Modelling the pulse population-wide nucleic acid screening in mitigating and stopping COVID-19 outbreaks in China.
During 2021-2022, mainland China experienced multiple times of local COVID-19 outbreaks in several cities, including Yangzhou, Xi'an etc., and the Chinese government persistently adopted the zero-COVID policy in combating with the local outbreaks. We develop a mathematical model with pulse population-wide nucleic acid screening, part of the zero-COVID policy, to reveal its role in controlling the spread of COVID-19. We calibrate the model by fitting the COVID-19 epidemic data of the local outbreaks in Yangzhou and Xi'an, China. Sensitivity analysis is conducted to investigate the impact of population-wide nucleic acid screening on controlling the outbreak of COVID-19. Without the screening, the cumulative number of confirmed cases increases by [Formula: see text] and [Formula: see text] in Yangzhou and Xi'an, respectively. Meanwhile, the screening program helps to shorten the lockdown period for more than one month when we aim at controlling the cases into zero. Considering its role in mitigating the epidemics, we observe a paradox phenomenon of the screening rate in avoiding the runs on medical resource. That is, the screening will aggravate the runs on medical resource when the screening rate is small, while it helps to relieve the runs on medical resource if the screening rate is high enough. We also conclude that the screening has limited effects on mitigating the epidemics if the outbreak is in a high epidemic level or there has already been runs on medical resources. Alternatively, a smaller screening population per time with a higher screening frequency may be a better program to avoid the runs on medical resources. The population-wide nucleic acid screening strategy plays an important role in quickly controlling and stopping the local outbreaks under the zero-COVID policy. However, it has limited impacts and even increase the potential risk of the runs on medical resource for containing the large scale outbreaks.


Work, career satisfaction, and the position of general internists in the south of Spain.
A progressive dissatisfaction has been noted among many internists, and the future of the specialty represents a matter of concern. The objectives of this study were to analyze career satisfaction among 182 internists from 34 hospitals in the south of Spain and to assess the opinion of 47 other health care professionals who frequently interact with internists on the present and future role of the specialty. Ours was a multi-institutional, cross-sectional survey of internists that focused on demographics/practice characteristics, education/research, career satisfaction, and opinions regarding the future of internal medicine. Also included were interactive, interdisciplinary focus groups of family physicians, sub-specialists, and managers. The internists were asked to complete a questionnaire that contained items and factors that were measured on a 5-point Likert scale and quantitatively analyzed; the opinions of the focus groups were qualitatively analyzed. The internists surveyed dedicated most of their time to treating hospitalized patients rather than to diagnostic procedures and technical assessment. Some 54% and 57% of the internists pursued continuing medical education and research, respectively, in their free time. The internists were satisfied with the content of their work and with their interpersonal relationships, but they were dissatisfied with their physical/instrumental environment, management policies, and degree of work stability. No differences were detected in relation to age, gender, community factor, or professional category. With regard to the future of the specialty, the main opportunity detected by internists was a closer collaboration with primary care. An analysis of the strengths, weaknesses, future opportunities and threats to internal medicine expressed by the seven focus groups was highly concordant and added worthwhile information and clear proposals for the development of the specialty. Internists in the south of Spain were satisfied with the content of their work and dissatisfied with health care management and job stability. The future of internal medicine was felt to lie in a deeper collaboration between internists and their colleagues in primary care.


N,N'-Di-cyclo-hexyl-N-(phthaloylglyc-yl)urea.
The mol-ecular structure of the title compound {systematic name: 1,3-di-cyclo-hexyl-1-[2-(1,3-dioxo-2,3-di-hydro-1H-isoindol-2-yl)acet-yl]urea}, C23H29N3O4, derived from N,N'-di-cyclo-hexyl-urea, shows that the tertiary N atom substituted by a cyclo-hexyl and phthaloylglycyl groups adopts a perfectly planar geometry (bond-angle sum = 360.0°). In the same way as for N,N'-di-cyclo-hexyl-urea, the extended structure of the title compound features N-H⋯O hydrogen bonds, which generate chains of mol-ecules running in the [001] direction.


Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentalomas.
Dideoxy sequencing is the most commonly used method for detecting the BRAF(V600E) mutation in thyroid cancer and melanoma. However, this gold standard method often makes less definite results in detecting the BRAF(V600E) mutation when there are relatively low amounts of the mutant template in biopsy specimens, which are invariably contaminated with normal tissues. Pyrosequencing, which measures the incorporation of each of the four nucleotides at each template position and indicates the amounts of mutant template present, may be more useful in such situations. To investigate the diagnostic efficiency of pyrosequencing for the mutant BRAF allele in ultrasound (US)-guided fine needle aspiration biopsies (FNABs) of thyroid incidentalomas. A total of 101 thyroid incidentaloma cases were included prospectively. Cytological diagnoses of the FNAB samples were made according to the American Thyroid Association (ATA) guidelines, 2006. The presence of the BRAF(V600E) mutation was investigated by pyrosequencing and dideoxy sequencing. On the basis of cytological analysis, the thyroid incidentalomas were classified into benign (n = 43), malignant (n = 30), indeterminate or suspicious neoplasm (n = 24), and nondiagnostic (n = 4) categories. Pyrosequencing detected the BRAF(V600E) mutation in 30 cases: 22 malignant cases, 7 indeterminate cases, and 1 nondiagnostic case. Dideoxy sequencing also detected the BRAF(V600E) mutation in 28 of the same cases but failed to clearly distinguish the mutant allele from the wild-type allele in one indeterminate case and one nondiagnostic case. Histopathological analysis ascertained that all BRAF(V600E)-positive cases were papillary thyroid carcinomas. Pyrosequencing may be suitable for detecting the BRAF(V600E) mutation in thyroid incidentaloma and may be superior to dideoxy sequencing when low amounts of the mutant template are present in the biopsy.


Clinical significance of auditory target P300 subcomponents in psychosis: Differential diagnosis, symptom profiles, and course.
Reduced auditory target P300 amplitude is a leading biomarker for psychotic disorders, although its relevance for differential diagnosis and link to specific clinical features (symptom profiles, functional impairment, and course) are unclear. This study aims to clarify the clinical significance of auditory target P300 using concurrent and retrospective clinical data from a longitudinal cohort with psychosis. 92 cases from an epidemiological study of first-admission psychosis were assessed using an auditory oddball paradigm at 15-year follow-up along with 44 never-psychotic adults. Subcomponents of auditory target P300 amplitude (i.e., a central positive P3a, a parietal positive P3b, and a frontal negative slow wave) were isolated using temporal-spatial principal component analysis. P3a amplitude was blunted across psychotic disorders relative to non-psychotic adults. P3b amplitude was reduced in schizophrenia specifically, including cases initially misclassified at baseline. The frontal negative slow wave did not distinguish among groups. P3b amplitude reduction was associated with several clinical features at the concurrent assessment, as well as previous time points, including recovery from psychosis even 5 years earlier and functioning even 15 years earlier. Auditory target P300 amplitude yields both a schizophrenia-specific component (i.e., P3b) and a transdiagnostic psychosis component (i.e., P3a). The P3b component may also shed light on prognosis, real-world functioning, and course, as well as help to reduce misdiagnosis of psychotic disorders. Prospective studies are needed to test whether P3b tracks or predicts clinical status.


Comparing the Effects of a Pine (Pinus radiata D. Don) Bark Extract with a Quebracho (Schinopsis balansae Engl.) Extract on Methane Production and In Vitro Rumen Fermentation Parameters
The aim of this study was to compare the effects of a pine (Pinus radiata D. Don) bark extract (PBE) with a quebracho (Schinopsis balansae Engl.) extract (QTE) on methane (CH4) production and in vitro rumen fermentation parameters. A forage diet supplemented with PBE or QTE (0, 2 and 4% dry matter (DM) basis) was incubated for 24 h to determine in vitro DM disappearance (IVDMD), CH4, volatile fatty acids (VFA), and ammonia nitrogen (NH3-N) production. Differences were analyzed using Tukey's test, orthogonal contrasts, hierarchical clustering heatmap (HCH), and principal component analysis (PCA). Both extracts (4% DM) decreased butyrate (Bu; p = 0.001), CH4 (p = 0.005), total VFA (p < 0.001), and NH3-N (p = 0.006) production and increased acetate (Ac; p = 0.003) without affecting the partitioning factor (p = 0.095). Propionate (Pr; p = 0.016) was increased, whereas IVDMD (p = 0.041) was decreased with QTE (4% DM). The inclusion of QTE (2% DM) decreased CH4 production (p = 0.005) and the (Ac + Bu)/Pr ratio (p = 0.003), whereas PBE (2% DM) decreased the NH3-N (p = 0.006) and total VFA production (p < 0.001). The HCH and PCA indicate a negative correlation (r = −0.93; p < 0.001) between CH4 production and tannins. In conclusion, PBE shares many of the effects generated by QTE on ruminal fermentation, although the magnitude of these effects depends on concentration. The PBE could be used as an additive in ruminant diets to reduce CH4 and NH3-N production without reducing IVDMD or increasing propionate, but further in vivo studies are required to clarify its effects on animal production.


Differential mobility spectrometry coupled to mass spectrometry (DMS-MS) for the classification of Spanish PDO paprika.
Ion mobility spectrometry (IMS) has proved its huge potential in many research areas, especially when hyphenated with chromatographic techniques or mass spectrometry (MS). However, focusing on food analysis, and particularly in classification and authentication issues, very few applications have been reported. In this study, differential mobility spectrometry coupled to mass spectrometry (DMS-MS) is presented for the first time as an alternative and high-throughput technique for food classification and authentication purposes using a fingerprinting strategy. As a study case, 70 Spanish paprika samples (from La Vera, Murcia, and Mallorca) were analyzed by DMS-MS to address their classification -using partial least squares regression-discriminant analysis (PLS-DA)- and authentication -through soft independent modeling of class analogy (SIMCA). As a result, after external validation, complete sample classification according to their geographical origin and excellent La Vera and Mallorca sample authentication were reached.


The relationship between eating behaviors and obesity in African American and Caucasian women.
The primary goal of this study was to determine the relevance of four self-reported eating behaviors (eating before bedtime, eating between meals, feeling hungry within 3 h of eating, and eating beyond satiation) as risk factors for overweight and obesity. The sample consisted of 35- to 49-year-old, premenopausal African American (n=580) and Caucasian (n=398) women, randomly selected from the membership of a large urban prepaid health plan. Eating beyond satiation was the only behavior associated with body mass index (BMI). The odds of becoming obese increased 6-fold for Caucasian women and 15-fold for African American women who ate beyond satiation everyday compared to those who rarely or never ate beyond satiation. Additionally, eating beyond satiation was also the only eating behavior associated with the age of obesity onset. Focusing on this eating behavior in weight loss programs may be important.


A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression.
We report a Caucasian boy with intractable epilepsy and global developmental delay. Whole-exome sequencing identified the likely genetic etiology as a novel p.K212E mutation in the X-linked gene HSD17B10 for mitochondrial short-chain dehydrogenase/reductase SDR5C1. Mutations in HSD17B10 cause the HSD10 disease, traditionally classified as a metabolic disorder due to the role of SDR5C1 in fatty and amino acid metabolism. However, SDR5C1 is also an essential subunit of human mitochondrial RNase P, the enzyme responsible for 5'-processing and methylation of purine-9 of mitochondrial tRNAs. Here we show that the p.K212E mutation impairs the SDR5C1-dependent mitochondrial RNase P activities, and suggest that the pathogenicity of p.K212E is due to a general mitochondrial dysfunction caused by reduction in SDR5C1-dependent maturation of mitochondrial tRNAs.


Feasibility of using a chlorination step to reduce excess sludge in activated sludge process.
The ultimate disposal of excess sludge generated from activated sludge processes has been one of the most challenging problems for wastewater treatment utilities. Previous work has shown that excess sludge can be minimized successfully by using sludge ozonation to dissolve it into substrates to be oxidized in the aeration tank. However, this approach is a costly option. Therefore, as an alternative solution, we propose to use chlorination to replace ozonation in excess sludge minimization in the light of operational cost. To investigate the feasibility of this low cost approach, this paper mainly focuses on the effect of chlorination on sludge reduction rate, formation of trihalomethanes, sludge settleability, and effluent quality. Two identical activated sludge membrane bioreactors were continuously operated with synthetic wastewater under the same operation conditions for several months. During this period, one pilot unit was used as the reference system without chlorination of excess sludge, while another served as a testing unit, where excess sludge was taken out for conducting chlorination at a dose of 133mg/g MLSS every day and the chlorinated liquor was then returned to the aeration tank. The sludge production rate and the water quality of both the units were analyzed daily. It was observed that the sludge production could readily be reduced by 65% once the chlorination treatment was involved. However, the chlorination treatment also resulted in poor sludge settleability as well as significant increase of soluble chemical oxygen demand in the effluent, which creates potential difficulties in the operation of a conventional treatment plant with gravity clarifiers. However, it has been demonstrated that by integrating the immersed membrane into the activated sludge process these difficulties can be overcome effectively.


Coincidental finding of May-Hegglin anomaly in a patient with end-stage renal failure.
We present two cases of May-Hegglin anomaly incidentally discovered in a patient and his brother during investigation of the patient for end-stage renal failure and workup for renal transplantation. Routine laboratory tests were performed and included a basically normal clotting profile. Ultrastructural studies of the May-Hegglin inclusions proved diagnostic, findings were compared with those of two similar granulocyte inclusion bodies, and nomenclature discrepancies that still exist in most references are again emphasized. The finding of the May-Hegglin anomaly in our patient appears to be incidental to the underlying renal disease. A successful renal transplant has been carried out in this patient. We now report on a patient and his brother in which the MHA was discovered during workup of the patient for end-stage renal failure and renal transplantation. No association between the underlying renal disease and the MHA could be demonstrated.


Mortality attributed to respiratory problems among finisher pigs in the United States.
In the 1995 National Swine Study of the United States National Animal Health Monitoring System, producers identified respiratory problems as the leading cause of death in pigs during the grower/finisher phase of production. Over a six-month period, 61.7 +/- 4.1% (mean +/- SEM) of operations reported at least one death attributed to respiratory problems among finisher pigs (based on 388 operations representing operations with > or = 300 finisher pigs in 16 states). Mean mortality attributed to respiratory problems was 0.9 +/- 0.1% of finisher pigs per operation. Stepwise logistic regression (using SAS) was used to identify factors associated with operations attributing at least one death to respiratory problems, and to identify factors associated with reporting > or = 2% mortality attributed to respiratory problems. Final models were run with SUDAAN to account for the sampling strategy. Attributing at least one death to respiratory problems was associated with having > or = 3000 pigs enter the grower/finisher unit over a six-month period; diagnosis of Haemophilus (or Actinobacillus) in the past 12 months; and keeping pigs in the grower/finisher unit > 120 days (as compared to < 100 days). Not having a farrowing facility, mean weaning age < 28 days, and < 50% of finisher pigs on solid concrete only were associated with reporting > or = 2% mortality attributed to respiratory problems.


Transfection of primary central and peripheral nervous system neurons by electroporation.
Neurons are difficult cells to transfect. Many methods that work routinely for immortalized tissue culture cells or primary cultures of nonneuronal cells are ineffective, toxic, or both when applied to neurons. This chapter describes a protocol that optimizes electroporation-based transfection of chick embryonic peripheral and central neurons. The key features required for successful electroporation and recovery of transfected neurons are high cell density, correct applied voltage and pulse duration, and the presence of calcium ions in the electroporation medium. Less important features are temperature, postporation rest, and the general composition of the electroporation medium. We emphasize the rationale for each element in our method and provide information useful for optimizing the procedure for other neurons.


Prototype End-of-Life Quality Measures Based on MDS 3 Data.
The Nursing Home Compare (NHC) report card does not include end-of-life (EOL) quality measures (QMs). To develop and examine the properties of EOL QMs. A total of 39,590 nursing home decedents in 626 facilities in New York State in fiscal year 2012. Statistical analyses of Minimum Data Set 3 data, including multivariable regression analyses and descriptive statistics. Death in the hospital, number of hospitalizations, pain, and depression during the last 90 days before death. Overall, 32% of residents died in the hospital. They averaged 0.49 hospitalizations in the last 90 days before death, 10% reported moderate to severe pain, and 17% had depressive symptoms. The EOL QMs exhibited variation across facilities similar to that observed for other QMs. They showed low or moderate correlations. The pain and depression QMs were significantly better among nursing homes ranked by NHC as 4 and 5 stars compared with those ranked as 1 and 2 stars for most dimensions. The hospitalizations QMs were significantly better among nursing homes ranked by NHC as 4 and 5 stars compared with those ranked as 1 and 2 stars only when compared on the staffing dimension. The Minimum Data Set 3 includes much information that can be used to assess quality of EOL care in nursing homes. The prototype measures we developed could be improved if information about advance directives and the nonclinical aspects of care, such as comfort and emotional support for both the resident and the family and respect for resident and family preferences, were collected.


Pharmaceutical brand substitution in Australia--are there multiple switches per prescription?
In Australia, brand substitution by pharmacists has been possible since 1994. There is no limit to the number of substitutions per prescription. Doctors have expressed concern that patients may receive a different product each time their prescription repeats are dispensed, which has the potential to confuse patients. It is unknown how often multiple substitutions per prescription occur. We aimed to identify the number of switches per prescription for a range of medicines and to determine the number of different brand and generic products supplied on each prescription. Repatriation Pharmaceutical Benefits Scheme prescription claims between 1 January 2001 and 28 February 2006 were identified for atenolol, citalopram, enalapril, metformin, omeprazole, ramipril, and simvastatin. Original prescriptions with five repeats and all supplies dispensed were included. Switches were identified if a different product was supplied on consecutive repeat dispensings. 533,279 original prescriptions were included. 488,735 (92%) had no switches on repeats and 37,513 (7%) had only one switch. Only 1% of all prescriptions had more than one switch identified on repeats, and in most cases only two different products were supplied. None of the prescriptions had a different product supplied on each dispensing. Multiple switches per prescription are uncommon and multiple different products are rarely supplied on repeats of the same prescription. The rules of the brand substitution policy appear to be adequate in allowing brand choice for patients, without leading to multiple switches per prescription.


Measurement of tracheal humidity and temperature.
After tracheostomy, patients often present with chest complaints. Measurement of objective parameters of the tracheal climate is important to evaluate 'artificial noses' or humidifying devices. The purpose of this study was to present an experimental setup for measurement of tracheal temperature and humidity for possible use in clinical studies in tracheotomized patients. The study design was a prospective study. Patients with tracheal stoma were chosen as study participants. Tracheal temperature and humidity during the respiratory cycle were measured using a miniaturized thermocouple and a humidity sensor connected to a suction system. Accurate measurement of tracheal temperature and humidity was feasible in patients with tracheal stoma. Tracheal humidity and temperature values measured in this study were similar to values reported earlier by other working groups. The experimental setup presented may reliably be used in the evaluation of 'artificial noses' or other passive humidifiers in tracheotomized patients.


Laser microdissection in CNS research.
The complexity of the brain makes the investigation of anatomically defined regions using manual dissection techniques problematic. With these manual dissection techniques, only a mixture of many different cell types can be obtained. This leads to averaging the contents of all the different cell types, making it nearly impossible to observe effects that are specific to one type of cell. Laser microdissection enables individual cell-types to be dissected accurately from the brain for subsequent analysis of the genome, proteome or, most frequently, the transcriptome. Investigating only functionally relevant cells with high specificity provides unambiguous data, resulting in faster identification of potential targets, the elucidation of drug mode-of-action, as well as aiding identification of biomarkers for diagnostics use.


The fine specificity of antigen and Ia determinant recognition by T cell hybridoma clones specific for pigeon cytochrome c.
The activation of proliferative T lymphocytes normally involves the simultaneous recognition of a particular foreign antigen and a particular Ia molecule on the surface of antigen-presenting cells, the phenomenon of major histocompatibility complex (MHC) restriction. An analysis of T cell clones specific for pigeon cytochrome c, from B10.A and B10.S(9R) strains of mice, revealed the unusual finding that several of the clones could respond to antigen in association with Ia molecules from either strain. Using these cross-reactive clones, we performed experiments which demonstrated that both the Ia molecule and the T cell receptor contribute to the specificity of antigen recognition; however, MHC-linked low responsiveness to tuna cytochrome c (an immune response gene defect) could not be attributed solely to the efficacy with which the Ia molecules associated with the antigen. These results imply that antigen and Ia molecules are not recognized independently, but must interact at least during the process of T cell activation.


Temporality of heparin-induced antibodies: a retrospective study in outpatients undergoing hemodialysis on unfractionated heparin.
Heparin-induced antibodies (HIA) are responsible for causing heparin-induced thrombocytopenia and thrombosis. Research has shown that the temporality of heparin-induced antibodies does not follow the classic immunologic response. The immunobiology of HIA generation remains unclear with varying in vitro and in vivo data. Outpatients undergoing hemodialysis (HD) are exposed to heparin chronically. The HIA immune response can therefore be investigated in vivo in this population. We examined the time between the start of HD using unfractionated heparin and HIA levels in 212 outpatients during a 6-year period. Antibodies were detected on enzyme-linked immunosorbent assay. HIA levels were analyzed to determine significance of the trend over time. HIA subgroups were also analyzed for correlation with subsequent thrombotic events and platelet count during follow up. Overall, the HIA response in HD was found to peak early with waning antibody response despite continued exposure to heparin. The peak prevalence of a strong immune response (optical density > 1.000) was early and short lived, while weaker immune response (optical density 0.400-1.000) persisted for the first 6 months then declined. The mean follow-up time per patient was 2.3 ± 1.4 years. Despite circulating HIA, including high titers, no patients developed HIT in this sample. There was no association between HIA and thrombocytopenia. There was increased incidence of thrombosis in patients with strong HIA compared to other groups, but this did not achieve statistical significance. The data suggest a significant temporal pattern of HIA in outpatients undergoing HD using unfractionated heparin. Positive HIA was not found to be significantly associated with thrombocytopenia or thrombosis risk in these patients. However, while not achieving statistical significance, subsequent thrombotic events occurred most frequently in the strong positive HIA group (optical density > 1.000). Further research into HIA and risk of thrombosis in this population is needed.


Life history variation within a parthenogenetic population of Daphnia parvula (Crustacea: Cladocera).
Evidence for genetically determined life history variability within a population or a species is rare. In this three year experimental examination of a parthenogenetically reproducing population of the planktonic crustacean Daphnia parvula, we found evidence for a succession of clones or groups of clones that exhibited distinctive body size and reproductive differences that were maintained after numerous generations under standardized conditions in the laboratory. The D. parvula population reached maximum density in the fall and maintained relatively high densities through the winter and spring. Isolates from this fall-winter-spring period all had a larger body size at death and higher fecundity when compared with summer isolates under natural food and temperature conditions. These differences could not be accounted for by differences in temperature and food abundance among the seasons. An additional difference in these experiments was a shift in reproductive effort by the summer isolate which produced a higher proportion of its offspring in the first two broods. The shift in life history characteristics and a summer decline of the Daphnia parvula population was correlated with both an increase in inedible and perhaps toxic blue-green algae and an increase in a dipteran predator Chaoborus. Comparison of the survivorship curves for all of the seasonal life history experiments indicated that D. parvula survivorship was not lower during the summer discounting a toxic effect from blue-green algae. Positive population growth on natural food in the laboratory at this time indicated food was not limiting and that predation was the probable cause of the population decline.Laboratory life history experiments under standardized food and temperature conditions were run with D. parvula isolates from the spring and summer plankton. Genetically based differences as determined in these experiments were smaller body size, lower fecundity, smaller brood size, and shorter life span for the summer animals relative to spring animals. Thirty seven percent of the summer animals also reproduced at an earlier age under standardized conditions. The shift in reproductive effort to earlier broods by summer animals rnder natural conditions appeared to be a phenotypic response as the summer isolate did not produce a higher proportion of its offspring in early broods under standardized conditions.When estimates of predatory mortality were added to the life tables of the standardized experiments, the earlier reproduction of some of the summer animals allowed a population increase under a regime of intense predation. Life tables for the spring animals predicted a population decline under these circumstances. Predictable seasonal changes in biotic factors such as predation suggest a mechanism whereby diverse life history patterns with corresponding differences in r may be maintained within a population.


HSP27 regulates IL-1 stimulated IKK activation through interacting with TRAF6 and affecting its ubiquitination.
Heat shock protein 27 (HSP27) is an ubiquitiously expressed protein, which has been mediated in various biological functions. Here, we present a novel mechanism utilized by HSP27 in regulating IL-1beta induced NF-small ka, CyrillicB activation. Both over-expression and RNAi experiments indicate that HSP27 physically interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6) and promotes TRAF6 ubiquitination. Over-expressed HSP27 augments IL-1beta induced TRAF6 ubiquitination and Ismall ka, CyrillicB kinase (IKK) activation. On the other hand, IL-1beta stimulation reduces endogenous HSP27/TRAF6 association, but inhibiting HSP27 phosphorylation by using SB202190, an inhibitor of p38, and MAPKAPK2 RNAi increases HSP27/TRAF6 association and thereby enhances TRAF6 ubiquitination, IKK phosphorylation as well as NF-small ka, CyrillicB activation. Furthermore, co-transfection study shows that HSP27 S78/82A, two phosphorylated serine site deficient mutants, but not wild-type HSP27 (HSP27 WT) and HSP27 S15A mutant increases TRAF6 ubiquitination and thereby mediates IL-1beta triggered IKK phosphorylation. Taken together, our data indicate that HSP27 regulates IL-1beta triggered NF-small ka, CyrillicB activation via a feedback loop which includes the interaction between HSP27 phosphorylation and ability of HSP27 to bind with TRAF6. The findings of this study reveal a novel mechanism by which HSP27 controls cytokine stimulation.


Assessing PM2.5 Model Performance for the Conterminous U.S. with Comparison to Model Performance Statistics from 2007-2015.
Previous studies have proposed that model performance statistics from earlier photochemical grid model (PGM) applications can be used to benchmark performance in new PGM applications. A challenge in implementing this approach is that limited information is available on consistently calculated model performance statistics that vary spatially and temporally over the U.S. Here, a consistent set of model performance statistics are calculated by year, season, region, and monitoring network for PM2.5 and its major components using simulations from versions 4.7.1-5.2.1 of the Community Multiscale Air Quality (CMAQ) model for years 2007-2015. The multi-year set of statistics is then used to provide quantitative context for model performance results from the 2015 simulation. Model performance for PM2.5 organic carbon in the 2015 simulation ranked high (i.e., favorable performance) in the multi-year dataset, due to factors including recent improvements in biogenic secondary organic aerosol and atmospheric mixing parameterizations in CMAQ. Model performance statistics for the Northwest region in 2015 ranked low (i.e., unfavorable performance) for many species in comparison to the 2007-2015 dataset. This finding motivated additional investigation that suggests a need for improved speciation of wildfire PM2.5emissions and modeling of boundary layer dynamics near water bodies. Several limitations were identified in the approach of benchmarking new model performance results with previous results. Since performance statistics vary widely by region and season, a simple set of national performance benchmarks (e.g., one or two targets per species and statistic) as proposed previously are inadequate to assess model performance throughout the U.S. Also, trends in model performance statistics for sulfate over the 2007 to 2015 period suggest that model performance for earlier years may not be a useful reference for assessing model performance for recent years in some cases. Comparisons of results from the 2015 base case with results from five sensitivity simulations demonstrated the importance of parameterizations of NH3 surface exchange, organic aerosol volatility and production, and emissions of crustal cations for predicting PM2.5 species concentrations.


Indian Society for Assisted Reproduction Consensus Guidelines on Preimplantation Genetic Testing in In vitro Fertilization Clinics.
What are the good practice guidelines for Pre implantation genetic testing applicable in INDIA? Pre-Implantation Genetic Testing (PGT) is not new in India. It is used to identify euploid embryos for transfer, thus enabling couples to achieve a healthy pregnancy. There has been a lot of controversy surrounding PGT in the international forums; most of these debates have failed to reach a consensus on whether PGT should be offered or its concerns be validated more. This is the report of a 2-day consensus meeting where two moderators were assigned to a group of experts to collate information on Pre implantation genetic testing and embryo biopsy practices in INDIA. This meeting utilised surveys, available scientific evidence and personal laboratory experience into various presentations by experts on pre-decided specific topics. Expert professionals from ISAR representing clinical, embryological and genetic fields. The report is divided into various components defining the terminologies, the various requirements, qualifications, recommendations on PGT -A,M,SR, and quality management: the report and recommendations of the expert panel reflect the discussion on each of the topics and try to lay down good practice points for labs to follow. The recommendations are solely based on expert opinion. Future availability of data may warrant an update of the same. These guidelines can help labs across the country to standardise their PGT services and improve clinical outcomes. The consensus meeting and writing of the paper was supported by funds from CooperSurgical India.


Substance P, neurokinins A and B, and synthetic tachykinin peptides protect mesencephalic dopaminergic neurons in culture via an activity-dependent mechanism.
We evaluated the neuroprotective potential of tachykinin peptides using a model system in which mesencephalic dopaminergic (DA) neurons die spontaneously and selectively as they mature. The three native tachykinins, substance P (SP), neurokinin (NK) A, and NKB afforded substantial protection against DA cell demise. The selective NK1 receptor antagonist [D-Pro9,[spiro-gamma-lactam] Leu10,Trp11]substance P (GR71251) was sufficient in itself to suppress the effect of SP, whereas a cotreatment with GR71251 and the NK3 receptor antagonist (R)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (SB218795) was required to prevent the effects of both NKA and NKB. Consistent with these results, D-Ala-[L-Pro9,Me-Leu8]substance P(7-11) (GR73632), a selective agonist of NK1 receptors and [pro7]-NKB, a selective agonist of NK3 receptors, conferred protection to DA neurons, whereas (Lys3, Gly8-R-gamma-lactam-Leu9)neurokinin A(3-10) (GR64349), which activates specifically NK2 receptors, did not. DA neurons rescued by tachykinins accumulated [3H]DA efficiently, which suggests that they were also totally functional. Neuroprotection by tachykinins was highly selective for DA neurons, rapidly reversed upon treatment withdrawal, and reproduced by but independent of glial cell line-derived neurotrophic factor. Survival promotion by tachykinins was abolished by blocking voltage-gated Na+ channels with tetrodotoxin or N-type voltage-gated Ca2+ channels with omega-conotoxin-MVIIA, which indicates that an increase in neuronal excitability was crucially involved in this effect. Together, these data further support the notion that the survival of mesencephalic DA neurons during development depends largely on excitatory inputs, which may be provided in part by tachykinins.


Design, synthesis and biological activity of novel triketone-containing quinoxaline as HPPD inhibitor.
4-Hydroxyphenyl pyruvate dioxygenase (EC 188.8.131.52, HPPD) is one of the important target enzymes used to address the issue of weed control. HPPD-inhibiting herbicides can reduce the carotenoid content in plants and hinder photosynthesis, eventually causing albinism and death. Exploring novel HPPD-inhibiting herbicides is a significant direction in pesticide research. In the process of exploring new high-efficiency HPPD inhibitors, a series of novel quinoxaline derivatives were designed and synthesized using an active fragment splicing strategy. The title compounds were unambiguously characterized by infrared, 1 H NMR, 13 C NMR, and high-resolution mass spectroscopy. The results of the in vitro tests indicated that the majority of the title compounds showed potent inhibition of Arabidopsis thaliana HPPD (AtHPPD). Preliminary bioevaluation results revealed that a number of novel compounds displayed better or excellent herbicidal activity against broadleaf and monocotyledonous weeds. Compound III-5 showed herbicidal effects comparable to those of mesotrione at a rate of 150 g of active ingredient (ai)/ha for post-emergence application. The results of molecular dynamics verified that compound III-5 had a more stable protein-binding ability. Molecular docking results showed that compound III-5 and mesotrione shared homologous interplay with the surrounding residues. In addition, the enlarged aromatic ring system adds more force, and the hydrogen bond formed can enhance the synergy with π-π stacking. The present work indicates that compound III-5 may be a potential lead structure for the development of new HPPD inhibitors.


Human Fc receptors: critical targets in the treatment of autoimmune diseases and transplant rejections.
The receptors for the Fc region of immunoglobulins (FcR) are members of the immunoglobulin superfamily. They are expressed on various hematopoietic cells and constitute a link between humoral and cell-mediated immunity. The activation and downmodulation of immune responses are controlled by signals from activating and inhibitory FcR, expressed on the surface of immune cells. The signaling regions, defined as immunoreceptor-tyrosine-based activation motif and immunoreceptor-tyrosine-based inhibitory motif, are contained within the cytoplasmic domain of FcR or of the adaptor proteins associated with FcR. Activating and inhibitory FcR are usually coexpressed on the surface of the same cell and coengaged by the same ligand, functioning in concert to keep a balanced immune response. Impairment of the functional balance between activating and inhibitory FcR leads either to hyperactivity to foreign and self antigens or to unresponsiveness as seen in many autoimmune diseases and infections. Pathologic conditions in which immunoglobulin-FcR interactions play a major role, as well as the outcome of treatment with intravenous immunoglobulin and monoclonal antibodies, may be influenced by targeting FcR.


Enhanced surveillance for adverse events following immunization during the 2019 typhoid conjugate vaccine campaign in Harare, Zimbabwe.
During February 25-March 4, 2019, Zimbabwe's Ministry of Health and Child Care conducted an emergency campaign using 342,000 doses of typhoid conjugate vaccine (TCV) targeting individuals 6 months-15 years of age in eight high-risk suburbs of Harare and up to 45 years of age in one suburb of Harare. The campaign represented the first use of TCV in Africa outside of clinical trials. Three methods were used to capture adverse events during the campaign and for 42 days following the last dose administered: (1) active surveillance in two Harare hospitals, (2) national passive surveillance, and (3) a post-campaign coverage survey. Thirty-nine adverse events were identified during active surveillance, including 19 seizure cases (16 were febrile), 16 hypersensitivity cases, 1 thrombocytopenia case, 1 anaphylaxis case, and two cases with two conditions. Only 21 (54%) of 39 patients were hospitalized and 38 recovered without sequelae. Attack rates per 100,000 TCV doses administered were highest for seizures (6.27) and hypersensitivity (5.02). Only 6 adverse events were reported through passive surveillance by facilities other than the two active surveillance hospitals. A total of 177 (10%) of 1,817 vaccinees surveyed reported experiencing an adverse event during the post-campaign coverage survey, of which 25 (14%) sought care. In line with previous evaluations of TCV, enhanced adverse event monitoring during an emergency campaign supports the safety of TCV. The majority of reported events were minor or resulted in recovery without long-term sequelae. Attack rates for seizures and hypersensitivity were low compared with previous active surveillance studies conducted in Kenya and Burkina Faso. Strengthening adverse event monitoring in Zimbabwe and establishing background rates of conditions of interest in the general population may improve future safety monitoring during new vaccine introductions.


Phase I studies of rodorubicin single bolus and daily times five, once every three weeks in patients with advanced solid tumors.
Rodorubicin (Cytorhodin S, HLB 817) is a new tetraglycosidic anthracycline with interesting preclinical antitumor activity. We have performed two sequential phase I studies with the drug. In the first study Rodorubicin was administered as a single i.v. administration over 30-360 min, once every 3 weeks. The second study concerned a daily times five i.v. bolus schedule. Thirty patients entered these studies. Regardless of schedule, the dose limiting toxicity appeared to be proteinuria, which was reversible after discontinuation of the drug. Phlebitis was a cumbersome side-effect and it was initially considered to determine the MTD in the once every 3 weeks schedule, but finally it could be prevented by giving the drug as a bolus injection into a rapidly running infusion. Nausea and vomiting were infrequent and mild. Neither myelotoxicity nor alopecia were observed. However, even at low cumulative doses the drug was found to be cardiotoxic using both schedules of administration. Seven out of 12 patients developed grade 1-3 cardiotoxicity, most of them above a cumulative dose of more than 4000 micrograms/m2. These side-effects preclude a dose recommendation for phase II studies with these schedules.


[MRI artifacts caused by keepers in a dental arch].
This research was designed to observe the degree of artifacts caused by 1-4 keepers. Samples were imaged in a living human subject by 0.15 Tesla MR devices in sagital plane. Results were analyzed and the maximal diameters of artifacts were measured. The maximal diameters of the artifacts caused by 1-4 keepers were 101-109.6mm. Even with four keepers in the dental arch, the degree of artifact is still limited.


The in vitro and in vivo behaviour of retinal pigment epithelial cells cultured on ultrathin collagen membranes.
The transplantation of pigment epithelial cells as a therapeutic modality for retinal degeneration requires that the transplanted cells form a monolayer in the subretinal space that will establish communication with photoreceptors. Since previous studies have shown that transplanted cells in suspension do not form a monolayer, it will be necessary to transplant preformed pigment epithelial cell monolayers at the location of the exposed photoreceptors. To establish cell monolayers, retinal pigment epithelial (RPE) cells were cultured on ultrathin collagen membranes. Cells were examined for morphology, for characteristics of differentiation and viability. Membrane degradation and long-term biocompatibility in vivo were assessed following subconjunctival and subretinal implantation in rabbits. These studies have shown that RPE cells adhere, proliferate, form monolayers, and acquire differentiated properties on a collagen membrane that has features similar to Bruch's membrane. Membranes transplanted subconjunctivally and subretinally exhibit excellent biocompatibility without any evidence of inflammation or rejection. RPE cells cultured on collagen membranes acquire differentiated characteristics similar to those of RPE cells in vivo and form complete monolayers that are amenable to be transplanted to the subretinal space. The collagen membranes are non-toxic and do not elicit any rejection or inflammatory response when implanted subconjunctivally or subretinally in rabbits.


Prevalence of antibodies to peste des petits ruminants virus before and during outbreaks of the disease in Awash Fentale district, Afar, Ethiopia.
The present study was conducted to assess the seroprevalence of peste des petits ruminants (PPR) in sheep and goats in Awash Fentale district, Afar, Ethiopia. Small ruminants in the district had poor herd immunity at the first visit and succumb to the disease then after. The seroprevalence during the time of an outbreak was much higher compared with the initial levels: 7.3% and 42.6% in sheep and goats, respectively. The higher seroprevalence figure in goats was suggestive of their relative susceptibility to PPR compared with sheep.


Qualitative review of early experiences of off-site COVID-19 testing centers and associated considerations.
Given the predicted need for continued SARS-CoV-2 diagnostic testing, as well as the evolving availability and types of diagnostic tests, off-site COVID-19 testing centers (OSCTC) leaders need timely guidance to ensure they are meeting the needs of their unique populations. This research discusses the challenges and offers considerations for healthcare organizations and others when setting up and running OSCTCs. It also provides a springboard to engage policy makers and leaders in the healthcare community in a discussion about emergency preparedness, and how to better respond to testing needs going forward.


Effects of long spray-chilling on water pocket development in ribeyes.
Water Pocket (WP) is a defect on beef that may lead to significant economic losses. Our hypothesis is that longer spray-chilling time increases WP incidence on ribeyes (M. longissimus thoracis). Ribeyes (28,801) were visually evaluated for the presence of WP after 24 or 72h of spray chilling. Additionally, 252 beef sides were evaluated prior to chilling to predict WP development after 24h of spray chilling. Also, the 12th rib fat thickness was measured on 313 sides and the sides were assigned to two categories of WP or no WP to evaluate fat thickness as an indicator for WP. Subcutaneous fat softness is not related to WP development, longer spray-chilling does not increase the incidence of WP in ribeyes, and thinner subcutaneous fat is an indicator for WP development.


Lowly-expressed lncRNA GAS5 facilitates progression of ovarian cancer through targeting miR-196-5p and thereby regulating HOXA5.
This investigation was aimed at extrapolating whether and how lncRNA GAS5, miR-196a-5p and HOXA5 altered progression of ovarian cancer (OA). Totally 195 pairs of OA tissues and adjacent normal tissues were collected. Also si-GAS5, pcDNA-GAS5, miR-196a-5p mimic, miR-196a-5p inhibitor and negative control (NC) were, respectively, transfected into OA cells. Besides, dual-luciferase reporter gene assay was performed to validate the targeted relationships between GAS5 and miR-196a-5p, as well as between miR-196a-5p and HOXA5. The impacts of GAS5, miR-196a-5p and HOXA5 on viability, proliferation and apoptosis of OA cells were appraised via conduction of colony formation assay, MTT assay and flow cytometry assay. Lower GAS5 expression and higher miR-196a-5p expression were associated with larger tumor size (≥5 cm) and more advanced FIGO stage (III-IV) of OA patients (P < 0.05). Transfection of si-GAS5, miR-196a-5p mimic or si-HOXA5 conferred OA cells with stronger viability, faster proliferation and smaller percentage of apoptosis (P < 0.05). After injecting mice models with si-GAS5, miR-196a-5p mimic or si-HOXA5, a larger tumor size was also observed within the rats (P < 0.05). GAS5 was indicated to directly target miR-196a-5p and modify its expression, and the targeted relationship also seemed to exist between miR-196a-5p and HOXA5 (P < 0.05). The HOXA5 was found to reverse the effects imposed by miR-196a-5p on viability, proliferation and apoptosis of OA cells (P < 0.05). LncRNA GAS5 depressed OA development by targeting miR-196a-5p and thereby down-regulating HOXA5 expression, providing substance for developing lncRNA-based strategies to treat OA.


[Spontaneous or idiopathic colonic perforation in the newborn (author's transl)].
The present research informes about aetiology, pathology, clinic and therapy of spontaneous or idiopathic perforations of the colon in the newborn. According to our experiences it is a matter of a multifactorial proceeding like perforations in other parts of the gastrointestinal tract. The hitherto existing clinical and experimental experiences indicate that the ischemic component plays an important part in the aetiology of this disease. Only the knowledge of the polyaetiology of idiopathic perforations--which are more properly subsumed under the term necrotizing gastroenterocolitis--and an early diagnosis by a gynaecologist or a pediatrician as well as an early surgical intervention can save the lives of those newborns.


Extraspinal articular tuberculosis: An 11-year retrospective study of demographic features and clinical outcomes in East London.
To describe demographic features, clinical outcomes and diagnostic delay amongst patients with extra-spinal articular tuberculosis (TB) in a low-incidence setting. Cases of TB treated at our institution between 2004 and 2014 were identified via the London TB register (LTBR). Demographic features of extra-spinal articular TB cases were compared to controls with TB at all other sites. For articular cases (excluding individuals <16 years or with spinal TB without peripheral joint involvement) clinical data were retrospectively collected. 6,146 TB patients were identified over the study period; 146 (2.4%) cases had extra-spinal articular infection. There was no difference in median age between extra-spinal articular TB cases and controls with TB at other sites (31 vs 32 years, p = 0.57). Articular cases were more likely to be male (70.6% vs 59.5%, p = 0.007), Bangladeshi (28.7% vs 18.0%) or Pakistani (24.0% vs 16.1%) and were less likely to be Black-African (9.5% vs 19.8%) (p < 0.001). 93 cases were included in the case series; 85 (88.5%) were migrants and 83 (89.2%) were South Asian. Knee and elbow joints were affected in 22 (23.7%) and 18 (19.4%) cases respectively. The median durations of pre-healthcare and healthcare associated delay were 16 and 6 weeks respectively. Where mycobacterial culture was performed, 57/75 (76%) were positive for Mycobacterium tuberculosis. 86 (92.5%) cases received standard quadruple therapy for a median of 6 months (IQR 6-9). Recurrence of TB infection occurred in 4 (4.3%) cases and there were no TB related deaths. Seven (7.6%) cases required surgical intervention. Extra-spinal articular TB more commonly affected men and people of South Asian ethnicity. Significant diagnostic delays were identified, including avoidable healthcare-associated delays.


An opinion on Wastewater-Based Epidemiological Monitoring (WBEM) with Clinical Diagnostic Test (CDT) for detecting high-prevalence areas of community COVID-19 Infections.
Wastewater-Based Epidemiological Monitoring (WBEM) is an efficient surveillance tool during the COVID-19 pandemic as it meets all requirements of a complete monitoring system including early warning, tracking the current trend, prevalence of the disease, detection of genetic diversity as well asthe up-surging SARS-CoV-2 new variants with mutations from the wastewater samples. Subsequently, Clinical Diagnostic Test is widely acknowledged as the global gold standard method for disease monitoring, despite several drawbacks such as high diagnosis cost, reporting bias, and the difficulty of tracking asymptomatic patients (silent spreaders of the COVID-19 infection who manifest nosymptoms of the disease). In this current reviewand opinion-based study, we first propose a combined approach) for detecting COVID-19 infection in communities using wastewater and clinical sample testing, which may be feasible and effective as an emerging public health tool for the long-term nationwide surveillance system. The viral concentrations in wastewater samples can be used as indicatorsto monitor ongoing SARS-CoV-2 trends, predict asymptomatic carriers, and detect COVID-19 hotspot areas, while clinical sampleshelp in detecting mostlysymptomaticindividuals for isolating positive cases in communities and validate WBEM protocol for mass vaccination including booster doses for COVID-19.


PEG-grafted liposomes for enhanced antibacterial and antibiotic activities: An in vivo study.
Staphylococcus aureus (S. aureus) biofilm-associated infections are a primary concern for public health worldwide. Current therapeutics cannot penetrate the biofilms efficiently, resulting in low drug concentrations at the infected sites and increasing the frequency of drug usage. To solve this issue, nanotechnology platforms seem to be a promising approach. In this study, the potential therapeutic effects of (PEG)ylated liposome (PEG-Lip) for the delivery of nafcillin (NF) antibiotic were assessed. The results demonstrated that NF-loaded liposome (Lip-NF) and NF-loaded PEG-Lip (PEG-Lip-NF) released 76.4 and 62% of the loaded NF, respectively, in a controlled manner after 50 h. Also, it was found that PEG-Lip-NF, compared to Lip-NF and NF, was more effective against a methicillin-susceptible S. aureus (MSSA; minimum inhibitory concentration (MIC): 1.0 ± 0.03, 0.5 ± 0.02, and 0.25 ± 0.01 μg/mL; and minimum biofilm inhibitory concentration (MBIC50): 4.0 ± 0.18, 1.0 ± 0.04, and 0.5 ± 0.02 μg/mL for NF, Lip-NF, and PEG-Lip-NF, respectively). PEG-Lip-NF, compared to NF and Lip-NF, could also more efficiently decrease the side effects of NF through improving human MG-63 osteoblast cell viability (cell viability at 100 μM of NF: 76, 68, and 38% for PEG-Lip-NF, Lip-NF, and NF, respectively). PEG-Lip-NF, compared to control, NF, and Lip-NF groups, was more efficacious by 45, 25, and 10%, respectively, to decrease the virulence of MSSA bacteremia through inhibiting the weight loss of the infected mice. Also, PEG-Lip-NF and Lip-NF, compared to control and NF groups, caused a considerable decrease in the mortality rate in a murine model of bacteremia (number of dead mice: 0, 0, 2, and 8 out of 15 for PEG-Lip-NF, Lip-NF, NF, and control groups, respectively). Overall, the results of this study demonstrated that the loading of NF into PEG-Lip is a promising strategy to decrease the side effects of NF with improved antibacterial effects for the treatment of MSSA biofilm-associated infections.


Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1.
Calpain I (mu-calpain) and II (m-calpain) are well known calcium-activated neutral cysteine proteases. Many reports have shown that activation of calpain is related to cataract formation, neuronal degeneration, blood clotting, ischemic injuries, muscular dystrophy and cornified cell envelope (CE) formation. Here, we report that insoluble CE formation was reduced after treatment with calpain I inhibitor (N-acetyl-leucyl-leucyl-norleucinal) on normal human epidermal keratinocytes (NHEK), whereas serine and thiol protease inhibitors had no effect on the reduction of CE. When NHEK cells were confluent, keratinocytes were treated with various concentrations (0.5 microM-0.5 mM) of calpain I inhibitor or serine and thiol protease inhibitors under calcium induced differentiation. Insoluble CE formation was reduced about 90% in the 50 microM calpain inhibitor I treated group by day 9 of culture, whereas insoluble CE was reduced only 10% in the same condition. Interestingly TGase activity was blocked by 90% in the 0.5 mM calpain inhibitor treated group within 72 h, whereas TGase activity was retained by 80% in the 0.5 mM serine protease inhibitor treated group at 7 day treatment. Therefore it can be suggested that cysteine protease calpains might be responsible for the activation of the TGase 1 enzyme to complete insoluble CE formation during epidermal differentiation.


Probing protein structure by solvent perturbation of nuclear magnetic resonance spectra. Nuclear magnetic resonance spectral editing and topological mapping in proteins by paramagnetic relaxation filtering.
Soluble spin labels, which "bleach" the surface proton resonances of a protein to n.m.r. measurements, can provide useful information about protein conformation and dynamics. The use of the soluble nitroxide, TEMPOL, has been explored to show the correlation of the paramagnetic perturbations of protein two-dimensional n.m.r. data with proton exposure to the free radical in hen egg-white lysozyme. The results demonstrate that the nitroxide approaches the protein randomly, and that the extent of the observed paramagnetic effects reflects the native folding pattern of the protein. A correlation of spectral simplification with the known tertiary structure establishes the feasibility of new strategies for topological mapping of surface and buried protons of the protein. Application to the elucidation of protein structure and to the study of dynamical processes is discussed.


Backlogs are a dynamic system, not a warehousing problem.
Addressing casework backlogs would seem to represent "low hanging fruit" for increasing offender apprehension and improving justice. Yet, after years of grant funding for backlog reduction and capacity building, backlogged cases, especially DNA cases, continue to increase in U.S. forensic laboratories. Why? This paper suggests a shift from linear, mechanical thinking to a systems thinking approach may help to see ways to leverage laboratories from dysfunctional operational states burdened by history to new ways of seeing themselves as part of a system of systems. The A3 method is offered as a practical approach to initiating a systems approach.


iPSCs: On the Road to Reprogramming Aging.
Aging is characterized by irreversible loss of physiological integrity, often accompanied by an organism's loss of function and increased vulnerability to death. Defects in the mechanisms preserving cellular homeostasis over time may give rise to accelerated aging. Somatic cell reprogramming of aged cells can be associated with rejuvenation, erasing certain age-associated features, and illustrating the reversibility potential of aging. Here, we focus on recent advances in the generation of human induced pluripotent stem cells from progeroid syndromes and late-onset diseases such as Alzheimer's or Parkinson's. These cellular models have contributed to a better understanding of such pathologies, as well as to the development of novel therapeutic approaches. We also discuss different strategies to identify and target age-associated reprogramming barriers to facilitate the treatment of age-related disorders.


Why are medical research articles tweeted? The news value perspective.
Counts of tweets mentioning research articles are potentially useful as social impact altmetric indicators, especially for health-related topics. One way to help understand what tweet counts indicate is to find factors that associate with the number of tweets received by articles. Using news value theory, this study examined six characteristics of research papers that may cause some articles to be more tweeted than others. For this, we manually coded 300 medical journal articles about COVID-19. A statistical analysis showed that all six factors that make articles more newsworthy according to news value theory (importance, controversy, elite nations, elite persons, scale, news prominence) associated with higher tweet counts. Since these factors are hypothesised to be general human news selection criteria, the results give new evidence that tweet counts may be indicators of general interest to members of society rather than measures of societal impact. This study also provides a new understanding of the strong positive relationship between news mentions and tweet counts for articles. Instead of news coverage attracting tweets or the other way round (journalists noticing highly tweeted articles and writing about them), the results are consistent with newsworthy characteristics of articles attracting both tweets and news mentions.


Synthesis of fluorine-18 labeled 21-fluoroprogesterone.
21-Fluoroprogesterone has been synthesized by the nucleophilic displacement of the mesyl group of the 21-hydroxypregn-4-ene-3,20-dione 21-methanesulfonate by fluoride ion, as formed from the solvolysis of potassium fluoride in acetonitrile, using 18-Crown-6 as the catalyst. In a similar manner, the synthesis of 21-fluoroprogesterone labeled with fluorine-18 has been accomplished, producing approximately 800 muCi of product from 6 mCi of K18F in one hour. This demonstrates that 18F labeled molecules of potential values as readiopharmaceuticals can be prepared rapidly in sufficient yield to allow animal investigation.


Modification and optimization of the inhibition of HIV-1 cell-to-cell transmission assay.
HIV-1 infection is caused by cell-free and cell-associated viruses. Currently most of the assays used to screen potential HIV-1 entry inhibitors focus on the inhibition of cell-free viruses. One assay that is widely employed is the TZM-bl neutralization assay that uses pseudotyped viruses. However, a study by Abela et al. showed that many inhibitors that potently inhibit cell-free HIV-1 in this assay can be less effective against the cell-to-cell transmission of the virus. These researchers then designed a method to screen entry inhibitors for activity against cell-associated HIV-1, using pseudotyped viruses. The main limitation of this method, however, was that it can only be reliably employed against viruses that cannot infect target cells as cell-free virion in the absence of a polycation supplement such as DEAE (diethylaminoethyl). Thus, in the current study we provide modifications to this method that solves the problem and makes it possible to study entry inhibitors against cell-to-cell infection of both polycation depend and independent viruses. The main modification involves the introduction of the relative light unit (RLU) vs. virus producing 293-T cells / corresponding supernatants graph. This graph is used to select a virus input that only allows for the detection of cell-associated viruses infection.•The method is a modification of the cell-to-cell transmission assay published by Abela et al.•The method allows for the study of the inhibition of cell-to-cell transmission of both polycation dependent and independent HIV-1 pseudoviruses.


Selective expression of progesterone receptor in malignant melanoma was inversely correlated with PCNA.
To investigate the role of progesterone receptor (PR) expression in malignant melanoma (MM), PR and proliferative cell nuclear antigen (PCNA) expression were immunohistochemistrically evaluated in a series of 35 specimens of MM, and the correlation between the immunohistochemistrical findings and clinicopathological data was also analyzed. PR expression was detected in 25.7% (9/35) of the patients with MM. No PR expression was observed in nevi. PR expression was inversely correlated with PCNA expression (r=-0.353, P=0.026). PR expression was slightly increased in females, subjects aged under 55 y, those with ulceration, non-acral subtype and diagnosis delay longer than 1 y, but the difference was not statistically significant. Selective expression of progesterone receptor in malignant melanoma might be correlated with inhibited tumor growth.


Airborne respiratory aerosol transport and deposition in a two-person office using a novel diffusion-based numerical model.
The COVID-19 pandemic was caused by the SARS-CoV-2 coronaviruses transmitted mainly through exposure to airborne respiratory droplets and aerosols carrying the virus. To assess the transport and dispersion of respiratory aerosols containing the SARS-CoV-2 virus and other viruses in a small office space using a diffusion-based computational modeling approach. A 3-D computational model was used to simulate the airflow inside the 70.2 m3 ventilated office. A novel diffusion model accounting for turbulence dispersion and gravitational sedimentation was utilized to predict droplet concentration transport and deposition. The numerical model was validated and used to investigate the influences of partition height and different ventilation rates on the concentration of respiratory aerosols of various sizes (1, 10, 20, and 50 µm) emitted by continuous speaking. An increase in the hourly air change rate (ACH) from 2.0 to 5.6 decreased the 1 μm droplet concentration inside the office by a factor of 2.8 and in the breathing zone of the receptor occupant by a factor of 3.2. The concentration at the receptor breathing zone is estimated by the area-weighted average of a 1 m diameter circular disk, with its centroid at the center of the receptor mannequin mouth. While all aerosols were dispersed by airflow turbulence, the gravitational sedimentation significantly influenced the transport of larger aerosols in the room. The 1 and 10 μm aerosols remained suspended in the air and dispersed throughout the room. In contrast, the larger 20 and 50 μm aerosols deposited on the floor quickly due to the gravitational sedimentation. Increasing the partition between cubicles by 0.254 m (10") has little effect on the smaller aerosols and overall exposure. This paper provides an efficient computational model for analyzing the concentration of different respiratory droplets and aerosols in an indoor environment. Thus, the approach could be used for assessing the influence of the spatial concentration variations on exposure for which the fully mixed model cannot be used.


Early diagnosis of diabetic neuropathy using double-shock stimulation of peripheral nerves.
The purpose of this study was to determine the changes in the amplitudes of a sensory nerve action potential (NAP) to a conditioning stimulus given prior to a test stimulus at 2-8 ms intervals in healthy subjects and patients with diabetes mellitus with no clinical signs of neuropathy and normal nerve conduction velocities (NCVs), to be able to diagnose peripheral neuropathy at its very early stages. NAPs in the superficial branch of the radial nerve were recorded in healthy subjects (28 women and 7 men) and type II diabetes patients without neuropathy (22 women and 12 men). Radial nerve was first stimulated with a single shock and then with double shocks at intervals of 2, 3, 4, 5, 6, 7, and 8 ms; NAP amplitudes and NAP1/NAP2 ratios were calculated in normals and diabetics. NCVs were within the normal ranges (>50 m/s) in all subjects. Of the independent variables--group (control, patient), sex (male, female), and hand (right, left)--only group significantly influenced NAP amplitude; mean NAP amplitude (single shock) was significantly lower in patients than controls. NAP1/NAP2 ratios were slightly below one (facilitation) in controls; it was above one at 1-8 ms stimulus intervals (inhibition) in diabetics, which was strongest at smallest intervals, gradually decreasing, and almost disappearing as the stimulus interval approached 8 ms. Using double-shock stimuli, an early diagnosis of peripheral neuropathy would be possible in diabetics without clinical signs of peripheral neuropathy and exhibiting no slowing in NCV.


Cardiopulmonary Effects and Pharmacokinetics of Dexmedetomidine Used as an Adjunctive Analgesic to Regional Anesthesia of the Oral Cavity with Levobupivacaine in Dogs.
This study investigated the cardiopulmonary effects and pharmacokinetics of dexmedetomidine (DEX) used as an adjunctive analgesic for regional anesthesia of the oral cavity with levobupivacaine in anesthetized dogs. Forty dogs were randomly assigned to four groups of 10 dogs. All dogs received levobupivacaine (4 blocks) with DEX IO (infraorbital block, n = 10) or IA (inferior alveolar block, n = 10) or placebo (PLC; n = 10) or DEX (n = 10) was injected intravenously (IV) after administration of levobupivacaine. The dose of DEX was always 0.5 µg/kg. Cardiopulmonary parameters were recorded, and blood was drawn for the quantification of DEX in plasma using LC-MS/MS. Heart rate was lower in all LB + DEX groups, while mean arterial pressure (MAP) was higher in the LB + DEX IV and LB + DEX IA groups compared to the LB + PLC IV group. Compared to DEX IV, IO and IA administration resulted in lower MAP up to 2 min after application. Absorption of DEX was faster at IO administration (Cmax and Tmax were 0.47 ± 0.08 ng/mL and 7.22 ± 1.28 min and 0.76 ± 0.09 ng/mL and 7.50 ± 1.63 min for the IO and IA block, respectively). The IA administration resulted in better bioavailability and faster elimination (t1/2 was 63.44 ± 24.15 min and 23.78 ± 3.78 min for the IO and IA block, respectively). Perineural administration of DEX may be preferable because of the less pronounced cardiovascular response compared to IV administration.


Microbial activity and distribution during enhanced contaminant dissolution from a NAPL source zone.
Laboratory experiments were conducted to assess microbial reductive dechlorination in one-dimensional sand columns containing a 10 cm long source zone of uniformly distributed residual tetrachloroethene (PCE) nonaqueous phase liquid (NAPL), a 10 cm long transition zone directly down-gradient of the source zone containing some nonuniformly distributed NAPL ganglia, and a 40 cm long plume region down-gradient of the transition zone. The activity and distribution of Sulfurospirillum multivorans, a PCE-to-1,2-cis-dichloroethene (cis-DCE) dechlorinating bacterium, was evaluated in columns containing either a mixed-NAPL (0.25 mol/mol PCE in hexadecane) or pure PCE-NAPL. Significant dechlorination of PCE to cis-DCE was observed in the mixed-NAPL column, resulting in 53% PCE-NAPL mass recovery in the effluent with PCE-NAPL dissolution enhanced by up to 13.6-fold (maximum) and 4.6-fold (cumulative) relative to abiotic dissolution. Quantitative real-time PCR targeting pceA, the PCE reductive dehalogenase gene of S. multivorans, revealed that S. multivorans cells were present in the NAPL source zone, and increased in numbers (i.e., grew) throughout the source and transition zones. In contrast, minimal reductive dechlorination and microbial growth were observed in the column containing pure PCE-NAPL, where aqueous-phase PCE concentrations reached saturation. These results demonstrate that microbial growth within NAPL source zones is possible, provided that contaminant concentrations remain below levels toxic to the dechlorinating organisms, and that microbial growth can result in significant bioenhanced NAPL dissolution.


Benzodiazepine receptor antagonism improves reaction time in latent hepatic encephalopathy.
Endogenous benzodiazepine-like substances are thought to play a role in the development of hepatic encephalopathy (HE). Ten patients with sub-clinical or latent hepatic encephalopathy (LHE) and ten normal controls were cognitively assessed pre- and post-infusion of 0.2 mg of the benzodiazepine (BZ) antagonist flumazenil in a placebo-controlled, cross-over, double-blind design. Flumazenil infusion resulted in a significant improvement in simple reaction time in patients, but not in controls. Saline infusion had no effect on any of the cognitive measures in either group. Flumazenil appeared to have a particular enhancing effect on the cognitive, as opposed to the motor, component of the reaction time task. This finding supports the view that the benzodiazepine/GABA system is implicated in the bradyphrenia that is characteristic of chronic liver disease, even before hepatic encephalopathy is apparent. We conclude that benzodiazepine receptor antagonism may improve cognitive function, particularly speed of information processing, in patients with latent hepatic encephalopathy.


[Determination of thyroxine and triiodothyronine in the thyroid glands of encephalectomized rat fetuses].
Concentration of thyroxin and triiodothyronine in the thyroid gland of encephalectomized and intact fetuses of rats with normal and prolonged gestation period was determined by means of isotope methods. Encephalectomy of 19-day old fetuses did not produce any significant effect on the concentration of thyroid hormones in the gland 2 and 4 days after the operation. The results obtained pointed to the absence of the hypothalamic control over the thyroid function in prenatal development of rats.


Design of external quality assessment schemes and definition of the roles of their providers in future epidemics.
During an epidemic, individual test results form the basis of epidemiological indicators such as case numbers or incidence. Therefore, the accuracy of measures derived from these indicators depends on the reliability of individual results. In the COVID-19 pandemic, monitoring and evaluating the performance of the unprecedented number of testing facilities in operation, and novel testing systems in use, was urgently needed. External quality assessment (EQA) schemes are unique sources of data reporting on testing performance, and their providers are recognised contacts and support for test facilities (for technical-analytical topics) and health authorities (for planning the monitoring of infection diagnostics). To identify information provided by SARS-CoV-2 genome detection EQA schemes that is relevant for public health microbiology, we reviewed the current literature published in PubMed between January, 2020, and July, 2022. We derived recommendations for EQA providers and their schemes for best practices to monitor pathogen-detection performance in future epidemics. We also showed laboratories, test facilities, and health authorities the information and benefits they can derive from EQA data, and from the non-EQA services of their providers.


General practitioners' views on shared decision making: a qualitative analysis.
Despite rhetoric about increasing partnership in the consultation, shared decision making (SDM) is not necessarily happening in practice. As patient involvement in decision making cannot be achieved without general practitioners' (GPs) co-operation, attention to their concerns is essential. Previous research has used simulated patients to explore this area. Here, data from consultations and interviews with patients and GPs were used in focus group discussions enabling GPs to ground their views of the practical application of SDM in their own and other participants' real life practice. The following ideas were discussed; what constitutes SDM in practice, negotiation about treatment, perceptions of patients' viewpoints and perceived barriers to SDM. Agreement with SDM in theory may not translate into practice. The process outlined is being developed in order to establish whether the techniques could provide a supportive environment in which GPs can make changes to their practice to increase patient participation.


The association between measured and clinically assessed amniotic fluid volume and fetal growth and nutrition.
A close correlation was found between amniotic fluid volume measured by using para-aminohippuric acid and the clinical assessment of volume. No correlation was found between measured amniotic fluid volume and fetal weight, length, or weight for gestational age.


[Cost of therapy for neurodegenerative diseases. Applying an activity-based costing system].
To apply the activity based costing (ABC) model to calculate the cost of therapy for neurodegenerative disorders in order to improve hospital management and allocate resources more efficiently. We used the case study method in the Francolí long-term care day center. We applied all phases of an ABC system to quantify the cost of the activities developed in the center. We identified 60 activities; the information was collected in June 2009. The ABC system allowed us to calculate the average cost per patient with respect to the therapies received. The most costly and commonly applied technique was psycho-stimulation therapy. Focusing on this therapy and on others related to the admissions process could lead to significant cost savings. ABC costing is a viable method for costing activities and therapies in long-term day care centers because it can be adapted to their structure and standard practice. This type of costing allows the costs of each activity and therapy, or combination of therapies, to be determined and aids measures to improve management.


ENhANCE trial protocol: A multi-centre, randomised, phase IV trial comparing the efficacy of oxycodone/naloxone prolonged release (OXN PR) versus oxycodone prolonged release (Oxy PR) tablets in patients with advanced cancer.
Oxycodone is a frequently used opioid in cancer. Opioid-induced constipation (OIC) is common. Oxycodone/Naloxone Prolonged Release (OXN PR) contains naloxone, which mitigates OIC. Trials have either focused on non-cancer pain, or conducted before significant experience of using OXN PR. This trial aims to: demonstrate (1) analgesic equivalence between OXN PR and Oxycodone Prolonged Release (Oxy PR), and (2) superiority of constipation outcomes in OXN PR compared to Oxy PR in cancer pain. Unlike other trials, it will only include patients with at least moderate pain scores (≥4/10), allow usual laxatives, and exclude potential liver dysfunction. This is a multi-centre, open-label, randomised, phase IV study of OXN PR vs Oxy PR in patients with cancer-related pain. The primary outcome is pain difference on Brief Pain Inventory-Short Form (BPI-SF) at 5 weeks. Secondary outcomes are comparison of other pain outcomes (BPI-SF) and neuropathic pain measures (Leeds Assessment of Neuropathic Symptoms & Signs (S-LANNS)), constipation (Bowel Function Index (BFI)), quality of life (EORTC-QLQ-C30), rescue analgesia use, total opioid dose, and total laxative dose over 5 weeks. The comparison of analgesic efficacy between both arms, and superiority of constipation in the OXN PR arm will add new knowledge on the comparisons of both agents, and oxycodone independently. This trial will extend knowledge of the effectiveness, safety, and adverse effect profiles of both drugs in terms of pain, constipation, quality of life outcomes for patients with cancer pain, and provide clinicians with high quality data to guide decision making. Name of the registry: ANZCTR. ACTRN12619001282178. 17/09/2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377673&isReview=trueProtocol version 2.1_28 August 2020.


Management of biliary symptoms after bariatric surgery.
Biliary disease requiring intervention can be complicated in the postbariatric surgery patient. A retrospective review was completed to identify patients who underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy from September 2001 to September 2014, and those who underwent biliary intervention were identified. A total of 1527 patients underwent bariatric surgery during the study period. Of the 1,112 patients without prior cholecystectomy, 91 (8%) had biliary symptoms requiring intervention. Ninety patients underwent cholecystectomy, with 86 successfully completed laparoscopically. Six patients required laparoscopy-assisted percutaneous transgastric endoscopic retrograde cholangiopancreatography along with cholecystectomy to clear gallstones from the common bile duct. Three patients who had undergone cholecystectomy before bariatric surgery developed primary common bile duct stones. Surgery for biliary disease after bariatric surgery can be completed successfully with minimal complications, and percutaneous transgastric endoscopic retrograde cholangiopancreatography has a high success rate of access to and clearance of the biliary tree.


Maintenance of acute morphine tolerance in mice by selective blockage of kappa opioid receptors with norbinaltorphimine.
In this study we investigated the effect of the highly selective kappa opioid antagonist, norbinaltorphimine (norBNI) on the development of tolerance to a single dose of morphine. Mice were pretreated with 100 mg/kg of morphine sulfate (morphine), s.c. and 2 h later, norBNI (20 mg/kg s.c.) was administered and various times after this pretreatment, antinociceptive ED50 value of morphine was determined in the tail-flick assay. Twenty-four and 72 h after morphine injection, ED50 values of morphine were significantly increased by about 2.5-fold from those of their control mice that received saline instead of the tolerance-inducing dose of morphine. In a second set of experiments, animals were pretreated similarly with morphine and norBNI and 72 h after morphine injection, various opioid agonists were applied by the i.c.v. or i.t. route to see whether or not any cross-tolerance had developed to these agonists. The ED50 of i.c.v.-administered morphine was significantly greater than that of the non-pretreated controls. A small degree of cross-tolerance was observed with U-50,488H but not with DPDPE [D-Pen2,D-Pen5]enkephalin (DPDPE) at the supraspinal site. At the spinal site, tolerance to morphine was not observed. These results suggest that antagonism at kappa opioid sites after morphine administration, modulates positively the development of opioid tolerance.


Smoothness preserving layout for dynamic labels by hybrid optimization.
Stable label movement and smooth label trajectory are critical for effective information understanding. Sudden label changes cannot be avoided by whatever forced directed methods due to the unreliability of resultant force or global optimization methods due to the complex trade-off on the different aspects. To solve this problem, we proposed a hybrid optimization method by taking advantages of the merits of both approaches. We first detect the spatial-temporal intersection regions from whole trajectories of the features, and initialize the layout by optimization in decreasing order by the number of the involved features. The label movements between the spatial-temporal intersection regions are determined by force directed methods. To cope with some features with high speed relative to neighbors, we introduced a force from future, called temporal force, so that the labels of related features can elude ahead of time and retain smooth movements. We also proposed a strategy by optimizing the label layout to predict the trajectories of features so that such global optimization method can be applied to streaming data. Supplementary material is available in the online version of this article at 10.1007/s41095-021-0231-y.


Ischemic brain tissue salvaged from infarction by the GP IIb/IIIa platelet antagonist tirofiban.
In an open pilot study, the authors tested whether the nonpeptide glycoprotein (GP) IIb/IIIa antagonist tirofiban, a highly effective and selective blocker of platelet aggregation, prevents the transition of ischemic brain tissue into the infarct proper as defined by MRI (perfusion-weighted/T2-weighted) in patients with acute ischemic stroke. The infarct volume (T2 lesion after 1 week) was smaller in treated patients (n = 10) compared with matched control subjects (n = 10; p = 0.029) with similar initial perfusion deficit (TTP-maps). The authors conclude that GP IIb/IIIa antagonists have therapeutic potential in acute stroke therapy.


Conformational transitions between Na+-bound and K+-bound forms of (Na+ + K+)-ATPase, studied with formycin nucleotides.
1. Fluorescence measurements have shown that formycin triphosphate (FTP) or formycin diphosphate (FDP) bound to (Na+ + K+)-ATPase (ATP phosphohydrolase, EC 220.127.116.11) in Na+-containing media can be displaced by the following ions (listed in order of effectiveness): Tl+, K+, Rb+, NH4+, Cs+. 2. The differences between the nucleotide affinities displayed by the enzyme in predominantly Na+ and predominantly K+ media in the absence of phosphorylation, are thought to reflect changes in enzyme conformation. These changes can therefore be monitored by observing the changes in fluorescence that accompany net binding or net release of formycin nucleotides. 3. The transition from a K+-bound form (E2-(K)) to an Na+-bound form (E1-Na) is remarkably slow at low nucleotide concentrations, but is accelerated if the nucleotide concentration is increased. This suggests that the binding of nucleotide to a low-affinity site on E2-(K) accelerates its conversion to E1-Na; it supports the hypothesis that during the normal working of the pump, ATP, acting at a low affinity site, accelerates the conversion of dephosphoenzyme, newly formed by K+-catalysed hydrolysis of E2P, to a form in which it can be phosphorylated in the presence of Na+. 4. The rate of the reverse transformation, E1-Na to E2-(K), varies roughly linearly with the K+ concentration up to the highest concentration at which the rate can be measured (15 mM). Since much lower concentrations of K+ are sufficient to displace the equilibrium to the K-form, we suggest that the sequence of events is: (i) combination of K+ with low affinity (probably internal) binding sites, followed by (ii) spontaneous conversion of the enzyme to a form, E2-(K), containing occluded K+. 5. Mg2+ or oligomycin slows the rate of conversion of E1-Na to E2-(K) but does not significantly affect the rate of conversion of E2-(K) to E1-Na. 6. In the light of these and previous findings, we propose a model for the sodium pump in which conformational changes alternate with trans-phosphorylations, and the inward and outward fluxes of both Na+ and K+ each involve the transfer of a phosphoryl group as well as a change in conformation between E1 and E2 forms of the enzyme or phosphoenzyme.


Progesterone-binding globulin interaction with its steroid ligands: study of the protein binding site topography using spin labeled steroids and electron spin resonance spectroscopy.
The binding site topography of progesterone-binding globulin (PBG) purified from pregnant guinea pig serum was examined using synthesized spin-labeled ligands and electron spin resonance (ESR) spectroscopy. A series of deoxycorticosterone-nitroxide (DOC-NO) derivatives were prepared, bearing the free radical on the side chain at increasing distance (d) from the steroid nucleus. The ability of the spin-labeled steroids to specifically bind to PBG was assessed by measurement of their relative binding affinity as compared to progesterone. ESR spectra of the bound steroid nitroxide radical were used to calculate the rotational correlation times tau c for the nitroxides as a function of their distance d to the protein-bound steroid nucleus. The data showed that the side chain nitroxide exhibited an unrestrained rotation in a water-like environment when d reached about 18 A. This would correspond to a PBG steroid binding site depth of about 28 A and suggests that the bound steroid in the PBG site is oriented with the side chain at C-17 directed toward the outside of the protein binding crevice.


Etanercept: An overview.
Etanercept, a competitive inhibitor of TNF-alpha, is currently FDA approved for psoriatic arthritis and rheumatoid arthritis. The molecular structure of etanercept, its mechanism of action, and results of clinical trials involving patients with psoriasis will be reviewed.


Primary central nervous system lymphoma presenting as autonomic dysfunction.
We describe a patient with primary central nervous system lymphoma (PCNSL) who presented with symptoms of subacute onset of dysautonomia. Autonomic testing indicated a peripheral autonomic neuropathy while magnetic resonance imaging revealed brainstem involvement. We propose that this patient's autonomic dysfunction could be the result of a paraneoplastic syndrome and PCNSL should be considered in the differential diagnosis of dysautonomia.


National and local trends in CT colonography reimbursement: past, present, and future.
Computed tomographic colonography (CTC) was first introduced in the mid-1990s as a minimally invasive technology for colorectal cancer screening. Given its potential to significantly change colorectal cancer screening practices in the United States, it has attracted widespread multidisciplinary interest among radiologists, gastroenterologists, colorectal surgeons, and primary care physicians. Because of its potential for widespread utilization and the potential associated costs, it has also attracted much scrutiny from payers. The authors discuss the coding and reimbursement history of CTC, outline strategies for obtaining local coverage for CTC, and attempt to outline some of the possible future influences on CTC reimbursement.


Sensitivity and power deposition in a high-field imaging experiment.
Image signal-to-noise ratio and power dissipation are investigated theoretically up to 400 MHz. While the text is mathematical, the figures give insights into predictions. Hertz potential is introduced for probe modeling where charge separation cannot be ignored. Using a spherical geometry, the potential from current loops that would produce a homogeneous static B1 field is calculated; at high frequency it is shown to create an unnecessarily inhomogeneous field. However, a totally homogeneous field is shown to be unattainable. Boundary conditions are solved for circularly polarized fields, and strategies for limited shimming of the sample B1 field are then presented. A distinction is drawn between dielectric resonance and spatial field focusing. At high frequency, the region of maximum specific absorption is shown to move inside the sample and decrease. From the fields in both rotating frames, the signal-to-noise ratio is derived and compared with the traditional, low-frequency formulation. On average, it is mostly found to be slightly larger at high frequency. Nevertheless, the free induction decay is sometimes found to be annulled.


Specific two-photon fluorescent probe for cysteine detection in vivo.
Cysteine (Cys), an essential amino acid, plays several crucial functions in numerous biological processes. Notably, the detection of Cys is critical to disease diagnosis. Fluorescent probes that can quickly detect Cys will help to study the mechanism of certain diseases. Herein, a new fluorescent probe, ANP, which is based on 6-acetyl-N-methyl-2-naphthyl amine, has been developed for Cys detection over Hcy and GSH in vivo. The addition of thiol on α,β-unsaturated ketone promotes 87-fold fluorescence turn-on response with a 65 nM limit of detection. The high two-photon efficiency of the probe ANP (cross-section = 22.3) makes it a suitable probe for evaluating Cys in living cells without background fluorescence interference. Its application was extended to monitor the Cys distribution in live cells and tissues.


Associations of the IL12B promoter polymorphism in longitudinal data from asthmatic patients 7 to 42 years of age.
The IL12B gene encodes the p40 chain of IL-12, a proinflammatory cytokine that antagonizes TH2 expression and hence may play a critical role in the pathogenesis of airway inflammation observed in asthma. A promoter polymorphism of the gene was recently shown to be associated with asthma severity in children but only in heterozygotes. The aim of the present study was to test the hypothesis that the IL12B promoter polymorphism is associated with asthma susceptibility, severity, and related phenotypes in a cohort with longitudinal phenotypic data, from childhood to adulthood. Four hundred one 7-year-old children (106 control children, 295 asthmatic children) and 83 10-year-old children with severe asthma were recruited from a 1957 birth cohort. Atopic status and respiratory functions were determined at ages 7, 10, 14, 21, 28, 35, and 42 years. At age 42 years, blood samples were taken from 244 individuals for genotyping and the determination of plasma IgE levels and PHA- and house dust mite-induced IFN-gamma responses. Genotyping was done by the PCR restriction fragment length polymorphism method, using Alu I, and confirmed in 10% of the samples by direct sequencing. The IL12B genotypes were not associated with asthma susceptibility, severity, or atopy at ages 7 and 42 years. Total serum IgE levels at age 42 of men with at least one CTCTAA allele were higher than those homozygous for the GC allele (P = .042), whereas no difference was observed for women. At all ages, female subjects with at least 1 copy of the CTCTAA allele had lower mean percent predicted levels of FEV1 and FVC compared with those without this allele; these differences were significant at ages 10 and 14 years (P < .05) and in the asthmatic subgroup at age 7 years (P = .001). In this long-term study of asthmatic subjects with comprehensive data on asthma severity, we found no evidence to support the presence of a heterozygote effect of the IL12B promoter polymorphism on the level of asthma in early childhood or adulthood. The polymorphism was also not associated with asthma susceptibility, but the CTCTAA allele may have been associated with elevated serum IgE levels in male subjects and reduced pulmonary function in female subjects in early childhood.


Early pregnancy serum IGFBP-1 relates to lipid profile in overweight and obese women.
Lower level of insulin-like growth factor-binding protein (IGFBP-1) has been observed in insulin resistance, while higher level of matrix metalloproteinase-8 (MMP-8) has been linked to obesity. The aim here was to study in overweight and obese women, typically manifesting with insulin resistance, whether IGFBP-1 and MMP-8 are related to and reflect systemic low-grade inflammation, metabolism and diet. Fasting serum from overweight and obese pregnant women (n = 100) in early pregnancy were analysed for IGFBP-1, phosphorylated IGFBP-1 (phIGFBP-1) and MMP-8. High-sensitivity CRP and GlycA were used as markers for low grade inflammation. GlycA and lipids were quantified using NMR. IGFBP-1 associated negatively with GlycA, evidenced by higher concentrations in the lowest quartile (median 1.53 (IQR 1.45-1.72)) compared to the highest (1.46 (1.39-1.55)) (P = 0.03). Several lipid metabolites, particularly HDL-cholesterol, correlated inversely with phIGFBP-1 (FDR<0.1). Nutritional status and diet contributed to the levels of IGFBP-1, demonstrated as an inverse correlation with maternal weight (Spearman r = -0.205, P = 0.04) and dietary intake of vitamin A (r = -0.253, P = 0.014) and a direct correlation with dietary intake of polyunsaturated fatty acids (Spearman r = 0.222, P = 0.03). MMP-8 correlated inversely with pyridoxine (r = -0.321, P = 0.002) and potassium (r = -0.220, P = 0.033). Maternal serum IGFBP-1 may contribute to maternal lipid metabolism in overweight and obese women during early pregnancy. These findings may be of importance in identification of metabolic disturbances preceding the adverse metabolic outcomes in pregnancy.


The effect of substrate composition and condition on resorption by isolated osteoclasts.
Osteoclasts isolated from 10-day-old rabbits were studied in a cell culture system to obtain further insight into the possible mechanisms involved in the process of bone resorption. Osteoclasts were cultured on the surfaces of devitalized mammalian bones, a composite of polycrystalline synthetic hydroxyapatite and geological single crystal hydroxyapatite. The structural interaction of osteoclasts with these various substrates was morphologically characterized by using a scanning electron microscope. Viable osteoclasts were observed to adhere and extend pseudopodia and filopodia for all cases of calcium-phosphate surfaces. However, actual resorbing process was only observed in devitalized bone surfaces. Resorption pits of various sizes were found in multiple series and showed a preference for mineral-exposed area over collagen-exposed area. The difference observed between resorption of those areas of bone surface and the failure of osteoclasts to resorb non-tissue substrates are discussed in relation to current theories of the mechanisms of mineral dissolution and resorption in mammalian calcified tissues.