Genetic characterization of large parathyroid adenomas

In this study, we genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated in our institution during 2005–2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P<0.001). Further analysis of 21 LPTAs revealed low MIB1 proliferation index (0.1–1.5%), MEN1 mutations in five cases, and one HRPT2 (CDC73) mutation. Total or partial loss of parafibromin expression was observed in ten tumors, two of which also showed loss of APC expression. Using array CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%), and loss in 11q (33%). Totally, 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11, and 15q and gains in 3q, 5, 7p, 8p, 16q, 17p, and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes most frequently gain of 5 and loss of chromosome 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r=0.48, P=0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

<div><h3>Background</h3><p>Primary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.</p> <h3>Methodology/Principal Findings</h3><p>PRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (<em>PRLR</em>) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In <em>in vitro</em> studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, <em>PRLR</em> gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.</p> <h3>Conclusions</h3><p>We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.</p> </div

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Musik med mening : FMT som stöd i barns utveckling vid skolstart

Barn föds med olika förutsättningar för inlärning. Med MUISK och/eller FMT kan man redan före skolstart se vilka barn som kan komma att behöva extra stöd vid läs- och skrivinlärning och i ett tidigt stadium erbjuda FMT. Med hjälp av Lasse Hjelms utvecklade terapimodell och observationsschema skapas ny förutsättning för att tidigt ringa in vilka insatser som kan vara till gagn för barnet. FMT är en bland andra insatser, i den mån skolan kan erbjuda detta. I det här arbetet beskriver jag en del av den praktik jag gjort i grundskolans år ett till tre. Mina studier har visat att FMT kan stärka barns tilltro till sin egen förmåga. Att de vågar ta egna initiativ och får uppleva känslan av att lyckas, stärker deras självkänsla och har i sin tur en positiv inverkan på skolarbetet

Primary Hyperparathyroidism : A Study of Cardiovascular Dysfunction and its Reversibility After Parathyroidectomy

Cardiovascular risk in primary hyperparathyroidism (HPT) is controversial, and studies mainly from Europe associate HPT with increased cardiovascular morbidity and mortality. Cardiovascular morphology and function were evaluated prospectively in 31 consecutive HPT patients (mean serum calcium 2.97±0.04) and randomly enrolled controls matched for age and sex. Patients were re-examined at normocalcemia about one year after parathyroidectomy. HPT patients showed an operatively reversible disturbance in endothelial vasodilatory function that seemed unrelated to an early sign of atherosclerosis, i.e. thickness of carotid artery intima-media complex. Acute hypercalcemia in healthy subjects induced a similar impairment in endothelial function, which suggests a dependence on biochemical rather than structural vascular changes in HPT. Echocardiography showed left ventricular diastolic dysfunction and supernormal systolic performance being reversed after operation. Left ventricular mass tended to be irreversibly increased. During exercise HPT patients exhibited greater rise in systolic blood pressure compared to controls and an increased number of premature ventricular beats. This indicated increased work load and a propensity for fatal cardiac events. Following surgery, an improvement with less pronounced ST-segment depression was seen. 24-hour ambulatory blood pressure monitoring showed irreversibly increased levels despite maintained diurnal rhythm, while 24-hour heart rate variability analysis displayed blunted nocturnal increase of low and very low frequency bands that was corrected postoperatively. Parathyroidectomy seems to alleviate most of the cardiovascular disturbances in HPT, except for hypertension. This is consistent with the normalised longevity in HPT treated with parathyroidectomy and supports active treatment of HPT

Effects of primary hyperparathyroidism on oral health. A longitudinal register-based study

Objectives: To analyze the effects of primary hyperparathyroidism on oral health and to investigate if the effects are linked to severity of the disease.Subjects and Methods: This prospective cohort study involved 6151 primary hyperparathyroidism patients registered in the Scandinavian Quality Registry of Thyroid, Parathyroid, and Adrenal surgery and the National Cancer Register after parathyroidectomy (exposure) during 2011-2017 (patient cohort) and 60,654 individuals without primary hyperparathyroidism (reference cohort), matched by age, gender, and county of resident at the date of parathyroidectomy. The outcomes were tooth extractions and periodontal interventions. The risk for the outcomes was assessed by Poisson regression models.Results: After adjusting for covariates, the patient cohort had a higher incidence rate of tooth extraction during the two-year period after parathyroidectomy (IRR = 1.15; 95% CI = 1.01-1.31), but a lower incidence rate of periodontal interventions during the four- to six-year period after parathyroidectomy (IRR = 0.88; 95% CI = 0.79-0.99). Furthermore, patients with more severe primary hyperparathyroidism were more likely to have tooth extractions and periodontal interventions after parathyroidectomy.Conclusions: The risk of tooth extraction increased slightly during the first two years after parathyroidectomy. Thereafter, the oral health effects subsided. Pre-surgical serum ionized calcium levels and adenoma weight may indicate negative dental outcomes after parathyroidectomy.Peer reviewe

The preoperative localisation of small parathyroid adenomas improves when adding Tc-99m-Sestamibi SPECT to multiphase contrast-enhanced CT

Objectives To investigate the incremental value of Sestamibi SPECT combined with a non-enhanced and contrast-enhanced CT, using SPECT/CT, for the preoperative localisation of small parathyroid adenomas (PTA). Methods Retrospectively, 147 patients surgically cured from primary hyperparathyroidism, as verified by biochemistry 6 months postoperatively, were included. All patients had preoperatively undergone a dual time 99mTechnetium-Sestamibi SPECT (S) with multiphase CT including native (N), arterial (A) and venous (V) phases. Independently, two radiologists blinded from both the surgical and the preoperative imaging reports, sequentially performed PTA localisation starting with either [A] or [V], thereafter [A + N] or [V + N] and finally with the complete [A + N + S] or [V + N + S]. PTA localisation was reported for each image-set. The readers results were combined and the diagnostic performance for each image set was determined. Sensitivity was also calculated for the different quartiles of PTA weight distribution. Results The median adenoma weight was 315 mg. No statistically significant differences in diagnostic performance between arterial and venous based image sets were found. The net effect of adding [N] was to increase specificity. Sestamibi SPECT significantly increased the overall diagnostic accuracy for arterial- and venous-based image sets, p = 0.0008 and p = 0.001, respectively. [A + N + S] was found to have the highest diagnostic performance with 86.5% sensitivity and 94.9% overall accuracy. [A + N + S] was particularly advantageous for locating PTA in the lower weight quartiles. Conclusions Native CT-phase and dual time point Sestamibi SPECT increase specificity and sensitivity, respectively. These, in combination with a single contrast-enhanced CT-phase is the most optimal examination protocol for preoperative localisation of PTA using SPECT/CT

Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib

The ATP-regulated K+ channel (KATP) plays an essential role in the control of many physiological processes, and contains a ATP-binding site. Tyrosine kinase inhibitors (TKI) are commonly used drugs, that primarily target ATP-binding sites in tyrosine kinases. Herein, we used the patch-clamp technique to examine the effects of three clinically established TKIs on KATP channel activity in isolated membrane patches, using a pancreatic β-cell line as a KATP channel source. In excised inside-out patches, the activity of the KATP channel was dose-dependently inhibited by imatinib with half-maximal concentration of approximately 9.4 μM. The blocking effect of imatinib was slow and reversible. No effect of imatinib was observed on either the large (KBK) or the small (KSK) conductance, Ca2+-regulated K+ channel. In the presence of ATP/ADP (ratio 1) addition of imatinib increased channel activity approximately 1.5-fold. Sunitinib and nilotinib were also found to decrease KATP channel activity. These findings are compatible with the view that TKIs, designed to interact at the ATP-binding pocket on the tyrosine receptor, also interact at the ATP-binding site on the KATP channel. Possibly, this might explain some of the side effects seen with TKIs.National Institute of Biomedical Imaging and BioengineeringOpen access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]