Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer.

BACKGROUND: High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. METHODS: Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. RESULTS: The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5%. Most (93%) of the patients had estrogen receptor (ER) positive tumors (≥ 1% ER+), and 82% had progesterone receptor (PgR) positive tumors (≥ 10% PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (ß 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (ß 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (ß 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (ß 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (ß -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression. CONCLUSION: Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies.

High-density lipoprotein-cholesterol, daily estradiol and progesterone, and mammographic density phenotypes in premenopausal women.

High-density lipoprotein-cholesterol (HDL-C) may influence the proliferation of breast tumor cells, but it is unclear whether low HDL-C levels, alone or in combination with cyclic estrogen and progesterone, are associated with mammographic density, a strong predictor of breast cancer development. Fasting morning serum concentrations of HDL-C were assessed in 202 premenopausal women, 25 to 35 years of age, participating in the Norwegian Energy Balance and Breast Cancer Aspects (EBBA) I study. Estrogen and progesterone were measured both in serum, and daily in saliva, throughout an entire menstrual cycle. Absolute and percent mammographic density was assessed by a computer-assisted method (Madena), from digitized mammograms (days 7-12). Multivariable models were used to study the associations between HDL-C, estrogen and progesterone, and mammographic density phenotypes. We observed a positive association between HDL-C and percent mammographic density after adjustments (P = 0.030). When combining HDL-C, estradiol, and progesterone, we observed among women with low HDL-C (<1.39 mmol/L), a linear association between salivary 17ß-estradiol, progesterone, and percent and absolute mammographic density. Furthermore, in women with low HDL-C, each one SD increase of salivary mid-menstrual 17ß-estradiol was associated with an OR of 4.12 (95% confidence intervals; CI, 1.30-13.0) of having above-median percent (28.5%), and an OR of 2.5 (95% CI, 1.13-5.50) of having above-median absolute mammographic density (32.4 cm(2)). On the basis of plausible biologic mechanisms linking HDL-C to breast cancer development, our findings suggest a role of HDL-C, alone or in combination with estrogen, in breast cancer development. However, our small hypothesis generating study requires confirmation in larger studies.

Gene variations in oestrogen pathways, CYP19A1, daily 17ß-estradiol and mammographic density phenotypes in premenopausal women.

INTRODUCTION: High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women. METHODS: Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17ß-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17ß-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models. RESULTS: The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17ß-estradiol. We observed an 87% lower level of daily 17ß-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m(2)) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm(2)); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)). CONCLUSION: Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.

A statistical framework for the interpretation of mtDNA mixtures: forensic and medical applications.

BACKGROUND: Mitochondrial DNA (mtDNA) variation is commonly analyzed in a wide range of different biomedical applications. Cases where more than one individual contribute to a stain genotyped from some biological material give rise to a mixture. Most forensic mixture cases are analyzed using autosomal markers. In rape cases, Y-chromosome markers typically add useful information. However, there are important cases where autosomal and Y-chromosome markers fail to provide useful profiles. In some instances, usually involving small amounts or degraded DNA, mtDNA may be the only useful genetic evidence available. Mitochondrial DNA mixtures also arise in studies dealing with the role of mtDNA variation in tumorigenesis. Such mixtures may be generated by the tumor, but they could also originate in vitro due to inadvertent contamination or a sample mix-up. METHODS/PRINCIPAL FINDINGS: We present the statistical methods needed for mixture interpretation and emphasize the modifications required for the more well-known methods based on conventional markers to generalize to mtDNA mixtures. Two scenarios are considered. Firstly, only categorical mtDNA data is assumed available, that is, the variants contributing to the mixture. Secondly, quantitative data (peak heights or areas) on the allelic variants are also accessible. In cases where quantitative information is available in addition to allele designation, it is possible to extract more precise information by using regression models. More precisely, using quantitative information may lead to a unique solution in cases where the qualitative approach points to several possibilities. Importantly, these methods also apply to clinical cases where contamination is a potential alternative explanation for the data. CONCLUSIONS/SIGNIFICANCE: We argue that clinical and forensic scientists should give greater consideration to mtDNA for mixture interpretation. The results and examples show that the analysis of mtDNA mixtures contributes substantially to forensic casework and may also clarify erroneous claims made in clinical genetics regarding tumorigenesis.

Fibromyalgia patients' communication of cues and concerns: interaction analysis of pain clinic consultations.

OBJECTIVES: Clinicians' recognition of patients' concerns is an important component of effective treatment and care. During a consultation, patients often do not express their concerns directly, but rather present them indirectly as hints or cues. The aim of this study was to explore the types of concerns and cues patients expressed in an initial consultation with a nurse at a pain clinic, how and who initiated these cues and concerns, and predictors of these expressions. METHODS: Initial consultations between patients with fibromyalgia [n=58, 85% female, duration 30 minutes, mean age 47.8 y (SD 10.7)] and clinical nurse specialists (n=5) were videotaped. Patients' cues and concerns were coded using the Verona Coding Definitions of Emotional Sequences. Nurses' responses to patients' cues and concerns were evaluated using the Hierarchical Coding Scheme of Comforting Strategies. In addition, pain intensity and duration, overall evaluation of health, affect at the start of the consultation, and psychological distress were evaluated. RESULTS: Patients expressed more cues than concerns, mostly about pain, interpersonal relationships, and/or emotional reactions. Both the lack of empathic responding and unspecific empathic responding were associated with the expression of an increased number of cues in the consultation, whereas higher evaluation of health was associated with less cues. More concerns were expressed by patients when nurses exhibited a high level of empathic responding and when the patient entered the consultation with a higher level of negative effect. DISCUSSION: Findings from this study highlight the importance of a patient centered communication style to facilitate the expression of cues and concerns.

Cross-sex hormone treatment does not change sex-sensitive cognitive performance in gender identity disorder patients.

Cognitive performance in untreated early onset gender identity disorder (GID) patients might correspond to their born sex and not to their perceived gender. As a current mode of intervention, cross-sex hormone treatment causes considerable physical changes in GID patients. We asked, as has been suggested, whether this treatment skews cognitive performance towards that of the acquired sex. Somatically healthy male and female early onset GID patients were neuropsychologically tested before, 3 and 12 months after initiating cross-sex hormone treatment, whereas untreated healthy subjects without GID served as controls (C). Performance was assessed by testing six cognitive abilities (perception, arithmetic, rotation, visualization, logic, and verbalization), and controlled for age, education, born sex, endocrine differences and treatment by means of repeated measures analysis of variance. GID patients and controls showed an identical time-dependent improvement in cognitive performance. The slopes were essentially parallel for males and females. There was no significant three-way interaction of born sex by group by time for the six investigated cognitive abilities. Only education and age significantly influenced this improvement. Despite the substantial somatic cross-sex changes in GID patients, no differential effect on cognition over time was found between C and GID participants. The cognitive performance of cross-sex hormone-treated GID patients was virtually identical to that of the control group. The documented test-retest effect should be taken into consideration when evaluating treatment effects generally in psychiatry.

[Regional cerebral perfusion before and after parathyroidectomy]. / Regional cerebral perfusjon før og etter paratyreoidektomi.

BACKGROUND: Single photon emission computerised tomography (SPECT) is used to study cerebral blood-flow and cerebral metabolism in various neuropsychiatric disorders. Reduced regional cerebral blood flow has been demonstrated in patients with depression and chronic fatigue, symptoms that are common in primary hyperparathyroidism. The aim of this study was to reveal possible changes in regional cerebral blood flow in patients with primary hyperparathyroidism before and after operative treatment. METHODS: Prospective study of regional cerebral blood flow in 16 consecutive women of median age 72 (range 50-82 years) using SPECT with 99m Tc-labelled hexamethylpropylenamine oxime. The measurements were performed before and two, four and twelve months after parathyroidectomy. The Montgomery and Asberg depression rating scale (MADRS) was used as a parallel clinical test. RESULTS: Reduced (pathological) regional cerebral blood flow was seen before operation in 14 patients, 13 with solitary adenoma and one with double adenoma. After surgery, this improved to normal values in 13, but was further reduced in one. In two patients with preoperative normal regional cerebral blood flow, both of them asymptomatic and with diffuse hyperplasia, a slight reduction was demonstrated. Eight patients had a pathological preoperative MADRS score, which normalised in seven after surgical treatment. CONCLUSION: The finding of reduced regional cerebral blood flow in patients with primary hyperparathyroidism followed by significant improvement after operation might have bearing upon the case for surgical treatment.