Parafibromin as a Diagnostic Instrument for Parathyroid Carcinoma-Lone Ranger or Part of the Posse?

The diagnosis of parathyroid carcinoma requires an invasive growth pattern or metastases detected at histopathological examination; unfortunately, not all carcinomas exhibit visible malignant properties at the initial assessment. Therefore, immunohistochemical markers have been sought for the recognition of parathyroid malignancy. In 2003, the Hyperparathyroidism 2 (HRPT2) gene was found mutated in the majority of sporadic parathyroid carcinomas investigated, and studies regarding the protein product parafibromin proposed loss of nuclear parafibromin as a highly sensitive marker for the detection of parathyroid carcinoma. Recent studies have not fully reproduced these findings, as subsets of carcinomas display positive parafibromin immunoreactivity, and fractions of adenomas demonstrate absent expression. Overall, parafibromin is a marker of value to the endocrine pathologist, but it cannot be recommended as a sole indicator of parathyroid carcinoma. Additional markers such as protein gene product 9.5 (PGP9.5) and adenomatous polyposis coli (APC) could complement parafibromin when assessing malignant potential of parathyroid tumours

Synaptonemal Complex Components Persist at Centromeres and Are Required for Homologous Centromere Pairing in Mouse Spermatocytes

Recent studies in simple model organisms have shown that centromere pairing is important for ensuring high-fidelity meiotic chromosome segregation. However, this process and the mechanisms regulating it in higher eukaryotes are unknown. Here we present the first detailed study of meiotic centromere pairing in mouse spermatogenesis and link it with key events of the G2/metaphase I transition. In mouse we observed no evidence of the persistent coupling of centromeres that has been observed in several model organisms. We do however find that telomeres associate in non-homologous pairs or small groups in B type spermatogonia and pre-leptotene spermatocytes, and this association is disrupted by deletion of the synaptonemal complex component SYCP3. Intriguingly, we found that, in mid prophase, chromosome synapsis is not initiated at centromeres, and centromeric regions are the last to pair in the zygotene-pachytene transition. In late prophase, we first identified the proteins that reside at paired centromeres. We found that components of the central and lateral element and transverse filaments of the synaptonemal complex are retained at paired centromeres after disassembly of the synaptonemal complex along diplotene chromosome arms. The absence of SYCP1 prevents centromere pairing in knockout mouse spermatocytes. The localization dynamics of SYCP1 and SYCP3 suggest that they play different roles in promoting homologous centromere pairing. SYCP1 remains only at paired centromeres coincident with the time at which some kinetochore proteins begin loading at centromeres, consistent with a role in assembly of meiosis-specific kinetochores. After removal of SYCP1 from centromeres, SYCP3 then accumulates at paired centromeres where it may promote bi-orientation of homologous centromeres. We propose that, in addition to their roles as synaptonemal complex components, SYCP1 and SYCP3 act at the centromeres to promote the establishment and/or maintenance of centromere pairing and, by doing so, improve the segregation fidelity of mammalian meiotic chromosomes

Frequent Promoter Hypermethylation of the APC and RASSF1A Tumour Suppressors in Parathyroid Tumours

BACKGROUND: Parathyroid adenomas constitute the most common entity in primary hyperparathyroidism, and although recent advances have been made regarding the underlying genetic cause of these lesions, very little data on epigenetic alterations in this tumour type exists. In this study, we have determined the levels of promoter methylation regarding the four tumour suppressor genes APC, RASSF1A, p16(INK4A) and RAR-beta in parathyroid adenomas. In addition, the levels of global methylation were assessed by analyzing LINE-1 repeats. METHODOLOGY/PRINCIPAL FINDINGS: The sample collection consisted of 55 parathyroid tumours with known HRPT2 and/or MEN1 genotypes. Using Pyrosequencing analysis, we demonstrate APC promoter 1A and RASSF1A promoter hypermethylation in the majority of parathyroid tumours (71% and 98%, respectively). Using TaqMan qRT-PCR, all tumours analyzed displayed lower RASSF1A mRNA expression and higher levels of total APC mRNA than normal parathyroid, the latter of which was largely conferred by augmented APC 1B transcription levels. Hypermethylation of p16(INK4A) was demonstrated in a single adenoma, whereas RAR-beta hypermethylation was not observed in any sample. Moreover, based on LINE-1 analyses, parathyroid tumours exhibited global methylation levels within the range of non-neoplastic parathyroid tissues. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that APC and RASSF1A promoter hypermethylation are common events in parathyroid tumours. While RASSF1A mRNA levels were found downregulated in all tumours investigated, APC gene expression was retained through APC 1B mRNA levels. These findings suggest the involvement of the Ras signaling pathway in parathyroid tumorigenesis. Additionally, in contrast to most other human cancers, parathyroid tumours were not characterized by global hypomethylation, as parathyroid tumours exhibited LINE-1 methylation levels similar to that of normal parathyroid tissues

Burnout, working conditions and gender— results from the northern SwedenMONICAStudy,”BMCPublic Health,

Abstract Background: Sick-leave because of mental and behavioural disorders has increased considerably in Sweden since the late nineties, and especially in women. The aim of this study was to assess the level of burnout in the general working population in northern Sweden and analyse it's relation to working conditions and gender. Methods: In this cross-sectional study the survey from the MONICA-study (Monitoring of Trends and Determinants in Cardiovascular Disease) in northern Sweden 2004 was used. A burnout instrument, the Shirom Melamed Burnout Questionnaire (SMBQ), was incorporated in the original survey which was sent to a random sample of 2500 individuals with a response rate of 76%. After including only actively working people, aged 25-64 years, our study population consisted of 1000 participants (497 women and 503 men). ANOVA and multiple linear regression models were used. Results: The prevalence of a high level of burnout (SMBQ >4.0) was 13%. Women had a higher level of burnout than men with the most pronounced difference in the age group 35-44 years. In both sexes the level of burnout decreased with age. Demand and control at work, and job insecurity were related to burnout. In women the level of education, socioeconomic position, work object, and working varying hours were of importance. Interaction effects were found between sex and work object, and sex and working hours. In a multiple regression analysis almost half of the gender difference could be explained by work related and life situational factors. Conclusions: Working life conditions contributed to the level of burnout in this actively working sample from the general population in northern Sweden. Especially in women, socioeconomic position was associated with burnout. The high level of burnout in women compared to men was partly explained by more unfavourable working conditions and life situational factors. Efforts to level out gender differences in burnout should probably focus on improving both working and socioeconomic conditions for women

CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin

Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8(+) Trm cells on a compartmental and functional basis. In human skin epithelia, CD8(+)CD49a(+) Trm cells produced interferon-γ, whereas CD8(+)CD49a(−) Trm cells produced interleukin-17 (IL-17). In addition, CD8(+)CD49a(+) Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8(+)CD49a(+) Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8(+)CD49a(–) Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8(+) Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases

Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study

n/aOriginal Publication:Charlotte M Hoog, Olle Brostrom, Tomas Lindahl, Andreas Hillarp, Gerd Larfars and Urban Sjoqvist, Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study, 2010, BMC GASTROENTEROLOGY, (10), 113.http://dx.doi.org/10.1186/1471-230X-10-113Licensee: BioMed Centralhttp://www.biomedcentral.com