SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression.

Puberty is regulated by epigenetic mechanisms and is highly sensitive to metabolic and nutritional cues. However, the epigenetic pathways mediating the effects of nutrition and obesity on pubertal timing are unknown. Here, we identify Sirtuin 1 (SIRT1), a fuel-sensing deacetylase, as a molecule that restrains female puberty via epigenetic repression of the puberty-activating gene, Kiss1. SIRT1 is expressed in hypothalamic Kiss1 neurons and suppresses Kiss1 expression. SIRT1 interacts with the Polycomb silencing complex to decrease Kiss1 promoter activity. As puberty approaches, SIRT1 is evicted from the Kiss1 promoter facilitating a repressive-to-permissive switch in chromatin landscape. Early-onset overnutrition accelerates these changes, enhances Kiss1 expression and advances puberty. In contrast, undernutrition raises SIRT1 levels, protracts Kiss1 repression and delays puberty. This delay is mimicked by central pharmacological activation of SIRT1 or SIRT1 overexpression, achieved via transgenesis or virogenetic targeting to the ARC. Our results identify SIRT1-mediated inhibition of Kiss1 as key epigenetic mechanism by which nutritional cues and obesity influence mammalian puberty.

Thermal ablation of a confluent lesion in the porcine kidney with a clinically available MR-HIFU system.

The incidence of small renal masses (SRMs) sized <4 cm has increased over the decades (as co-findings/or due to introduction of cross sectional imaging). Currently, partial nephrectomy (PN) or watchful waiting is advised in these patients. Ultimately, 80-90% of these SRMs require surgical treatment and PN is associated with a 15% complication rate. In this aging population, with possible comorbidities and poor health condition, both PN and watchful waiting are non-ideal treatment options. This resulted in an increased need for early, non-invasive treatment strategies such as MR-guided high intensity focused ultrasound (MR-HIFU). (i) To investigate the feasibility of creating a confluent lesion in the kidney using respiratory-gated MR-HIFU under clinical conditions in a pre-clinical study and (ii) to evaluate the reproducibility of the MR-HIFU ablation strategy. Healthy pigs (n = 10) under general anesthesia were positioned on a clinical MR-HIFU system with integrated cooling. A honeycomb pattern of seven overlapping ablation cells (4 × 4 × 10 mm3, 450 W, <30 s) was ablated successively in the cortex of the porcine kidney. Both MR thermometry and acoustic energy delivery were respiratory gated using a pencil beam navigator on the contralateral kidney. The non-perfused volume (NPV) was visualized after the last sonication by contrast-enhanced (CE) T 1-weighted MR (T 1 w) imaging. Cell viability staining was performed to visualize the extent of necrosis. RESULTS: a median NPV of 0.62 ml was observed on CE-T 1 w images (IQR 0.58-1.57 ml, range 0.33-2.75 ml). Cell viability staining showed a median damaged volume of 0.59 ml (IQR 0.24-1.35 ml, range 0-4.1 ml). Overlooking of the false rib, shivering of the pig, and too large depth combined with a large heat-sink effect resulted in insufficient heating in 4 cases. The NPV and necrosed volume were confluent in all cases in which an ablated volume could be observed. Our results demonstrated the feasibility of creating a confluent volume of ablated kidney cortical tissue in vivo with MR-HIFU on a clinically available system using respiratory gating and near-field cooling and showed its reproducibility.

The diagnostic performance of 18F-FDG PET/CT, CT and MRI in the treatment evaluation of ablation therapy for colorectal liver metastases: A systematic review and meta-analysis.

PURPOSE: Uncertainty exists regarding the optimal imaging modality for timely detection of disease progression (DP) after ablation therapy for colorectal liver metastases. We evaluated the diagnostic accuracy of 18F-FDG PET(/CT), CT and MRI for detection of DP following ablation therapy. METHODS: A systematic search was performed on May 18, 2016. The analysis included studies that reported on the diagnostic accuracy of 18F-FDG PET(/CT), CT and/or MRI for post-ablative evaluation of patients with liver metastases. Primary outcome was the diagnostic accuracy of the imaging modalities for detection of DP. Methodological quality was assessed using the QUADAS-2 tool. Pooled sensitivities and specificities were estimated using bivariate random-effects models. RESULTS: Ten studies were included in the meta-analysis, including seven comparative studies. Nine reported data on diagnostic accuracy of 18F-FDG PET(/CT), seven on CT imaging. Only two studies reported the diagnostic accuracy of MRI, hence not included in the meta-analysis. Quality assessment raised concerns about the risk of bias regarding the use of the reference standard, blinding of the index tests and the follow-up time. Pooled sensitivity was respectively 84.6% (75.0-90.6) and 53.4% (29.0-76.4) for 18F-FDG PET(/CT) and CT (P = 0.005). Pooled specificity was respectively 92.4% (86.5-95.9) and 95.7% (87.5-98.6) (P = 0.392). CONCLUSION: 18F-FDG PET/(CT) yields a higher sensitivity for detecting DP after ablation therapy compared with CT and has a comparably high specificity. These findings indicate that the use of 18F-FDG PET(/CT) in this setting particularly allows for minimization of the false-negative rate compared with CT without compromising the low false-positive rate.

Moderate-to-deep sedation technique, using propofol and ketamine, allowing synchronised breathing for magnetic resonance high-intensity focused ultrasound (MR-HIFU) treatment for uterine fibroids: a pilot study.

BACKGROUND: Magnetic resonance high-intensity focused ultrasound (MR-HIFU) treatment for uterine fibroids is rapidly gaining popularity as a treatment modality. This procedure is generally uncomfortable, painful, and requires minimal or absence of movement and an MR-HIFU synchronised breathing pattern of the patient. Procedural sedation and analgesia protocols have become the standard practice in interventional radiology departments worldwide. The aim of this study was to explore if a sedation regimen with low-dose propofol and ketamine performed by trained non-medical sedation practitioners could result in relief of discomfort for the patient and in adequate working conditions for MR-HIFU treatment for uterine fibroids. METHODS: In this study, conducted from August 2013 until November 2014, 20 patients were subjected to MR-HIFU treatment of uterine fibroids. Patients were deeply sedated using intravenous propofol and esketamine according to a standardised hospital protocol to allow synchronisation of the breathing pattern to the MR-HIFU. The quality of sedation for MR-HIFU and complications were recorded and analysed. The side effects of the sedation technique, the propofol and esketamine consumption rate, the duration of recovery, and patient satisfaction after 24 h were examined. RESULTS: A total of 20 female patients (mean age 42.4 [range 32-53] years) were enrolled. Mean propofol/esketamine dose was 1309 mg/39.5 mg (range 692-1970 mg/ 23.6-87.9 mg). Mean procedure time was 269 min (range 140-295 min). Application of the sedation protocol resulted in a regular breathing pattern, which could be synchronised with the MR-HIFU procedures without delay. The required treatment was completed in all cases. There were no major adverse events. Hypoxemia (oxygen desaturation <92%) and hallucinations were not observed. CONCLUSIONS: The use of a specific combination of IV propofol and esketamine for procedural sedation and analgesia reduced the discomfort and pain during MR-guided HIFU treatments of uterine fibroids. The resulting regular breathing pattern allowed for easy synchronisation of the MR-HIFU procedure. Based on our results, esketamine and propofol sedation performed by trained non-medical sedation practitioners is feasible and safe, has a low risk of major adverse events, and has a short recovery time, avoiding a session of general anaesthesia.

18F-FDG PET as novel imaging biomarker for disease progression after ablation therapy in colorectal liver metastases.

PURPOSE: Recurrent disease following thermal ablation therapy is a frequently reported problem. Preoperative identification of patients with high risk of recurrent disease might enable individualized treatment based on patients' risk profile. The aim of the present work was to investigate the role of metabolic parameters derived from the pre-ablation 18F-FDG PET/CT as imaging biomarkers for recurrent disease in patients with colorectal liver metastases (CLM). METHODS: Included in this retrospective study were all consecutive patients with CLM treated with percutaneous or open thermal ablation therapy who had a pre-treatment baseline 18F-FDG PET/CT available. Multivariable cox regression for survival analysis was performed using different models for the metabolic parameters (SULpeak, SULmean, SULmax, partial volume corrected SULmean (cSULmean), and total lesion glycolysis (TLG)) corrected for tumour and procedure characteristics. The study endpoints were defined as local tumour progression free survival (LTP-FS), new intrahepatic recurrence free survival (NHR-FS) and extrahepatic recurrence free survival (EHR-FS). Clinical and imaging follow-up data was used as the reference standard. RESULTS: Fifty-four patients with 90 lesions were selected. Univariable cox regression analysis resulted in eight models. Multivariable analysis revealed that after adjusting for lesion size and the approach of the procedure, none of the metabolic parameters were associated with LTP-FS or EHR-FS. Percutaneous approach was significantly associated with a shorter LTP-FS. It was demonstrated that lower values of SULpeak, SULmax, SULmean , and cSULmean are associated with a significant better NHR-FS, independent of the lesion size and number and prior chemotherapy. CONCLUSION: We found no association between the metabolic parameters on pre-ablation 18F-FDG PET/CT and the LTP-FS. However, low values of the metabolic parameters were significantly associated with improved NHR-FS. The clinical implication of these findings might be the identification of high-risk patients who might benefit most from adjuvant or combined treatment strategies.

Yttrium-90 radioembolization for colorectal cancer liver metastases: a prospective cohort study on circulating angiogenic factors and treatment response.

BACKGROUND: Yttrium-90 radioembolization (90Y-RE) as a treatment for liver tumours induces radiation damage and hypoxia in liver tissue, which is also a trigger for systemic release of angiogenic factors, potentially stimulating tumour growth. We examined changes in circulating angiogenic factors following 90Y-RE and investigated the association between response and angiogenic factors. In this prospective study, 42 patients with unresectable, chemorefractory metastatic colorectal cancer (CRCLM) were treated with 90Y-RE. Blood samples were collected pre-treatment and at 0, 1, 3, 7 and 30 days of follow-up. Response was measured with MRI according to RECIST 1.1 at 1 month and subsequently 3-month interval until progressive disease (PD) occurred. Associations between circulating angiogenic factors and response were examined with linear mixed model analysis. RESULTS: Following 90Y-RE, three angiogenic factors demonstrated an increase in plasma levels, i.e., vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and angiopoietin-2 (Ang-2). Non-responders (= PD at 1-month follow-up, n = 10) had a significant increase of Ang-2 and HGF at 3 and 7 days post treatment compared to responders (= stable disease or better, n = 32), who showed little to no changes in plasma levels (respectively p = 0.01 and p = 0.007). Median overall survival was 9.2 months (95% confidence interval 6.1-12.4). CONCLUSIONS: Significant increases in plasma levels of Ang-2 and HGF in the first week after treatment were associated with rapid progressive disease of liver lesions at 1 month after 90Y-RE. Combination of 90Y-RE with anti-angiogenic therapy may reduce these effects and result in better response.

The role of 90Y-radioembolization in downstaging primary and secondary hepatic malignancies: a systematic review.

Radioembolization (RE) is an emerging treatment strategy for patients with primary hepatic malignancies and metastatic liver disease. Though RE is primarily performed in the palliative setting, a shift toward the curative setting is seen. Currently, hepatic resection and in selected cases liver transplantation are the only curative options for patients with a hepatic malignancy. Unfortunately, at diagnosis most patients are not eligible for liver surgery due to the imbalance between the necessary liver resection and the remaining liver remnant. However, in borderline resectable cases, tumor volume reduction and/or increasing the future liver remnant can lead to a resectable situation. The combination of selective tumor treatment, the induction of hypertrophy of untreated liver segments, and its favourable toxicity profile make RE an appealing strategy for downstaging. The present review discusses the possibilities for RE in the preoperative setting as a downstaging tool or as a bridge to liver transplantation.

Meta-analysis of the concordance of histological grade of breast cancer between core needle biopsy and surgical excision specimen.

BACKGROUND: With the increasing use of neoadjuvant chemotherapy and minimally invasive ablative therapy in breast cancer, pretreatment assessment of tumour grade on core needle biopsy (CNB) is increasingly needed. However, grading on CNB is possibly less accurate than grading based on the surgical excision specimen. A systematic review and meta-analysis of the literature was conducted to derive a reliable estimate of the agreement in tumour grading between CNB and subsequent surgical excision. METHODS: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria, Embase, PubMed and the Cochrane Library were searched. Pooled proportions of agreement in grading between CNB and the excision specimen, Cohen's κ and percentages of overestimation and underestimation were calculated. Random-effects models were applied because of substantial heterogeneity, assessed by I2 test. Determinants of the level of agreement in grading were explored with meta-regression. RESULTS: Thirty-four articles were included in the systematic review (6029 patients) and 33 in the meta-analysis (4980 patients). Pooled agreement and κ were 71·1 (95 per cent c.i. 68·8 to 73·3) per cent and 0·54 (0·50 to 0·58) respectively. Underestimation and overestimation occurred in 19·1 (17·1 to 21·3) and 9·3 (7·7 to 11·4) per cent respectively. Meta-regression showed associations between agreement of histological type (positive association) and proportion of patients with oestrogen receptor-positive disease (negative association) and grade agreement. CONCLUSION: Grading on CNB corresponds moderately with grading based on excision specimens, with underestimation in about one in five patients. Incorrect CNB tumour grading has limited clinical implications, as multiple factors influence decision-making for adjuvant systemic therapy.

Performance analysis of a dedicated breast MR-HIFU system for tumor ablation in breast cancer patients.

MR-guided HIFU ablation is a promising technique for the non-invasive treatment of breast cancer. A phase I study was performed to assess the safety and treatment accuracy and precision of MR-HIFU ablation in breast cancer patients (n=10) using a newly developed MR-HIFU platform dedicated to applications in the breast. In this paper a technical analysis of the performance of the dedicated breast MR-HIFU system during breast tumors ablation is described. The main points of investigation were the spatial targeting accuracy and precision of the system and the performance of real-time respiration-corrected MR thermometry.The mean targeting accuracy was in the range of 2.4-2.6 mm, whereas the mean targeting precision was in the range of 1.5-1.8 mm. To correct for respiration-induced magnetic field fluctuations during MR temperature mapping a look-up-table (LUT)-based correction method was used. An optimized procedural sedation protocol in combination with the LUT-based correction method allowed for precise MR thermometry during the ablation procedure (temperature standard deviation <3 °C). No unwanted heating in the near field (i.e. skin) nor in the far field (pectoral muscle) was detected.The newly developed dedicated breast MR-HIFU system allows for safe, accurate and precise ablation of breast tumors.

Effectiveness of Repeat Radiotherapy for Painful Bone Metastases in Clinical Practice: A 10 Year Historical Cohort Study.

AIMS: Repeat radiotherapy for palliation of painful bone metastases is often prescribed to non-responders or those with recurrent pain, although studies on retreatment remain scarce. We assessed the effectiveness of retreatment for painful bone metastases in terms of pain relief in everyday clinical practice and identified factors associated with response. MATERIALS AND METHODS: We carried out a single-institution 10 year retrospective cohort study among 247 patients retreated for painful bone metastases. Response was defined as a decrease in pain between 2 and 12 weeks after retreatment. The overall pain response rate was calculated in an evaluable-patients-only analysis and a worst-case analysis. Multivariate logistic regression analyses were used to identify factors associated with pain response. RESULTS: A follow-up of ≥2 weeks was available in 162 of 247 patients (65%). The overall pain response was 66% (95% confidence interval 58-73%) in an evaluable-patients-only analysis and 43% (95% confidence interval 37-50%) in a worst-case analysis. Response to first irradiation (odds ratio 2.16, P = 0.049) and use of systemic therapy (odds ratio 0.39, P = 0.037) were independently associated with the response to retreatment. The median overall survival was 7.1 months. CONCLUSION: In everyday clinical practice, retreatment for painful bone metastases leads to pain reduction in 66% of evaluable patients and 43% of patients in a worst-case analysis. Patients who responded to initial radiotherapy were more likely to respond again and those on systemic therapy were less likely to respond. Overall, repeat radiotherapy should be considered in patients with persisting bone pain.

Sentinel lymph node localization with contrast-enhanced ultrasound and an I-125 seed: an ideal prospective development study.

INTRODUCTION: Our aim was to evaluate the development of microbubble-enhanced sentinel lymph node (SLN) localization with placement of an I-125 seed in breast cancer patients as a potential alternative for SLN localization with nanocolloid. The study is conducted and reported following the IDEAL recommendations for evaluation of a new technique at Stage 2a (Prospective Development Study). METHODS: Fourteen consecutive patients with 15 lesions underwent microbubble-enhanced SLN localization with placement of an I-125 seed after the standard SLN localization (nanocolloid). We placed an I-125 seed within or near the SLN following its identification using intradermally injected microbubbles. The SLN was excised guided by nanocolloid and the SLN containing the I-125 seed was searched for. All technical modifications are described and standardized outcomes measured. RESULTS: Twelve (80%) microbubble procedures with I-125 seed placements were technically successful. In three cases no microbubble-enhancing lymph node could be detected. Intraoperatively, we found nine I-125 seeds within 0.5 cm of the nanocolloid confirmed SLN. One I-125 seed was found next to a non-SLN and two I-125 seeds were not near any lymph node. Overall, the procedure was successful in 60% (9 out of 15) of the cases. CONCLUSION: Given the low success rate, we conclude that microbubble-enhanced SLN is not a viable alternative to the standard SLN procedure. Modifications to this technique did not improve its performance. Planned study (NTR3690 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3690) was stopped early due to this conclusion and results reported in order to provide a full and transparent record of the evolution of technique.

Prediction of positive resection margins in patients with non-palpable breast cancer.

BACKGROUND: In patients undergoing breast conserving surgery for non-palpable breast cancer, obtaining tumour free resection margins is important to prevent reexcision and local recurrence. We developed a model to predict positive resection margins in patients undergoing breast conserving surgery for non-palpable invasive breast cancer. METHODS: A total of 576 patients with non-palpable invasive breast cancer underwent breast conserving surgery in five hospitals in the Netherlands. A prediction model for positive resection margins was developed using multivariate logistic regression. Calibration and discrimination of the model were assessed and the model was internally validated by bootstrapping. RESULTS: Positive resection margins were present in 69/576 (12%) patients. Factors independently associated with positive resection margins included mammographic microcalcifications (OR 2.14, 1.22-3.77), tumour size (OR 1.75, 1.20-2.56), presence of DCIS (OR 2.61, 1.41-4.82), Bloom and Richardson grade 2/3 (OR 1.82, 1.05-3.14), and caudal location of the lesion (OR 2.4, 1.35-4.27). The model was well calibrated and moderately able to discriminate between patients with positive versus negative resection margins (AUC 0.70, 95% CI, 0.63-0.77, and 0.69 after internal validation). CONCLUSION: The presented prediction model is moderately able to differentiate between women with high versus low risk of positive margins, and may be useful for surgical planning and preoperative patient counselling.

Simultaneous R2*, R2, and R2' quantification by combining S0 estimation of the free induction decay with a single spin echo: A single acquisition method for R2 insensitive quantification of holmium-166-loaded microspheres.

PURPOSE: To present a new method, S0 estimation of the free induction decay combined with a single spin echo measurement (SOFIDSE), that enables simultaneous measurements of R2*, R2, and R2' in order to quantify the local concentration of holmium microspheres (Ho-MS) for radioembolization. THEORY AND METHODS: SOFIDSE estimates R2* and the signal magnitude at time point 0, S0, from a multigradient echo readout of the free induction decay and subsequently estimates R2 using S0 and a single spin echo, from which R2' is deducted. The method was evaluated by comparing SOFIDSE R2 values with values obtained from shifted spin echo (SSE) measurements on a phantom setup containing Ho-MS and from dual spin echo measurements on a healthy volunteer. RESULTS: On average, SOFIDSE showed a small overestimation of R2 values compared with SSE independent of the microsphere concentration. R2' values determined by subtraction of either SOFIDSE R2 or SSE R2 from R2* showed excellent agreement (correlation coefficient = 1; P = 9 · 10(-11)). The Ho-MS-induced R2' values obtained by SOFIDSE were insensitive to the R2 value of the tissue in which they resided. CONCLUSION: SOFIDSE enables quantification of Ho-MS, in media with spatially or temporally varying R2 values, in a single acquisition.

Feasibility of reducing the maximum shelf life of red blood cells stored in additive solution: a dynamic simulation study involving a large regional blood system.

BACKGROUND AND OBJECTIVE: Recent studies suggest that transfusion of old red blood cell (RBC)s, mainly those close to the 42-day maximum shelf life (MSL), is associated with increased morbi-mortality. Although there is no formal proof supporting a causal relationship, the precautionary principle asks for corrective interventions whenever they do not bring about other risks or unjustified costs. Here, we investigated the feasibility of reducing the MSL. MATERIALS AND METHODS: A trace simulation model was used to analyse the repercussions of several MSLs on a large regional blood system. The baseline model was fed with real input and output data from years 2009 to 2010 and validated against real inventory data. Shortage and outdate rates and inventory levels for each blood group were derived assuming 42-, 35-, 28-, 21- and 14-day MSLs, as well as several distribution rules and supply shocks (periods without blood collections). RESULTS: The model shows that MSL could be reduced to 28-35 days without major increases in the shortage or outdate rates, even after supply shocks. At the 21-day MSL, the inventory capability to compensate supply shocks was severely reduced and translated into large shortage rates. The later were higher for group O and Rh-negative RBCs as compared to group A and Rh-positive, respectively. CONCLUSION: Reductions of MSL to 28-35 days seem feasible and riskless and do not require major changes in the inventory management policies. Consequently, and giving preponderance to the precautionary principle, the Catalan Blood Agency has decided to reduce the MSL of RBCs from 42 to 35 days.

Hepatocellular carcinoma: Dutch guideline for surveillance, diagnosis and therapy.

UNLABELLED: Hepatocellular carcinoma (HCC) is rare in the Netherlands, even though the incidence has increased quite sharply in recent years. Standard treatment options consist of surgery, orthotopic liver transplantation, radiofrequency ablation, transarterial chemoembolisation (TACE) and systemic therapy with sorafenib. The consensus-based Dutch HCC guideline, established in 2013, serves to guide surveillance, diagnosis and treatment options: Surveillance should be performed by ultrasound at six-month intervals in well-defined cirrhotic patients and in selected high-risk hepatitis B carriers; A nodule > 1 cm in cirrhotic patients with arterial hypervascularity and venous or delayed phase washout at four-phase CT or MRI scan establishes the diagnosis of HCC; In patients with HCC without underlying cirrhosis, resection should be considered regardless of tumour size; In cirrhotic HCC patients, tumour stage, severity of underlying cirrhosis, and performance status determine treatment options. The algorithm of the Barcelona Clinic Liver Cancer (BCLC) staging system should be followed; Patients with Child-Pugh A-B cirrhosis (CP < 8 points) and performance status 0-2 are candidates for any active treatment other than transplantation; In early stage HCC (BCLC stage 0 or A, compensated cirrhosis without portal hypertension) surgical resection, liver transplantation, or radiofrequency ablation should be considered; In intermediate stage HCC (BCLC stage B) TACE and÷ or radiofrequency ablation should be considered; In advanced stage HCC (BCLC stage C) sorafenib should be considered. CONCLUSION: The Dutch HCC guideline offers advice for surveillance, diagnosis and treatment of HCC.

(31)P magnetic resonance spectroscopy of the breast and the influence of the menstrual cycle.

Phosphorus metabolite ratios are potential biomarkers in breast cancer diagnosis and treatment monitoring. Our purpose was to investigate the metabolite ratios phosphomonoester to phosphodiester, phosphoethanolamine (PE) to glycerophosphoethanolamine (GPE), and phosphocholine (PC) to glycerophosphocholine (GPC) in glandular breast tissue, and the potential effect of the menstrual cycle, using (31)P magnetic resonance spectroscopy (MRS) at 7T. Seven women with regular menstrual cycles each underwent four examinations using a 3D (31)P multi-echo magnetic resonance spectroscopic imaging sequence. Peak integrals were assessed using IDL and JMRUI software. First, T2 relaxation times were calculated using multi-echo data pooled across subjects and time points. Subsequent, metabolite ratios were calculated for each phase of the menstrual cycle using the calculated T2 values to account for when combining the free induction decay and all five echoes. The metabolite ratios were calculated both on group level and individually. T2 decay fits resulted in a T2 relaxation time for PE of 154 ms (95 % CI 144-164), for PC of 173 ms (95 % CI 148-205), for Pi of 188 ms (95 % CI 182-193), for GPE of 48 ms (95 % CI 44-53), and for GPC of 23 ms (95 % CI 21-26). The metabolite ratios analyzed on group level showed negligible variation throughout the menstrual cycle. Individual results did show an apparent intra-individual variation; however, not significant due to the measurements' uncertainty. To conclude, phospholipids in glandular tissue as measured with (31)P MRS at 7 T are not significantly affected by the menstrual cycle.

3-T breast magnetic resonance imaging in patients with suspicious microcalcifications on mammography.

OBJECTIVE: To investigate the diagnostic value of 3-Tesla (T) breast MRI in patients presenting with microcalcifications on mammography. METHODS: Between January 2006 and May 2009, 123 patients with mammographically detected BI-RADS 3­5 microcalcifications underwent 3-T breast MRI before undergoing breast biopsy. All MRIs of the histopathologically confirmed index lesions were reviewed by two breast radiologists. The detection rate of invasive carcinoma and ductal carcinoma in situ (DCIS) was evaluated, as well as the added diagnostic value of MRI over mammography and breast ultrasound. RESULTS: At pathology, 40/123 (33%) lesions proved malignant; 28 (70%) DCIS and 12 (30%) invasive carcinoma. Both observers detected all invasive malignancies at MRI, as well as 79% (observer 1) and 86% (observer 2) of in situ lesions. MRI in addition to conventional imaging led to a significant increase in area under the receiver operating characteristic (ROC) curve from 0.67 (95% CI 0.56­0.79) to 0.79 (95% CI 0.70­0.88, observer 1) and to 0.80 (95% CI 0.71­0.89, observer 2), respectively. CONCLUSIONS: 3-T breast MRI was shown to add significant value to conventional imaging in patients presenting with suspicious microcalcifications on mammography. KEY POINTS: • 3-T MRI is increasingly used for breast imaging in clinical practice. • On 3-T breast MRI up to 86% of DCIS lesions are detected. • 3-T MRI increases the diagnostic value in patients with mammographically detected microcalcifications.

The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17ß-estradiol.

Besides its quintessential role in reproduction, 17ß-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (Gq-mER) ligand STX rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB receptors to G protein-coupled inwardly rectifying K(+) channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110ß subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the estrogen receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.