Primary Hyperparathyroidism Influences the Expression of Inflammatory and Metabolic Genes in Adipose Tissue

Background: Primary hyperparathyroidism (PHPT) is characterised by increased production of parathyroid hormone (PTH) resulting in elevated serum calcium levels. The influence on bone metabolism with altered bone resorption is the most studied clinical condition in PHPT. In addition to this, patients with PHPT are at increased risk of non-skeletal diseases, such as impaired insulin sensitivity, arterial hypertension and increased risk of death by cardiovascular diseases (CVD), possibly mediated by a chronic low-grade inflammation. The aim of this study was to investigate whether adipose tissue reflects the low-grade inflammation observed in PHPT patients. Methodology/Principal Findings: Subcutaneous fat tissue from the neck was sampled from 16 non-obese patients with PHPT and from 16 patients operated for benign thyroid diseases, serving as weight-matched controls. RNA was extracted and global gene expression was analysed with Illumina BeadArray Technology. We found 608 differentially expressed genes (q-value,0.05), of which 347 were up-regulated and 261 were down-regulated. Gene ontology analysis showed that PHPT patients expressed increased levels of genes involved in immunity and defense (e.g. matrix metallopeptidase 9, S100 calcium binding protein A8 and A9, CD14, folate receptor 2), and reduced levels of genes involved in metabolic processes. Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes. Conclusions/Significance: Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD

Allmennprevensjon i straffeutmålingen : hvorvidt Høyesteretts bruk og vektlegging av allmennpreventive hensyn i straffeutmålingsvurderingen gjenspeiler noen utvalgte presumsjoner for hvordan allmennprevensjonens funksjoner påvirkes

Avhandlingens tema er allmennprevensjon i straffeutmålingen. Problemstillingen som herunder er valgt, er å undersøke om Høyesteretts bruk og vektlegging av allmennpreventive hensyn i straffeutmålingsvurderingen gjenspeiler noen utvalgte presumsjoner for hvordan allmennprevensjonens funksjoner påvirkes. Presumsjonene skal utledes av en redegjørelse for allmennprevensjonens begrunnelse og funksjoner. Presumsjonene som er valgt for hvordan allmennprevensjonens funksjoner påvirkes: For det første hvorvidt den straffbare adferd er umoralsk. Videre om oppdagelsesrisikoen for den straffbare adferd er lav. Dernest hvor lang tid som er gått siden den straffbare adferd fant sted, og endelig hvilke hensyn som gjør seg særskilt gjeldende på noen utvalgte strafferettslige områder og typetilfeller. Presumsjonene tilsier hvordan allmennpreventive hensyn skal vektlegges i en straffeutmålingsvurdering. Det vil derfor være av interesse å undersøke om dette gjenspeiles i Høyesteretts avgjørelser. For å muliggjøre en slik undersøkelse er det hensiktsmessig at oppgaven deles i to. Det skal derfor først gis en oversikt over de mer grunnleggende aspektene ved allmennprevensjons innhold i strafferettslig sammenheng. Dette vil gjøres i del 2. Hensikten med å først gi en slik grundig teoretisk fremstilling er for det første å underbygge de her utvalgte presumsjoner, og for det andre å legge til rette for en undersøkelse av om Høyesteretts bruk og vektlegging stadfester, forkaster eller nyanserer antakelsene. Undersøkelsen skal deretter foretas i del 3

Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels

PURPOSE: To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor-positive breast cancers. EXPERIMENTAL DESIGN: Breast cancer tissue samples were collected before and following 4 months of neoadjuvant therapy with letrozole (2.5 mg o.d.), and tissue estrogen levels measured using a highly sensitive RIA after high-pressure liquid chromatography purification. RESULTS: Letrozole suppressed pretreatment tumor levels of E(2), E(1), and E(1)S by 97.6%, 90.7%, and 90.1%, respectively. These data reveal that letrozole suppresses tissue estrogen levels significantly below what has previously been recorded with anastrozole (89.0%, 83.4%, and 72.9% suppression, respectively) using the same methods. To confirm the differential effect of letrozole and anastrozole on each plasma estrogen fraction, we re-analyzed plasma samples obtained from a previous intrapatient cross-over study comparing letrozole and anastrozole using an improved RIA (detection limits of 0.67, 1.14, and 0.55 pmol/L for E(2), E(1), and E(1)S, respectively). Letrozole consistently suppressed each plasma estrogen fraction below the levels recorded for anastrozole: E(2) (average suppression by 95.2% versus 92.8%; P = 0.018), E(1) (98.8% suppression versus 96.3%; P = 0.003), and E(1)S (98.9% suppression versus 95.3%; P = 0.003). CONCLUSION: Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer

Patients divided into tertiles according to serum levels of PTH.

<p>Values are given as mean (standard deviation) or median (25th–75th percentile). PTH, 1,25(OH)₂D and ALP were log-transformed before used in the analyses. BMI, body mass index; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone; iCa, ionised calcium; APL, alkaline phosphatase; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; eGFR, estimated glomerular filtration rate; BMD, bone mineral density. P-values for linear trend over tertiles.</p>a<p>Values are numbers (percentages), differences across tertiles are assessed with a chi-square test.</p>d<p>Age, BMI and gender were used as covariates.</p

Relations between the genotype variations of the SNPs studied and bone mineral density in lumbar spine, femoral neck and distal radius.

<p>SNP, single nucleotide polymorphism; VDR, vitamin D receptor.</p>1<p>p-values are based on linear regression with age, gender and body mass index as covariates. Minor allele considered as dominant.</p>2<p>p-values are based on linear regression with age, gender and body mass index as covariates. Minor allele considered as recessive. After Bonferroni-correction a p-value <0.007 is considered to be statistically significant.</p

Patients divided into tertiles according to serum levels of 1,25(OH)₂D.

<p>Values are given as mean (standard deviation) or median (25th–75th percentile). PTH, 1,25(OH)₂D and ALP were log-transformed before used in the analyses. BMI, body mass index; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone; iCa, ionised calcium; APL, alkaline phosphatase; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; eGFR, estimated glomerular filtration rate; BMD, bone mineral density. P-values for linear trend over tertiles.</p>a<p>Values are numbers (percentages), differences across tertiles are assessed with a chi-square test.</p>d<p>Age, BMI and gender were used as covariates.</p

Vitamin D metabolism.

<p>1,25(OH)₂D and PTH influence vitamin D metabolism by positive (+) or negative (−) regulation of the activity of the 1α-hydroxylase and the 24-hydroxylase. 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 24,25(OH)₂D, 24,25-dihydroxyvitamin D; 1,24,25(OH)₃D, 1,24,25-trihydroxyvitamin D.</p

Patients divided into tertiles according to serum levels of 25(OH)D.

<p>Values are given as mean (standard deviation) or median (25th–75th percentile). PTH, 1,25(OH)₂D and ALP were log-transformed before used in the analyses. BMI, body mass index; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone; iCa, ionised calcium; APL, alkaline phosphatase; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; eGFR, estimated glomerular filtration rate; BMD, bone mineral density. P-values for linear trend over tertiles.</p>a<p>Values are numbers (percentages), differences across tertiles are assessed with a chi-square test.</p>b<p>Age was used as covariate.</p>c<p>Age and BMI were used as covariates.</p>d<p>Age, BMI and gender were used as covariates.</p

Selected SNPs analysed in 52 individuals with primary hyperparathyroidism.

<p>Only samples without missing values were included in the analyses. P-values for Hardy Weinberg equilibrium are based on a chi-squared test. SNP, single nucleotide polymorphism; HWE, Hardy Weinberg equilibrium; VDR, vitamin D receptor.</p