Next-generation phenotyping using computer vision algorithms in rare genomic neurodevelopmental disorders.
The interpretation of genetic variants after genome-wide analysis is complex in heterogeneous disorders such as intellectual disability (ID). We investigate whether algorithms can be used to detect if a facial gestalt is present for three novel ID syndromes and if these techniques can help interpret variants of uncertain significance. Facial features were extracted from photos of ID patients harboring a pathogenic variant in three novel ID genes (PACS1, PPM1D, and PHIP) using algorithms that model human facial dysmorphism, and facial recognition. The resulting features were combined into a hybrid model to compare the three cohorts against a background ID population. We validated our model using images from 71 individuals with Koolen-de Vries syndrome, and then show that facial gestalts are present for individuals with a pathogenic variant in PACS1 (p = 8 × 10-4), PPM1D (p = 4.65 × 10-2), and PHIP (p = 6.3 × 10-3). Moreover, two individuals with a de novo missense variant of uncertain significance in PHIP have significant similarity to the expected facial phenotype of PHIP patients (p < 1.52 × 10-2). Our results show that analysis of facial photos can be used to detect previously unknown facial gestalts for novel ID syndromes, which will facilitate both clinical and molecular diagnosis of rare and novel syndromes.


Approaches for improving sexuality and sexual health care in mental health settings: A qualitative study exploring clinicians' own perspectives.
There is an acknowledged professional practice gap regarding sexuality and sexual health related needs within mental health settings in Australia and internationally. Yet little is known about how clinicians can be best supported or enabled to improve sexuality-related practice, from their own perspective. This is important, given the sensitive and complex nature of sexuality and sexual health within the context of mental distress and service provision. This article reports a follow-up study, where mental health clinicians who participated in an initial study were invited to reflect on and discuss the (finalized) results and recommendations generated. The aim was to generate insights into the tools, strategies, and approaches participants felt would best equip and support clinicians to better incorporate sexuality and sexual health into their work. Six clinicians from three disciplines (mental health nursing, psychology, and psychiatry) participated in in-depth interviews to reflect on a plain language summary of the initial study. Three interconnected themes were generated via reflexive thematic analysis: (1) access to knowledge and information; (2) support from peers, senior colleagues, and workplaces; and (3) enacting a focus on sexuality-related care. These findings provide valuable insights into how clinicians may want to be supported in relation to (improving) their sexuality-related practice. The analysis also demonstrates the importance of a multifaceted approach to improving sexuality-related care in mental health and other health settings. This knowledge will contribute to directing future research and development of interventions, tools, strategies, or other approaches to this end.


Characterization of root-yield-1.06, a major constitutive QTL for root and agronomic traits in maize across water regimes.
A previous study on maize F(2:3) families derived from Lo964xLo1016 highlighted one QTL in bin 1.06 (hereafter named root-yield-1.06) affecting root and agronomic traits of plants grown in well-watered (WW) and water-stressed (WS) conditions. Starting from different F(4) families, two pairs of near isogenic lines (NILs) were developed at root-yield-1.06. The objective of this study was to evaluate root-yield-1.06 effects across different water regimes, genetic backgrounds, and inbreeding levels. The NILs per se and their crosses with Lo1016 and Lo964 were tested in 2008 and 2009 near to Bologna, with the well-watered (WW) and water-stressed (WS) treatments providing, on average, 70 mm and 35 mm of water, respectively. For NILs per se, the interactions QTL x water regime and QTL x family were negligible in most cases; the QTL additive effects across families were significant for several traits, especially root clump weight. For NILs crosses, analogously to NILs per se, the interactions were generally negligible and the additive effects across water regimes and families were significant for most traits, especially grain yield. A meta-analysis carried out considering the QTLs described in this and previous studies inferred one single locus as responsible for the effects on roots and agronomic traits. Our results show that root-yield-1.06 has a major constitutive effect on root traits, plant vigour and productivity across water regimes, genetic backgrounds, and inbreeding levels. These features suggest that root-yield-1.06 is a valuable candidate for cloning the sequence underlying its effects and for marker-assisted selection to improve yield stability in maize.


Dietary proanthocyanidins boost hepatic NAD(+) metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats.
Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD(+)) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD(+) precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD(+). Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD(+) availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD(+) levels.


DeadEasy Mito-Glia: automatic counting of mitotic cells and glial cells in Drosophila.
Cell number changes during normal development, and in disease (e.g., neurodegeneration, cancer). Many genes affect cell number, thus functional genetic analysis frequently requires analysis of cell number alterations upon loss of function mutations or in gain of function experiments. Drosophila is a most powerful model organism to investigate the function of genes involved in development or disease in vivo. Image processing and pattern recognition techniques can be used to extract information from microscopy images to quantify automatically distinct cellular features, but these methods are still not very extended in this model organism. Thus cellular quantification is often carried out manually, which is laborious, tedious, error prone or humanly unfeasible. Here, we present DeadEasy Mito-Glia, an image processing method to count automatically the number of mitotic cells labelled with anti-phospho-histone H3 and of glial cells labelled with anti-Repo in Drosophila embryos. This programme belongs to the DeadEasy suite of which we have previously developed versions to count apoptotic cells and neuronal nuclei. Having separate programmes is paramount for accuracy. DeadEasy Mito-Glia is very easy to use, fast, objective and very accurate when counting dividing cells and glial cells labelled with a nuclear marker. Although this method has been validated for Drosophila embryos, we provide an interactive window for biologists to easily extend its application to other nuclear markers and other sample types. DeadEasy MitoGlia is freely available as an ImageJ plug-in, it increases the repertoire of tools for in vivo genetic analysis, and it will be of interest to a broad community of developmental, cancer and neuro-biologists.


[Effect of indomethacin on the development of noradrenaline-induced heart lesions in rats].
The isolated perfused rat heart was used to study the damaging effect of noradrenaline. This effect is observed when noradrenaline is added to the perfusate. The degree of cellular damage was assessed from creatine phosphokinase release into the perfusate. Pretreatment of rats with indomethacin increases heart injury induced by noradrenaline. The results of the experiments suggest that the effect of indomethacin is related to its ability to inhibit the synthesis of prostaglandins.


Pain intensity, disability and depression in individuals with chronic back pain.
to measure the pain intensity, identify the disability and depression levels in people with chronic back pain and to correlate these variables. A cross-sectional, descriptive and exploratory study was undertaken at the Pain Treatment Clinic of the University of São Paulo at Ribeirão Preto Hospital das Clínicas, between February and June 2012, after receiving approval from the Ethics Committee at the University of São Paulo at Ribeirão Preto College of Nursing. sixty subjects with chronic back pain participated. The instruments used were: the 11-point Numerical Category Scale, the Roland-Morris Disability Questionnaire and the Beck Depression Inventory. To analyze the data, the arithmetic means, standard deviations and Spearman's correlation coefficient were calculated. the findings show that the participants presented high pain, disability and depression levels. The correlation between pain intensity and disability and between pain intensity and depression was positive and weak and, between disability and depression, positive and moderate. the study variables showed moderate and weak indices and the mutual correlations were positive.


Imaging diagnosis: Multiple cartilaginous exostoses and calcinosis circumscripta occurring simultaneously in the cervical spine of a dog.
An 8-month-old female Saint Bernard dog was presented with gait abnormalities consistent with a left-lateralizing cervical myelopathy. Imaging revealed a large, irregular soft tissue and mineral mass at the level of C1 and C2. The lesion was successfully excised, and histopathology was performed, revealing evidence of both multiple cartilaginous exostoses and calcinosis circumscripta. To the authors' knowledge, this is the first report comparing features using magnetic resonance imaging, computed tomography, and radiography. Additionally, multiple cartilaginous exostoses have not previously been reported to occur in combination with calcinosis circumscripta.


Regenerating Salivary Glands in the Microenvironment of Induced Pluripotent Stem Cells.
This report describes our initial attempt to regenerate salivary glands using induced pluripotent stem (iPS) cells in vivo and in vitro. Glandular tissues that were similar to the adult submandibular glands (SMGs) and sublingual glands could be partially produced by the transplantation of iPS cells into mouse salivary glands. However, the tumorigenicity of iPS cells has not been resolved yet. It is well known that stem cells affect their microenvironment, known as a stem cell niche. We focused on the niche and the interaction between iPS cells and salivary gland cells in our study on salivary gland regeneration. Coculture of embryonic SMG cells and iPS cells have better-developed epithelial structures and fewer undifferentiated specific markers than monoculture of embryonic SMG cells in vitro. These results suggest that iPS cells have a potential ability to accelerate differentiation for salivary gland development and regeneration.


Role of N-linked glycosylation in biosynthesis, trafficking, and function of the human glucagon-like peptide 1 receptor.
The family B G protein-coupled glucagon-like peptide 1 (GLP-1) receptor is an important drug target for treatment of type 2 diabetes. Like other family members, the GLP-1 receptor is a glycosylated membrane protein that contains three potential sites for N-linked glycosylation within the functionally important extracellular amino-terminal domain. However, the roles for each potential site of glycosylation in receptor biosynthesis, trafficking, and function are not known. In this work, we demonstrated that tunicamycin inhibition of glycosylation of the GLP-1 receptor expressed in CHO cells interfered with biosynthesis and intracellular trafficking, thereby eliminating natural ligand binding. To further investigate the roles of each of the glycosylation sites, site-directed mutagenesis was performed to eliminate these sites individually and in aggregate. Our results showed that mutation of each of the glycosylation sites individually did not interfere with receptor expression on the cell surface, ligand binding, and biological activity. However, simultaneous mutation of two or three glycosylation sites resulted in almost complete loss of GLP-1 binding and severely impaired biological activity. Immunostaining studies demonstrated receptor biosynthesis but aberrant trafficking, with most of the receptor trapped in the endoplasmic reticulum and golgi compartments and little of the receptor expressed on the cell surface. Interestingly, surface expression, ligand binding, and biological activity of these mutants improved significantly when biosynthesis was slowed using low temperature (30 degrees C). These data suggest that N-linked glycosylation of the GLP-1 receptor is important for its normal folding and trafficking to the cell surface.


[Mechanisms of human orientation sensitivity of the vision system. Part I. Behavioral characteristics of human orientation sensitivity. Influence of task type, experimental conditions and gender].
Orientation sensitivity in human visual system was investigated in three experiments. In the first experiment 134 subjects were to determine the orientation of the segments of short lines, by "selecting" it from a set of reference orientations (Benton's test). In the second experiment 41 subject, which was chosen from participants of the first experiment, were to estimate the proximity of oblique lines to the vertical, horizontal, and 45° axis. In the third experiment participants were to identify the orientation of cardinal (0° and 90°) and oblique (45° and 135°) lines. It was shown that the cardinal orientations were defined more accurately and faster than the oblique ones. Error type depended on experimental conditions: participant answers tilted to horizontal under normal illumination in the presence of peripheral visual information, but they tilted to vertical under low illumination (3 lux.). Women performed worse only those tasks which require precise determination of the line orientation. It was assumed that the metric spatial characteristics determined better by males then females. The oblique effect was more pronounced in females, presumably due to gender differences in brain organization of the multimodal reference frame.


On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment.
Thrombotest (TT) values were studied in patients fed an ordinary diet and on continuous and well controlled warfarin therapy because of deep venous thrombosis or pulmonary embolism. The aim was to characterize the effect of single and multiple administrations (daily during one week) of vitamin K1 (Konakion), vitamin K-rich vegetables such as spinach and broccoli, and table wine. Single administration of 250 micrograms vitamin K1, 250 g spinach, 250 g broccoli and 37.5 cl wine did not result in TT-values outside the therapeutic range. However, when Konakion, broccoli and spinach were given daily during one week the TT-values tended to rise above the therapeutic limit, requiring dose adjustment. On the basis of this study it appears that excessive intake of vitamin K-rich food and a moderate intake of alcohol on one occasion may be permitted during anticoagulant therapy.


Aerosols containing Legionella pneumophila generated by shower heads and hot-water faucets.
Shower heads and hot-water faucets containing Legionella pneumophila were evaluated for aerosolization of the organism with a multistage cascade impaction air sampler. Air was collected above two shower doors and from the same rooms approximately 3 ft (91 cm) from the shower doors while the hot water was running. Low numbers (3 to 5 CFU/15 ft3 [0.43 m3] of air) of L. pneumophila were recovered above both shower doors, but none was recovered from the air in either room outside the shower door. Approximately 90% (7 of 8 CFU) of the L. pneumophila recovered were trapped in aerosol particles between 1 and 5 micron in diameter. Air was collected 1 to 3 ft (30 to 91 cm) from 14 sinks while the hot water was running. Low numbers (1 to 5 CFU/15 ft3 of air) were recovered from 6 of 19 air samples obtained. Approximately 50% (6 of 13 CFU) of the organisms recovered were trapped in aerosol particles between 1 and 8 microns in diameter. Shower heads and hot-water taps containing L. pneumophila can aerosolize low numbers of the organism during routine use. The aerosol particle size is small enough to penetrate to the lower human respiratory system. Thus, these sites may be implicated as a means of transmission of L. pneumophila from potable water to the patient.


Case Report: Erythema Multiforme Induced by Lithium Contact.
Erythema multiforme (EM) is an acute, self-limited mucocutaneous disease with diverse triggering factors, and the recurrences are quite common. A 24-year old male presented with multiple erythematous, itchy papules and plaques on multiple sites. He has worked in a lithium battery factory and experienced the chemical burn 2 weeks ago. A histopathologic examination on right wrist showed a scattered lymphocytic infiltration, vacuolar degeneration, and necrotic keratinocyte. The final diagnosis was EM after occupational lithium exposure. He was treated by oral methylprednisolone and experienced recurrences after returning to the same workplace after remission. Although the precise pathogenesis is unknown, the pathogenesis of EM by lithium is related to the effect of lithium on immune system, different from other etiologies. To our knowledge, our case is the first report of EM following the chemical burn and occupational lithium exposure. We report this as an interesting case of EM.


Site-specific periosteal cells with distinct osteogenic and angiogenic characteristics.
This study aimed to investigate the site-specific characteristics of rat mandible periosteal cells (MPCs) and tibia periosteal cells (TPCs) to assess the potential application of periosteal cells (PCs) in bone tissue engineering (BTE). MPCs and TPCs were isolated and characterized. The potential of proliferation, migration, osteogenesis and adipogenesis of MPCs and TPCs were evaluated by CCK-8, scratch assay, Transwell assay, alkaline phosphatase staining and activity, Alizarin Red S staining, RT‒qPCR, and Western blot (WB) assays, respectively. Then, these cells were cocultured with human umbilical vein endothelial cells (HUVECs) to investigate their angiogenic capacity, which was assessed by scratch assay, Transwell assay, Matrigel tube formation assay, RT‒qPCR, and WB assays. MPCs exhibited higher osteogenic potential, higher alkaline phosphatase activity, and more mineralized nodule formation, while TPCs showed a greater capability for proliferation, migration, and adipogenesis. MPCs showed higher expression of angiogenic factors, and the conditioned medium of MPCs accelerated the migration of HUVECs, while MPC- conditioned medium induced the formation of more tubular structure in HUVECs in vitro. These data suggest that compared to TPCs, MPCs exert more consequential proangiogenic effects on HUVECs. PCs possess skeletal site-specific differences in biological characteristics. MPCs exhibit more eminent osteogenic and angiogenic potentials, which highlights the potential application of MPCs for BTE. Autologous bone grafting as the main modality for maxillofacial bone defect repair has many limitations. Constituting an important cell type in bone repair and regeneration, MPCs show greater potential for application in BTE, which provides a promising treatment option for maxillofacial bone defect repair.


Evaluation of staphylococcal food contamination in four different culture media.
The efficiency of Baird-Parker agar, mannitol-salt agar, Vogel-Johnson agar and Giolitti-Cantoni broth for the detection of Staphylococcus aureus from food samples, was studied by comparing the numbers of Staphylococcus recovered from the samples, the degree of selectivity reached and the recovery of coagulase and thermonuclease positive staphylococci. Lowest counts of Staphylococcus were obtained with Giolitti-Cantoni broth. The mannitol-salt agar proved to be the most efficient media system with respect to the number of staphylococci recovered and the degree of selectivity reached. None of these media was highly selective for the isolation and detection of S. aureus; therefore, it is necessary to identify the isolated colonies in all cited media, in order to use rightly the current guidelines for microbiological quality of foods.


[Bone matrix gelatin. Clinical application in 38 cases].
Bone matrix gelatin (BMG) was prepared and used clinically as graft-stuff in 38 patients. It was used to fill the bone defects resulted from excision of benign bone tumors (22 patients) and debridement of chronic osteomyelitis (3), to treat delayed union of fractures (5), and to make posterior spinal fusion (8). Fourty-five days after operation, speckles or flakes of dense shadow appeared in the film at the original defects and fields. In 2 to 6 months, bony union took place in 36 patients (95%). Failure was noted in 2 patients with chronic osteomyelitis. Because of its excellent osteo-inductive property and nonantigenic treat, BMG has been proved to be an ideal substitute for bone graft. It is easy to prepare, safe for storage at room temperature and sound for transportation.


How Racism "Gets Under the Skin": An Examination of the Physical- and Mental-Health Costs of Culturally Compelled Coping.
Historically and contemporarily, Black Americans have been compelled to use effortful coping styles characterized by high behavioral and emotional restraint in the face of systematic racism. Lynch and colleagues have previously conceptualized a class of regulatory strategies-overcontrolled coping-characterized by emotional suppression, hypervigilance for threat, and high distress tolerance, which bear close analogy to coping styles frequently used among individuals facing chronic racial stress. However, given the inherent culture of racism in the United States, engaging in highly controlled coping strategies is often necessitated and adaptive, at least in the short term. Thus, for Black Americans this class of coping strategies is conceptualized as culturally compelled coping rather than overcontrolled coping. In the current article, I offer a critical examination of the literature and introduce a novel theoretical model-culturally compelled coping-that culturally translates selected components of Lynch's model. Cultural translation refers to considering how the meaning, function, and consequences of using overcontrolled coping strategies changes when considering how Black Americans exist and cope within a culture of systematic racism. Importantly, this model may offer broad implications for future research and treatment by contextualizing emotion regulation as a central mechanism, partially answering how racism "gets under the skin" and affects the health of Black Americans.


Future Trends of the Primary Healthcare System in Iran: A Qualitative Study.
Primary healthcare system in Iran has played an extensive role in promoting people health in the past decades. However, regarding universal developments in the different global aspects effective on health, the performance of this system has been influenced significantly. The aim of the present research is to identify the future trends of the primary health care in Iran. The participants of this qualitative case study were experts in primary healthcare, which were selected and interviewed through purposive sampling method. The interview process was saturated after 25 interviews, so we stopped the process at this point. Framework analysis based on STEEP model used to analysis the interviews. The most important social/value, technological, economic, environmental, and political future trends of primary healthcare in Iran included demographic transition, epidemiological transition, social and cultural changes, emergence of modern and advanced technologies, internet and cyberspace, budgeting limitations, resource management, changing paradigm from volume to value in providing health services, environmental pollutions, natural disasters, health governance, intellectual paradigm of senior officials, regional security, international development, and other internal factors of the health system. The identified factors can be turned into opportunities for Iran primary healthcare system if health planners and policymakers have a deep and accurate look at these influential factors and manage them properly.


Spectral Grouping of Electrically Encoded Sound Predicts Speech-in-Noise Performance in Cochlear Implantees.
Cochlear implant (CI) users exhibit large variability in understanding speech in noise. Past work in CI users found that spectral and temporal resolution correlates with speech-in-noise ability, but a large portion of variance remains unexplained. Recent work on normal-hearing listeners showed that the ability to group temporally and spectrally coherent tones in a complex auditory scene predicts speech-in-noise ability independently of the audiogram, highlighting a central mechanism for auditory scene analysis that contributes to speech-in-noise. The current study examined whether the auditory grouping ability also contributes to speech-in-noise understanding in CI users. Forty-seven post-lingually deafened CI users were tested with psychophysical measures of spectral and temporal resolution, a stochastic figure-ground task that depends on the detection of a figure by grouping multiple fixed frequency elements against a random background, and a sentence-in-noise measure. Multiple linear regression was used to predict sentence-in-noise performance from the other tasks. No co-linearity was found between any predictor variables. All three predictors (spectral and temporal resolution plus the figure-ground task) exhibited significant contribution in the multiple linear regression model, indicating that the auditory grouping ability in a complex auditory scene explains a further proportion of variance in CI users' speech-in-noise performance that was not explained by spectral and temporal resolution. Measures of cross-frequency grouping reflect an auditory cognitive mechanism that determines speech-in-noise understanding independently of cochlear function. Such measures are easily implemented clinically as predictors of CI success and suggest potential strategies for rehabilitation based on training with non-speech stimuli.


Periodic habitat loss alters the competitive coexistence between brown trout and bullheads in a small stream over 34 years.
1. Changes in the population density of juvenile sea trout Salmo trutta L. and bullheads Cottus gobio L. were compared in a small stream over 34 years. Both species have a similar diet and obviously live in the same general habitat. Habitat loss was most marked in seven summer droughts: severest in 1976, 1983, 1984, 1995, and less severe but followed by autumn droughts in 1969, 1989 and 1993. The contrasting effects of habitat loss on the two species were examined. 2. For both species, the Ricker curvilinear model significantly fit (P < 0.001) the relationship between initial egg density and survivor density for successive life stages, even though egg densities were much lower for bullheads than trout. These analyses provided evidence for density-dependent population regulation and also identified extreme outliers, most being for year-classes affected by summer droughts. 3. The variable effects of changes in habitable area (= % wettable area in sampling section) were quantified by using the residuals, each residual being the absolute value expressed as a percentage of the expected value from the Ricker curve. Significant relationships between the residuals and habitable area showed that habitat loss had a marked effect on survivor density, this being negative for 0+ and 1+ trout, and positive for 0+, 1+ and 2+/3+ bullheads. 4. Therefore, during periods of habitat loss in the summer months, bullhead density increased at the expense of trout density. Low flows and a decrease in wettable area were associated with a marked reduction in habitat quality for drift-feeding trout and an increase in habitat quality, and perhaps also quantity, for benthic-feeding bullheads. This case study shows that, during a major perturbation, the relationship between the densities of two species can change markedly in favour of the less numerous species. The competitive coexistence between the two species is therefore a dynamic process that changes through time with periodic changes in the environment.


Prediction of malignancy in cystic neoplasms of the pancreas: a population-based cohort study.
Pancreatic cystic neoplasms (PCNs) are being detected with increased frequency. The aims of this study were to determine the incidence of malignancy and develop an imaging-based system for prediction of malignancy in PCN. We conducted a retrospective cohort study of patients ≥18 years of age with confirmed PCN from January 2005 to December 2010 in a community-based integrated care setting in Southern California. Patients with history of acute or chronic pancreatitis were excluded. Malignancy diagnosed within 3 months of cyst diagnosis was considered as pre-existing. Subsequent incidence of malignancy during surveillance was calculated based on person-time at risk. Age- and gender-adjusted standardized incidence ratio (SIR) was calculated with the non-cyst reference population. Recursive partitioning was used to develop a risk prediction model based on cyst imaging features. We identified 1,815 patients with confirmed PCN. A total of 53 (2.9%) of patients were diagnosed with cyst-related malignancy during the study period. The surveillance cohort consisted of 1,735 patients with median follow-up of 23.4 months. Incidence of malignancy was 0.4% per year during surveillance. The overall age- and gender-adjusted SIR for pancreatic malignancy was 35.0 (95% confidence level 26.6, 46.0). Using recursive partitioning, we stratified patients into low (<1%), intermediate (1-5%), and high (9-14%) risk of harboring malignant PCN based on four cross-sectional imaging features: size, pancreatic duct dilatation, septations with calcification as well as growth. Area under the receiver operator characteristic curve for the prediction model was 0.822 (training) and 0.808 (testing). Risk of pancreatic malignancy was lower than previous reports from surgical series but was still significantly higher than the reference population. A risk stratification system based on established imaging criteria may help guide future management decisions for patients with PCN.


Characteristics of women diagnosed with mpox infection compared to men: A case series from Brazil.
Cisgender men were mostly affected during the 2022 mpox multinational outbreak, with few cases reported in women. This study compares the characteristics of individuals diagnosed with mpox infection according to gender in Rio de Janeiro. We obtained surveillance data of mpox cases notified to Rio de Janeiro State Health Department (June 12 to December 15, 2022). We compared women (cisgender or transgender) to men (cisgender or transgender) using chi-squared, Fisher's exact, and Mood's median tests. A total of 1306 mpox cases were reported; 1188 (91.0%) men (99.8% cisgender, 0.2% transgender), 108 (8.3%) women (87.0% cisgender, 13.0% transgender), and 10 (0.8%) non-binary persons. Compared to men, women were more frequently older (40+years: 34.3% vs. 25.1%; p < 0.001), reported more frequent non-sexual contact with a potential mpox case (21.4% vs. 9.8%; p = 0.004), fewer sexual partnerships (10.9 vs. 54.8%; p < 0.001), less sexual contact with a potential mpox case (18.5% vs. 43.0%; p < 0.001), fewer genital lesions (31.8% vs. 57.9%; p < 0.001), fewer systemic mpox signs/symptoms (38.0% vs. 50.1%; p = 0.015) and had a lower HIV prevalence (8.3% vs. 46.3%; p < 0.001), with all cases among transgender women. Eight women were hospitalized; no deaths occurred. The highest number of cases among women were notified in epidemiological week 34, when the number of cases among men started to decrease. Women diagnosed with mpox presented differences in epidemiological, behavioral, and clinical characteristics compared to men. Health services should provide a comprehensive assessment that accounts for gender diversity.


[Anti-allergic effects of tazanolast [butyl 3'-(1H-tetrazol-5-yl) oxanilate, WP-833] metabolites].
WP-833 is an orally active new antiallergic drug. The effects of WP-833 metabolites on experimental allergic reactions were investigated in various animal models. MTCC [3'-(1H-tetrazol-5-yl) oxanilic acid], the main metabolite of WP-833, dose-dependently inhibited 48-hr homologous passive cutaneous anaphylaxis (PCA) in rats and 8-day PCA in guinea pigs after intravenous administration. The inhibitory effect of MTCC on PCA was nearly equal to that of WP-833. MTCC also inhibited 48hr PCA in rats after the peroral administration, although its inhibitory effect was about 6 times weaker than that of WP-833. MTCC also showed a dose-dependent inhibition on the release of histamine or slow reacting substance of anaphylaxis (SRS-A) from passively sensitized rat peritoneal mast cells and guinea pig lung fragments in vitro with a similar potency to WP-833. MTA [3-(1H-tetrazol-5-yl) aniline] and MTAA [3'-(1H-tetrazol-5-yl) acetanilide], other metabolites of WP-833, inhibited PCA and anaphylactic histamine release from rat peritoneal mast cells at considerably higher doses than WP-833, and they showed no effects on the release of histamine and SRS-A from guinea pig lung fragments. Moreover, only small amounts of MTA and MTAA were detected in the blood after the oral administration of WP-833. From these results, it was suggested that MTCC may be the main active metabolite of WP-833.


Atherosclerosis, Periodontal Disease, and Treatment with Resolvins.
This review aims to discuss the existing evidence on the link between atherosclerosis and periodontitis by particularly presenting new findings that link the pathology and therapy of these diseases. Acute vascular ischemic events that can lead to stroke or myocardial infarction are initiated by inflammatory processes leading to rupture or erosion of plaques susceptible to thrombosis ("high risk" or "vulnerable"). These are highly inflamed plaques residing in the media and adventitia that may not be detected by angiography measurments of luminal narrowing. Statistically significant excess risk for atherosclerotic cardiovascular disease has been reported in persons with periodontitis independent of established risk factors. We hypothesized that the systemic pathologic links also represent potential therapeutic links. We recently demonstrated that periodontal inflammation promotes atherosclerotic plaque inflammation and destabilization. As discrete pathological regions, these plaques with a high susceptibility to rupture can be imaged and differentiated from lower risk plaques. In cholesterol-fed rabbits with periodontal disease, circulating inflammatory mediators were also significantly elevated thereby contributing to "vulnerable blood," a systemic characteristic of high risk for cardiovascular events. New studies show that certain lipid mediators, including lipoxins and resolvins, are potent in preventing and possibly treating a number of inflammation-associated diseases, including periodontitis and vascular inflammation. The concept of the vulnerable patient and the pro-resolving approach open new terrain for discovery of paradigm-changing therapies for the prevention and treatment of two of the most common diseases of man. Importantly, lipoxins and resolvins are natural receptor agonists that do not exhibit the same pro-atherogenic side effects attributed to anti-inflammatory medications (e.g., NSAIDs) but rather coordinate resolution of inflammation and a return to homeostasis.


Distress and rumor exposure on social media during a campus lockdown.
During crisis events, people often seek out event-related information to stay informed of what is happening. However, when information from official channels is lacking or disseminated irregularly, people may be at risk for exposure to rumors that fill the information void. We studied information-seeking during a university lockdown following an active-shooter event. In study 1, students in the lockdown (n = 3,890) completed anonymous surveys 1 week later. Those who indicated receiving conflicting information about the lockdown reported greater acute stress [standardized regression coefficient (b) = 0.07; SE = 0.01; 95% confidence interval (CI), 0.04, 0.10]. Additionally, those who reported direct contact with close others via text message (or phone) and used Twitter for critical updates during the lockdown were exposed to more conflicting information. Higher acute stress was reported by heavy social media users who trusted social media for critical updates (b = 0.06, SE = 0.01; 95% CI, 0.03, 0.10). In study 2, we employed a big data approach to explore the time course of rumor transmission across 5 hours surrounding the lockdown within a subset of the university's Twitter followers. We also examined the patterning of distress in the hours during the lockdown as rumors about what was happening (e.g., presence of multiple shooters) spread among Twitter users. During periods without updates from official channels, rumors and distress increased. Results highlight the importance of releasing substantive updates at regular intervals during a crisis event and monitoring social media for rumors to mitigate rumor exposure and distress.


[Luminescence characteristics of mitochondrial actin-like protein].
Investigations comparing tryptophan fluorescence of mitochondrial actin-like protein with that of skeletal and smooth muscle actins have shown that the mitochondrial protein is characterized by a fluorescence spectrum peak at a longer wavelength (337 nm), by a certain broadening of this peak (56 nm) and by a reduction in the lifespan of the excited state of tryptophanyls (2.7 ns). The data obtained suggest the existence of peculiarities in the structure of mitochondrial actin-like protein.


C-reactive protein as a screening test for cardiovascular risk in a multiethnic population.
Small increases in the inflammatory marker C-reactive protein (CRP) are predictive of vascular events among asymptomatic individuals. There are few data supporting the use of CRP as a risk marker among nonwhite individuals. 1250 adults of South Asian, Chinese, European, and Aboriginal ancestry were randomly sampled from 4 communities in Canada. Participants provided fasting blood samples for CRP, glucose, lipids, and coagulation factors, and they had undergone a carotid B-mode ultrasound. Cardiovascular disease was determined by history and electrocardiogram. The age- and sex-adjusted mean CRP was 3.74 mg/L (standard error, 0.14) among Aboriginals, 2.59 mg/L (0.12) among South Asians, and 1.18 mg/L (0.13) among Chinese compared with 2.06 mg/L (0.12) among Europeans (overall P<0.0001). Differences in the CRP concentration between ethnic groups were substantially diminished, but not abolished, after adjustment for metabolic factors. CRP was independently associated with CVD after adjusting for the Framingham risk factors, atherosclerosis, anthropometric measurements, and ethnicity (OR=1.03 for a 0.1-increase in CRP; P=0.02). CRP varies substantially between people of different ethnic origin and is influenced by their differences in metabolic factors. Prospective validation of CRP as a risk predictor for cardiovascular disease among nonwhite ethnic groups is required.


Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy.
Mitochondrial dysfunction has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through poorly defined mechanisms. Melatonin supplementation has been found to protect liver function in diabetes and obesity. Here, we intensively explored the role and mechanism of melatonin in the development of NAFLD. We demonstrated that the onset of diet-induced NAFLD greatly caused NR4A1 upregulation in hepatocytes, leading to the activation of DNA-PKcs and p53. On the one hand, p53 aided Drp1 migration in the mitochondria and consequently drove mitochondrial fission. On the other hand, p53 repressed Bnip3 transcription and expression, resulting in mitophagy arrest. The excessive fission and deficient mitophagy dramatically mediated mitochondrial dysfunction, including extensive mPTP opening, reduction in mitochondrial potential, oxidative stress, calcium overload, mitochondrial respiratory collapse, and ATP shortage. However, genetic deletion of NR4A1 or DNA-PKcs could definitively reverse NAFLD progression and the mitochondrial dysfunction. Similarly, melatonin supplementation could robustly reduce the damage to liver and mitochondrial structure and function in NAFLD. Mechanistically, melatonin halted fission but recovered mitophagy via blockade of NR4A1/DNA-PKcs/p53 pathway, finally improving mitochondrial and liver function in the setting of NAFLD. Our results identify NR4A1/DNA-PKcs/p53 pathway as the novel molecular mechanism underlying the pathogenesis of NAFLD via regulation of Drp1-mediated mitochondrial fission and Bnip3-related mitophagy. Meanwhile, we also confirm that melatonin has the ability to cut off the NR4A1/DNA-PKcs/p53 pathway, which confers a protective advantage to hepatocytes and mitochondria. The manipulation of NR4A1/DNA-PKcs/p53 pathway by melatonin highlights a new entry point for treating NAFLD.


A semi-mechanistic model for the effects of a novel glucagon receptor antagonist on glucagon and the interaction between glucose, glucagon, and insulin applied to adaptive phase II design.
A potent novel compound (MK-3577) was developed for the treatment of type 2 diabetes mellitus (T2DM) through blocking the glucagon receptor. A semi-mechanistic model was developed to describe the drug effect on glucagon and the interaction between glucagon, insulin, and glucose in healthy subjects (N = 36) during a glucagon challenge study in which glucagon, octreotide (Sandostatin), and basal insulin were infused for 2 h starting from 3, 12, or 24 h postdose of a single 0-900 mg MK-3577 administration. The drug effect was modeled by using an inhibitory E max model (I max = 0.96 and IC50 = 13.9 nM) to reduce the ability of glucagon to increase the glucose production rate (GPROD). In addition, an E max model (E max = 0.79 and EC50 = 575 nM) to increase glucagon secretion by the drug was used to account for the increased glucagon concentrations prechallenge (via compensatory feedback). The model adequately captured the observed profiles of glucagon, glucose, and insulin pre- and postchallenge. The model was then adapted for the T2DM patient population. A linear model to correlate fasting plasma glucose (FPG) to weighted mean glucose (WMG) was developed and provided robust predictions to assist with the dose adjustment for the interim analysis of a phase IIa study.


Rarity of PTEN deletions and EGFR amplification in malignant gliomas of childhood: results from the Children's Cancer Group 945 cohort.
In reporting on molecular studies involving malignant gliomas in adults, authors have noted that deletions of PTEN and amplification of EGFR are common and may contribute to tumor development, providing a rationale for a number of therapies aimed at these molecular targets. The frequency of comparable abnormalities has not been defined in a sizable pediatric cohort. To address this issue, we examined tumor samples from the Children's Cancer Group 945 study, a large randomized trial of treatment for childhood malignant gliomas. Tissue sections in 62 evaluable cases were examined, and the tumors were isolated by microdissection. Polymerase chain reaction amplification was used to detect PTEN mutations. Deletions of PTEN were also assessed by fluorescence in situ hybridization (FISH) in 27 cases and loss of heterozygosity analysis in 54; EGFR was assessed using immunohistochemistry to identify areas with maximal EGFR expression, followed by FISH to determine EGFR amplification. Alteration of the PTEN sequence was detected in just one of 62 tumors, in conjunction with loss of chromosome 10; PTEN deletions without mutation were evident in seven additional tumors. The PTEN alterations were more common in glioblastoma multiforme (seven of 25 tumors) than other tumor subgroups (one of 37 tumors) (p = 0.0056). Although 14 of 38 evaluable tumors had increased EGFR expression compared to normal tissue, only one tumor exhibited amplification of EGFR. Alterations in PTEN and amplification of EGFR are uncommon in pediatric malignant gliomas, in contrast to adult malignant gliomas. From this one can infer that the pediatric and adult tumors involve distinct molecular causes. The results of this study have important implications for the adaptation of glioma therapies aimed at molecular targets in adults to the treatment of childhood gliomas, and highlight the need for investigations of therapies specifically directed toward childhood tumors.


Columnar cell lesions of the canine mammary gland: pathological features and immunophenotypic analysis.
It has been suggested that columnar cell lesions indicate an alteration of the human mammary gland involved in the development of breast cancer. They have not previously been described in canine mammary gland. The aim of this paper is describe the morphologic spectrum of columnar cell lesions in canine mammary gland specimens and their association with other breast lesions. A total of 126 lesions were subjected to a comprehensive morphological review based upon the human breast classification system for columnar cell lesions. The presence of preinvasive (epithelial hyperplasia and in situ carcinoma) and invasive lesions was determined and immunophenotypic analysis (estrogen receptor (ER), progesterone receptor (PgR), high molecular weight cytokeratin (34betaE-12), E-cadherin, Ki-67, HER-2 and P53) was perfomed. Columnar cell lesions were identified in 67 (53.1%) of the 126 canine mammary glands with intraepithelial alterations. They were observed in the terminal duct lobular units and characterized at dilated acini may be lined by several layers of columnar epithelial cells with elongated nuclei. Of the columnar cell lesions identified, 41 (61.2%) were without and 26 (38.8%) with atypia. Association with ductal hyperplasia was observed in 45/67 (67.1%). Sixty (89.5%) of the columnar cell lesions coexisted with neoplastic lesions (20 in situ carcinomas, 19 invasive carcinomas and 21 benign tumors). The columnar cells were ER, PgR and E-cadherin positive but negative for cytokeratin 34betaE-12, HER-2 and P53. The proliferation rate as measured by Ki-67 appeared higher in the lesions analyzed than in normal TDLUs. Columnar cell lesions in canine mammary gland are pathologically and immunophenotypically similar to those in human breast. This may suggest that dogs are a suitable model for the comparative study of noninvasive breast lesions.


Cloning and identification of the product of the dnaE gene of Escherichia coli.
We successively subcloned the dnaE gene of Escherichia coli into pBR322, resulting in a plasmid that contains 4.6 kilobases of E. coli DNA. This plasmid can complement a dnaE temperature-sensitive mutation. A restriction map of the dnaE gene and the surrounding 10.7-kilobase region of the E. coli chromosome was determined. A unique HindIII restriction endonuclease site within the cloned segment of DNA was identified as a site required for expression of the dnaE gene. By using the maxicell plasmid-directed protein synthesizing system, we demonstrated that dnaE codes for the alpha subunit of DNA polymerase III.


Mini-cognitive testing in patients with age-related macular degeneration.
To compare Mini-Cognitive (Mini-Cog) Screening test results between patients with age-related macular degeneration (AMD) and age-matched controls. Two hundred and twenty-nine patients were included in the study. Patients were divided into 3 groups: 56 patients with exudative AMD, mean age of 76 ± 8 years; 82 patients with dry AMD, mean age of 77 ± 9 years; and 91 controls, mean age of 75 ± 8 years. The Mini-Cog test, used to screen patients with early cognitive impairment, was introduced to the three groups of patients at the settings of an ophthalmology outpatient clinic. Test scores were compared between the groups. The mean for the Mini-Cog test scores was 3.5 (95% confidence interval, 3.15-3.85) for the dry AMD group, 3.95 (95% confidence interval, 3.51-4.39) for the exudative AMD group, and 4.63 (95% confidence interval, 4.45-4.80) for the control group. There was no statistically significant difference between the scores of AMD groups, however, both AMD groups received significantly lower scores than controls (P < 0.0001). Patients with age-related macular degeneration in this study demonstrated lower mean scores in the Mini-Cog test than age-matched controls. The Mini-Cog test may be easily applied at an office setting of ophthalmology outpatient clinics, and may help in the early diagnosis of cognitive impairment in the patients with AMD.


Direct evidence for a stimulatory effect of hyperglycemia per se on peripheral glucose disposal in type II diabetes.
The effect of hyperglycemia per se on glucose uptake by muscle tissue was quantitated in six controls and six type II diabetics by the forearm technique, under conditions of insulin deficiency induced by somatostatin (SRIF) infusion (0.7 mg/h). Blood glucose concentration was clamped at its basal value during the first 60 min of SRIF infusion and then raised to approximately 200 mg/dl by a variable glucose infusion. Plasma insulin levels remained at or below 5 microU/ml during SRIF infusion, including the hyperglycemic period. No appreciable difference between controls and diabetics was present in the basal state as to forearm glucose metabolism. After 60 min of SRIF infusion and euglycemia, forearm glucose uptake fell consistently from 2.1 +/- 0.7 mg X liter-1 X min-1 to 1.0 +/- 0.6 (P less than 0.05) and from 1.7 +/- .2 to 0.4 +/- 0.3 (P less than 0.02) in the control and diabetic groups, respectively. The subsequent induction of hyperglycemia caused a marked increase in both the arterial-deep venous blood glucose difference (P less than 0.02-0.01) and forearm glucose uptake (P less than 0.01-0.005). However, the response in the diabetic group was significantly greater than that observed in controls. The incremental area of forearm glucose uptake was 276 +/- 31 mg X liter-1 X 90 min and 532 +/- 81 in the control and diabetic groups, respectively (P less than 0.02). In the basal state, the forearm released lactate and alanine both in controls and diabetic subjects at comparable rates. No increment was observed after hyperglycemia, despite the elevated rates of glucose uptake. It is concluded that (1) hyperglycemia per se stimulates forearm glucose disposal to a greater extent in type II diabetics than in normal subjects; and (2) the resulting increment of glucose disposal does not accelerate the forearm release of three carbon compounds. The data support the hypothesis that hyperglycemia per se may play a compensatory role for the defective glucose disposal in type II diabetes.


Effects of dietary ratio of linoleic to linolenic acid on performance, antibody production, and in vitro lymphocyte proliferation in two strains of leghorn pullet chicks.
The effects of dietary ratio of linoleic acid to linolenic acid on performance, mitogenic lymphocyte proliferation, and antibody production were evaluated in Leghorn pullets during a rigorous vaccination program. Diets were supplemented with flaxseed and corn oil to achieve 4 dietary ratios of linoleic acid to linolenic acid [17:1 (control), 8:1, 4:1, or 2:1]. Each diet was fed to HyLine Brown or W-36 pullets from 1 d to 16 wk of age. Day-old pullets were randomly assigned to 8 replicate cages with 12 pullets per cage; the density was reduced to 8 pullets per cage at 11 wk of age. Dietary treatments did not affect body weight, feed consumption, or pullet mortality. At 12 wk of age, an interaction between diet and strain (P < or = 0.004) showed Hy-Line W-36 pullets fed the 2:1 ratio had greater antibody production against Newcastle disease virus (NDV) vaccine than those fed diets with higher ratios. At wk 16, pullets fed ratios of 4:1 and 2:1 had the greatest antibody production against NDV vaccine. Antibody production against infectious bursal disease virus (IBDV) vaccine was also increased (P < 0.04) by ratios of 4:1 (2.244 optical density; OD) or 2:1 (2.508 OD) as compared with the control diet (1.576 OD). Hy-Line Brown pullets had greater antibody production against infectious bronchitis virus vaccine compared with Hy-Line W-36 pullets at 16 wk of age. These results indicate that feeding a reduced dietary ratio of linoleic to linolenic acid by adding flaxseed to the diets enhanced antibody response to NDV and IBDV vaccines without any negative effects on pullet performance.


Regulation of the growth and functions of cloned murine large granular lymphocyte lines by resident macrophages.
Using cloned lines with the morphology of large granular lymphocytes (LGL) from BALB/c mice, we studied the exact requirements for proliferation and their functional characteristics, as well as their regulation. Although these cloned LGL lines were interleukin 2 (IL-2) dependent for growth, experiments using human recombinant IL-2 (rIL-2), known to be active on murine cells, indicated that IL-2 was a necessary but not sufficient factor. Coexistance of normal macrophages in addition to rIL-2 was found to support continuous proliferation of cloned LGL in vitro. This role of macrophages could be replaced by partially purified IL-1 derived from macrophage-conditioned medium. An IL-2 binding assay using 125I-rIL-2 suggested that the role of normal macrophages was to selectively induce and/or maintain high affinity IL-2 receptors (IL-2R) (Kd, 0.2-0.5 nM) without affecting low affinity ones (Kd, 10-30 nM). Functional studies indicated that most of the LGL clones killed various combinations of representative groups of natural killer (NK)-susceptible target cells, including leukemic cells (YAC-1, RL male 1), virus-infected cells (HeLa-measles, HeLa-herpes simplex virus), and normal bone marrow cells (BMC), whereas none of them affected any of NK-resistant target cells, including uninfected HeLa cells. Some of these clones also suppressed in vitro hematopoiesis. Such characteristic cytotoxic spectra, as well as serological phenotypes (Thy-1+, Lyt-1-2-, asialo GM1-positive, T200+, TdT-, Fc receptor-positive) indicated that these LGL clones exactly represent endogenous NK cells, rather than a variety of anomalous killer cells generated in various culture conditions. Although there was significant heterogeneity of cytotoxic spectrum among LGL clones, no clonotypic distribution of specificities was observed. Normal macrophages were found to modulate the functional expression of LGL clones. They augmented the cytotoxic potential of the clones against leukemic and virus-infected targets, but suppressed intrinsic reactivity against normal BMC. Similarly, LGL clones maintained with macrophages showed much less suppressive effect on in vitro hematopoiesis. The present observations on the interaction of cloned LGL and normal macrophages provide a basic explanation for the mechanisms by which the immediate responsiveness to IL-2 of the NK effector system, without exogenous stimulation, and the functional selectivity toward abnormal rather than normal cells, are actively maintained in vivo.


Lossless image compression with multiscale segmentation.
This paper is concerned with developing a lossless image compression method which employs an optimal amount of segmentation information to exploit spatial redundancies inherent in image data. Multiscale segmentation is obtained using a previously proposed transform which provides a tree-structured segmentation of the image into regions characterized by grayscale homogeneity. In the proposed algorithm we prune the tree to control the size and number of regions thus obtaining a rate-optimal balance between the overhead inherent in coding the segmented data and the coding gain that we derive from it. Another novelty of the proposed approach is that we use an image model comprising separate descriptions of pixels lying near the edges of a region and those lying in the interior. Results show that the proposed algorithm can provide performance comparable to the best available methods and 15-20% better compression when compared with the JPEG lossless compression standard for a wide range of images.


Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents.
Visceral afferents are the information superhighway from the gut to the central nervous system. These sensory nerves express a wide range of membrane receptors that can modulate their sensitivity. In this themes article, we concentrate on those receptors that enhance the excitability of visceral afferent neurons. Some receptors are part of a modality-specific transduction pathway involved in sensory signaling. Others, which are activated by substances derived from multiple cellular sources during ischemia, injury, or inflammation, act in a synergistic fashion to cause acute or chronic sensitization of the afferent nerves to mechanical and chemical stimuli. Such hypersensitivity is the hallmark of conditions such as irritable bowel syndrome. Accordingly, these receptors represent a rational target for drug treatments aimed at attenuating both the inappropriate visceral sensation and the aberrant reflex activity that are the foundation for alterations in bowel function.


Polygalacturonase is a virulence factor in Agrobacterium tumefaciens biovar 3.
Agrobacterium tumefaciens biovar 3 causes both crown gall and root decay of grapes. All biovar 3 strains, regardless of their tumorigenicity, produce in culture a single polygalacturonase with a pI around 4.5. A. tumefaciens biovar 3 strain CG49 was mutagenized with Tn5 by using pSUP2021 as a suicide vector. A mutant strain, CG50, lacking polygalacturonase activity was isolated. The mutation was due to a single Tn5 insertion in an 8.5-kb EcoRI fragment that also contained the polygalacturonase structural gene. The polygalacturonase-encoding pehA gene was cloned in Escherichia coli by using the plasmid pBluescript as a vector. Activity-stained isoelectric focusing gel analysis demonstrated that E. coli cells harboring the pehA+ recombinant plasmid pCPP2067 produced a polygalacturonase in culture with the same pI as the enzyme produced by CG49. The pehA gene was localized within a 2.5-kb HindIII-SalI fragment. This fragment was used as a probe in Southern hybridization analysis and showed that no closely related genes are present in A. tumefaciens biovars 1 or 2, Rhizobium leguminosarum, or Bradyrhizobium japonicum. The polygalacturonase mutant was unable to induce root decay in grapes (Vitis vinifera cv. Chardonnay) and was substantially less tumorigenic than the wild type in grape stems when low levels of inoculum were used, although both strains were equally tumorigenic in potato disc assays. The results indicate that polygalacturonase is a virulence factor in both the root decay and crown gall incited in grapes by A. tumefaciens biovar 3.


Influence of serum adiponectin level and SNP +45 polymorphism of adiponectin gene on myocardial fibrosis.
Adiponectin plays an important role in the development of hypertension, atherosclerosis, and cardiomyocyte hypertrophy, but very little was known about the influence of serum adiponectin or the adiponectin gene polymorphism on myocardial fibrosis. Our study investigates the influence of the SNP +45 polymorphism of the adiponectin gene and serum levels of adiponectin on myocardial fibrosis in patients with essential hypertension. A case-control study was conducted on 165 hypertensive patients and 126 normotensive healthy controls. The genotypes of adiponectin gene polymorphisms were detected by the polymerase chain reaction (PCR) method. Serum concentrations of procollagen were measured by a double antibody sandwich enzyme-linked immunosorbent assay (ELISA) in all subjects. The integrated backscatter score (IBS) was measured in the left ventricular myocardium using echocardiography. The serum levels of adiponectin in hypertensive patients were significantly lower than those in the normal control group ((2.69±1.0) μg/ml vs. (4.21±2.89) μg/ml, respectively, P<0.001). The serum levels of type-I procollagen carboxyl end peptide (PICP) and type-III procollagen ammonia cardinal extremity peptide (PIIINP) in the hypertension group were significantly higher than those in the control group. In the hypertension group, serum levels of adiponectin were significantly and negatively related to the average acoustic intensity and corrected acoustic intensity of the myocardium (r=0.46 and 0.61, respectively, P<0.05 for both). The serum levels of PICP and PIIINP were significantly different among the three genotypes of SNP +45 (P<0.01). Logistic regression analyses showed that sex and genotype (GG+GT) were the major risk factors of myocardial fibrosis in hypertensive patients (OR=5.343 and 3.278, respectively, P<0.05). These data suggest that lower levels of adiponectin and SNP +45 polymorphism of the adiponectin gene are likely to play an important role in myocardial fibrosis in hypertensive patients.


Structural characteristics analysis of the hind wings in a bamboo weevil (Cyrtotrachelus buqueti).
The finite element method is a powerful tool for evaluating the experimental results. It can help to study the flight mechanism of insects and the structural characteristics of flying wings. Therefore, the research object based on the hind wings of Cyrtotrachelus buqueti (C. buqueti) was completed here. A finite element model with a length of 45 mm in the spanwise direction and a 16 mm width in the chordwise direction were established. We used a three-dimensional (3D) scanner to scan a real hind wing to obtain point cloud images. The physical model of the hind wing was carried out by using both the software Imageware and Unigraphics NX. To quantify the quality of the finite element model of the hind wing, the material properties of the wing membranes and veins were conducted by the tensile testing machine. The structural static properties of the hind wing, including static characteristics analysis and natural vibration modal analysis, were analysed by ANSYS; the stress and deflection under uniformly distributed load, bending moment, and torque were, respectively, shown. It was found that the model only had a small deformation, which shows that the hind wings of C. buqueti have excellent structural properties.


Aroma characterization of five microalgae species using solid-phase microextraction and gas chromatography-mass spectrometry/olfactometry.
In this study, aroma compounds produced by three marine microalgae species (Crypthecodinium cohnii, Schizochytrium limacinum and Tetraselmis chuii) and two fresh water microalgae (Chlorella vulgaris and Chlorella protothecoides) important for nutritional applications were identified by means of solid-phase microextraction followed by gas chromatography-mass spectrometry (GC-MS), GC-olfactometry (GCO) and a sensory panel. Principal components analysis (PCA) was applied to the instrumental and sensory analysis data to visualize differences between the samples in terms of descriptive attributes and volatile compounds. Accordingly, C. cohnii was characterised by a high level of sulfur compounds (dimethyl sulfide, ethanethiol), and ester and alcohol compounds associated with distinct 'sulfur-cabbage', 'fruity', 'rosy', and 'boiled potato' aroma notes. While S. limacinum was characterised more by aldehydes and alcohol compounds associated with 'mushroom', 'cucumber', and 'fatty-grassy' aroma characteristics, the other three samples showed relatively higher levels of ketone and terpene compounds with 'woody' and 'cereal-like' sensory characteristics.


Identification of precursor forms of free prostate-specific antigen in serum of prostate cancer patients by immunosorption and mass spectrometry.
The structural features of the free prostate-specific antigen (F-PSA) present in human blood have not been clarified up to now, and it is, therefore, not known why F-PSA is not complexed by the protease inhibitors that are present in human blood in large amounts. This lack of information is mainly attributable to the low amount of F-PSA in serum, which makes the isolation and structural characterization very difficult, especially when only limited amounts of individual sera are available. It has now been demonstrated that F-PSA occurs as a mixture of different pro-PSA forms (zymogen forms) in the sera of prostate cancer patients, and that, in some of these sera, a form with the regular NH2 terminus of PSA is present as well. Among the five serum samples investigated, all contained the (-7), (-5), and (-4) pro-PSA forms, whereas the (-1) and (-2) forms were only present in three of them. These three samples also contained the form with the regular NH2 terminus. The (-3) and (-6) pro-PSA forms have not been detected thus far. The F-PSA has been isolated by immunosorption from the individual sera using streptavidin-coated magnetic beads. The pro-PSA forms were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry after producing peptides by endoproteinase from Lysobacter enzymogenes digestion of the SDS-PAGE-separated F-PSA band. The structural identity of the (-7)pro-PSA form was further proven by sequencing of that particular peptide using electrospray ionization quadrupole time-of-flight mass spectrometry.


Vertical structure of the ionosphere and upper neutral atmosphere of saturn from the pioneer radio occultation.
Radio occultation measurements at S band (2.293 gigahertz) of the ionosphere and upper neutral atmosphere of Saturn were obtained during the flyby of the Pioneer 11 Saturn spacecraft on 5 September 1979. Preliminary analysis of the occultation exit data taken at a latitude of 9.5 degrees S and a solar zenith angle of 90.6 degrees revealed the presence of a rather thin ionosphere, having a main peak electron density of about 9.4 x 10/(3) per cubic centimeter at an altitude of about 2800 above the level of a neutral number density of 10(19) per cubic centimeter and a lower peak of about 7 x 10(3) per cubic centimeter at 2200 kilometers. Data in the neutral atmosphere were obtained to a pressure level of about 120 millibars. The temperature structure derived from these data is consistent with the results of the Pioneer 11 Saturn infrared radiometer experiment (for a helium fraction of 15 percent) and with models derived from Earth-based observations for a helium fraction by number of about 4 to 10 percent. The helium fraction will be further defined by mutual iteration with the infrared radiometer team.


Evaluation of an abbreviated impactor for fine particle fraction (FPF) determination of metered dose inhalers (MDI).
Abbreviated impactors have been developed recently to allow more rapid evaluation of inhalation products as alternates to the eight-stage Andersen Cascade Impactor (ACI) which has been widely used in the pharmaceutical industry for assessing aerodynamic particle size distribution. In this paper, a two-stage abbreviated impactor, Westech Fine Particle Dose Impactor (WFPD), was used to characterize the aerodynamic particle size of metered dose inhaler (MDI) products, and the results were compared with those obtained using the standard eight-stage ACI. Seven commercial MDI products, with different propellants (chlorofluorocarbon/hydrofluoroalkane) and formulation types (suspension/solution, dry/normal/wet), were tested in this study by both WFPD and ACI. Substantially equivalent measures of fine particle fraction were obtained for most of the tested MDI products, but larger coarse particle fraction and extra-fine particle fraction values were measured from WFPD relative to those measured using the ACI. Use of the WFPD also produced more wall loss than the ACI. Therefore, it is recommended that the system suitability be evaluated on a product-by-product basis to establish substantial equivalency before implementing an abbreviated impactor measurement methodology for routine use in inhaler product characterization.


Evidence for an RNA-based catalytic mechanism in eukaryotic nuclear ribonuclease P.
Ribonuclease P is the enzyme responsible for removing the 5'-leader segment of precursor transfer RNAs in all organisms. All eukaryotic nuclear RNase Ps are ribonucleoproteins in which multiple protein components and a single RNA species are required for activity in vitro as well as in vivo. It is not known, however, which subunits participate directly in phosphodiester-bond hydrolysis. The RNA subunit of nuclear RNase P is evolutionarily related to its catalytically active bacterial counterpart, prompting speculation that in eukaryotes the RNA may be the catalytic component. In the bacterial RNase P reaction, Mg(II) is required to coordinate the nonbridging phosphodiester oxygen(s) of the scissile bond. As a consequence, bacterial RNase P cannot cleave pre-tRNA in which the pro-Rp nonbridging oxygen of the scissile bond is replaced by sulfur. In contrast, the RNase P reaction in plant chloroplasts is catalyzed by a protein enzyme whose mechanism does not involve Mg(II) coordinated by the pro-Rp oxygen. To determine whether the mechanism of nuclear RNase P resembles more closely an RNA- or a protein-catalyzed reaction, we analyzed the ability of Saccharomyces cerevisiae nuclear RNase P to cleave pre-tRNA containing a sulfur substitution of the pro-Rp oxygen at the cleavage site. Sulfur substitution at this position prohibits correct cleavage of pre-tRNA. Cleavage by eukaryotic RNase P thus depends on the presence of a thio-sensitive ligand to the pro-Rp oxygen of the scissile bond, and is consistent with a common, RNA-based mechanism for the bacterial and eukaryal enzymes.


Astrocytes Downregulate Inflammation in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: Applicability to COVID-19.
Background: An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS. Methods: First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0-2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum. Results: We detected that AstroRx cells were capable to suppress T-cell proliferation in vitro after exposure to the mitogen concanavalin A (ConA). In vivo, AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals (P = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice (P < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx. Conclusions: Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.


Eradication of helicobacter pylori for non-ulcer dyspepsia.
Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. To determine the effect of H pylori eradication on dyspepsia symptoms and quality of life scores in patients with non-ulcer dyspepsia. Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. Seven randomised controlled trials were included in the systematic review. Five trials compared proton pump inhibitor dual or triple therapy with a proton pump inhibitor + placebo antibiotics, and evaluated dyspepsia at 6-12 months in 1,385 patients. H pylori eradication was significantly superior to placebo in treating non ulcer dyspepsia (relative risk reduction = 7%; 95% CI = 1% to 12%; p=0.02) and there was no significant heterogeneity between the studies. The number needed to treat to cure one case of dyspepsia = 19 (95% CI = 11 to 132). A further two trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. H pylori eradication may be an effective therapy for H pylori positive non-ulcer dyspepsia. This result is not robust and further evidence on the efficacy of H pylori eradication in non ulcer dyspepsia would be helpful. The effect is modest and economic models would help establish whether this approach is cost-effective. This review will be updated as results from other ongoing trials (Malfertheiner 2000) are made available.


The heparan sulfate-specific epitope 10E4 is NO-sensitive and partly inaccessible in glypican-1.
The monoclonal antibody 10E4, which recognizes an epitope supposed to contain N-unsubstituted glucosamine, is commonly used to trace heparan sulfate proteoglycans. It has not been fully clarified if the N-unsubstituted glucosamine is required for antibody recognition and if all heparan sulfates carry this epitope. Here we show that the epitope can contain N-unsubstituted glucosamine and that nitric oxide-generated deaminative cleavage at this residue in vivo can destroy the epitope. Studies using flow cytometry and confocal immunofluorescence microscopy of both normal and transformed cells indicated that the 10E4 epitope was partially inaccessible in the heparan sulfate chains attached to glypican-1. The 10E4 antibody recognized mainly heparan sulfate degradation products that colocalized with acidic endosomes. These sites were greatly depleted of 10E4-positive heparan sulfate on suramin inhibition of heparanase. Instead, there was increased colocalization between 10E4-positive heparan sulfate and glypican-1. When both S-nitrosylation of Gpc-1 and heparanase were inhibited, detectable 10E4 epitope colocalized entirely with glypican-1. In nitric oxide-depleted cells, there was both an increased signal from 10E4 and increased colocalization with glypican-1. In suramin-treated cells, the 10E4 epitope was destroyed by ascorbate-released nitric oxide with concomitant formation of anhydromannose-containing heparan sulfate oligosaccharides. Immunoisolation of radiolabeled 10E4-positive material from unperturbed cells yielded very little glypican-1 when compared with specifically immunoisolated glypican-1 and total proteoglycan and degradation products. The 10E4 immunoisolates were either other heparan sulfate proteoglycans or heparan sulfate degradation products.


Chronic industrial exposure to lead in 63 subjects. I. Clinical and erythrokinetic findings.
Clinical, biochemical, haematological and erythrokinetic studies were performed on 63 adult males with prolonged lead exposure. Their most common symptoms and findings were abdominal pain (62%), gingival lead lines (48%), headache and/or dizziness (33%), muscle cramps (32%), anaemia (19%), and fatigue (18%). Colicky abdominal pain (27%) and gingival lead lines correlated with urinary lead excretion. Anaemia was mild, but more frequent in the subjects with the greatest urinary lead excretion. Other associated findings were: higher reticulocyte counts and more basophilic stippling of the RBCs, more sideroblasts and greater erythroid hyperplasia of the bone marrow, more reduction in 51Cr-tagged RBC survival time, smaller RBC mass, a more rapid plasma iron clearance, a greater plasma iron turnover and greater utilization of 59Fe in subjects with urinary lead excretion of greater than 100 microng/day in comparison with the remainder and normal controls. These findings suggest that minimal chronic exposure to lead causes an increased haemolysis with resulting increased production of erythrocytes.


Responses of tendon organs in a lizard.
1. In the lizard Tiliqua the tendons of the caudo-femoralis muscle are supplied by a nerve which runs separately from the muscle nerve. 2. Recordings of afferent discharges in the tendon nerve revealed the presence in the tendon of stretch-sensitive mechanoreceptors which responded to both passive changes in limb position and to muscle contraction. 3. A preparation of the tendon and its nerve were dissected free of surrounding tissue and studied in isolation while recording the activity of single functional units. The minimum tension in the tendon necessary for a maintained response from a receptor lay in the range 5-35 g (mean 16 g) and the firing rates at these tensions were in the range 5-14 impulses/sec (mean 9 impulses/sec). 4. Receptors showed a steep increase in firing rate with increase in tension up to about 120 g. The firing rate 30 sec after the onset of a tension change did not exceed 40 impulses/sec. 5. During the tension change the receptor responded with a burst of impulses whose frequency depended on the velocity of stretch. With large, rapidly rising tension steps peak firing rates of up to 300 impulses/sec were observed. 6. Tension and length changes recorded during rapid tendon-stretches were very similar, with little sag in tension at the new length. The response of all units however continued to fall throughout the stretch. Some of the possible causes of this adaptation have been discussed.


'Artiphysiology' reveals V4-like shape tuning in a deep network trained for image classification.
Deep networks provide a potentially rich interconnection between neuroscientific and artificial approaches to understanding visual intelligence, but the relationship between artificial and neural representations of complex visual form has not been elucidated at the level of single-unit selectivity. Taking the approach of an electrophysiologist to characterizing single CNN units, we found many units exhibit translation-invariant boundary curvature selectivity approaching that of exemplar neurons in the primate mid-level visual area V4. For some V4-like units, particularly in middle layers, the natural images that drove them best were qualitatively consistent with selectivity for object boundaries. Our results identify a novel image-computable model for V4 boundary curvature selectivity and suggest that such a representation may begin to emerge within an artificial network trained for image categorization, even though boundary information was not provided during training. This raises the possibility that single-unit selectivity in CNNs will become a guide for understanding sensory cortex.


Barriers and facilitators to PDMP IS Success in the US: A systematic review.
Prescription Drug Monitoring Programs (PDMP) help prevent prescription drug misuse and promote appropriate pain management. Despite these benefits and PDMP mandates in most states, PDMPs face challenges that hinder their success. This paper uses the Delone and McLean Information Success (IS) Model to review the current literature for barriers and facilitators to PDMP quality, use, intention to use and user satisfaction in the United States (U.S.). Scopus, PubMed and Embase databases were searched due to their relevance to information technology, education and research. There were 142 and 183 barriers and facilitators, respectively, found in 44 peer reviewed articles. Barriers to PDMP quality, use and user satisfaction include lack of interstate data sharing, access difficulties, lack of time, inability to delegate access, lack of knowledge or awareness of the PMDP, and lack of EHR integration. Facilitators to PDMP quality, use and user satisfaction include interstate data connections, real-time data updates, EHR integration, and access delegation. Interstate data sharing, EHR integration and expanding access to delegates were common themes found. Some results were found to be contradictory such as mandating use. PDMP users can use these findings to assess current barriers to PDMP success in the U.S. and draw possible solutions from the list of facilitators. Practitioners should consider the context of their state and organization when determining which facilitators would most promote PDMP IS success. Combining facilitators may be the best route to PDMP IS success in certain situations.


Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.


Correspondence-Aware Manifold Learning for Microscopic and Spatial Omics Imaging: A Novel Data Fusion Method Bringing Mass Spectrometry Imaging to a Cellular Resolution.
High-dimensional molecular measurements are transforming the field of pathology into a data-driven discipline. While hematoxylin and eosin (H&E) stainings are still the gold standard to diagnose diseases, the integration of microscopic and molecular information is becoming crucial to advance our understanding of tissue heterogeneity. To this end, we propose a data fusion method that integrates spatial omics and microscopic data obtained from the same tissue slide. Through correspondence-aware manifold learning, we can visualize the biological trends observed in the high-dimensional omics data at microscopic resolution. While data fusion enables the detection of elements that would not be detected taking into account the separate data modalities individually, out-of-sample prediction makes it possible to predict molecular trends outside of the measured tissue area. The proposed dimensionality reduction-based data fusion paradigm will therefore be helpful in deciphering molecular heterogeneity by bringing molecular measurements such as mass spectrometry imaging (MSI) to the cellular resolution.


Small-bowel endoscopy.
An overview of the scientific literature on small-bowel enteroscopy demonstrates that sonde enteroscopy is becoming more and more limited in its indications. Push enteroscopy is now a well-accepted modality for evaluation of the patient with small-bowel disease, including those with undiagnosed causes for gastrointestinal bleeding, various types of malabsorption, and radiological abnormalities. Intraoperative enteroscopy has very specific indications, and there is a high rate of positive findings. It appears that an enterotomy with passage of a shorter, more maneuverable enteroscope is an acceptable way to evaluate the small bowel, although use of a sonde enteroscope may be an innovative method for intraoperative enteroscopy. In the evaluation of patients with iron-deficiency anemia or occult gastrointestinal bleeding in whom colonoscopy is negative, it is evidently more cost-effective to use a dedicated push enteroscope early on. The use of two different instruments--a gastroscope followed by a dedicated push enteroscope--is more expensive, and probably does not increase the yield for pathology. Many lesions that are responsible for obscure bleeding are actually located within reach of an upper intestinal endoscope, but are not recognized. This is probably due to inexperience on the part of the original endoscopist, who may see the pathology, but does not invoke it as the cause for bleeding. Outcome studies are now being performed, and there are some interesting considerations for combination hormonal therapy in patients with recurrent obscure bleeding, which most likely emanates from small-bowel arteriovenous malformations.


Binding enhancements of antibody functionalized natural and synthetic fibers.
Development of low cost biosensing using convenient and environmentally benign materials is important for wide adoption and ultimately improved healthcare and sustainable development. Immobilized antibodies are often incorporated as an essential biorecognition element in point-of-care biosensors but these proteins are costly. We present a strategy of combining convenient and low-cost surface functionalization approaches for increasing the overall binding activity of antibody functionalized natural and synthetic fibers. We demonstrate a simple one-step in situ silica NP growth protocol for increasing the surface area available for functionalization on cotton and polyester fabrics as well as on nanoporous cellulose substrates. Comparing this effect with the widely adopted and low cost plant-based polyphenol coating to enhance antibody immobilization, we find that both approaches can similarly increase overall surface activity, and we illustrate conditions under which the two approaches can produce an additive effect. Furthermore, we introduce co-immobilization of antibodies with a sacrificial "steric helper" protein for further enhancing surface activities. In combination, several hundred percent higher activities compared to physical adsorption can be achieved while maintaining a low amount of antibodies used, thus paving a practical path towards low cost biosensing.


Radiographic and symptomatic brain ischemia in CEA and CAS: A systematic review and meta-analysis.
In a systematic review, we compared ratio of new periprocedural radiographic brain ischemia (RBI) to the number of strokes and TIAs among patients undergoing carotid endarterectomy (CEA) and carotid artery stenting (CAS). We searched 5 databases for entries related to brain ischemia in CEA or CAS from inception through September 2015. We included articles with CEA or CAS and systematic performance of preprocedural and postprocedural brain MRI and reporting of RBI and stroke incidence. We calculated a symptomatic risk ratio of number of strokes and TIAs to RBI. Random effects models were used. Fifty-nine studies (5,431 participants) met the inclusion criteria. There were 22 cohorts in CEA, 34 in CAS with distal protection, 8 in CAS with proximal protection, 9 in CAS without protection, and 9 in CAS with unspecified devices. Overall, 30.7% (95% confidence interval [CI] 26.6%-34.7%) had RBI, while 3.2% (95% CI 2.6%-3.8%) had clinical strokes or TIAs, with a stroke and TIA to RBI weighted ratio of 0.18 (95% CI 0.15-0.22). CEA had lower incidence of RBI compared to CAS (13.0% vs 37.4%) and also lower number of strokes and TIAs (1.8% vs 4.1%). The stroke and TIA to RBI ratio did not differ across 5 different types of carotid interventions (p = 0.58). One in 5 persons with periprocedural radiographic brain ischemia during CEA and CAS had strokes and TIAs. The stable ratio of stroke and TIA to radiographic ischemia suggests that MRI ischemia could serve as a surrogate measure of periprocedural risk.


The Fermi-Dirac distribution provides a calibrated probabilistic output for binary classifiers.
Binary classification is one of the central problems in machine-learning research and, as such, investigations of its general statistical properties are of interest. We studied the ranking statistics of items in binary classification problems and observed that there is a formal and surprising relationship between the probability of a sample belonging to one of the two classes and the Fermi-Dirac distribution determining the probability that a fermion occupies a given single-particle quantum state in a physical system of noninteracting fermions. Using this equivalence, it is possible to compute a calibrated probabilistic output for binary classifiers. We show that the area under the receiver operating characteristics curve (AUC) in a classification problem is related to the temperature of an equivalent physical system. In a similar manner, the optimal decision threshold between the two classes is associated with the chemical potential of an equivalent physical system. Using our framework, we also derive a closed-form expression to calculate the variance for the AUC of a classifier. Finally, we introduce FiDEL (Fermi-Dirac-based ensemble learning), an ensemble learning algorithm that uses the calibrated nature of the classifier's output probability to combine possibly very different classifiers.


Mobile health interventions in multiple sclerosis: A systematic review.
Persons with multiple sclerosis (pwMS) might be particularly well suited to benefit from digital health applications because they are, on average, younger and less severely disabled than patients with many other chronic diseases. Many digital health applications for pwMS have been developed. Analysis of the evidence of digital health applications to improve health outcomes from a patient perspective. A systematic review was performed on all randomized controlled trials (RCTs) that have studied mobile health interventions for pwMS, that is, which can be applied with a smartphone, tablet, or laptop to improve patient-reported outcomes. Of the 1127 articles identified in the literature search, 13 RCTs fit the inclusion criteria. Two trials studied messaging systems, two depression interventions, one addressed MS fatigue, five cognition, and three mobility issues, of which two focused on spasticity management. One trial aimed to enhance physical activity. Most were pilot studies that cannot yield definitive conclusions regarding efficacy. One depression intervention and one fatigue intervention showed significant results across several outcomes. Several mobile self-guided digital health applications for pwMS have been tested in RCTs, and two interventions targeting depression and fatigue have demonstrated significant effects. Challenges remain regarding implementation into routine care.


Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection.
Following emergence in late 2019, SARS-CoV-2 rapidly became pandemic and is presently responsible for millions of infections and hundreds of thousands of deaths worldwide. There is currently no approved vaccine to halt the spread of SARS-CoV-2 and only very few treatment options are available to manage COVID-19 patients. For development of preclinical countermeasures, reliable and well-characterized small animal disease models will be of paramount importance. Here we show that intranasal inoculation of SARS-CoV-2 into Syrian hamsters consistently caused moderate broncho-interstitial pneumonia, with high viral lung loads and extensive virus shedding, but animals only displayed transient mild disease. We determined the infectious dose 50 to be only five infectious particles, making the Syrian hamster a highly susceptible model for SARS-CoV-2 infection. Neither hamster age nor sex had any impact on the severity of disease or course of infection. Finally, prolonged viral persistence in interleukin 2 receptor gamma chain knockout hamsters revealed susceptibility of SARS-CoV-2 to adaptive immune control. In conclusion, the Syrian hamster is highly susceptible to SARS-CoV-2 making it a very suitable infection model for COVID-19 countermeasure development.


Host-Specific Serum Factors Control the Development and Survival of Schistosoma mansoni.
Schistosomiasis is a neglected tropical disease (NTD) caused by blood-dwelling flatworms which develop from skin-penetrating cercariae, the freely swimming water-borne infective stage of Schistosoma mansoni, into adult worms. This natural course of infection can be mimicked in experimental mouse models of schistosomiasis. However, only a maximum of 20-30% of penetrated cercariae mature into fecund adults. The reasons for this are unknown but could potentially involve soluble factors of the innate immune system, such as complement factors and preexisting, natural antibodies. Using our recently developed novel serum- and cell-free in vitro culture system for newly transformed schistosomula (NTS), which supports long-term larval survival, we investigated the effects of mouse serum and its major soluble complement factors C1q, C3, C4 as well as preexisting, natural IgM in vitro and assessed worm development in vivo by infecting complement and soluble (s)IgM-deficient animals. In contrast to sera from humans and a broad variety of mammalian species, serum from mice, surprisingly, killed parasites already at skin stage in vitro. Interestingly, the most efficient killing component(s) were heat-labile but did not include important members of the perhaps best known family of heat-labile serum factors, the complement system, nor consisted of complement-activating natural immunoglobulins. Infection of complement C1q and sIgM-deficient mice with S. mansoni as well as in vitro tests with sera from mice deficient in C3 and C4 revealed no major role for these soluble factors in vivo in regard to parasite maturation, fecundity and associated immunopathology. Rather, the reduction of parasite maturation from cercariae to adult worms was comparable to wild-type mice. This study reveals that not yet identified heat-labile serum factors are major selective determinants of the host-specificity of schistosomiasis, by directly controlling schistosomal development and survival.


Self-Healing Label Materials Based on Photo-Cross-Linkable Polymeric Films with Dynamic Surface Structures.
Spatially controlling the evolution of surface structures may provide an effective strategy for patterning surface roughness and facilitating the construction of various functional surfaces. In this study, we report a photo-cross-linkable polymeric film with dynamic surface micro/nanostructures. The surface structures of the un-cross-linked regions can be eliminated under saturated humidity, which can be utilized to create patterned roughness on the film. One potential application of this patternable platform is as a "smart" label material for graphical symbols. Various graphical symbols can be programmed onto this film by partially erasing its surface roughness, enabling visibility due to the difference in light scattering between different areas of the film. When a thus-prepared label was blurred by mechanical scratches, it could be healed under saturated humidity, and its original readability could be fully restored. Furthermore, the patterned rough surface created using our approach can also be very useful in many other research fields, such as surface wettability and cell behavior manipulation.