). Theoretical results show that the fragmentation induced by the hydride transfer occurs after the release of AuH. Moreover, the fragmentation of n-heptane was successfully avoided when the reaction took place in a high-pressure reactor. This implies that Au(+) is a potential reagent ion to ionize linear and even the branched alkanes.


Embryonic and adult synaptic proteome perturbations after maternal immune activation: Identification of persistent changes relevant for early intervention.
Maternal infections during pregnancy pose an increased risk for neurodevelopmental psychiatric disorders (NPDs) in the offspring. Here, we examined age- and sex-dependent dynamic changes of the hippocampal synaptic proteome after maternal immune activation (MIA) in embryonic and adult mice. Adult male and female MIA offspring exhibited social deficits and sex-specific depression-like behaviours, among others, validating the model. Furthermore, we observed dose-, age-, and sex-dependent synaptic proteome differences. Analysis of the embryonic synaptic proteome implicates sphingolipid and ketoacid metabolism pathway disruptions during neurodevelopment for NPD-pertinent sequelae. In the embryonic hippocampus, prenatal immune activation also led to changes in neuronal guidance, glycosphingolipid metabolism important for signalling and myelination, and post-translational modification of proteins that regulate intercellular interaction and developmental timing. In adulthood, the observed changes in synaptoneurosomes revealed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, and hormone-mediated metabolism. Importantly, 68 of the proteins with differential abundance in the embryonic brains of MIA offspring were also altered in adulthood, 75% of which retained their directionality. These proteins are involved in synaptic organisation, neurotransmitter receptor regulation, and the vesicle cycle. A cluster of persistently upregulated proteins, including AKT3, PAK1/3, PPP3CA, formed a functional network enriched in the embryonic brain that is involved in cellular responses to environmental stimuli. To infer a link between the overlapping protein alterations and cognitive and psychiatric traits, we probed human phenome-wise association study data for cognitive and psychiatric phenotypes and all, but PORCN were significantly associated with the investigated domains. Our data provide insights into the dynamic effects of an early prenatal immune activation on developing and mature hippocampi and highlights targets for early intervention in individuals exposed to such immune challenges.


The Prevalence and Replication Capacity of a Tibetan Dominant HBV Strain, C/D Recombinant.
This study aimed to estimate the distribution of hepatitis B virus (HBV) C/D recombinant in Han and Tibet patients with chronic hepatitis B (CHB) and then learn such strain's replication capacity in vivo. A total of 331 serum samples were collected from Han outpatients from Sichuan Province and Tibetan outpatients from Tibet. Viral genotypes in these samples were identified. An HBV replicative plasmid of C/D recombinant was constructed with selected genome. Sequentially, HBV replicative mouse models were established and the replication capacity of the viral strain was studied in vivo. In the 314 Han patients, 66% (207) were infected by genotype B strain while 31% (96) were by genotype C strain. Only 1% (3) were by C/D recombinant. In the 17 Tibetan patients, 41% (7) were by genotype D and 35% (6) by C/D recombinant. A plasmid with 1.3 copies of C/D recombinant genome was constructed. And its replication intermediates were found at similar levels to that of genotype D strain. Thus, C/D recombinant, the dominant viral strain in Tibet, was rather rare in the genotype B predominated Han patients from Sichuan Province. And the C/D recombinant replicated at a similar level to viral strain of genotype D in vivo.


A study of fertility patterns of ever married women in oman.
To examine the relation between age, education, residence and fertility rate and change in fertility rate between 1994/95 and 1999/2000. The data for the study was extracted from the Oman National Health Survey, 2000. The birth histories data was used to extract data on woman years and births in the periods 1990 to 1994 and 1995 to 2000. The marital fertility rate in 1999/2000 was 7.12 births. The rates for rural and urban dwellers were 8.07 and 6.75 respectively in 1999/2000. Corresponding rates in 1994/95 (8.65, 8.30 and 9.69 respectively) were significantly higher than those in 1999/2000 for all categories, indicating a reduction in rates. In both periods the higher the education level of the mother the lower her fertility. Education was a strong determinant of fertility. This study confirms that the higher the education of the woman the lower her fertility and that fertility is on the decline in Oman.


Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway.
The mechanisms that govern the maintenance and differentiation of tissue-specific progenitors in development and tissue regeneration are poorly understood. We show that development of Sox2+ progenitors in the lung endoderm is regulated by histone deacetylases 1 and 2 (Hdac1/2). Hdac1/2 deficiency leads to a loss of Sox2 expression and a block in proximal airway development. This is mediated in part by derepression of Bmp4 and the tumor suppressor Rb1, which are direct transcriptional targets of Hdac1/2. In contrast to development, postnatal loss of Hdac1/2 in airway epithelium does not affect the expression of Sox2 or Bmp4. However, postnatal loss of Hdac1/2 leads to increased expression of the cell-cycle regulators Rb1, p21/Cdkn1a, and p16/Ink4a, resulting in a loss of cell-cycle progression and defective regeneration of Sox2+ lung epithelium. Thus, Hdac1/2 have both common and unique targets that differentially regulate tissue-specific progenitor activity during development and regeneration.


Sensitivity improvement of infrared imaging video bolometer for divertor plasma measurement.
The sensitivity of an infrared imaging video bolometer (IRVB) was improved for the measurement of relatively low energy plasma radiation from the viewpoint of the metal foil absorber material. The photon energy of the radiation was considered up to 1 keV for the divertor plasma measurement. The thickness of the foil absorber was evaluated not only for conventional heavy elements, e.g., platinum, but also for light elements by the relation between the photon energy and attenuation length and by mechanical strength. A heat-transfer calculation using ANSYS suggested that light elements with practical foil thickness provide a higher temperature rise of the foil absorber compared with heavier elements with practical foil thickness. The maximum of the temperature rise was evaluated using He-Ne laser irradiation onto absorber samples. The material dependence of the temperature rise has a similar tendency between calculations and experiments. Experimentally, the sensitivity of the IRVB improved from 280 to 110 µW/cm2 using titanium with 1 µm thickness compared with conventional platinum with 2.5 µm thickness. Consequently, the signal-to-noise ratio of the IRVB could be improved from 2.8 to 9.1.


A synopsis of the 3rd annual Cancer Proteomics Conference.
The 3rd annual 'Cancer Proteomics Conference', organized by Select Biosciences (Sudbury, UK), was held in Berlin, Germany, 8-9 June 2010. With the aim of strengthening the links between scientists from Europe, as well as international investigators worldwide, more than 200 delegates attended, representing various countries. The Conference covered many topics in proteomics, including the use of proteomics for cancer therapeutic development, diagnostic applications, biomarker discovery, post-translational modifications and clinical proteomics, as well as new proteomic technologies, which may facilitate future progress. One distinct feature of this meeting was that the Conference was co-located with the 'Advances in Antibody and Peptide Therapeutics' meeting. Delegates had access to both meetings, allowing for enhanced interaction among investigators from the closely linked fields of research.


Preclinical Investigation of Transdermal Route for Enhanced Bio-performance of Duloxetine HCl.
The aim of the study was to develop and optimise drug-in-adhesive (DIA) transdermal patch of duloxetine HCl for enhanced drug delivery. DIA patch so developed reduced the dose and dosing frequency by enhancing bio-performance of the drug. A transdermal DIA patch having Duro-Tak 87-2287 as DIA polymer and Transcutol P as permeation enhancer loaded with 40% drug previously complexed with MeβCD duly characterised (FTIR, DSC, and SEM) was developed for in vivo study. Pharmacokinetic parameters of developed formulation were assessed and compared with oral route of administration. Among various permeation enhancers (PEs), Transcutol P exhibited most enhanced permeation (ER ≈ 1.99) in terms of flux and Q24 compared to control group having. Mean of maximum plasma concentration (Cmax) and area under time-concentration curve (AUC0-72) in Wistar rats (n = 6) for transdermal patch (10 mg/kg) was found to be 70.31 ± 11.2 ng/ml and 2997.29 ± 387.4 ng/ml*h, respectively, and were considerably higher than oral dose of DLX (20 mg/kg and 10 mg/kg). Albeit, T1/2 was higher in case of transdermal delivery, but this was due to sustained behaviour of delivery system. These findings highlight the significance of both inclusion complexation and transdermal delivery of DLX using DIA patch for efficient drug absorption.


[Surgical treatment of laryngomalacia in children].
Laryngomalacia is the most common congenital malformation of the larynx which causes stridor in newborns and infants. The stridor is inspiratory and it is first noted at birth but sometimes may not develop until 2 weeks of age. It increases in severity during crying, nursing, agitation, excitement and is made worse with head flexion or supination. Other symptoms such as supraclavicular, intraclavicular, intercostal and abdominal retractions may be associated. Boys are affected over twice as often as girls. Diagnosis of laryngomalacia is made by rigid or flexible laryngoscopy. Although this disorder is usually self-limited, in some cases the symptoms are so severe that operative intervention cannot be avoided. Between 2002 and 2005, 13 infants were operated for severe form of laryngomalacia in the Pediatric ENT Dept in Poznań. In all patients the rigid or flexible laryngoscopy was performed to confirm the diagnosis. Then aryepiglottoplasty or epiglottoplasty were performed in all cases. It involved excision of the redundant mucosa over the arytenoid cartilages, the offending parts of he aryepiglottic folds, and trimming the lateral edges of the epiglottis, using microlaryngeal scissors and forceps. In all children symptoms such as: laryngeal stridor, feeding difficulties and dyspnea improved or completely resolved. In one case post-operative ventilation for several hours was required. All patients except one demonstrated significant airway improvement in the immediate postoperative period. Direct laryngoscopy must be performed prior to the aryepiglottoplasty to decide what amount of tissue to resect. Endoscopic aryepiglottoplasty with use of microlaryngeal instruments is an effective and safe method of the treatment of severe form of laryngomalacia. It is better to perform this procedure in general anesthesia without intubation.


The hypotensive effect of captopril in hypertensive patients is age-related.
The hypotensive action of the angiotensin-converting enzyme inhibitor captopril was investigated in 13 hypertensive patients in relation to their age, body weight, the pretreatment level of plasma renin activity (PRA), serum creatinine concentration and suppression of angiotensin II (PA II) by captopril. Captopril was administered in biweekly doubling doses (15 mg, 50 mg and finally 100 mg t.i.d.). The change in systolic blood pressure produced by captopril was significantly (p less than or equal to 0.05 or less) related to age (r = 0.67), to weight (r = 0.55), to the initial PRA levels (r = -0.63) and to the drop in PA II (r = 0.67) but not to the serum creatinine concentration. The change in diastolic blood pressure was also (p less than or equal to 0.05 or less) related to age (r = 0.59), to the pretreatment PRA level (r = -0.71) and to the fall in PA II (r = 0.70) but not to weight or to serum creatinine concentration. Our data suggest that the hypotensive action of captopril is more pronounced in younger hypertensive patients.


Improved scar in postburn patients following interferon-alpha2b treatment is associated with decreased angiogenesis mediated by vascular endothelial cell growth factor.
Hypertrophic scar (HTS) after thermal injury is a dermal fibroproliferative disorder, which leads to considerable morbidity. Previous clinical studies from our laboratory have suggested that interferon-alpha2b (IFN-alpha2b) improves scar quality as a result of the suppression of fibroblast function. More recently, our work has demonstrated that the improvement of scar in patients with HTS after IFN-alpha2b treatment may be associated with a decreased number of fibrocytes and/or altered fibrocyte function. In this study, we report that the improvement of HTS after IFNalpha-2b treatment may be associated with a decrease in angiogenesis. Using immunohistochemistry, we demonstrate an increase in angiogenesis in HTS compared to normal skin, and also show an increase in the expression of vascular endothelial cell growth factor (VEGF) in HTS. Subsequently, we demonstrate a significant reduction in angiogenesis in HTS tissue from patients after treatment with systemic IFN-alpha2b. By using a [3H] thymidine incorporation assay, we demonstrate that IFN-alpha2b suppresses the proliferation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. In addition, IFN-alpha2b inhibits VEGF-induced proliferation and tube formation by using HUVECs. All these effects may be a result of the blocking of VEGF receptor expression on endothelial cells by IFN-alpha2b. Taken together with previous results, the present study suggests that the improvement of scar quality in HTS patients after IFN-alpha2b treatment may also be associated with decreased angiogenesis in HTS. The current in vitro results may provide some insights into the scar improvement that is seen with systemic IFN-alpha2b treatment.


Transduction of Functionally Contrasting Signals by Two Mycobacterial PPE Proteins Downstream of TLR2 Receptors.
As pathogen-associated molecular pattern sensors, the TLRs can detect diverse ligands to elicit either proinflammatory or anti-inflammatory responses, but the mechanism that dictates such contrasting immune responses is not well understood. In this work, we demonstrate that proline-proline-glutamic acid (PPE)17 protein of Mycobacterium tuberculosis induces TLR1/2 heterodimerization to elicit proinflammatory-type response, whereas PPE18-induced homodimerization of TLR2 triggers anti-inflammatory type responses. Ligation of TLR1/2 caused an increased recruitment of IL-1R-associated kinase (IRAK)1, MyD88, and protein kinase C (PKC)ε to the downstream TLR-signaling complex that translocated PKCε into the nucleus in an IRAK1-dependent manner. PKCε-mediated phosphorylation allowed the nuclear IRAK3 to be exported to the cytoplasm, leading to increased activation of ERK1/2, stabilization of MAPK phosphatase 1 (MKP-1), and induction of TNF-α with concomitant downregulation of p38MAPK. Silencing of TLR1 inhibited PPE17-triggered cytoplasmic export of IRAK3 as well as TNF-α induction, suggesting an important role of TLR1/2 heterodimer in regulating proinflammatory responses via the IRAK3-signaling pathway. In contrast, PPE18-mediated homodimerization of TLR2 caused poorer cytoplasmic export of nuclear IRAK3 and MKP-1 stabilization, resulting in increased p38MAPK activation. Our study hints to a novel mechanism that implicates PKCε-IRAK3-MKP-1 signaling in the regulation of MAPK activity and inflammatory cascades downstream of TLR2 in tuberculosis.


Genetics of Alzheimer's disease.
Alzheimer's disease is the leading cause of dementia in the elderly. Most patients do not have an obvious family history and are classified as sporadic. Genetic factors in early and late-onset Alzheimer's disease are now well documented. This paper reviews the known genetic loci associated with Alzheimer's disease with an emphasis on the role of apolipoprotein E in late-onset familial and sporadic disease. Apolipoprotein E allele 4 is a susceptibility gene that is found in approximately 50% of patients with Alzheimer's disease. Hypotheses about apolipoprotein E function that may lead to Alzheimer's disease are also discussed.


Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr.
The prevalence of childhood cancer attributable to genetic predisposition was generally considered very low. However, recent reports suggest that at least 10% of pediatric cancer patients harbor a germline mutation in a cancer predisposition gene. Although some of these children will have a family history suggestive of a cancer predisposition syndrome, many others will not. Evidence from recent pediatric studies suggests that surveillance and early detection of cancer in individuals carrying a germline cancer predisposing mutation may result in improved outcomes. However, there is a lack of consistency in the design of cancer surveillance regimens across centers both nationally and internationally. To standardize approaches, the Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) convened a workshop, during which consensus screening recommendations for children with the most common cancer predisposition syndromes were developed. In general, we considered a 5% or greater chance of developing a childhood cancer to be a reasonable threshold to recommend screening. Conditions for which the cancer risk was between 1% to 5% were addressed individually. In a series of manuscripts accompanying this article, we provide recommendations for surveillance, focusing on when to initiate and/or discontinue specific screening measures, which modalities to use, and the frequency of screening. Points of controversy are also reviewed. We present the outcome of our deliberations on consensus screening recommendations for specific disorders in 18 position articles as Open Access publications, which are freely available on an AACR-managed website. Clin Cancer Res; 23(11); e1-e5. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Ensuring a competent public health responder workforce: The CDC experience.
From 2009 to 2016, the Centers for Disease Control and Prevention (CDC) activated its Incident Management System for a public health emergency 91 percent of the time. The CDC must ensure its workforce is prepared for the evolving nature of emergencies. The purpose of this assessment was to identify perceived preparedness and response training needs for the CDC responder workforce. Between November 2012 and January 2013, focus groups and in-depth interviews were conducted with CDC responders, including senior leaders. The evaluation questions were: (1) How well does the current training system prepare CDC staff to respond to emergency events? (2) What gaps exist in the current training system? and (3) What trainings are essential and should be included in the training system? Eight focus groups were conducted with 51 responders and 18 interviews with response leaders. Themes were identified for each main outcome measure and translated to training improvements. The CDC workforce received foundational training. Recommendations are provided to better prepare responders during an emergency. Periodic assessments are necessary to expand training and remain responsive to the complexities of emerging threats.