Jörgen Nordenström

Effect of Surgery on Cardiovascular Risk Factors in Mild Primary Hyperparathyroidism

CONTEXT Mild primary hyperparathyroidism (pHPT) seems to have a good prognosis, and indications for active treatment (surgery) are widely discussed. The extraskeletal effects of PTH, such as insulin resistance, arterial hypertension, and cardiovascular (CV) risk, may however be reversible by operation. OBJECTIVE Our aim was to study biochemical markers of bone turnover, indices of the metabolic syndrome, and various risk markers for CV disease in patients with mild pHPT randomized to observation without surgery or operative treatment and followed for 2 yr. DESIGN/SETTING/PATIENTS A total of 116 patients (mean age, 63 +/- 8 yr; 19 men and 97 women) who on May 1, 2008, had performed the 2-yr visit in a randomized study on mild pHPT (serum calcium at baseline, 2.69 +/- 0.11 mmol/liter) and where frozen samples were available from baseline and follow-up participated in the study. RESULTS Calcium and PTH levels were normalized after surgery, and biochemical markers of bone turnover decreased by 35%, followed by a significant increase in BMD in the spine (2.7%; P < 0.01) and femoral neck (1.1%; P < 0.02) compared with the observation group. No significant differences were observed between the groups for blood pressure, markers of insulin resistance, detailed cholesterol metabolism, adipokines, or parameters of inflammation and CV surrogate markers. CONCLUSIONS We observed expected effects on biochemical markers of bone turnover and bone mass after surgical treatment of mild pHPT, with stable values in the group randomized to observation. For a variety of measures of the metabolic syndrome, adipokines, and CV risk factors, no benefit of operative treatment could be demonstrated. Neither did we observe any deleterious effects of conservative management in the 2-yr perspective.

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, p16INK4A and RAR-β 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 p16INK4A was demonstrated in a single adenoma, whereas RAR-β 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.

Building for change: university hospital design for future clinical learning

Abstract Recent developments in the way health care is organized and delivered have rendered many old hospital structures obsolete. The creation of an entire new university hospital for tertiary health care, clinical research and education has made it necessary to discuss and define what pedagogical strategies should be used in this new setting and how physical structures can support learning. Contemporary health care is per se interprofessionally team-based, but most health care education is still performed in silos, separated for each profession. When building a new hospital new possibilities arise to create an interprofessional and learner-centered environment with an adjusted physical infrastructure and spaces for learning. The old hospital conserved highly discipline-based (and professionally isolated) curriculas and didactically oriented; all manifested in the physical environments. However, the New Karolinska University Hospital presents a shift towards a pedagogy characterized by learning centeredness, interprofessionalism clearly expressed in the architecture, design and allocation of spaces within the new buildings. The aim of this article is to highlight the considerations that have been made during the process to design and plan for the new university hospital.

Genome-wide and locus specific alterations in CDC73/HRPT2-mutated parathyroid tumors.

Mutations in the hyperparathyroidism type 2 (HRPT2/CDC73) gene and alterations in the parafibromin protein have been established in the majority of parathyroid carcinomas and in subsets of parathyroid adenomas. While it is known that CDC73-mutated parathyroid tumors display specific gene expression changes compared to CDC73 wild-type cases, the molecular cytogenetic profile in CDC73-mutated cases compared to unselected adenomas (with an expected very low frequency of CDC73 mutations) remains unknown. For this purpose, nine parathyroid tumors with established CDC73 gene inactivating mutations (three carcinomas, one atypical adenoma and five adenomas) were analyzed for copy number alterations and loss of heterozygosity using array-comparative genomic hybridization (a-CGH) and single nucleotide polymorphism (SNP) microarrays, respectively. Furthermore, CDC73 gene promoter methylation levels were assessed using bisulfite Pyrosequencing. The panel included seven tumors with single mutation and three with double mutations of the CDC73 gene. The carcinomas displayed copy number alterations in agreement with previous studies, whereas the CDC73-mutated adenomas did not display the same pattern of alterations at loci frequently deleted in unselected parathyroid tumors. Furthermore, gross losses of chromosomal material at 1p and 13 were significantly (p = 0.012) associated with parathyroid carcinomas as opposed to adenomas. Quantitative PCR-based copy number loss regarding CDC73 was observed in three adenomas, while all the carcinomas were diploid or showed copy number gain for CDC73 gene. Hypermethylation of the CDC73 gene promoter was not observed. Our data could suggest that CDC73-mutated parathyroid adenomas exhibit a partly unique cytogenetic profile in addition to that of carcinomas and unselected adenomas. Furthermore, CDC73-mutated carcinomas displayed losses at 1p and 13 which are not seen in CDC73-mutated adenomas, making these regions of interest for further studies regarding malignant properties in tumors from CDC73-mutated cases. However, due to the small sample size, validation of the results in a larger cohort is warranted.