Development of an antibody that binds sulfur mustard.

An antibody that binds bis(2-chloroethyl) sulfide (sulfur mustard) was developed. The immunizing antigen was prepared from the hapten 4-(2-chloroethyl)benzoic acid covalently bound to keyhole limpet hemocyanin (KLH). The antibody was monitored by a solid phase enzyme-linked immunosorbent assay (ELISA). The test antigen consisted of a second hapten, 8-chlorocaprylic acid, covalently bound to bovine serum albumin (BSA). The test antigen was absorbed to the wells of 96-well plates. The immunizing and test antigens contain a common chloroethyl moiety. Thiodiglycol, the principal hydrolysis product of sulfur mustard, does not react with the antibody. This antibody, because of its specificity, has the potential to be a valuable tool for mustard research and forensic detection.     

Inflammatory cell infiltrate in a responding metastatic nodule after vaccine-based immunotherapy

A patient with von Hippel Lindau disease, bilateral symmetric renal cell carcinoma and pulmonary metastases treated with immunotherapy is the subject of this study. A left kidney and tumour mass were removed and the tumour cells used to make an autologous tumour/bacille Calmette–Guérin (BCG) vaccine as part of the treatment protocol. The patient's pulmonary nodules responded, but the remaining renal nodule subsequently grew. Samples of both tumours were obtained allowing for an internally controlled evaluation of the histological and immunohistologic differences between a responding and non-responding tumour nodule after therapy. The immunotherapy protocol is designed to promote a T cell response to autologous tumour. Cellular infiltrates were demonstrated in both responding and non-responding nodules compared with the pretreatment tumour specimen, but the responding nodule contained proportionately more T cells as well as markedly increased numbers of plasma cells and granulocytes. This suggested that several arms of the immune system may have been operative in the responding nodule.     

Recurrent Poisoning in Children: A Review

The literature on poisoning accidents or ingestion of toxicsubstances in children is reviewed. Special emphasis is givento the phenomenon of recurrent or repeat episodes. Recommendationsare made concerning means for identifying children who are atrisk for repeat poison episodes, as well as for developing methodsof intervention to prevent such occurrences.     

Blurring artifacts in megavoltage radiography with a flat-panel imaging system: comparison of Monte Carlo simulations with measurements

Originally designed for use at medical-imaging x-ray energies, imaging systems comprising scintillating screens and amorphous Si detectors are also used at the megavoltage photon energies typical of portal imaging and industrial radiography. While image blur at medical-imaging x-ray energies is strongly influenced both by K-shell fluorescence and by the transport of optical photons within the scintillator layer, at higher photon energies the image blur is dominated by radiation scattered from the detector housing and internal support structures. We use Monte Carlo methods to study the blurring in a notional detector: a series of semi-infinite layers with material compositions, thicknesses, and densities similar to those of a commercially available flat-panel amorphous Si detector system comprising a protective housing, a gadolinium oxysulfide scintillator screen, and associated electronics. We find that the image blurring, as described by a point-spread function (PSF), has three length scales. The first component, with a submillimeter length scale, arises from electron scatter within the scintillator and detection electronics. The second component, with a millimeter-to-centimeter length scale, arises from electrons produced in the front cover of the detector. The third component, with a length scale of tens of centimeters, arises from photon scatter by the back cover of the detector. The relative contributions of each of these components to the overall PSF vary with incident photon energy. We present an algorithm that includes the energy-dependent sensitivity and energy-dependent PSF within a ray-tracing formalism. We find quantitative agreement (approximately 2%) between predicted radiographs with radiographs of copper step wedges, taken with a 9 MV bremsstrahlung source and a commercially available flat-panel system. The measured radiographs show the blurring artifacts expected from both the millimeter-scale electron transport and from the tens-of-centimeters length scale arising from the scattered photon transport. Calculations indicate that neglect of the energy-dependent blurring would lead to discrepancies in the apparent transmission of these wedges of the order of 9%.     

Fusion protein vesicle-associated membrane protein 2 is implicated in IFN-gamma-induced piecemeal degranulation in human eosinophils from atopic individuals

BACKGROUND: Exocytosis is an integral event during IFN-gamma-induced piecemeal degranulation in eosinophils. In many tissues soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), including vesicle-associated membrane protein (VAMP), act as specific intracellular receptors to allow granule fusion with the membrane during degranulation. However, the mechanisms underlying eosinophil piecemeal degranulation induced by IFN-gamma are not well understood. OBJECTIVE: We sought to assess whether eosinophils express the vesicular SNARE protein VAMP-2 and to determine the involvement of VAMP-2 in IFN-gamma-induced piecemeal degranulation. METHODS: Human peripheral blood eosinophils (> or =97%) from atopic subjects were subjected to RT-PCR and sequence analysis with specific primers for VAMP-2 mRNA. Western blotting and flow cytometric analysis were carried out to confirm the identity of VAMP-2 and its susceptibility to cleavage by tetanus toxin. Confocal laser scanning microscopy imaging was conducted on double-labeled cytospin preparations of eosinophils at 0, 5, 10, 30, and 60 minutes and 16 hours of IFN-gamma (500 U/mL) stimulation. RESULTS: Eosinophils expressed VAMP-2 mRNA (n = 4 donors), which exhibited 100% homology with human VAMP-2 cDNA on sequencing. Eosinophils were also found to express tetanus toxin-sensitive VAMP-2 protein. RANTES and VAMP-2 immunofluorescence were observed to colocalize to similar intracellular structures by means of confocal imaging. IFN-gamma induced a rapid translocation of VAMP-2(+) organelles toward the cell membrane in correlation with RANTES. CONCLUSIONS: These findings suggest that exocytosis in human eosinophils is regulated by SNAREs, with a specific role indicated for VAMP-2 in piecemeal degranulation.     

Self-management and spina bifida: A systematic review of the literature

BackgroundSelf-management is critical to optimizing the health of individuals with a chronic condition or disability and is, therefore, a central concept in individual and family-centered healthcare delivery. The purpose of this review is to report the state of the science of self-management for individuals with spina bifida (SB) from a lifespan perspective.ObjectiveThis review will summarize the (a) development and use of self-management skills and behaviors across the life span, (b) factors related to self-management behaviors, (c) development of generic or condition-specific measures of self-management used with a spina bifida population, and (d) development and/or outcomes of interventions to improve self-management in SB.MethodsThe search strategy was limited to primary research articles published between 2003 and 2019 and followed PRISMA guidelines. The databases searched included: PubMed, CINAHL, PsycINFO, Web of Science, Cochrane, and Google Scholar. Studies that addressed self-management concepts in individuals throughout the life span and published in English were included.ResultsThe search yielded 108 citations and 56 articles met inclusion/exclusion criteria. A systematic narrative synthesis was reported. The level of evidence identified was primarily Level III articles of good quality. Multiple demographic, environmental, condition and process factors were related to self-management behaviors. SB self-management instruments and intervention development and testing studies were identified.ConclusionsThis review provides a synthesis of the state of the science of self-management including factors related to self-management behaviors, preliminary evidence of instruments for use in SB, factors important to consider in the development and testing of future interventions, and gaps in the literature.     

Costs of Immunization Programs for 10 Vaccines in 94 Low- and Middle-Income Countries From 2011 to 2030

ObjectivesUnderstanding the level of investment needed for the 2021-2030 decade is important as the global community faces the next strategic period for vaccines and immunization programs. To assist with this goal, we estimated the aggregate costs of immunization programs for ten vaccines in 94 low- and middle-income countries from 2011 to 2030.MethodWe calculated vaccine, immunization delivery and stockpile costs for 94 low- and middle-income countries leveraging the latest available data sources. We conducted scenario analyses to vary assumptions about the relationship between delivery cost and coverage as well as vaccine prices for fully self-financing countries.ResultsThe total aggregate cost of immunization programs in 94 countries for 10 vaccines from 2011 to 2030 is $70.8 billion (confidence interval: $56.6-$93.3) under the base case scenario and $84.1 billion ($72.8-$102.7) under an incremental delivery cost scenario, with an increasing trend over two decades. The relative proportion of vaccine and delivery costs for pneumococcal conjugate, human papillomavirus, and rotavirus vaccines increase as more countries introduce these vaccines. Nine countries in accelerated transition phase bear the highest burden of the costs in the next decade, and uncertainty with vaccine prices for the 17 fully self-financing countries could lead to total costs that are 1.3-13.1 times higher than the base case scenario.ConclusionResource mobilization efforts at the global and country levels will be needed to reach the level of investment needed for the coming decade. Global-level initiatives and targeted strategies for transitioning countries will help ensure the sustainability of immunization programs.     

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1^asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1^asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1^asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1^asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Cost-effectiveness of using hepatitis C viremic hearts for transplantation into HCV-negative recipients

Outcomes following hepatitis C virus (HCV)-viremic heart transplantation into HCV-negative recipients with HCV treatment are good. We assessed cost-effectiveness between cohorts of transplant recipients willing and unwilling to receive HCV-viremic hearts. Markov model simulated long-term outcomes among HCV-negative patients on the transplant waitlist. We compared costs (2018 USD) and health outcomes (quality-adjusted life-years, QALYs) between cohorts willing to accept any heart and those willing to accept only HCV-negative hearts. We assumed 4.9% HCV-viremic donor prevalence. Patients receiving HCV-viremic hearts were treated, assuming $39 600/treatment with 95% cure. Incremental cost-effectiveness ratios (ICERs) were compared to a $100 000/QALY gained willingness-to-pay threshold. Sensitivity analyses included stratification by blood type or region and potential negative consequences of receipt of HCV-viremic hearts. Compared to accepting only HCV-negative hearts, accepting any heart gained 0.14 life-years and 0.11 QALYs, while increasing costs by $9418/patient. Accepting any heart was cost effective (ICER $85 602/QALY gained). Results were robust to all transplant regions and blood types, except type AB. Accepting any heart remained cost effective provided posttransplant mortality and costs among those receiving HCV-viremic hearts were not >7% higher compared to HCV-negative hearts. Willingness to accept HCV-viremic hearts for transplantation into HCV-negative recipients is cost effective and improves clinical outcomes.     

Latency to enter a mirrored chamber: a novel behavioral assay for anxiolytic agents

Many animal species exhibit approach-avoidance responses upon the novel placement of a mirror into an individual animal's environment. With a view toward identifying new behavioral measures with qualitatively or quantitatively different responses to anxiolytic agents, we developed a mirrored chamber apparatus for which adult male BALB/cByJ mice showed an extended latency to enter. Administration of diazepam significantly reduced this latency to enter a mirrored chamber in a dosage-dependent manner. The psychomotor stimulant, methylphenidate, had no effect on latency to enter the mirrored chamber at a dose which stimulated locomotor activity to the same extent as diazepam. Thus, the decreased latency to enter the mirrored chamber brought about by diazepam seems unlikely to reflect the motor effects of this benzodiazepine. The potency of diazepam was significantly lower in the mirrored chamber assay than it was on three other measures of exploratory activity--"head-dipping" performance, plus-maze performance and locomotor activity stimulation. The findings of our study indicate that the mirrored chamber method is simple to carry out, nonpunishing, rapid and quantitative and that it possesses pharmacological attributes which distinguish its response to anxiolytics from other assays of exploratory behavior.