Cell-mediated immunity to histocompatibility antigens : controlling factors, with emphasis on Graft-versus-host reactions in mice

Graft-versus-Host (GvH) disease is characterized by weight loss, diarrhea, skin lesions, hypofunction of the immune system with concomitant infections, etc. This syndrome is potentially lethal. GvH reactions, which underly this disease, may occur when immunocompetent T lymphocytes are transplanted into a host, which is unable to eliminate the intrusive donor lymphocytes and which confronts the graft with a sufficient degree of histoincompatibility. The type of T lymphocyte which plays a central role in GvH reactions seems to be the Lyt-1+ T cell, which probably is analogous to the helper T cell. This cell type may activate other subsets of T lymphocytes, viz., cytotoxic T cells and suppressor T cells, which may lead to GvH disease, depending on the experimental conditions and antigenic differences between donor and host, The GvH reaction is not only interesting from the point of view of the ensuing syndrome, but can also be used to study certain fundamental immunological problems, such as which histocompatibility antigens evoke the strongest immune reactions, which cell types are involved, do these cell types synergize, etc. We approached these questions in experimental studies with mice. To study such problems one has to have an appropriate assay. We made use of a delayed-type hypersensitivity (DTH) assay which is appropriate to measure the anti-host immune reactivity during acute and delayed GvH reactions in mic

Prognostic value of microvessel density in stage II and III colon cancer patients:a retrospective cohort study

Background Microvessel density (MVD), as a derived marker for angiogenesis, has been associated with poor outcome in several types of cancer. This study aimed to evaluate the prognostic value of MVD in stage II and III colon cancer and its relation to tumour-stroma-percentage (TSP) and expression of HIF1A and VEGFA. Methods Formalin-fixed paraffin-embedded (FFPE) colon cancer tissues were collected from 53 stage II and 54 (5-fluorouracil-treated) stage III patients. MVD was scored by digital morphometric analysis of CD31-stained whole tumour sections. TSP was scored using haematoxylin-eosin stained slides. Protein expression of HIF1A and VEGFA was determined by immunohistochemical evaluation of tissue microarrays. Results Median MVD was higher in stage III compared to stage II colon cancers (11.1% versus 5.6% CD31-positive tissue area, p <0.001). High MVD in stage II patients tended to be associated with poor disease free survival (DFS) in univariate analysis (p = 0.056). In contrast, high MVD in 5FU-treated stage III patients was associated with better DFS (p = 0.006). Prognostic value for MVD was observed in multivariate analyses for both cancer stages. Conclusions MVD is an independent prognostic factor associated with poor DFS in stage II colon cancer patients, and with better DFS in stage III colon cancer patients treated with adjuvant chemotherapy

Diabetic peripheral neuropathy : advances in diagnosis and strategies for screening and early intervention

Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. It is a leading cause of lower-limb amputation and disabling neuropathic pain. Amputations in patients with diabetes have a devastating effect on quality of life and are associated with an alarmingly low life expectancy (on average only 2 years from the amputation). Amputation also places a substantial financial burden on health-care systems and society in general. With the introduction of national diabetes eye screening programmes, the prevalence of blindness in working-age adults is falling. This is not the case, however, with diabetes related amputations. In this Review, we appraise innovative point-of-care devices that enable the early diagnosis of DPN and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN. We also propose a framework for screening and early multifactorial interventions as the best prospect for preventing or halting DPN and its devastating sequelae

Good governance: Navigating on purpose and complexity-based principles

Long-term investors face the same challenges as the companies they invest in. Investors need to have a clear purpose as a beacon for their strategies and a worldview that is in line with reality. Via different financial instruments and investment vehicles, long-term investors are ultimately invested in companies. To make their portfolio long-term financially sustainable and resilient to shocks, long-term investors need to search for companies that have both a clear purpose and a realistic worldview. This chapter takes a deeper look into the companies in which long-term investors are invested and what makes these companies sustainable from a governance perspective

KCNQ1 and lymphovascular invasion are key features in a prognostic classifier for stage II and III colon cancer

Background: The risk of recurrence after resection of a stage II or III colon cancer, and therefore qualification for adjuvant chemotherapy (ACT), is traditionally based on clinicopathological parameters. However, the parameters used in clinical practice are not able to accurately identify all patients with or without minimal residual disease. Some patients considered ‘low-risk’ do develop recurrence (undertreatment), whilst other patients receiving ACT might not have developed recurrence at all (overtreatment). We previously analysed tumour tissue expression of 28 protein biomarkers that might improve identification of patients at risk of recurrence. In the present study we aimed to build a prognostic classifier based on these 28 biomarkers and clinicopathological parameters. Methods: Classification and regression tree (CART) analysis was used to build a prognostic classifier based on a well described cohort of 386 patients with stage II and III colon cancer. Separate classifiers were built for patients who were or were not treated with ACT. Routine clinicopathological parameters and tumour tissue immunohistochemistry data were included, available for 28 proteins previously published. Classification trees were pruned until lowest misclassification error was obtained. Survival of the identified subgroups was analysed, and robustness of the selected CART variables was assessed by random forest analysis (1000 trees). Results: In patients not treated with ACT, prognosis was estimated best based on expression of KCNQ1. Poor disease-free survival (DFS) was observed in those with loss of expression of KCNQ1 (HR = 3.38 (95% CI 2.12 – 5.40); p < 0.001). In patients treated with ACT, key prognostic factors were lymphovascular invasion (LVI) and expression of KCNQ1. Patients with LVI showed poorest DFS, whilst patients without LVI and high expression of KCNQ1 showed most favourable survival (HR = 7.50 (95% CI 3.57—15.74); p < 0.001). Patients without LVI and loss of expression of KCNQ1 had intermediate survival (HR = 3.91 (95% CI 1.76 – 8.72); p = 0.001). Conclusion: KCNQ1 and LVI were identified as key features in prognostic classifiers for disease-free survival in stage II and III colon cancer patients

Microbiota composition and mucosal immunity in patients with asymptomatic diverticulosis and controls

Introduction The etiology of diverticulosis is still poorly understood. However, in patients with diverticulitis, markers of mucosal inflammation and microbiota alterations have been found. The aim of this study was to evaluate potential differences of the gut microbiota composition and mucosal immunity between patients with asymptomatic diverticulosis and controls. Methods We performed a prospective study on patients who underwent routine colonoscopy for causes not related to diverticular disease or inflammatory bowel disease. Participants were grouped based on the presence or absence of diverticula. Mucosal biopsies were obtained from the sigmoid and transverse colon. Microbiota composition was analyzed with IS-pro, a 16S-23S based bacterial profiling technique. To predict if patients belonged to the asymptomatic diverticulosis or control group a partial least squares discriminant analysis (PLS-DA) regression model was used. Inflammation was assessed by neutrophil and lymphocyte counts within the taken biopsies. Results Forty-three patients were enrolled. Intestinal microbiota profiles were highly similar within individuals for all phyla. Between individuals, microbiota profiles differed substantially but regardless of the presence (n = 19) of absence (n = 24) of diverticula. Microbiota diversity in both sigmoid and transverse colon was similar in all participants. We were not able to differentiate between diverticulosis patients and controls with a PLS-DA model. Mucosal lymphocyte counts were comparable among both groups; no neutrophils were detected in any of the studied biopsies. Conclusions Microbiota composition and inflammatory markers were comparable among asymptomatic diverticulosis patients and controls. This suggests that the gut microbiota and mucosal inflammation do not play a major role in the pathogenesis of diverticula formation