Dendritic cells retrovirally overexpressing IL-12 induce strong Th1 responses to inhaled antigen in the lung but fail to revert established Th2 sensitization

It has been postulated that low-level interleukin (IL)-12 production of antigen-presenting cells is associated with the risk of developing atopic asthma. To study the relationship between IL-12 production capacity of dendritic cells (DCs) and development of T helper type 2 (Th2) responses in the lung, we genetically engineered DCs to constutively overexpress bioactive IL-12. Retrovirally mediated overexpression of IL-12 in DCs strongly polarized naive ovalbumin (OVA)-specific CD4+ T cells toward Th1 effector cells in vitro. After intratracheal injection, OVA-pulsed IL-12-overexpressing DCs failed to induce Th2 responses in vivo and no longer primed mice for Th2-dependent eosinophilic airway inflammation upon OVA aerosol challenge, readily observed in mice immunized with sham-transfected, OVA-pulsed DCs. Analysis of a panel of cytokines and chemokines in the lung demonstrated that the lack of Th2 sensitization was accompanied by increased production of the Th1 cytokine interferon-gamma (IFN-gamma), chemokines induced by IFN-gamma, and the immunoregulatory cytokine IL-10. When Th2 priming was induced using OVA/alum prior to intratracheal DC administration, DCs constitutively expressing IL-12 were no longer capable of preventing eosinophilic airway inflammation and even enhanced it. These data show directly that high-level expression of IL-12 in DCs prevents the development of Th2 sensitization. Enhancing IL-12 production in DCs should be seen as a primary prevention strategy for atopic disorders. Enhancing IL-12 production in DCs is less likely to be of benefit in already Th2-sensitized individuals.     

Identification of the palliative phase in people with dementia: a variety of opinions between healthcare professionals

Background

People with dementia can benefit from a palliative care approach. Recommendations, such as those of the EAPC have been proposed to strengthen the provision of palliative care for this group of patients. Yet, it remains challenging for professionals to identify when a person with dementia is in need of palliative care. The objective of this study therefore was to explore when professionals in long-term care settings consider a person with dementia in need of palliative care.

Methods

Teams with in total 84 professionals working in 13 long-term care settings from 6 countries (France, Germany, Italy, Norway, Poland and the Netherlands) received a case-vignette concerning a person with dementia recently admitted to a nursing home. Teams were asked to discuss when they considered people with dementia eligible for palliative care. The constant comparative method was used to analyse their answers.

Results

Three different time points in the disease trajectory when people with dementia were considered to be eligible for palliative care were extracted: (1) early in the disease trajectory; (2) when signs and symptoms of advanced dementia are present; and (3) from the time point that curative treatment of co-morbidities is futile. Yet, none of these time points was uniformly considered by the professional teams across Europe. In some cases, professionals working in the same nursing home didn’t even reach consensus when considering persons with dementia eligible for palliative care.

Conclusion

The results of the study identified that professionals across Europe have different opinions regarding the time point when to consider a person with dementia in need of palliative care.

     

Predicting blood pressure outcomes using single-item physician-administered measures: a retrospective pooled analysis of observational studies in Belgium

BackgroundPatient adherence is often not monitored because existing methods of evaluating adherence are either burdensome or do not accurately predict treatment outcomes.AimTo examine whether two simple, single-item physician-administered measures of patient adherence to antihypertensive medication are predictive of blood pressure outcomes.MethodUsing pooled data from five observational studies, a sample was identified of 9725 patients who were assessed using two single-item physician-administered measures of adherence to antihypertensive medication: the first item of the Basel Assessment of Adherence Scale (BAAS) and the Visual Analogue Scale (VAS). These two assessment tools were administered by GPs during regular appointments with patients. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and combined SBP/DBP were measured at baseline and at 90 days.ResultsBAAS-identified adherent patients achieved lower mean SBP and DBP compared with non-adherent patients at 90 days (P<0.001), and had odds ratios of achieving blood pressure control of 0.66 (95% confidence intervals (CI) = 0.61 to 0.73, P<0.001) for SBP, 0.69 (95% CI = 0.62 to 0.76, P<0.001) for DBP, and 0.65 (95% CI = 0.59 to 0.72, P<0.001) for combined SBP/DBP. For VAS-identified adherent patients, the odds ratios of achieving blood pressure control were 0.93 (95% CI = 0.86 to 1.00, P<0.001) for SBP, 0.79 (95% CI = 0.73 to 0.85, P<0.001) for DBP, and 0.91 (95% CI = 0.84 to 0.99, P<0.001) for combined SBP/DBP.ConclusionsThe first item of the BAAS and the VAS are independent predictors of blood pressure control. These methods can be integrated seamlessly into routine clinical practice by allowing GPs to quickly evaluate a patient’s adherence and tailor treatment recommendations accordingly.     

Detection of Chikungunya Virus Antigen by a Novel Rapid Immunochromatographic Test

Chikungunya fever is a mosquito-borne disease of key public health importance in tropical and subtropical countries. Although severe joint pain is the most distinguishing feature of chikungunya fever, diagnosis remains difficult because the symptoms of chikungunya fever are shared by many pathogens, including dengue fever. The present study aimed to develop a new immunochromatographic diagnosis test for the detection of chikungunya virus antigen in serum. Mice were immunized with isolates from patients with Thai chikungunya fever, East/Central/South African genotype, to produce mouse monoclonal antibodies against chikungunya virus. Using these monoclonal antibodies, a new diagnostic test was developed and evaluated for the detection of chikungunya virus. The newly developed diagnostic test reacted with not only the East/Central/South African genotype but also with the Asian and West African genotypes of chikungunya virus. Testing of sera from patients suspected to have chikungunya fever in Thailand (n = 50), Laos (n = 54), Indonesia (n = 2), and Senegal (n = 6) revealed sensitivity, specificity, and real-time PCR (RT-PCR) agreement values of 89.4%, 94.4%, and 91.1%, respectively. In our study using serial samples, a new diagnostic test showed high agreement with the RT-PCR within the first 5 days after onset. A rapid diagnostic test was developed using mouse monoclonal antibodies that react with chikungunya virus envelope proteins. The diagnostic accuracy of our test is clinically acceptable for chikungunya fever in the acute phase.     

Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management

Noninvasive prenatal testing by massive parallel sequencing of maternal plasma DNA has rapidly been adopted as a mainstream method for detection of fetal trisomy 21, 18 and 13. Despite the relative high accuracy of current NIPT testing, a substantial number of false-positive and false-negative test results remain. Here, we present an analysis pipeline, which addresses some of the technical as well as the biologically derived causes of error. Most importantly, it differentiates high z-scores due to fetal trisomies from those due to local maternal CNVs causing false positives. This pipeline was retrospectively validated for trisomy 18 and 21 detection on 296 samples demonstrating a sensitivity and specificity of 100%, and applied prospectively to 1350 pregnant women in the clinical diagnostic setting with a result reported in 99.9% of cases. In addition, values indicative for trisomy were observed two times for chromosome 7 and once each for chromosomes 15 and 16, and once for a segmental trisomy 18. Two of the trisomies were confirmed to be mosaic, one of which contained a uniparental disomy cell line. As placental trisomies pose a risk for low-grade fetal mosaicism as well as uniparental disomy, genome-wide noninvasive aneuploidy detection is improving prenatal management.     

Genetic landscape of RASopathies in Chinese: Three decades' experience in Hong Kong

RASopathies are a group of genetic disorders due to dysregulation of the RAS‐MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety‐one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well‐known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re‐evaluation of the current tumor surveillance recommendation maybe warranted.     

60 hertz magnetic field exposure assessment for an investigation of leukemia in telephone lineworkers

The purpose of this paper is to present the assessment of magnetic field exposure conducted as a part of a nested case-control investigation of leukemia mortality in telephone lineworkers. For the purposes of exposure classification, telephone company jobs were initially divided into two classes: those with potential for working in an electric environment, referred to as linework jobs, and those not working in an electric environment, referred to as nonlinework jobs. Linework jobs were further divided into the following four categories: outside plant technicians (OPT), installation/maintenance/repair (IMR) technicians, central office technicians (COT), and cable splicing technicians (CST). These job groupings were based on similarity of work tasks and exposure environments. Emdex data-logging dosimeters were used to measure personal exposures to ELF magnetic fields for 204 telephone company workers. Three general classes of exposure indices were calculated for each exposure record: measures of central tendency, measures of peak or maximum exposure, and measures of exposure variability. CSTs had the highest full-shift mean and median exposure, 4.3 and 3.2 mG, respectively. CSTs also ranked the highest, with average peak, average 95th percentile, and average time above background equal to 99.2 mG, 11.1 mG, and 156 min, respectively. In addition, the results suggest the OPT and IMR technicians have exposures similar to nonlineworkers. Exposure classifications, therefore, which misclassify all lineworkers into one “telephone lineworker” job grouping are not appropriate and future studies should concentrate on cable splicing technicians.     

Comparison of ureteral and cervical descents during vaginal hysterectomy for uterine prolapse

Objective: The study measured ureteral and cervical locations during vaginal hysterectomy for prolapse and the extent of parametrial ligament shortening possible. Study Design: Cervical and ureteral position were measured in 26 women undergoing uterine prolapse correction. Parametrial clamp tip location was also measured. Results: The cervix lay between 0 and –14.5 cm (below) the hymen (mean ± SD –5.35 ± 3.96 cm) and the ureters lay +5.0 to –4.0 cm (mean ± SD +1.89 ± 1.99 cm). Correlation of ureteral with cervical position was 0.69 (P < .01) and correlation with ipsilateral uterosacral ligament clamp positions was 0.80 (P < .01). Regression line slope relating cervical descent and cervix to ureter distance was 0.65, indicating that for every 3 cm of cervical descent there was 2 cm widening of the gap between the cervix and ureters and 1 cm descent of the ureter. Conclusion: For every 3 cm of cervical descent the ureters descend 1 cm, thereby widening the ureterocervical gap and permitting ligament shortening during vaginal hysterectomy. (Am J Obstet Gynecol 1998;179:1405-10.)