Prediction of malignant behaviour of pheochromocytomas/sympathetic paragangliomas (PCCs/PGLs) is very difficult if not impossible on a histopathological basis. In a familial setting, it is well known that succinate dehydrogenase subunit B (SDHB)-associated PCC/PGL very often metastasise. Recently, absence of SDHB expression as measured through immunohistochemistry was shown to be an excellent indicator of the presence of an SDH germline mutation in PCC/PGL. SDHB loss is believed to lead to tumour formation by activation of hypoxia signals. To clarify the potential use of SDHB immunohistochemistry as a marker of malignancy in PCC/PGL and its association with classic hypoxia signalling we examined SDHB, hypoxia inducible factor-1a (Hif-1a) and its targets CA-9 and GLUT-1 expression on protein level using immunohistochemistry on a tissue micro array on a series of familial and sporadic tumours of 115 patients. Survival data was available for 66 patients. SDHB protein expression was lost in the tumour tissue of 12 of 99 patients. Of those 12 patients, 5 had an SDHB germline mutation, in 4 patients no germline mutation was detected and mutational status remained unknown in parts in 3 patients. Loss of SDHB expression was not associated with increased classic hypoxia signalling as detected by Hif-1a, CA-9 or GLUT-1 staining. Loss of SDHB expression was associated with an adverse outcome. The lack of correlation of SDHB loss with classic hypoxia signals argues against the current hypoxia hypothesis in malignant PCC/PGL. We suggest SDHB protein loss as a marker of adverse outcome both in sporadic and in familial PCC/PGL.

The Bethesda guidelines are useful for selecting patients for microsatellite instability testing. MLH1 and MSH2 testing should be recommended in all patients with colorectal cancer and microsatellite instability who fulfill at least one Bethesda criterion. MLH1 promoter methylation may accompany rather than initiate carcinogenesis in patients with colorectal cancer who have mismatch repair gene defects.

Background Porcine post-weaning diarrhea (PWD) has reemerged as an important topic in pig production, as common control strategies based on prophylactic use of antimicrobials and zinc oxide have been deemed unsustainable. The objectives of this study were to estimate the cumulative incidence of porcine post-weaning diarrhea with different etiologies in production systems weaning without zinc oxide and prophylactic antimicrobials, to assess risk factors for post-weaning diarrhea, and to estimate the impact of post-weaning diarrhea on growth rate. A cohort study was conducted at two commercial indoor producers weaning without medicinal zinc oxide and prophylactic antimicrobials. Results Piglets were included at birth (n = 300) and 272 survived until weaning. After insertion to the nursery units, the piglets were clinically examined every day for 14 days, and rectal swabs were collected and analyzed for enterotoxigenic Escherichia coli (ETEC) and rotavirus A. The cumulative incidences of PWD the first 14 days after insertion to the nursery units were 41.8% (CI 33.6, 50.4) and 51.1% (CI 42.3, 60.0) at the two producers, respectively. We found a low incidence of cases associated to ETEC, and detected a substantial proportion of cases associated to rotavirus. We observed a biphasic pattern in the assumed etiology with rotavirus occurring first, and then a shift towards cases associated to ETEC/non-ETEC hemolytic E. coli. Being offspring of older sows was a protective factor for the development of PWD (Hazard ratio = 0.88 [CI 0.78, 0.99] per unit increase in parity of the dam). Low birth weight reduced the post-weaning growth rate (− 5.2 g/day [CI − 7.5, − 2.9] per 100 g decrease in birthweight) and increased the hazard of developing PWD (Hazard ratio for birthweight below 1100 g: 2.30 [CI 1.41–3.74]). The combined effect of having diarrhea for 2 days or more and receiving antimicrobial treatment was associated with an increased average daily weight gain. Conclusions This study suggests novel insights regarding pathogen dynamics and risk factors for PWD in productions not using prophylactic antimicrobials and medicinal zinc. The findings may have important implications for both antimicrobial usage and prevention strategies.

DNA mismatch repair (MMR) is essential for the maintenance of replication fidelity. Its major task is to recognize mismatches as well as insertion/deletion loops of newly synthesized DNA strands. Although different players of human MMR have been identified, the regulation of essential steps of MMR is poorly understood. Because MMR is initiated in the nucleus, nuclear import might be a mechanism to regulate MMR. Nuclear targeting is accomplished by conserved signal sequences called nuclear localization signals (NLS), which represent clusters of positively charged amino acids (aa). hMLH1 contains two clusters of positively charged amino acids, which are candidate NLS sequences (aa 469-472 and 496-499), while hPMS2 contains one (aa 574-580). To study the effect of these clusters on nuclear import, NLS mutants of hMLH1 and hPMS2 were generated and expressed in 293T cells. The subcellular localization of the mutant constructs was monitored by confocal laser microscopy. We demonstrated that missense mutations of two signal sequences, one in hMLH1 and one in hPMS2, lead to impaired nuclear import, which was especially prominent for mutants of the hMLH1 residues K471 and R472; and hPMS2 residues K577 and R578.