Interventions Aimed at Increasing Dairy and/or Calcium Consumption of Preschool-Aged Children: A Systematic Literature Review.
Dairy product consumption is important during childhood, as dairy products provide nutrients to support growth and development. However, a high proportion of children globally are not meeting recommended daily intakes, which may have long-term health implications. Accumulating evidence suggests that interventions aimed at instilling healthy lifestyle habits are most effective when initiated during the preschool years. Therefore, the purpose of the review was to identify the characteristics of effective dairy and/or calcium interventions targeting preschool-aged children. A systematic literature review identified 14 intervention studies published between 1998⁻2018 addressing dairy/calcium intakes in the preschool population (1.5 to 5 years). Intervention reporting was assessed using intervention intensity, behavior change techniques and Workgroup for Intervention Development and Evaluation Research (WIDER), with the quality of studies evaluated using risk of bias and Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Five of the 14 studies included in the review reported significant improvements in children's dairy (4/5) or calcium (1/5) intake. Characteristics that may enable intervention effectiveness include the delivery of interventions in one setting (preschool facility), using specific behavior change techniques (environmental restructuring and teach to use prompts/cues), and targeting both parent and child. Overall, the interventions assessed demonstrated variable success and highlighted the need for developing effective interventions designed to increase dairy and/or calcium intakes in preschool-aged children.


Effect of heating/cooling dynamics in the hysteresis loop and tunable IR emissivity of VO2 thin films.
We experimentally investigate the semiconductor-to-metal transition (SMT) in vanadium dioxide thin films using an infrared thermographic technique. During the semiconductor to metal phase change process, VO2 optical properties dynamically change and infrared emission undergoes a hysteresis loop due to differences between heating and cooling stages. The shape of the hysteresis loop was accurately monitored under different dynamic heating/cooling rates. In order to quantify and understand the effects of different rates, we used a numerical modelling approach in which a VO2 thin layer was modeled as metamaterial. The main experimental findings are interpreted assuming that both the rate of formation and shape of metallic inclusions are tuned with the heating/cooling rate. The structural transition from monoclinic to tetragonal phases is the main mechanism for controlling the global properties of the phase transition. However, our experimental results reveal that the dynamics of the heating/cooling process can become a useful parameter for further tuning options and lays out a macroscopic optical sensing scheme for the microscopic phase change dynamics of VO2. Our study sheds light on phase-transition dynamics and their effect on the infrared emission spectra of VO2 thin films, therefore enabling the heating/cooling rate to be an additional parameter to control infrared emission characteristics of thermal emitters. The hysteresis loop represents the phase coexistence region, thus being of fundamental importance for several applications, such as the operation of radiative thermal logic elements based on phase transition materials. For such applications, the phase transition region is shifted for heating and cooling processes. We also show that, depending on the way the phase change elements are heated, the temperature operation range will be slightly modified.


A possible new tool for clinical diagnosis of melanoma: the computer.
The analysis of cutaneous melanoma images by two coupled computers (IBM 7350/4361) was carried out on twenty color slides. Each color slide was digitized with a spatial reduction of 25 X 25 microns. Classic technics of digital image analysis and new algorithms were used to improve the contrast on the full image or a portion of it, contrast a skin lesion with statistical information deduced from another lesion, evaluate the shape of the lesion, the roughness of the surface, and the transition region from the lesion to the normal skin, and analyze a lesion from the chromatic point of view. The theoretical reasons of interest are to have an objective method that is easy to standardize and reliably repeatable and to be able to analyze details not perceivable by the human eye. If the same technic are used in the evaluation of histologic characteristics of the lesions, a chance of making much more sophisticated clinicopathologic correlations will be available. The system needs to be improved at the technical level so that the response time of acquisition of the digitized images is shortened by the use of a digital television camera and the development of new computer programs to be run on a small computer. Evaluation of the system's sensitivity and specificity and an adequate clinical trial are needed.


Placental matrix metalloproteinase--1 expression is increased in labor.
Matrix metalloproteinases (MMPs) are now known to process a broad spectrum of cell surface molecules and to function in several important biological processes. Testing for differences in gene expression in human placental chorionic villi in the absence or presence of labor, using cDNA microarray analysis, revealed that labor was associated with increased expression of MMP-1 gene expression in 5 placentas collected after term normal spontaneous deliveries compared with 5 placentas collected after term nonlaboring cesarean deliveries. Fibronectin 1 and collagen XVII, 2 other proteins involved in the homeostasis of the extracellular matrix, were also found to be upregulated in labor. MMP-1 was further tested in individual samples and found to be consistently overexpressed in labor. While previous microarray analyses have focused on either uterine tissue or the fetal membranes, the data presented here indicate for the first time that placental chorionic villus genes are likely to affect the initiation of parturition through altered processing of cell surface molecules by MMP-1.


[Partial hydatidiform mole in Morocco: an epidemiological and clinical study].
This retrospective study reviewed cases of partial hydatidiform mole (PHM) diagnosed at the University Hospital in Casablanca from 2000 to 2010 in order to examine the epidemiological, clinical, therapeutic and progressive pathological factors associated with PHM. All PHM cases confirmed clinically and sonographically at pathological examination were included. We identified 24 cases of PHM among 60 748 births and 1704 abortions, giving a frequency of 0.4 per 1000 pregnancies and 1.4% of abortions. The mean age was 26 years (range: 16-55 years). The circumstances of discovery and clinical ultrasound varied: 79.2% of patients sought consultation for bleeding; clinical thyrotoxicosis syndrome was found in 1 patient (4.2%). Physical examination showed increased uterine size in 83.3% of cases associated with a latero-uterine mass in 25%. The diagnosis was supported by an ultrasound examination combined with measurement of plasma betaHCG. Histological confirmation was made in all cases and treatment was endo-uterine aspiration. Neoplastic drift was observed in 1 case (4.2%) which went into remission with chemotherapy.


Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy.
Proximal spinal muscular atrophy (SMA) is a motoneuron disease for which there is currently no effective treatment. In animal models of SMA, spinal motoneurons exhibit reduced axon elongation and growth cone size. These defects correlate with reduced beta-actin messenger RNA and protein levels in distal axons. We show that survival motoneuron gene (Smn)-deficient motoneurons exhibit severe defects in clustering Cav2.2 channels in axonal growth cones. These defects also correlate with a reduced frequency of local Ca2+ transients. In contrast, global spontaneous excitability measured in cell bodies and proximal axons is not reduced. Stimulation of Smn production from the transgenic SMN2 gene by cyclic adenosine monophosphate restores Cav2.2 accumulation and excitability. This may lead to the development of new therapies for SMA that are not focused on enhancing motoneuron survival but instead investigate restoration of growth cone excitability and function.


Influence of Annealing and Biaxial Expansion on the Properties of Poly(l-Lactic Acid) Medical Tubing.
Poly-l-lactic acid (PLLA) is one of the most common bioabsorbable materials in the medical device field. However, its use in load-bearing applications is limited due to its inferior mechanical properties when compared to many of the competing metal-based permanent and bioabsorbable materials. The objective of this study was to directly compare the influence of both annealing and biaxial expansion processes to improve the material properties of PLLA. Results showed that both annealing and biaxial expansion led to an overall increase in crystallinity and that the crystallites formed during both processes were in the α' and α forms. 2D-WAXS patterns showed that the preferred orientation of crystallites formed during annealing was parallel to the circumferential direction. While biaxial expansion resulted in orientation in both axial and circumferential directions, with relatively equal sized crystals in both directions, Da (112 Å) and Dc (97 Å). The expansion process had the most profound effect on mechanical performance, with a 65% increase in Young's modulus, a 45% increase in maximum tensile stress and an 18-fold increase in strain at maximum load. These results indicate that biaxially expanding PLLA at a temperature above Tcc is possible, due to the high strain rates associated with stretch blow moulding.


Mechanisms of cross-talk between the diet, the intestinal microbiome, and the undernourished host.
Undernutrition remains one of the most pressing global health challenges today, contributing to nearly half of all deaths in children under five years of age. Although insufficient dietary intake and environmental enteric dysfunction are often inciting factors, evidence now suggests that unhealthy gut microbial populations perpetuate the vicious cycle of pathophysiology that results in persistent growth impairment in children. The metagenomics era has facilitated new research identifying an altered microbiome in undernourished hosts and has provided insight into a number of mechanisms by which these alterations may affect growth. This article summarizes a range of observational studies that highlight differences in the composition and function of gut microbiota between undernourished and healthy children; discusses dietary, environmental and host factors that shape this altered microbiome; examines the consequences of these changes on host physiology; and considers opportunities for microbiome-targeting therapies to combat the global challenge of child undernutrition.


Microsatellites proximal to leptin and leptin receptor as risk factors for spina bifida.
Several recent studies have observed an association between neural tube defect risk and prepregnant obesity. This association was generally stronger for spina bifida and was observed irrespective of additional maternal factors, including periconceptional intake of vitamin supplements. Other studies have identified mutations within the genes that code for leptin (LEP) and its receptor (LEPR), which have been linked to obesity in mice and humans. We investigated the potential association between nucleotide variation at the LEP and LEPR loci, and increased risk of spina bifida. We searched specifically for allelic association at a pair of highly polymorphic microsatellites closely linked to either the LEP or LEPR gene. Data were derived from a population-based case-control study that had previously identified an association between a woman's prepregnant obesity and her risk of delivering an infant with spina bifida. A total of 56 spina bifida case infants and 126 nonmalformed control infants were genotyped for 10 microsatellite alleles closely linked to the LEP gene, and 49 cases and 125 controls were genotyped for 10 microsatellite alleles closely linked to the LEPR gene. In general, alleles were not observed to be exclusively associated with substantially greater spina bifida risk in the body mass index (BMI) category (obese) of >29 kg/m(2) compared with the BMI category (nonobese) of </=29 kg/m(2). Thus, these particular infant allelic variants did not appear to explain the previously reported elevated risk observed for women whose prepregnant BMI exceeded 29 kg/m(2). A modest elevated spina bifida risk, irrespective of maternal BMI, was observed for two LEP microsatellite alleles (257 and 271). These estimates, however, were imprecise. Compared with those infants who did not have either of these alleles and whose mother's prepregnant BMI was </=29 kg/m(2), we computed odds ratios for (1) having either the 257 or 271 allele and maternal BMI >29 kg/m; (2) having either allele and BMI </=29 kg/m(2); and (3) not having either allele but BMI >29 kg/m(2). The odds ratios (95% confidence interval) for these comparisons were: for allele 257, 4.5 (1.1-19.4), 1.9 (0.5-6.3), and 2.9 (1.3-6.4), respectively, and for allele 271, 6.7 (1.6-30.4), 2.7 (0.7-10.9), and 2.7 (1.2-5.9), respectively. Owing to the exploratory nature of this investigation, the significance of these latter results is unclear.


A backbone-reversed form of an all-beta alpha-crystallin domain from a small heat-shock protein (retro-HSP12.6) folds and assembles into structured multimers.
The structural consequences of polypeptide backbone reversal ("retro" modification) remain largely unexplored, in particular, for the retro forms of globular all-beta-sheet proteins. To examine whether the backbone-reversed form of a model all-beta-sheet protein can fold and adopt secondary and tertiary structure, we created and examined the recombinant retro form of a 110-residue-long polypeptide, an alpha-crystallin-like small heat-shock protein, HSP12.6, from C. elegans. Following intracellular overexpression in fusion with a histidine affinity tag in Escherichia coli, purification under denaturing conditions, and removal of denaturant through dialysis, retro-HSP12.6 was found to fold to a soluble state. The folded protein was examined using fluorescence and CD spectroscopy, gel filtration chromatography, non-denaturing electrophoresis, differential scanning calorimetry, and electron microscopy and confirmed to have adopted secondary structure and assembled into a multimer. Interestingly, like its parent polypeptide, retro-HSP12.6 did not aggregate upon heating; rather, heating led to a dramatic increase in structural content and the adoption of what would appear to be a very well folded state at high temperatures. However, this was essentially reversed upon cooling with some hysteresis being observed resulting in greater structural content in the heated-cooled protein than in the unheated protein. The heated-cooled samples displayed CD spectra indicative of structural content comparable to that of any naturally occurring globular protein. Attempts are being made to refine crystallization conditions for the folded protein.


Glutathione S-transferases interact with AMP-activated protein kinase: evidence for S-glutathionylation and activation in vitro.
AMP-activated protein kinase (AMPK) is a cellular and whole body energy sensor with manifold functions in regulating energy homeostasis, cell morphology and proliferation in health and disease. Here we apply multiple, complementary in vitro and in vivo interaction assays to identify several isoforms of glutathione S-transferase (GST) as direct AMPK binding partners: Pi-family member rat GSTP1 and Mu-family members rat GSTM1, as well as Schistosoma japonicum GST. GST/AMPK interaction is direct and involves the N-terminal domain of the AMPK β-subunit. Complex formation of the mammalian GSTP1 and -M1 with AMPK leads to their enzymatic activation and in turn facilitates glutathionylation and activation of AMPK in vitro. GST-facilitated S-glutathionylation of AMPK may be involved in rapid, full activation of the kinase under mildly oxidative physiological conditions.


The 10-month mortality rate among older patients treated for digestive system cancer during the first wave of the COVID-19 pandemic: The CADIGCOVAGE multicentre cohort study.
The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on cancer diagnosis and care pathways. Here, we assessed the mid-term impact of the COVID-19 pandemic on older adults with cancer before, during and after the lockdown period in 2020. We performed a retrospective, observational, multicentre cohort study of prospectively collected electronic health records. All adults aged 65 or over and having been newly treated for a digestive system cancer in our institution between January 2018 until August 2020 were enrolled. Data on 7,881 patients were analyzed. Although the overall 10-month mortality rate was similar in 2020 vs. 2018-2019, the mortality rate among for patients newly treated in the 2020 post-lockdown period was (after four months of follow-up) significantly higher. A subgroup analysis revealed higher mortality rates for (i) patients diagnosed in the emergency department during the pre-lockdown period, (ii) patients with small intestine cancer newly treated during the post-lockdown period, and (iii) patients having undergone surgery with curative intent during the post-lockdown period. However, when considering individuals newly treated during the lockdown period, we observed lower mortality rates for (i) patients aged 80 and over, (ii) patients with a biliary or pancreatic cancer, and (iii) patients diagnosed in the emergency department. There was no overall increase in mortality among patients newly treated in 2020 vs. 2018-2019. Longer follow-up is needed to assess the consequences of the pandemic. A subgroup analysis revealed significant intergroup differences in mortality.


Emergency Medicine Influencers' Twitter Use During the COVID-19 Pandemic: A Mixed-methods Analysis.
The objective of this study was to analyze the messages of influential emergency medicine (EM) Twitter users in the United States (US) during the early stages of the coronavirus disease 2019 (COVID-19) global pandemic by characterizing the themes, emotional tones, temporal viewpoints, and depth of engagement with the tweets. We performed a retrospective mixed-methods analysis of publicly available Twitter data derived from the publicly available "Coronavirus Tweet IDs" dataset, March 3, 2020-May 1, 2020. Original tweets and modified retweets in the dataset by 50 influential EM Twitter users in the US were analyzed using linguistic software to report the emotional tone and temporal viewpoint. We qualitatively analyzed a 25% random subsample and report themes. There were 1315 tweets available in the dataset from 36/50 influential EM Twitter users in the US. The majority of tweets were either positive (455/1315, 34.6%) or neutral (407/1315, 31%) in tone and focused on the present (1009/1315, 76.7%). Qualitative analysis identified six distinct themes, with users most often sharing news or clinical information. During the early weeks of the COVID-19 pandemic, influential EM Twitter users in the US delivered mainly positive or neutral messages, most often pertaining to news stories or information directly relating to patient care. The majority of these messages led to engagement by other users. This study underscores how EM influencers can leverage social media in public health outbreaks to bring attention to topics of importance.


Site-specific transposition of insertion sequence IS630.
IS630 is a 1.15-kilobase sequence in Shigella sonnei that, unlike many mobile elements, seems not to mediate cointegration between different replicons. To assess its transposition, we constructed composite elements containing inverted copies of IS630 flanking a drug resistance gene. We found that these composite elements transposed to plasmid ColE1 in Escherichia coli. DNA sequencing showed that transposition was, in all cases, to the dinucleotide sequence 5'-TA-3'. There were two preferred insertion sites which corresponded to the TA sequences in the inverted repeats of a 13-base-pair stem region of the [rho]-dependent transcription terminator. IS630 is flanked by TA, and nucleotide substitution by in vitro mutagenesis at these ends did not affect transposition activity of a composite element or its ability to insert preferentially into TA within the 13-base-pair inverted repeat sequences or to duplicate the target sequence.


Assessing Safe Discharge Criteria for Pediatric Oncology Patients Admitted for Febrile Neutropenia.
Recent studies suggest outpatient therapy, oral antibiotics, or earlier discharge could be appropriate in some pediatric patients admitted with febrile neutropenia; supporting data are lacking. Retrospective chart review of patients admitted from September 2005 through October 2016 identified 131 "early discharge" febrile neutropenia admissions with discharge absolute neutrophil count (ANC) <500/µl and negative cultures. All were afebrile and discharged without outpatient antibiotics. Eleven of 131 patients (8%) were readmitted. Two patients called back for late positive cultures. Nine were readmitted with febrile neutropenia; 2 had positive cultures on readmission. All 4 patients with positive cultures were safely treated with appropriate antibiotics. The remaining 7 patients had uneventful readmissions. Average ANC (SD) at discharge was lower for patients readmitted versus those not readmitted (69 [70] vs. 196 [145], P≤0.001), as was absolute phagocyte count (APC) at discharge (97 [82] vs. 453 [431], P≤0.001). APC on admission was not significantly lower for those readmitted (165 [254] vs. 321 [388], P=0.09). Few patients required readmission; those with bacterial infections were easily identified and appropriately treated. Higher ANC or APC criteria for discharge would increase length of hospital stay without decreasing morbidity. A subset of patients admitted with febrile neutropenia can be safely discharged before count recovery without oral antibiotics.


An in vitro comparison of microleakage of two self-etched adhesive and the one-bottle adhesive used in pit and fissure sealant with or without saliva contamination.
To minimize the deleterious effects of contaminated enamel on bonding, some authors have advocated the use of adhesive systems under the sealant. The aim of this study was to compare the microleakage of two self-etch and the one-bottle adhesive used in pit and fissure sealant with or without saliva contamination. Sixty extracted premolar teeth were assigned to the six groups. Group 1: Acid +saliva +single bond +sealant, Group 2: Acid +single bond +sealant, Group 3: Saliva +S (3) bond +sealant, Group 4: S (3) bond +sealant, Group 5: Saliva +protect bond +sealant, Group 6: Protect bond +sealant. The teeth were thermocycled and immersed in 2% basic fuchsine dye for 24 h, then sectioned and examined with a stereomicroscope under ×40 magnification. The results were evaluated with Kruskal-Wallis and Dunn tests. Group 2 has the lower microleakage scores than Groups 4 and 6. Also, Group 6 has the lower microleakage scores than Group 4, and generally an increase in microleakage was observed in each group related to contamination. The best technique of sealant therapy in saliva contaminated and non- contaminated condition is the use of acid-etching and bonding agent.


Additional value of auricular intradermal acupuncture alongside selective serotonin reuptake inhibitors: a single-blinded, randomized, sham-controlled preliminary clinical study.
To evaluate the antidepressant effects of auricular intradermal acupuncture (AIA) of areas innervated by both the auricular branch of the vagus nerve and the trigeminal nerve. Forty-nine patients with depression were randomly allocated into an AIA group (n = 25) and a sham AIA group (n = 24). Both groups received selective serotonin reuptake inhibitors (SSRIs) as conventional treatment. The AIA group received AIA stimulation, and the sham AIA group received sham AIA, which constituted being subjected to an attached needle that did not penetrate the skin. The needles were retained for 4 h each session, with five sessions a week for a total duration of 2 weeks. The outcomes were assessed by the 17-item Hamilton depression rating scale (HAMD-17), five factors (sleep disorder, retardation, cognitive dysfunction, anxiety/somatization, and weight) and self-rating depression scale (SDS) at weeks 0, 1, and 2. Fifty-four patients were randomly assigned to the AIA (n = 27) and sham AIA group (n = 27), of whom 25 patients in the AIA and 24 patients in the sham AIA group were analyzed. AIA-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores (p = 0.03) and SDS scores (p = 0.02) at week 2 compared to patients receiving sham AIA. The AIA intervention also produced a higher rate of clinically significant responses in sleep disorders (p = 0.07) compared to sham AIA. No adverse events occurred in either group. According to the findings of this preliminary study, AIA appears to have additional value compared to SSRIs alone in treating patients with depressive disorder.


The a3 problem solving report: a 10-step scientific method to execute performance improvements in an academic research vivarium.
The purpose of this study was to illustrate the application of A3 Problem Solving Reports of the Toyota Production System to our research vivarium through the methodology of Continuous Performance Improvement, a lean approach to healthcare management at Seattle Children's (Hospital, Research Institute, Foundation). The Report format is described within the perspective of a 10-step scientific method designed to realize measurable improvements of Issues identified by the Report's Author, Sponsor and Coach. The 10-step method (Issue, Background, Current Condition, Goal, Root Cause, Target Condition, Countermeasures, Implementation Plan, Test, and Follow-up) was shown to align with Shewhart's Plan-Do-Check-Act process improvement cycle in a manner that allowed for quantitative analysis of the Countermeasure's outcomes and of Testing results. During fiscal year 2012, 9 A3 Problem Solving Reports were completed in the vivarium under the teaching and coaching system implemented by the Research Institute. Two of the 9 reports are described herein. Report #1 addressed the issue of the vivarium's veterinarian not being able to provide input into sick animal cases during the work day, while report #7 tackled the lack of a standard in keeping track of weekend/holiday animal health inspections. In each Report, a measurable Goal that established the basis for improvement recognition was present. A Five Whys analysis identified the Root Cause for Report #1 as historical work patterns that existed before the veterinarian was hired on and that modern electronic communication tools had not been implemented. The same analysis identified the Root Cause for Report #7 as the vivarium had never standardized the process for weekend/holiday checks. Successful outcomes for both Reports were obtained and validated by robust audit plans. The collective data indicate that vivarium staff acquired a disciplined way of reporting on, as well as solving, problems in a manner consistent with high level A3 Thinking.


SNP marker detection and genotyping in tilapia.
We have generated a unique resource consisting of nearly 175 000 short contig sequences and 3569 SNP markers from the widely cultured GIFT (Genetically Improved Farmed Tilapia) strain of Nile tilapia (Oreochromis niloticus). In total, 384 SNPs were selected to monitor the wider applicability of the SNPs by genotyping tilapia individuals from different strains and different geographical locations. In all strains and species tested (O. niloticus, O. aureus and O. mossambicus), the genotyping assay was working for a similar number of SNPs (288-305 SNPs). The actual number of polymorphic SNPs was, as expected, highest for individuals from the GIFT population (255 SNPs). In the individuals from an Egyptian strain and in individuals caught in the wild in the basin of the river Volta, 197 and 163 SNPs were polymorphic, respectively. A pairwise calculation of Nei's genetic distance allowed the discrimination of the individual strains and species based on the genotypes determined with the SNP set. We expect that this set will be widely applicable for use in tilapia aquaculture, e.g. for pedigree reconstruction. In addition, this set is currently used for assaying the genetic diversity of native Nile tilapia in areas where tilapia is, or will be, introduced in aquaculture projects. This allows the tracing of escapees from aquaculture and the monitoring of effects of introgression and hybridization.


Increasing discrepancy of MR imaging and CSF study in patients with leptomeningeal seeding from lung adenocarcinoma after targeted therapy using a tyrosine kinase inhibitor.
To evaluate the correlation between contrast-enhanced (CE) MRI and cerebrospinal fluid (CSF) cytology for the evaluation of leptomeningeal metastasis (LM) on MRI after targeted therapy with tyrosine kinase inhibitors. We retrospectively reviewed the data of nonsmall cell lung cancer patients registered with NCT03257124 from May 2017 to December 2018, with progressive disease despite targeted therapy. Twenty-nine patients whose MRI scans exhibited LM at the time of registration were enrolled. During the targeted therapy with osimertinib, MRI scans, and subsequent CSF examinations were performed in every 2 months. In total, 113 MRI scans and CSF cytology data after treatment were collected. For each CE MRI scan, LM positivity was evaluated on 3D T1-weighted image (T1WI) and 2D FLAIR. The correlation between MRI and CSF cytology results and the diagnostic performance of MRI with CSF cytology as a reference standard were evaluated. After treatment, MRI revealed positivity for LM in 81 and negativity in 32. CSF results were positive in 69 examinations and negative in 44. The diagnostic accuracy of CE 3D T1WI and 2D FLAIR was 0.52 and 0.46, respectively. After targeted therapy, discrepancy in the CSF and MRI results tended to increase over time. The proportions of concordant MRI and CSF cytology results after targeted therapy were 66%, 58%, 62%, and 47% at the first, second, third, and fourth follow-up, respectively. The discrepancy of MRI in evaluation of LM and CSF cytology increases over time after targeted therapy with osimertinib. LM positivity on MRI could be a surrogate imaging marker in the pre- and immediate posttargeted-treatment with Osimertinib but not after sessions of osimertinib.


Edge effects and geometric constraints: a landscape-level empirical test.
Edge effects are pervasive in landscapes yet their causal mechanisms are still poorly understood. Traditionally, edge effects have been attributed to differences in habitat quality along the edge-interior gradient of habitat patches, under the assumption that no edge effects would occur if habitat quality was uniform. This assumption was questioned recently after the recognition that geometric constraints tend to reduce population abundances near the edges of habitat patches, the so-called geometric edge effect (GEE). Here, we present the first empirical, landscape-level evaluation of the importance of the GEE in shaping abundance patterns in fragmented landscapes. Using a data set on the distribution of small mammals across 18 forest fragments, we assessed whether the incorporation of the GEE into the analysis changes the interpretation of edge effects and the degree to which predictions based on the GEE match observed responses. Quantitative predictions were generated for each fragment using simulations that took into account home range, density and matrix use for each species. The incorporation of the GEE into the analysis changed substantially the interpretation of overall observed edge responses at the landscape scale. Observed abundances alone would lead to the conclusion that the small mammals as a group have no consistent preference for forest edges or interiors and that the black-eared opossum Didelphis aurita (a numerically dominant species in the community) has on average a preference for forest interiors. In contrast, incorporation of the GEE suggested that the small mammal community as a whole has a preference for forest edges, whereas D. aurita has no preference for forest edges or interiors. Unexplained variance in edge responses was reduced by the incorporation of GEE, but remained large, varying greatly on a fragment-by-fragment basis. This study demonstrates how to model and incorporate the GEE in analyses of edge effects and that this incorporation is necessary to properly interpret edge effects in landscapes. It also suggests that geometric constraints alone are unlikely to explain the variability in edge responses of a same species among different areas, highlighting the need to incorporate other ecological factors into explanatory models of edge effects.


Cardiac impairment and nitric oxide synthase activity in the chronic portal vein-stenosed rat.
Decreased cardiac contractility and beta-adrenergic responses have been observed in the chronic portal vein-stenosed (PVS) rat. Because nitric oxide (NO) may be increased in PVS and has been recognized as a negative inotropic agent, we investigated the induction of NO synthase (NOS2) and/or changes in constitutive NOS (NOS3) as factors in the cardiac dysfunction of the PVS rat. Ten to twelve days after portal vein stenosis or sham operation, cardiac function was evaluated in paced left ventricular papillary muscles (LVPM) and right ventricular strips (RV). To determine if NO modulation of contractile function was altered in PVS, we examined the increase in developed tension produced by the effect of Nomega-nitro-L-arginine (L-NNA) on the myocardial force-frequency relationship. Cardiac tissue NOS2 and NOS3 activities were assayed, Western blot analyses of NOS2 and NOS3 expression were performed, and circulating nitrate-nitrite (NOX) levels (an indicator of in vivo NOS activity) were assayed. Basal LVPM and RV contractile indexes were significantly reduced in PVS (30-50%), without a change in the relaxation rate. No between-group differences in the cardiac NOS2 or NOS3 enzymatic activities of PVS and sham-operated (SO) rats were observed. Western blots revealed no cardiac NOS2 expression in either SO or PVS rats. In contrast, NOS3 was expressed in both SO and PVS rats, but there was no quantitative difference in expression between the two groups. Changes in the cardiac force-frequency relationship (staircase effect) after L-NNA were consistent with NOS3 modulation of contractile function in both SO and PVS rats, but there was no between-group difference in the modulation. Circulating NOX concentrations did not differ between SO and PVS rats. In conclusion, protein expression data, enzymatic assays, end-product assays, and functional data indicate that between-group differences in NOS2 and NOS3 activity are not responsible for the cardiac impairment that has been observed in the chronic PVS rat.


Carbon balance of a mannitol fermentation and the biosynthetic pathway.
The carbon balance was determined for a fermentation in which mannitol is produced from glucose by an Aspergillus species. The products found were: cells (17% of carbon input), CO(2) (26%), mannitol (35%), glycerol (10%), erythritol (2.5%), glycogen (1%), and unidentified compounds (8%). Thus, 92% of the carbon input was accounted for. Cell-free enzyme studies showed that mannitol was synthesized via the reduction of fructose-6-phosphate and not by the direct reduction of fructose. If the cell yield from glucose was assumed to be 50% and the theoretical conversion efficiency from glucose to polyols was 90%, as calculated from the energy balance, then 34% of the glucose carbon was used for growth and 53% was used for polyol formation.


Defects in eye development in transgenic mice overexpressing the heparan sulfate proteoglycan agrin.
The importance of heparan sulfate proteoglycans (HSPGs) in neurodevelopment is becoming increasingly clear. However, studies on HSPGs are hampered by pleiotropic effects when synthesis or modification of heparan sulfate itself is targeted, and by redundancy when the core proteins are altered. Gain-of-function experiments can sometimes circumvent these issues. Here we establish that transgenic mice overexpressing the HSPG agrin have severe ocular dysgenesis. The defects occur through a gain-of-function mechanism and penetrance is dependent on agrin dosage. The agrin-induced developmental defects are highly variable, and include anophthalmia, persistence of vitreous vessels, and fusion of anterior chamber structures. A frequently observed defect is an optic stalk coloboma leading to the misdifferentiation of the optic stalk as retina, which becomes continuous with the forebrain. The defects in optic-stalk differentiation correlate with reduced sonic hedgehog immunoreactivity and overexpansion of the PAX6 domain from the retina into the optic stalk. The ocular phenotypes associated with agrin overexpression are dependent on genetic background, occurring with high penetrance in inbred C57BL/6J mice. Distinct loci sensitizing C57BL/6J mice to agrin-induced dysgenesis were identified. These results indicate that agrin overexpression will provide a tool to explore the molecular interactions of the extracellular matrix and cell surface in eye development, and provide a means for identifying modifier loci that sensitize mice to developmental eye defects.


Treatment of advanced head and neck cancer with cetuximab.
Cetuximab is a monoclonal antibody targeting the transmembrane receptor HER-1 (epidermal growth factor receptor, EGFR). In theory, inhibition of EGFR may influence tumor behavior since the receptor regulates many important tumor cell activities including tumor growth, angiogenesis, and inhibition of the apoptotic response to chemotherapy and radiotherapy. Available experimental data suggest that cetuximab may enhance the activity of chemotherapy and radiotherapy, reverse resistance to some anticancer drugs, and has itself anticancer activity. Early clinical data support the experimental results. This paper reviews the published findings on cetuximab in the treatment of advanced head and neck cancer and points out the future objectives of the clinical research on this drug.


[Clonidine supplemented analgesia and sedation in prevention of postoperative delirium].
In an open prospective study we investigated the efficacy of the supplementation of analgosedation by clonidine. 40 patients with oesophagus malignancy and definite alcohol abuse were on respiration therapy postoperatively after having been treated with oesophago-gastro anastomoses. With regard to manifestation intensity and development of withdrawal symptoms we found that during basic medication with piritramid-diazepam continuously i.v. administered clonidine can eliminate haemodynamic and psychovegetative symptoms related to alcohol withdrawal. The clonidine group required less analgosedation. The measurement of the urinary catecholamine output showed a normalised endogenous output. As a finding of importance the gastrovolume was reduced, and the haemodynamically firm, stable and less sedated patients of the clonidine group required fewer days of respiration therapy. Hence, the hazard of aspiration pneumonia and insufficienty anastomosis was lower. Risk of bradycardia of high potential danger did not occur with a median daily dosage of 1.09 mg/d clonidine. We consider clonidine to be a potent supplement to analgosedation for the surgical patient who is at high risk of alcohol withdrawal.


Characteristics of patients with neovascular age-related macular degeneration who are non-responders to intravitreal aflibercept.
To investigate the frequency and patient characteristics that influence anatomic response of intravitreal aflibercept in treatment-naïve neovascular age-related macular degeneration (AMD). Retrospective, interventional, consecutive case series. Three hundred and sixty-five eyes of 365 patients with AMD who underwent 3 monthly intravitreal aflibercept treatments with follow-up for at least 12 months were investigated. Treatment response was evaluated as follows. Responders were defined as those with complete resolution of exudation, including intraretinal oedema, subretinal fluid and pigment epithelial detachment, or more than a 100 µm decrease of central retinal thickness at 3 months compared with baseline. Non-responders were defined as patients exhibiting an increase in exudation or a decreased central retinal thickness of less than 100 µm. Nineteen (5.2%) of 365 eyes were identified as non-responders. The remaining were responders to intravitreal aflibercept. The non-responders group was significantly associated with choroidal vascular hyperpermeability on indocyanine green angiography and lower frequency of subretinal hyper-reflective materials on optical coherence tomography. The central choroidal thickness at baseline and after 3 monthly injections tended to be thicker in the non-responder group than the responder group, although the differences did not meet statistical significance (p=0.066 and p=0.051, respectively). Additional treatments with either intravitreal ranibizumab or PDT in combination with aflibercept were effective in 15 (79%) of 19 non-responders. Intravitreal aflibercept is effective for treating eye pathology in most naïve AMD cases. However, non-responsiveness may occur in small subgroup of patients with choroidal vascular hyperpermeability.


Established and emerging trends in computational drug discovery in the structural genomics era.
Bioinformatics and chemoinformatics approaches contribute to hit discovery, hit-to-lead optimization, safety profiling, and target identification and enhance our overall understanding of the health and disease states. A vast repertoire of computational methods has been reported and increasingly combined in order to address more and more challenging targets or complex molecular mechanisms in the context of large-scale integration of structure and bioactivity data produced by private and public drug research. This review explores some key computational methods directly linked to drug discovery and chemical biology with a special emphasis on compound collection preparation, virtual screening, protein docking, and systems pharmacology. A list of generally freely available software packages and online resources is provided, and examples of successful applications are briefly commented upon.


Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human kidney disease and is caused by germline mutations in PKD1 (85%) or PKD2 (15%). It has been estimated that around 1% of tubular cells give rise to cysts, and cell hyperproliferation has been noted to be a cardinal feature of cystic epithelium. Nevertheless, it is uncertain whether the increase in proliferative index observed is an early or late feature of the cystic ADPKD kidney. Two Pkd2 mouse mutants (WS25 and WS183) have been recently generated as orthologous models of PKD2. To determine the effect of Pkd2 dosage on cell proliferation, cyst formation and renal fibrosis, we studied renal tissue from Pkd2(WS25/WS25) and Pkd2(+/-) mice by histological analysis. We also examined the proliferative index in archival nephrectomy tissue obtained from patients with ADPKD and normal controls. The proliferative index of non-cystic tubules in Pkd2 mutant mice as assessed by proliferating cell nuclear antigen and Ki67-positive nuclei was between 1-2%, values 5-10 times higher than control tissue. Similarly, the proliferative index of non-cystic tubules in human ADPKD kidneys was 40 times higher than corresponding controls. In Pkd2 mutant mice, significant correlations were found between the fibrosis score and the mean cyst area as well as with the proliferative index. Of significance, proliferating tubular cells were uniformly positive for polycystin-2 expression in Pkd2(+/-) kidney. These results suggest that an increase in cell proliferation is an early event preceding cyst formation and can result from haploinsufficiency at Pkd2. The possible pathogenic link between tubular cell proliferation, interstitial fibrosis and cyst formation is discussed.


Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression.
Interleukin 10 (IL-10) is a cytokine with a variety of reported effects including inhibition of monocyte major histocompatibility complex (MHC) class II-dependent antigen presentation, type 1 helper T cell cytokine production, and inhibition of T cell proliferation. Herein we report the effect of IL-10 pretreatment on antigen presentation to tumor- and allo-specific CD8+ cytotoxic T lymphocytes (CTL). Prior incubation of human melanoma cells with recombinant IL-10 (rIL-10) for 48-72 h resulted in a dose-dependent, up to 100% inhibition, of autologous CTL-mediated, HLA-A2.1-restricted, tumor-specific lysis. Allo-specific CTL cytotoxicity against Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL) was also inhibited, demonstrating a protective effect also on lymphoid cells. In contrast, IL-10 pretreatment of allogeneic LCL or K562 targets had either no effect or slightly enhanced cytotoxic activity mediated by freshly isolated or IL-2-activated natural killer cells. Flow cytometric analysis with monoclonal antibodies against HLA-A2, or nonpolymorphic determinants of MHC class I proteins, revealed a 20-50% reduction in cell-surface expression, whereas intercellular adhesion molecules 1, and 2, and lymphocyte function-associated antigen 3 levels were not affected. In addition, relative to untreated target cells, IL-10 pretreated tumor cells were unaltered in their capacity to affect CTL-mediated lysis by cold target inhibition, demonstrating that the effect of IL-10 is unrelated to the initial binding of CTL to their targets. These results are compatible with an effect of IL-10 on the MHC class I antigen presentation pathway, and suggest a novel mechanism of immune tolerance, based on escape from CTL-mediated tumor and allo-transplant rejection.


Generating High Density, Low Cost Genotype Data in Soybean [Glycine max (L.) Merr.].
Obtaining genome-wide genotype information for millions of SNPs in soybean [Glycine max (L.) Merr.] often involves completely resequencing a line at 5X or greater coverage. Currently, hundreds of soybean lines have been resequenced at high depth levels with their data deposited in the NCBI Short Read Archive. This publicly available dataset may be leveraged as an imputation reference panel in combination with skim (low coverage) sequencing of new soybean genotypes to economically obtain high-density SNP information. Ninety-nine soybean lines resequenced at an average of 17.1X were used to generate a reference panel, with over 10 million SNPs called using GATK's Haplotype Caller tool. Whole genome resequencing at approximately 1X depth was performed on 114 previously ungenotyped experimental soybean lines. Coverages down to 0.1X were analyzed by randomly subsetting raw reads from the original 1X sequence data. SNPs discovered in the reference panel were genotyped in the experimental lines after aligning to the soybean reference genome, and missing markers imputed using Beagle 4.1. Sequencing depth of the experimental lines could be reduced to 0.3X while still retaining an accuracy of 97.8%. Accuracy was inversely related to minor allele frequency, and highly correlated with marker linkage disequilibrium. The high accuracy of skim sequencing combined with imputation provides a low cost method for obtaining dense genotypic information that can be used for various genomics applications in soybean.


Role of maize hybrids and their chemical composition in Fusarium infection and fumonisin production.
This study was designed to investigate the role of hybrids in maize Fusarium section Liseola interaction and fumonisin production, with particular emphasis on the occurrence and accumulation of hidden fumonisins in maize (masking phenomenon). In this 2 year study, naturally infected field crops were chosen with 10 maize hybrids, six of them grown in both years. Maize samples collected in 2010 showed a higher incidence of fungal infection as well as higher fumonisin contamination than those obtained in 2009 but a very similar incidence of F. section Liseola. Fumonisin masking was confirmed in raw maize, with a lower amount of hidden forms as compared to free fumonisins detected in the year with higher contamination. The chemical composition of the different hybrids was determined and correlated with the contamination data: the results obtained highlight the main role of fatty acids, with a higher fumonisin contamination in hybrids showing a higher linoleic acid content and a higher masking action in hybrids with higher oleic to linoleic ratio. These results represent a good basis to explain maize hybrid susceptibility to F. section Liseola infection, fumonisin contamination, and masking not related to a specific commercial hybrid but extendable to all hybrids.


The expression of enterotoxin A-B+ gene of V. cholerae in E. coli.
The cloning in E. coli of a cholerae toxin gene that is A-B+ has been successfully constructed by using DNA recombinant techniques. E. coli cells carrying the recombinant plasmid pMM-CTB have been shown to produce a large amount of CTB subunits which are secreted as extracellular proteins.


Molecular characterization of avipoxviruses circulating in Mozambique, 2016-2018.
Samples from 45 chickens, two turkeys, one peacock and one quail with symptoms of fowlpox were collected in Mozambique between November 2016 and January 2018. Phylogenetic analysis revealed that the samples contained avipoxviruses belonging to both clade A1 and clade A2. In addition, all of the Clade A1 viruses were positive by PCR for the integration of reticuloendotheliosis virus, while the clade A2 avipoxvirus samples were negative. This study confirms the circulation of clade A1 avipoxviruses in Mozambique in addition to identifying clade A2 for the first time in the country.


Are Ultrasonographic Measures of Cervical Flexor Muscles Correlated With Flexion Endurance in Chronic Neck Pain and Asymptomatic Participants?
This study compared the relationship between some clinical factors and the size of neck flexors in participants with or without chronic neck pain. In this case-control study, the correlation between flexor endurance capacity as well as thickness, cross-section area, and shape ratio of longus colli/capitis and sternocleidomastoid muscles were examined in 30 patients with chronic neck pain and 30 asymptomatic participants. The patients showed lower flexor endurance (P = 0.02), smaller thickness (P = 0.03), and cross-section area (P < 0.01) of longus colli as compared with controls. Longus capitis and sternocleidomastoid size were not different between the two groups. The flexor endurance showed a negative correlation with longus colli shape ratio (r = -0.38, P = 0.03) and a positive correlation with longus capitis cross-section area (r = 0.38, P = 0.03) in the patients with chronic neck pain. In the control group, flexor endurance was negatively correlated with longus colli shape ratio (r = -0.45, P = 0.01) but positively correlated with longus capitis thickness (r = 0.45, P = 0.01) and cross-section area (r = 0.38, P = 0.03). Neck disability and pain intensity indices were not significantly correlated with either flexor muscles endurance or size. The ultrasonographic measures of the deep neck flexor muscles and the flexor endurance test, being associated with each other, could successfully differentiate patients with chronic neck pain from asymptomatic participants. However, the endurance test scores were not correlated with self-reported disability or pain intensity indices.


[Diagnostics and interpretation of results in forensic toxicology of amphetamines].
Amphetamine and its analogues belong to the large group of psychoactive compounds. Due to the growing problem of amphetamine poisoning, author decided to review and improve the laboratory diagnostic procedures with regard to forensic toxicology analysis. Biological material of 8 persons taken during autopsy for routine toxicological tests was used to examine characteristic of biological matrix. Following excludion the presence of xenobiotics during expertise process, material was divided and kept in sealed containers, then analysed after defined time period: 0, 30 and 90 days. Blood, urine, liver, brain and kidney were considered, 96 samples were examined in total. Biological material was analysed using gas chromatography equipped with flame ionization detector (GC-FID), liquid chromatography with diode array detector (HPLC-DAD), and magnetic resonance spectrometer (H NMR). 1. Workout analytical GC-FID method enable to verify positive initial result of amphetamine and metamphetamine analysis in urine. 2. Biological matrix is composed mainly of low molecular aliphatic organical compounds which cause significant impact in analytical and opinion problem in amphetamine analysis. Its influence determine in proportion as time of biological material self-decomposition and noted cross-reactivity concern both immunological and chromatographic methods (HPLC-DAD). 3. H NMR method may be used to confirm amphetamine presence in biological material for confirmation of positive results obtained using immunological and enzymatic methods used in forensic toxicology.


Coordination of Di-Acetylated Histone Ligands by the ATAD2 Bromodomain.
The ATPase Family, AAA domain-containing protein 2 (ATAD2) bromodomain (BRD) has a canonical bromodomain structure consisting of four α-helices. ATAD2 functions as a co-activator of the androgen and estrogen receptors as well as the MYC and E2F transcription factors. ATAD2 also functions during DNA replication, recognizing newly synthesized histones. In addition, ATAD2 is shown to be up-regulated in multiple forms of cancer including breast, lung, gastric, endometrial, renal, and prostate. Furthermore, up-regulation of ATAD2 is strongly correlated with poor prognosis in many types of cancer, making the ATAD2 bromodomain an innovative target for cancer therapeutics. In this study, we describe the recognition of histone acetyllysine modifications by the ATAD2 bromodomain. Residue-specific information on the complex formed between the histone tail and the ATAD2 bromodomain, obtained through nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography, illustrates key residues lining the binding pocket, which are involved in coordination of di-acetylated histone tails. Analytical ultracentrifugation, NMR relaxation data, and isothermal titration calorimetry further confirm the monomeric state of the functionally active ATAD2 bromodomain in complex with di-acetylated histone ligands. Overall, we describe histone tail recognition by ATAD2 BRD and illustrate that one acetyllysine group is primarily engaged by the conserved asparagine (N1064), the "RVF" shelf residues, and the flexible ZA loop. Coordination of a second acetyllysine group also occurs within the same binding pocket but is essentially governed by unique hydrophobic and electrostatic interactions making the di-acetyllysine histone coordination more specific than previously presumed.


Quantitative genetic study of maximal electroshock seizure threshold in mice: evidence for a major seizure susceptibility locus on distal chromosome 1.
We conducted a quantitative trait locus (QTL) mapping study to dissect the multifactorial nature of maximal electroshock seizure threshold (MEST) in C57BL/6 (B6) and DBA/2 (D2) mice. MEST determination involved a standard paradigm in which 8- to 12-week-old mice received one shock per day with a daily incremental increase in electrical current until a maximal seizure (tonic hindlimb extension) was induced. Mean MEST values in parental strains were separated by over five standard deviation units, with D2 mice showing lower values than B6 mice. The distribution of MEST values in B6xD2 F2 intercrossed mice spanned the entire phenotypic range defined by parental strains. Statistical mapping yielded significant evidence for QTLs on chromosomes 1, 2, 5, and 15, which together explained over 60% of the phenotypic variance in the model. The chromosome 1 QTL represents a locus of major effect, accounting for about one-third of the genetic variance. Experiments involving a congenic strain (B6.D2-Mtv7(a)/Ty) enabled more precise mapping of the chromosome 1 QTL and indicate that it lies in the genetic interval between markers D1Mit145 and D1Mit17. These results support the hypothesis that the distal portion of chromosome 1 harbors a gene(s) that has a fundamental role in regulating seizure susceptibility.


Cardiac screening in school children: Combining auscultation and electrocardiography with a crowdsourcing model.
School-based cardiac screening is useful for identifying children and adolescents with a high risk of sudden cardiac death. However, because of challenges associated with cost, distance, and human resources, cardiac screening is not widely implemented, especially in rural areas with limited medical resources. This study aims to establish a cloud-based system suitable for mass cardiac screening of schoolchildren in rural areas with limited medical resources. Students from three schools were included. They or their guardians completed a simple questionnaire, administered in paper or electronic form. Heart sounds were recorded using an electronic stethoscope. Twelve-lead electrocardiograms (ECGs) were recorded and digitalized. The signals were transmitted through Bluetooth to a tablet computer and then uploaded to a cloud server over Wi-Fi. Crowdsourced pediatric cardiologists reviewed those data from a web-based platform and provided remote consultation. In cases in which abnormal heart sounds or ECGs were noted, the students were referred to the hospital for further evaluation. A total of 1004 students were enrolled in this study. Of the 138 students referred, 62 were diagnosed as having an abnormal heart condition and most had previously been undiagnosed. The interrater agreeability was high. An innovative strategy combining a cloud-based cardiac screening system with remote consultation by crowdsourced experts was established. This system allows pediatric cardiologists to provide consultation and make reliable diagnoses. Combined with crowdsourcing, the system constitutes a viable approach for mass cardiac screening in children and adolescents living in rural areas with insufficient medical resources.


Enhancement of RNA synthesis, protein synthesis, and abscission by ethylene.
Ethylene stimulated RNA and protein synthesis in bean (Phaseolus vulgaris L. var. Red Kidney) abscission zone explants prior to abscission. The effect of ethylene on RNA synthesis and abscission was blocked by actinomycin D. Carbon dioxide, which inhibits the effect of ethylene on abscission, also inhibited the influence of ethylene on protein synthesis. An aging period appears to be essential before bean explants respond to ethylene. Stimulation of protein synthesis by ethylene occurred only in receptive or senescent explants. Treatment of juvenile explants with ethylene, which has no effect on abscission also has no effect on protein synthesis. Evidence in favor of a hormonal role for ethylene during abscission is discussed.


Embracing dynamic public health policy impacts in infectious diseases responses: leveraging implementation science to improve practice.
The host-pathogen relationship is inherently dynamic and constantly evolving. Applying an implementation science lens to policy evaluation suggests that policy impacts are variable depending upon key implementation outcomes (feasibility, acceptability, appropriateness costs) and conditions and contexts. Experiences with non-pharmaceutical interventions (NPIs) including masking, testing, and social distancing/business and school closures during the COVID-19 pandemic response highlight the importance of considering public health policy impacts through an implementation science lens of constantly evolving contexts, conditions, evidence, and public perceptions. As implementation outcomes (feasibility, acceptability) changed, the effectiveness of these interventions changed thereby altering public health policy impact. Sustainment of behavioral change may be a key factor determining the duration of effectiveness and ultimate impact of pandemic policy recommendations, particularly for interventions that require ongoing compliance at the level of the individual. Updating public health policy recommendations as more data and alternative interventions become available is the evidence-based policy approach and grounded in principles of implementation science and dynamic sustainability. Achieving the ideal of real-time policy updates requires improvements in public health data collection and analysis infrastructure and a shift in public health messaging to incorporate uncertainty and the necessity of ongoing changes. In this review, the Dynamic Infectious Diseases Public Health Response Framework is presented as a model with a practical tool for iteratively incorporating implementation outcomes into public health policy design with the aim of sustaining benefits and identifying when policies are no longer functioning as intended and need to be adapted or de-implemented. Real-time decision making requires sensitivity to conditions on the ground and adaptation of interventions at all levels. When asking about the public health effectiveness and impact of non-pharmaceutical interventions, the focus should be on when, how, and for how long they can achieve public health impact. In the future, rather than focusing on models of public health intervention effectiveness that assume static impacts, policy impacts should be considered as dynamic with ongoing re-evaluation as conditions change to meet the ongoing needs of the ultimate end-user of the intervention: the public.


Allatostatin A-like immunoreactivity in the nervous system and gut of the larval midge Chironomus riparius: modulation of hindgut motility, rectal K+ transport and implications for exposure to salinity.
Evidence for the presence of allatostatin (AST) A-like neuropeptides in the larval midge Chironomus riparius is reported. Immunohistochemical studies on the nervous system and gut revealed the presence of AST A-like immunoreactive (AST-IR) cells and processes. The nerve cord contained AST-IR processes that originated from cells in the brain and travelled the length of nerve cord to the terminal ganglion. Within each ganglion, these processes gave rise to varicosities, suggesting that they formed synapses with neurons in the ganglia. Endocrine cells containing AST-IR were present in three regions of the midgut: near the attachment of the Malpighian tubules, between the anterior and posterior midgut, and in the vicinity of the gastric caecae. The terminal ganglion also contained four AST-IR cells that gave rise to axons that projected onto the hindgut and posterior midgut. Application of a cockroach AST to the semi-isolated hindgut of larval C. riparius led to dose-dependent inhibition of muscle contractions with an EC50 of ~10 nmol l(-1) and a decrease in rectal K(+) reabsorption resulting from reduced rectal Na(+)/K(+)-ATPase and vacuolar type H(+)-ATPase activities. The results suggest the presence of endogenous AST-like neuropeptides in larval C. riparius, where these factors play a role in the function of the gut. Furthermore, regulation of ion reabsorption by ASTs at the rectum could serve as an ideal mechanism of ion regulation in the face of abrupt and acute elevated salt levels.


Bifocal extra- and intradural melanocytoma of the spine: case report and literature review.
Spinal melanocytoma is one of the most infrequent space-occupying lesions of the central nervous system. To the best of our knowledge, this is the first report of primary bifocal intradural melanocytoma of heterogeneous pathological grade to date. We report the case of a 43-year old patient with primary bifocal melanocytoma, clinically and radiologically resembling benign schwannoma. The patient presented with myeloradiculopathy of the left C3 dermatome. Magnetic resonance imaging of the upper spine revealed two space-occupying lesions with paraspinal extension, initially diagnosed as neurofibroma. Definitive histopathological classification of both lesions was melanocytoma. Both tumours were only partially removed due to adherence to surrounding structures. The patient underwent stereotactic external beam irradiation (EBR). Follow-up at 1 year after surgery revealed no recurrence and the patient remained free of symptoms. The clinical, radiological and pathological features of this rare tumour entity are presented and the available literature is reviewed. Intradural melanocytoma, although exceedingly rare, requires a thorough work-up to exclude malignant melanoma. With only two previous reports of multifocal melanocytoma published in the literature, standard therapy has not yet been established and complete surgical removal remains the modality of choice. Patients should be closely monitored to detect local recurrence or malignant degeneration. EBR may be considered in cases where total excision is not achievable and reduces risk of local recurrences.


Protective effect of L-arginine on gentamicin-induced nephrotoxicity in rats.
L-arginine has a protective effect on gentamicin-induced renal failure and it may decrease the tubular reabsorption of another cationic substance, gentamicin due to its cationic structure. The aim of this study is to compare the possible protective effects of L-arginine and its inactive isomer D-arginine on gentamicin-induced nephrotoxicity in rats. Wistar albino rats were housed in metabolic cages and assigned to six groups as: control group, gentamicin (100 mg/kg), gentamicin + L-arginine (2 g/l), gentamicin + D-arginine (2 g/l), gentamicin + L-arginine + Nv-nitro-L-arginine methyl ester (L-NAME) (100 mg/l) and gentamicin + D-arginine + L-NAME. Gentamicin was administered by subcutaneous injections and the other drugs were added in drinking water for seven consecutive days. The animals were killed by decapitation and intracardiac blood and urine samples were obtained on the seventh day. Blood urea nitrogen, serum creatinine, sodium, potassium, urine gamma glutamyl transferase, creatinine, sodium, potassium and gentamicin levels were measured using High Performance Liquid Chromatography (HPLC) technique. Gentamicin treated group had significant increase in blood urea nitrogen, serum creatinine, fractional Na excretion and urine gamma glutamyl transferase levels, and significant decrease in creatinine clearance compared to the control group. L-arginine and D-arginine reversed these findings. L-NAME abolished the nephroprotective effect of L-arginine. The urinary levels of gentamicin were significantly increased in rats treated with L-arginine or D-arginine compared to those treated with gentamicin. L-arginine and D-arginine reversed the advanced degenerative changes due to gentamicin administration in histopathological examination. Our study revealed the protective effect of L-arginine on gentamicin-induced nephrotoxicity, the contribution of the cationic feature of L-arginine, and the major role of NO in this protective effect.


Constructing Identity Through Sex-Consumption: The Consumerist Narratives of Israeli Men Who Pay Women for Sex.
This study examined how consumerism shapes the identity construction processes of Israeli men who pay women for sex (MPWS). Using the theoretical framework of symbolic interaction and the theoretical concept of extended self, we explored how Israeli MPWS extend their selves through sex-consumption. To this end, we conducted in-depth semi-structured interviews with 23 Israeli MPWS. An interpretive epistemology and a constructivist grounded theory methodology guided the data-analysis. We conceptualized three dynamics of self-identity construction processes through sex-consumption: Extending the self through assimilation of products or experiences, Extending the self through the purchasing process, and Extending the self through consuming the imagined. The findings revealed a complex process, whereby MPWS attribute various and contradictory meanings to their possessions, their consumerist experiences, and their purchasing processes. We conclude that consumerism is central to the meanings that MPWS attribute to their engagement in the sex industry. Thus, the theoretical framework of consumerism should be further applied to future studies in this field in order to gain a nuanced and deeper understanding of MPWS and the phenomenon of sex consumption.


Effect of a phosphodiesterase-5A (PDE5A) gene polymorphism on response to sildenafil therapy in canine pulmonary hypertension.
Pulmonary hypertension (PH) is a common clinical condition associated with morbidity and mortality in both humans and dogs. Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor causing accumulation of cGMP, is frequently used for treatment of PH. The authors previously reported a PDE5A:E90K polymorphism in dogs that results in lower basal cyclic guanosine monophosphate (cGMP) concentrations than in wild-type dogs, which could contribute to variability in the efficacy of sildenafil. In this study, response to sildenafil therapy was evaluated in dogs with PH by comparing echocardiographic parameters, quality-of-life (QOL) score, and plasma cGMP concentrations before and after sildenafil therapy. Overall, tricuspid regurgitation estimated systolic pressure gradient (PG) and QOL score were significantly improved after sildenafil therapy, and the plasma cGMP concentration was significantly decreased. Dogs that had a heterozygous PDE5A status had a significantly worse QOL score when compared to the wildtype group after sildenafil treatment. The simple and multiple regression analyses revealed a significant but weak prediction for the percent reduction in QOL score with sildenafil treatment by plasma cGMP level and by the PDE5A:E90K polymorphic status. This study showed that sildenafil treatment improved PH in dogs, and the PDE5A:E90K polymorphism blunted the efficacy of sildenafil in terms of QOL improvement.


Highly Accurate CCSDT(Q)/CBS Reaction Barrier Heights for a Diverse Set of Transition Structures: Basis Set Convergence and Cost-Effective Approaches for Estimating Post-CCSD(T) Contributions.
The ability to accurately calculate reaction barrier heights is of central importance to many areas of chemistry. We report an extensive study examining the basis set convergence of post-CCSD(T) contributions (up to CCSDT(Q)) for a diverse set of 28 reaction barrier heights. In contrast to previous studies, we focus here on larger transition structures (TSs) involving 4-7 non-hydrogen atoms. The set of reaction barrier heights includes pericyclic, bipolar cycloaddition, cycloreversion, and multiple-proton transfer reactions. We find that in most cases post-CCSD(T) contributions converge rapidly toward the basis set limit, such that even double-ζ and truncated double-ζ basis sets provide useful estimates of the T-(T) and (Q) contributions, respectively. In addition, we find that due to the tendency of these small basis sets to systematically underestimate the T-(T) and (Q) components, scaling is an effective approach for improving performance. For example, scaling the T-(T)/cc-pVDZ contribution by 1.25 results in an RMSD of merely 0.4 kJ mol-1 relative to basis set limit reference values from W3lite-F12 theory. Similarly, calculating the (Q) contribution with a cc-pVDZ basis set without d functions and scaling by 1.6 results in an RMSD of 0.5 kJ mol-1. We also examine the magnitude of post-CCSD(T) contributions for a wide range of TSs. We find that for pericyclic, bipolar cycloaddition, and multiple-proton transfer reactions there is an effective cancellation between the T-(T) and (Q) components (i.e., they have opposite signs and are of similar magnitude), such that overall post-CCSD(T) contributions to the reaction barrier heights are below ∼1 kJ mol-1 (in absolute value). However, for the barrier heights of cycloreversion reactions, the T-(T) and (Q) components are both negative and large and consequentially post-CCSD(T) contributions reduce the reaction barrier heights by significant amounts ranging between 4.1 and 6.7 kJ mol-1.


Molecular depth profiling of histamine in ice using a buckminsterfullerene probe.
We employ a buckminsterfullerene ion source to probe the distribution of histamine molecules at the water-ice/vacuum interface. The experiments utilize secondary ion mass spectrometry to detect molecular ions that are desorbed from a frozen aqueous histamine solution. The results show that this cluster ion probe induces an extraordinarily high sputter yield of 2400 ice molecules per impact event as determined by a quartz crystal microbalance. As a consequence of this high yield, we show that it is possible to produce molecular depth profiles of the top several hundred nanometers below the ice surface without destruction of the molecular ion signal by accumulation of beam-induced chemical damage. Similar profiles are reported for desorbed neutral molecular fragments by utilizing a high-power femtosecond-pulsed laser for photoionization. While this type of information could not be achieved using atomic projectiles, it is possible to remove the damage induced by such projectiles by subsequent cluster bombardment. These experiments are particularly important for organic surface analysis since they suggest that cluster ion probes may successfully be employed to remove overlayers that may mask the desired molecular information in static secondary ion mass spectral analysis.


Distribution of acetylcholinesterase activity in the deutocerebrum of the sphinx moth Manduca sexta.
We have used a cytochemical technique to investigate the distribution of acetylcholinesterase (AChE) activity in the deutocerebrum of the brain of the sphinx moth Manduca sexta. To distinguish between extra- and intracellular pools of the enzyme, some brains were treated prior to histochemical staining with echothiophate, an irreversible AChE inhibitor which penetrates cell membranes very slowly and, therefore, inhibits only extracellular AChE. In the antennal nerve, fascicles of presumably mechanosensory fibers show echothiophate-insensitive AChE activity. They bypass the antennal lobe and project to the antennal mechanosensory and motor center of the deutocerebrum. In the antennal lobe, fibers in the coarse neuropil, cell bodies in the lateral cell group, and all glomeruli exhibit AChE activity. In most ordinary glomeruli, echothiophate-sensitive AChE activity is concentrated in the outer cap regions, corresponding to the terminal arborizations of olfactory afferents. A previously unrecognized glomerulus in the ventro-median antennal lobe shows uniform and more intense AChE-specific staining that the other glomeruli. No AChE activity appeared to be associated with male-specific pheromone-sensitive afferents in the macroglomerular complex. About 67 interneurons with somata in the lateral cell group of the antennal lobe show echothiophate-insensitive AChE activity. These neurons seem to be members of two types of antennal-lobe projection neurons with fibers passing through the outer-antennocerebral tract to the protocerebrum. AChE-stained arborizations of these neurons appear to invade all glomeruli, including three distinguishable subunits of the male-specific macroglomerular complex. In echothiophate-treated animals, the projections of one of these types of fiber form large terminals in the lateral horn of protocerebrum, which partly protrude into the adjacent glial cell layer. The results suggest that extracellularly accessible AChE is associated with ordinary olfactory receptor terminals but apparently not with pheromone-sensitive afferents. Intracellular AChE appears to be present in antennal mechanosensory fibers and in two types of olfactory projection neurons of the antennal lobe. The study provides further evidence for cholinergic neurotransmission of most antennal afferents. The AChE-containing interneurons might be cholinergic as well or use the enzyme for functions unrelated to hydrolysis of acetylcholine.


[Pathogenesis of apical periodontitis and its effects on the body].
During the last 25 years there have been major advances in understanding the etiology, pathogenesis and maintenance of inflammatory processes taking place in the periapical space. Polymicrobial infection of the pulp chamber is of primary importance in initiating periapical inflammation. Egress of bacteria and their antigenes stimulate the immune system to form a granulation tissue around the apical area. Local immune response eliminates excess number of invading organisms. However, in parallel with protective reactions, local activity of immunocompetent cells and their soluble products also contribute to tissue damage, bone resorption and perpetuation of inflammation. Present data indicate that interaction of T-lymphocytes and macrophages is crucial in this process.


Eliminating antibiotic prophylaxis for intravitreal injections: a consecutive series of 18,839 injections by a single surgeon.
By optimizing the protocol for intravitreal injections, the risk of endophthalmitis can be minimized. This study assesses the incidence of endophthalmitis and other complications after a consecutive series of intravitreal injections where all antibiotics were excluded. Injections were performed from August 1, 1997 to October 31, 2012 in outpatient examination rooms at the Retina Center of Minnesota by a single retinal surgeon, the lead author. Most injections were performed to treat exudative age-related macular degeneration. Other reasons included diabetic macular edema, cystoid macular edema because of retinal vein occlusions, cytomegalovirus retinitis, and severe uveitis. Injections were given with topical povidone-iodine, proparacaine, and tetracaine, a sterile eyelid speculum, and clean nonsterile gloves, but without any antibiotics. Data were retrospectively analyzed using billing codes from a computer database system. A total of 18,839 injections were given. Of these, the following injections were administered: bevacizumab, 15,479 (82.16%); ranibizumab, 1,669 (8.86%); triamcinolone acetonide (Kenalog-40), 1,014 (5.38%); pegaptanib sodium, 370 (1.96%); aflibercept, 148 (0.79%); dexamethasone implant, 88 (0.47%); triamcinolone acetonide (Triesence), 32 (0.17%); dexamethasone, 29 (0.15%); and ganciclovir, 10 (0.05%). There was one case of postinjection endophthalmitis. The incidence of endophthalmitis per injection was 0.0053%. A low incidence of endophthalmitis can be achieved when topical antibiotics are omitted.


Progressive multi-atlas label fusion by dictionary evolution.
Accurate segmentation of anatomical structures in medical images is important in recent imaging based studies. In the past years, multi-atlas patch-based label fusion methods have achieved a great success in medical image segmentation. In these methods, the appearance of each input image patch is first represented by an atlas patch dictionary (in the image domain), and then the latent label of the input image patch is predicted by applying the estimated representation coefficients to the corresponding anatomical labels of the atlas patches in the atlas label dictionary (in the label domain). However, due to the generally large gap between the patch appearance in the image domain and the patch structure in the label domain, the estimated (patch) representation coefficients from the image domain may not be optimal for the final label fusion, thus reducing the labeling accuracy. To address this issue, we propose a novel label fusion framework to seek for the suitable label fusion weights by progressively constructing a dynamic dictionary in a layer-by-layer manner, where the intermediate dictionaries act as a sequence of guidance to steer the transition of (patch) representation coefficients from the image domain to the label domain. Our proposed multi-layer label fusion framework is flexible enough to be applied to the existing labeling methods for improving their label fusion performance, i.e., by extending their single-layer static dictionary to the multi-layer dynamic dictionary. The experimental results show that our proposed progressive label fusion method achieves more accurate hippocampal segmentation results for the ADNI dataset, compared to the counterpart methods using only the single-layer static dictionary.


Morphological variations in pulmonary atresia with intact ventricular septum.
The morphological features of a series of 37 specimens of pulmonary atresia with intact ventricular septum were reviewed with particular emphasis on features which might influence the results of pulmonary valvotomy. The degree of right heart hypoplasia was quantified by measuring right and left heart dimensions and comparing them with 20 normal infant hearts. Right ventricular cavity size was usually smaller than normal but constituted a spectrum ranging from tiny to a dilated ventricle larger than normal. There was a positive correlation between triscuspid annular size and right ventricular size but no correlation between the size of the pulmonary artery and the right ventricle. Successful pulmonary valvotomy with subsequent adequate right ventricular function would have been precluded by a tiny right ventricular cavity or infundibular atresia in 14 specimens and by severe tricuspid stenosis or regurgitation in an additional 4. Severe right or left ventricular endocardial fibroelastosis may have adversely affected ventricular function in several others. Ten specimens displayed convex bulging of the left ventricular septal surface. If these these anatomical findings are representative for the condition as a whole, they provide a good explanation for its disastrous prognosis.


Seroepidemiologic survey for Coxiella burnetii among US military personnel deployed to Southwest and Central Asia in 2005.
We used a seroepidemiologic study to estimate Q fever (Coxiella burnetii) seroprevalence, seroincidence, and risk factors for seroconversion in two deployed military populations in 2005. The first study group resided in an area with a known Q fever outbreak history (Al Asad, Iraq). Of this population, 7.2% seroconverted for an incidence rate of 10.6 seroconversions per 1,000 person-months. The second population included personnel transiting through Qatar on mid-deployment leave from southwest/central Asia. In this group, we found 2.1% prevalence with 0.92 seroconversions per 1,000 person-months. However, no significant risk factors for Q fever seroconversion were found in either population.


Discrepancy of complete-arch titanium frameworks manufactured using selective laser melting and electron beam melting additive manufacturing technologies.
Titanium frameworks for implant-supported prostheses can be additively manufactured using different powder-based fusion technologies, including selective laser melting (SLM) and electron beam melting (EBM). Some manufacturers have developed a technique that combines the printing of the framework with the subsequent machining of the implant interface. Whether these technologies produce frameworks with acceptable accuracies is unclear. The purpose of this in vitro study was to evaluate the discrepancy obtained from the digitizing procedures of the definitive cast, the implant-prosthesis discrepancy, and the distortion of the manufacturing processes in the fabrication of titanium frameworks for implant-supported complete-arch prostheses manufactured using SLM and EBM additive manufacturing technologies. A completely edentulous mandibular definitive cast with 4 implant analogs and a replica of a screw-retained interim restoration was obtained. A standard tessellation language (STL) file of the framework design was prepared using dental software (Exocad). Six frameworks were manufactured using either SLM (3D Systems) or EBM (Arcam) technologies. Discrepancy (μm) was measured at the x- (mesiodistal), y- (buccolingual), and z- (occlusogingival) axes by using the formula 3D=x2+y2+z2 three times by best-fit superimposure of the definitive cast STL file, the definitive cast titanium framework, and the framework STL file by using a coordinate measuring machine (CMM) controlled by software (Geomagic). The Kruskal-Wallis and Mann-Whitney U statistical tests were used (α=.05). The digitizing procedures of the definitive cast showed a mean accuracy of 3 ±3 μm. Except for the z-axis (P<.05), no significant differences were observed between the SLM and EBM technologies for implant prosthesis discrepancy for the x- or y-axis (P>.05). The most favorable results were obtained in the z-axis, representing the occlusogingival direction. Three-dimensional discrepancy measurements in all comparisons ranged between (60 ±18 μm and 69 ±30 μm) and were not statistically significant (P>.05). The highest discrepancy was observed in the y-axis (37 to 56 μm), followed by the x- (16 to 44 μm) and z- (6 to 11 μm) axes (P<.05). The titanium frameworks analyzed for a complete-arch implant-supported prosthesis fabricated using either the SLM or EBM additive technologies showed a clinically acceptable implant-prosthesis discrepancy, where similar discrepancies on the x-, y-, and z-axes were found between the additive manufacturing technologies. Both technologies showed comparable abilities to manufacture the STL file additively on the x-, y-, and z-axes.


Adult growth hormone deficiency: current concepts.
The clinical syndrome of adult growth hormone deficiency (AGHD) was widely recognized in the 1980s. In this review, we first describe the clinical features and diagnosis of AGHD and then state the effects of growth hormone (GH) therapy for these patients. The main characteristics of AGHD are abnormal body composition, dyslipidemia, insulin resistance, and an impaired quality of life (QoL) due to decreased psychological well-being. For diagnosing AGHD, the international consensus guidelines have suggested that an insulin tolerance test (ITT) is the gold standard, but in Japan, the growth hormone releasing peptide-2 (GHRP-2) test is available and is recommended as a convenient and safe GH stimulating test. The cut-off for diagnosing severe AGHD is a peak GH concentration of 9 g/L during the GHRP-2 test. Since 2006, GH therapy has been approved for Japanese patients with severe AGHD. For adults, GH replacement therapy should be initiated at a low dose (3 g/kg body weight/day), followed by individualized dose titration while monitoring patients' clinical status and serum insulin-like growth factor-I (IGF-I) concentrations. A variety of favorable effects of GH replacement have been indicated; however, it has not yet been established fully whether there is a direct effect of GH treatment on reducing mortality.


The omega/lambda 5 surrogate immunoglobulin light chain is expressed on the surface of transitional B lymphocytes in murine bone marrow.
The membrane immunoglobulin heavy chain (micron) plays a feedback role during the pre-B stage of B lymphocyte differentiation. In pre-B cell lines, micron associates with two surrogate light chain proteins. The omega chain is disulfide linked to mu and was predicted to be the product of the lambda 5 gene. The iota chain is noncovalently associated with micron. We demonstrate that the omega protein is indeed the product of the lambda 5 gene and that mu, omega, and iota are coassociated in the same complex. Antibodies against the omega/lambda 5 protein demonstrate the existence of a subpopulation of "transitional" bone marrow B cells that express micron and omega on the cell surface. The majority of these cells also express surface kappa light chains, indicating that in B lymphoid ontogeny the lambda 5 gene is inactivated after the onset of kappa light chain expression.


Distribution of glucose transporter messenger RNA transcripts in tissues of rat and man.
We used the complementary DNA for the human hepatoma Hep G2 glucose transporter to determine the distribution of glucose transporter messenger RNA (mRNA) in rat and human tissues. Under stringent hybridization conditions, a single 2.8-kilobase (kb) transcript is seen in all rat and human tissues examined. The mRNA is most abundant in brain, and is especially enriched in the brain microvascular fraction. The mRNA abundance in rat muscle and fat is 5% that in brain. Rat liver (both adult and fetal) and human liver have very little 2.8-kb mRNA, but it is abundant in cultured human fibroblasts and EB virus-transformed lymphoblasts. The same size mRNA is present in leg muscle of two type II diabetic patients. A very homologous glucose transporter mRNA is expressed in both insulin-sensitive and -insensitive tissues of rat and man. Hepatocytes, which have abundant glucose transport, may express a homologous but nonidentical glucose transporter.


Adolescent experiences with online racial discrimination: Implications for prevention and coping.
Online aggression represents a wide range of negative experiences, including online discrimination targeting individuals based on race, but adolescent perspectives are not well-represented. We interviewed 15 adolescents regarding their experiences with online racial discrimination. After a phenomenological analysis, four main themes emerged: types of online racial aggression, processes supporting online racism, personal coping, and strategies to prevent online racial aggression. These themes provided insights into adolescent experiences, including feelings about targeted online racial discrimination, intersectionality with sexual harassment, and comfort through processing with friends. This study highlights adolescents' thoughts regarding advocacy, education, and social media reform to prevent online racial aggression. Future research should ensure that youth voices from minoritized racial backgrounds are integrated into efforts to address these critical social issues.


[The pathophysiology and treatment of autoimmune neuromuscular junction diseases].
The neuromuscular junction lacks the protection of the blood-nerve barrier and is vulnerable to antibody-mediated disorders. Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by autoantibodies against acetylcholine receptors (AChR) and muscle-specific receptor tyrosine kinase (MuSK)/LDL-receptor related protein 4 which are AChR-associated transmembrane post-synaptic proteins involved in AChR aggregation. The seropositivity rates for AChR positive and MuSK positive MG in Japan are 80-85% and 5-10%/less than 1%,respectively. The incidence of late-onset MG, defined as onset after age 50 years, has been increasing worldwide. A nationwide epidemiological survey in Japan also revealed that the rates of late-onset MG had increased from 20% in 1987 to 42% in 2006. In 2010, a guideline for standard treatments of late-onset MG was published by the Japanese Society of Neurological Therapeutics. Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction and approximately 60% of LEMS patients have a tumor, mostly small cell lung cancer (SCLC), as a paraneoplastic neurological syndrome. The clinical pictures of Japanese LEMS patients are as follows; male dominant sex ratio (3 : 1), mean age 62 years (17-80 years), 61% of LEMS have SCLC, and the remaining are without cancer. In less than 10% of cases there are signs of cerebellar dysfunctions (paraneoplastic cerebellar degeneration with LEMS; PCD-LEMS) as well, often associated with SCLC. Most patients benefit from 3, 4-diaminopyridine plus pyridostigmine. In paraneoplastic LEMS, treatment of the tumor often results in neurological improvement. In non-paraneoplastic LEMS, prednisone alone or combined with immunosuppressants are treatment options. In both MG and LEMS, where weakness is severe, plasma exchange or intravenous immunoglobulin treatment may provide short-term benefit.


Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro.
Harmine is a beta-carboline alkaloid present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In this study, we demonstrated the anti-angiogenic activity of harmine using in vivo and in vitro assay systems. In vivo anti-angiogenic activity was studied using B16F-10 melanoma cells which induced capillary formation in C57BL/6 mice. Intraperitoneal administration of harmine at 10 mg/kg body weight significantly decreased tumour directed capillary formation. A drastic elevation in serum pro-angiogenic factors such as vascular endothelial growth factor (VEGF), nitric oxide (NO) and pro-inflammatory cytokines in angiogenesis induced animals was significantly decreased by harmine treatment. At the same time harmine increased anti-tumour factors like interleukin-2 (IL-2) and tissue inhibitor metalloprotease (TIMP). Moreover nuclear factor (NF)-κB and other transcription factors like CREB, ATF-2 involved in tumour development and angiogenesis were also inhibited by harmine. Various in vitro assays also supported the anti-angiogenic activity of harmine. It reduced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). Direct treatment of the harmine also inhibited microvessel outgrowth from the rat aortic ring. Production of other factors by tumour cells which are involved in angiogenesis like cyclooxygenase (COX-2), inducible nitric oxide synthase (iNOS) and matrix metalloproteases (MMPs) were also decrease by the treatment with harmine. Our data suggest that harmine may be a strong angiogenic inhibitor with the ability to decrease the proliferation of vascular endothelial cells and to reduce expression of various pro-angiogenic factors.


Initiating Evaluation of Composite Outcome Measures for Psoriatic Arthritis: 2022 Updates From the GRAPPA-OMERACT Working Group.
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis (PsA) working group-comprising rheumatologists, dermatologists, methodologists, and patient research partners-provided updates at the GRAPPA 2022 annual meeting on its work to evaluate composite outcome measures for PsA. Ten composite outcome measures were considered. Initial steps were to define the population, the purpose of use, and the proposed pros and cons of the 10 candidate composite instruments for PsA. Preliminary Delphi exercises within the working group and GRAPPA stakeholders confirmed high priority for evaluating minimal disease activity (MDA); moderate priority for Disease Activity in PsA (DAPSA), American College of Rheumatology (ACR) response criteria, Psoriatic Arthritis Disease Activity Score (PASDAS), Composite Psoriatic Disease Activity Index (CPDAI), 3 visual analog scale (VAS), and 4VAS; and low priority for Disease Activity Score in 28 joints (DAS28), Psoriatic Arthritis Responder Criteria (PsARC), and Routine Assessment of Patient Index Data 3 (RAPID3). Further appraisal of candidate composite instruments is ongoing.


Mouse retina has oligonucleotide-induced gene repair activity.
To test the ability of murine retinal nuclear extracts to support in vitro oligonucleotide-mediated gene repair (OMGR)-a prerequisite to repairing endogenous gene lesions underlying inherited diseases of the neurosensory retina. An in vitro reaction assayed whether retinal extract and oligonucleotides could correct a mutation in an antibiotic (tetracycline) resistance gene in a plasmid. The in vitro gene repair reaction combined plasmid, repair oligonucleotide, and nuclear extract. Site-specific repair of the tetracycline gene point mutation was revealed in a bacterial readout system in which plasmid from the in vitro reaction was recovered and electroporated into Escherichia coli. Colony growth on tetracycline indicated repair of the point mutation. To confirm site-specific nucleotide repair, plasmids were sequenced or subjected to restriction fragment length polymorphism (RFLP) analysis. To quantify repair incidence, tetracycline-resistant colonies were normalized to ampicillin-resistant colonies. A repair oligonucleotide composed of RNA and DNA that contains one mismatched base relative to the target DNA induced an estimated 1 in 10(4) plasmids to be converted to wild type. If the extract was eliminated or boiled before reaction, no tetracycline-resistant colonies grew. Repair incidence increased with the concentration of retinal nuclear extract and oligonucleotide. Creating single-strand breaks in the plasmid caused a twofold increase in repair incidence. These in vitro assay data suggest that murine retina nuclei contain all the DNA repair factors necessary for OMGR, a finding that is prerequisite to attempting endogenous gene repair in mouse retina.