Vaccination of the Leishmania major susceptible BALB/c mouse. I. The precise selection of peptide determinant influences CD4+ T cell subset expression

BALB/c mice are susceptible to cutaneous lelshmanlasls uponinfection with Leishmania major while C57BL/6 are not. Thereis a major promastigote surface protease (PSP or gp63) whichis available in both native and recomblnant forms, and for whichthe primary amlno acid sequence is known. Immunization withPSP has been shown to offer some protection against challengewith the live organism. Therefore, we attempted to develop apeptide vaccine with PSP peptldes. In the first experiments,recall prollferatlve responses to PSP were measured using aset of 15mer peptldes spanning the entire PSP molecule whichallowed designation of major determinant regions in BALB/c,C57BL/6, and CBA mice. Several of these determinants were promiscuousand shared almost the identical core amlno acid residues inthe different strains. Immunization with major determinant peptldeswas recalled vigorously with L. major soluble antigen as wellas with PSP. The response to peptide was almost entirely T_h1as measured by a localized ELISA assay for single-cell productionof IFN-. A similar assay for IL-5, which overcomes problemsof sensitivity and inhibition by lymphoklnes produced by T_h1cells, Indicates very little production of T_h1 cells even byBALB/c. It was found that if a major responsive peak was examinedby recall with overlapping peptldes, the highest, central peptidegave a mainly Th1 response while the boundary, less efficientpeptldes gave more of a T_h2 response. Possible reasons for thiswere discussed. These results point to the importance of selectingthe exactly appropriate peptide in considering a vacclnogenthat might protect susceptible individuals. Even the choiceof a somewhat immunogenlc peptide within the determinant envelopemight actually exacerbate infection by steering the responsein a T_h2 direction.     

Evolutionary conservation of brain Thy-1 glycoprotein in vertebrates and invertebrates

The evolutionary conservation of brain Thy-1 glycoprotein in 24 vertebrate and invertebrate species has been investigated by means of a soluble phase radioimmunoassay (RIA) and by the "Western blot" technique. The brain glycoproteins from virtually all the vertebrate species inhibited the precipitation of mouse Thy-1.1 by a rabbit anti-rat Thy-1 antiserum. Most reagents also inhibited the binding of a mouse anti-rat Thy-1 monoclonal antibody to rat Thy-1. Whole tissue glycoproteins from earthworm, snail and oyster and ganglia glycoproteins of a locust species were also found to be inhibitory. Western blotting analysis on NaDod SO4 polyacrylamide gel electrophoresis under reducing conditions revealed a Thy-1 homologous molecule (22-25 KD) in mammals, birds, fish, reptiles and invertebrate species. The snail Thy-1-like molecule was eluted from the gel and was shown to specifically inhibit the serological reaction. The rabbit anti-rat Thy-1 antiserum also detected a doublet molecule of approximately 85,000 KD, which is conserved in all species, including yeast and bacteria. The origin and nature of the presumed glycoproteins is unknown. Our results suggest that the Thy-1 molecule has been conserved throughout metazoan evolution and that the Thy-1 gene is the most conserved among the immune related genes (immunoglobulins, beta 2-microglobulin and major histocompatibility) which share extensive amino acid homology.     

Hitting moving objects: is target speed used in guiding the hand?

We investigated what information subjects use when trying to hit moving targets. In particular, whether only visual information about the target's position is used to guide the hand to the place of interception or also information about its speed. Subjects hit targets that moved at different constant speeds and disappeared from view after varying amounts of time. This prevented the subjects from updating position information during the time that the target was invisible. Subjects hit further ahead of the disappearing point when the target moved faster, but not as much as they should have on the basis of the target's speed. This could be because more time is needed to perceive and use the correct speed than was available before the target disappeared. It could also be due to a speed-related misperception of the target's final position. The results of a second experiment were more consistent with the latter hypothesis. In a third experiment we moved the background to manipulate the perceived speed. This did not affect the hitting positions. We conclude that subjects respond only to the changing target position. Target speed influences the direction in which the hand moves indirectly, possibly via a speed-related misperception of position.     

Combining CGM and an Online Peer Support Community for Hispanic Adults with T2D: A Feasibility Study

Background:Previous research has identified that people with type 2 diabetes (T2D) within the Hispanic community would benefit from an online peer support community (OPSC) and continuous glucose monitoring (CGM) data to facilitate diabetes self-management.Methods:A mixed-methods feasibility study enrolled Hispanic, Spanish-speaking adults with T2D, not on insulin. Participants were provided with CGM and access to an OPSC for 12 weeks. Feasibility was assessed by number of eligible participants who enrolled, attrition, quantity of CGM data, validated clinical measures of self-efficacy, quality of life and adverse events. Engagement in the OPSC was measured using objective metrics on the online platform. Qualitative interviews were conducted upon conclusion of the intervention to assess feasibility, acceptability, participant satisfaction, and key recommendations for improvement.Results:Of 46 participants screened, 39 were eligible and 26 completed the study. Participants significantly improved self-efficacy scores. Posts in the OPSC related to goal setting had the highest engagement followed by mid-week and end of week check-in posts respectively. Participant interviews described challenges accessing the OPSC platform as a barrier to engagement. Despite this, all participants were satisfied with the intervention. Key recommendations for improvement included providing greater variety of and individualized education and the use of a peer support platform that is easily accessible.Conclusions:The CGM + OPSC intervention tailored to the Hispanic community with T2D was feasible, acceptable and satisfactory and improved participant self-efficacy for diabetes management which may lead to improved clinical outcomes.     

Case of benralizumab‐induced exacerbations of chronic spontaneous urticaria

The role of IL‐5 in chronic spontaneous urticarial (CSU) is unclear. It may be that benralizumab is an important bidirectional modifier of CSU; that is, blocking IL‐5 may improve CSU in some patients, but it is possible that it may worsen CSU in others.     

Prevention of colorectal cancer by colonoscopic surveillance in families with hereditary colorectal cancer

Objective. In recent years persons at risk for colorectal cancers (CRC) have been subjected to follow-up with colonoscopy in many centres. There is, however, limited knowledge about the effect of such interventions. The objective of this study was to report the results of our observations during the past 15 years. Material and methods. Healthy persons were included in the study according to their family history of CRCs, and prospectively followed with colonoscopies. Results. Altogether, 1133 individuals were included and observed for a total of 3474 follow-up years from the first to the last colonoscopy initiated by our activity. Mismatch repair (MMR) mutations were detected in 6.5% of cases. A total of 1383 polyps were removed, 72% were less than 5 mm in diameter. Findings were scored as hyperplastic polyps (n=887), adenomas with mild to moderate dysplasia (n=460), adenomas with high-grade dysplasia (n=30) and cancers (n=6). Two cancers were observed after the first colonoscopy, compared with 2.6 expected by chance and more than 20 expected under the hypothesis of predominant inherited diseases in the families. Observed annual incidence rates for adenomas were similar in all groups, while in the mutation carriers there was a higher frequency of progression to severe dysplasia or infiltrating cancer. Conclusions. A simple explanation for the combined findings may be that all selected families had a similar tendency to produce adenomas, while mutation carriers more frequently demonstrated dysplasia/cancer in the adenomas. The low annual incidence rates for CRC indicated that the removal of adenomas may have prevented cancers.     

Treatment of severe late-onset Perthes’ disease with soft tissue release and articulated hip distraction: revisited at skeletal maturity

Purpose  Late-onset Perthes’ disease is diagnosed after 9 years of age. Conservative treatment and conventional surgical techniques have limited ability to reduce the pressure in the joint or change the shape of the femoral head. We used a combination of soft tissue release and joint distraction with a hinged mono-lateral external fixator for these patients. Ten of our patients reached skeletal maturity and were evaluated. Methods  Clinical assessment included: Harris hip score, hip range-of-motion (ROM), limb length discrepancy, and the Oxford hip questionnaire for pain and function. Radiographic assessment included: Sharp transverse acetabular inclination, the uncoverage percentage, the epiphyseal index before surgery (modified Eyre–Brook), at frame removal, and, at last follow-up, the epiphyseal quotient (of Sjovall) and the Stulberg classification. Results  Our study included eight boys and two girls (mean age at surgery 12.3 years, range 9.4–15.1, mean age at last follow-up 18.1 years, range 15.2–22.8). The mean follow-up was 5.7 years (range 4.3–7.8). The mean Harris hip score was 86.3/100 (range 48.5–96); one patient had <85 points. The hip ROM was slightly limited in most patients, and seven patients had limb shortening between 1–4 cm. The mean Oxford hip questionnaire score was 17.4/60 (range 12–31). The mean Sharp transverse acetabular inclination of the affected side was 42° (range 36–54) compared to 39° for the unaffected side (P = 0.045). The mean uncoverage percentage was 37% (range 27–47) compared to 20% for the unaffected side (P = 0.017). The mean epiphyseal index was 0.71 (range 0.31–0.92) before surgery, 0.79 (range 0.50–0.93) at frame removal (P = 0.012), and 0.72 (range 0.51–0.89) at last follow-up (P = 0.646). The epiphyseal quotient for the eight unilateral cases was 0.72 (range 0.49–0.91), and the Stulberg classification was type III for three cases and type IV for seven. Conclusion  Patient satisfaction for function and pain following the combined procedure was good. Radiographic parameters did not change significantly. This should be regarded as a salvage procedure.