Ambulatory blood pressure monitoring and laboratory reactivity in type A behavior and components

Type A coronary-prone behavior has been characterized previously by cardiovascular hyperreactivity to laboratory stressors. The objectives of this study were: 1) to determine whether cardiovascular patterns under more naturalistic circumstances in the field were altered in Type A subjects, and 2) to determine whether these field patterns paralleled cardiovascular patterns to a series of stressors in the laboratory. Thirty-three healthy Type A and B men underwent 24-hr ambulatory blood pressure and heart rate monitoring during a normal day of activities. These subjects were also tested in the laboratory for blood pressure and heart rate responses to a series of stressor tasks: 1) cognitive (mental arithmetic), 2) perceptual motor (reaction time), and 3) physical (handgrip). Type A behavior and stylistic components were rated by structured interview. All studies were conducted double blindly. Type A subjects demonstrated greater cardiovascular reactivity to the laboratory cognitive stressor, but there was a mixture of differences between As and Bs in variability of ambulatory blood pressure and heart rate during different periods of the day. Yet, there were no differences in average blood pressure levels. The components of verbal competition and loudness of voice were positively associated with elevated average blood pressure and variability in the field, respectively, but not with laboratory hyperreactivity. Thus, this study confirmed laboratory-induced cardiovascular hyperreactivity in Type A behavior but, within its limitations, did not find a similarity between laboratory and field cardiovascular response patterns in these behavioral groups. The ambulatory blood pressure monitoring findings in the component groups may have prognostic significance and deserve further study.     

Distinct roles for CD4 and CD8 as co-receptors in T cell receptor signalling

We demonstrate that CD4 and CD8 modify signals induced through the T cell receptor for antigen (TCRαβ) in distinct fashions. Pretreatment of CD4⁺ lymph node T cells with CD4-specific monoclonal antibody results in a tenfold inhibition of DNA synthesis induced by anti-TCRαβ. In contrast, pretreatment of CD8⁺ T cells with CD8-specific mAb has no effect on DNA synthesis subsequently induced through TCRαβ. While inhibiting late activation signals, pretreatment with anti-CD4 does not detectably alter the pattern of anti-TCRαβ-induced tyrosine phosphorylation of cellular proteins, nor subsequent Ca²⁺ mobilization. The distinct biological consequences of anti-CD4 and anti-CD8 pretreatment correlate with the differential association of their respective ligands with the cellular protein tyrosine kinase, p56^lck. While both T cell lineages contain similar levels of cellular p56^lck, tenfold more is associated with CD4 than with CD8. This difference is associated with the differential effects of pretreatment with anti-CD4 and anti-CD8 on the distribution and activity of p56^lck. Further, antibody-mediated aggregation of TCRαβ on CD4⁺ T cells induces the appearance of a p56^lck species with decreased mobility in sodium dodecylsulfate-polyacrylamide gel electrophoresis. This effect is observed in CD4⁺ T cells exclusively and involves the fraction of p56^lck which is not associated with CD4. The results presented here demonstrate that the signalling elements which couple the antigen receptor to second messenger-generating systems are under distinct physical and/or functional constraints in the two T cell lineages.     

Large deformation three-dimensional image registration in image-guided radiation therapy

In this paper, we present and validate a framework, based on deformable image registration, for automatic processing of serial three-dimensional CT images used in image-guided radiation therapy. A major assumption in deformable image registration has been that, if two images are being registered, every point of one image corresponds appropriately to some point in the other. For intra-treatment images of the prostate, however, this assumption is violated by the variable presence of bowel gas. The framework presented here explicitly extends previous deformable image registration algorithms to accommodate such regions in the image for which no correspondence exists. We show how to use our registration technique as a tool for organ segmentation, and present a statistical analysis of this segmentation method, validating it by comparison with multiple human raters. We also show how the deformable registration technique can be used to determine the dosimetric effect of a given plan in the presence of non-rigid tissue motion. In addition to dose accumulation, we describe a method for estimating the biological effects of tissue motion using a linear-quadratic model. This work is described in the context of a prostate treatment protocol, but it is of general applicability.     

A calorimetric investigation of interactions in aqueous solutions of poly(oxyethylene), 1. Heats of mixing of oligomeric models

Heats of mixing with water as function of the composition of the mixtures for oligomeric models of poly(oxyethylene) at 25°C are reported, i. e. for compounds of the type XO(CH₂CH₂O)_nX (where X = H or CH₃ and n = 1, 2, 3, or 4) and CH₃O(CH₂CH₂O)_mH (where m = 1 or 2). These dependencies greatly depend on the character of the end groups and on the degree of oligomerization. A procedure has been suggested for the comparison between the heat of mixing of longer chains and that of shorter ones with elimination of the effect of end groups. On the same mass basis, longer chains release more heat than shorter ones in mixing with water for concentrated solutions; hence, one may assume some kind of cooperativity of ether oxygen atoms in the same chain by hydration.     

Optimization of peptide linker length in production of MHC class II/peptide tetrameric complexes increases yield and stability,and allows identification of antigen-specific CD4+T cells in peripheral blood mononuclear cells

Reliable, efficient systems for producing soluble HLA-DR molecules, suitable for multimerization and use as staining reagents, have proved elusive. We found that the addition of a flexible linker between peptide and N terminus of the DRB1*0101-chain (Crawford, F., Kozono, H., White, J., Marrack, P. and Kappler, J., Immunity 1998. 8: 675-682.), results in greater in vitro folding efficiency of Escherichia coli-expressed alpha- and beta-chains, and increases both the yield and stability of the DRA1*0101/DRB1*0101/peptide complexes. Although a 10-amino acid linker functioned efficiently for a 20mer epitope from HIV p24, a longer linker was required to produce a DR1 MHC class II tetramer with the influenza hemagglutinin epitope (HA(306-318)). The DR1-HA tetramer was able to stain positively over 98% of a specific clone (HA 1.7) with only a brief 30-min incubation. The tetrameric complexes detected clone cells diluted into PBMC, with high sensitivity, coupled with low background staining in CD4(+) cells. It was possible to detect antigen-specific CD4(+) T cells within a population of PBMC stimulated with the HA peptide. This demonstrates the potential to monitor CD4(+) T cell responses in peripheral blood in a number of clinical scenarios.     

Cognitive and behavioural correlates of non‐adherence to HIV anti‐retroviral therapy: Theoretical and practical insight for clinical psychology and health psychology

This cross‐sectional study identified variables associated with protease inhibitor (PI) non‐adherence in 179 patients taking anti‐retroviral therapy. Univariate analyses identified 11 variables associated with PI non‐adherence. Multiple logistic regression modelling identified three predictors of PI non‐adherence: low adherence self‐efficacy and seriousness of non‐adherence and HIV (p < .001), perceived absence of HIV associated illness (p < .01), and use of more than one type of recreational drug (p = .001). The model correctly classified 83.9% of the sample, offers psychologists insight into psychological barriers to treatment adherence to guide interventions for improving adherence, and supports a modified version of the reformulated health belief model.     

Emergence of SARS-CoV-2 B.1.1.7 Lineage at Outpatient Testing Site,Berlin, Germany,January–March 2021

Within 5 weeks in 2021, B.1.1.7 became the dominant severe acute respiratory syndrome coronavirus 2 lineage at an outpatient testing site in Berlin, Germany. Compared with outpatients with wild-type virus infection, patients with B.1.1.7 had similar cycle threshold values, more frequent sore throat and travel history, and less frequent anosmia/ageusia.     

Impact of antiangiogenic treatment on the erectile function in patients with advanced renal cell carcinoma

We longitudinally assessed erectile function as well as the willingness to use pro-erectile treatment in a cohort on AAT for advanced RCC. Thirty-seven patients with advanced RCC completed the five-item version of the International Index of Erectile Function (IIEF-5) and other interview items before (T0) and 12 weeks into therapy (T12) with AAT. Patients were further asked if they were willing to use and pay out-of-pocket for on-demand treatment with phosphodiesterase-5-inhibitors (PDE-5i). Statistical analysis was performed using nonparametric hypothesis testing. The IIEF-5 score at T12 was significantly decreased compared with T0 (p < .001). Subjective patient satisfaction regarding their sexual lives was associated with higher IIEF-5 scores at both time points (p = .006 and p = .03, respectively). At T12, subjective sexual contentment showed a nonsignificant trend towards decline (p = .074). Patients who opted for medical treatment of ED showed significantly better IIEF-5 scores at both time points compared with the rest of the cohort (p < .001 and p = .005, respectively). In summary, AAT seems to have a negative effect on erectile function in RCC patients, however, the role of psychosocial issues warrants further elucidation. Affected patients may benefit from a proactive approach promoting medical treatment of erectile dysfunction during AAT.     

Clinical Phenotype and Relevance of LRP5 and LRP6 Variants in Patients With Early-Onset Osteoporosis (EOOP)

Reduced bone mineral density (BMD; ie, Z-score ≤−2.0) occurring at a young age (ie, premenopausal women and men <50 years) in the absence of secondary osteoporosis is considered early-onset osteoporosis (EOOP). Mutations affecting the WNT signaling pathway are of special interest because of their key role in bone mass regulation. Here, we analyzed the effects of relevant LRP5 and LRP6 variants on the clinical phenotype, bone turnover, BMD, and bone microarchitecture. After exclusion of secondary osteoporosis, EOOP patients (n = 372) were genotyped by gene panel sequencing, and segregation analysis of variants in LRP5/LRP6 was performed. The clinical assessment included the evaluation of bone turnover parameters, BMD by dual-energy X-ray absorptiometry, and microarchitecture via high-resolution peripheral quantitative computed tomography (HR-pQCT). In 50 individuals (31 EOOP index patients, 19 family members), relevant variants affecting LRP5 or LRP6 were detected (42 LRP5 and 8 LRP6 variants), including 10 novel variants. Seventeen variants were classified as disease causing, 14 were variants of unknown significance, and 19 were BMD-associated single-nucleotide polymorphisms (SNPs). One patient harbored compound heterozygous LRP5 mutations causing osteoporosis-pseudoglioma syndrome. Fractures were reported in 37 of 50 individuals, consisting of vertebral (18 of 50) and peripheral (29 of 50) fractures. Low bone formation was revealed in all individuals. A Z-score ≤−2.0 was detected in 31 of 50 individuals, and values at the spine were significantly lower than those at the hip (−2.1 ± 1.3 versus −1.6 ± 0.8; p = .003). HR-pQCT analysis (n = 34) showed impaired microarchitecture in trabecular and cortical compartments. Significant differences regarding the clinical phenotype were detectable between index patients and family members but not between different variant classes. Relevant variants in LRP5 and LRP6 contribute to EOOP in a substantial number of individuals, leading to a high number of fractures, low bone formation, reduced Z-scores, and impaired microarchitecture. This detailed skeletal characterization improves the interpretation of known and novel LRP5 and LRP6 variants. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).