Investigating the genetic characteristics of CAD: Is there a role for myocardial perfusion imaging techniques?

Several environmental and genetic factors have been found to influence the development and progression of coronary artery disease (CAD). Although the effects of the environmental hazards on CAD pathophysiology are well documented, the genetic architecture of the disease remains quite unclear. A number of single-nucleotide polymorphisms have been identified based on the results of the genome-wide association studies. However, there is a lack of strong evidence regarding molecular causality. The minority of the reported predisposing variants can be related to the conventional risk factors of CAD, while most of the polymorphisms occur in non-protein-coding regions of the DNA. However, independently of the specific underlying mechanisms, genetic information could lead to the identification of a population at higher genetic risk for the long-term development of CAD. Myocardial single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are functional imaging techniques that can evaluate directly myocardial perfusion, and detect vascular and/or endothelial dysfunction. Therefore, these techniques could have a role in the investigation of the underlying mechanisms associated with the identified predisposing variants, advancing our understanding regarding molecular causality. In the population at higher genetic risk, myocardial SPECT or PET could provide important evidence through the early depiction of sub-clinical dysfunctions, well before any atherosclerosis marker could be identified. Notably, SPECT and PET techniques have been already used for the investigation of the functional consequences of several CAD-related polymorphisms, as well as the response to certain treatments (statins). Furthermore, therefore, in the clinical setting, the combination of genetic evidence with the findings of myocardial SPECT, or PET, functional imaging techniques could lead to more efficient screening methods and may improve decision making with regard to the diagnostic investigation and patients' management.

Inhibitory effect of submaximal doses of ghrelin on gonadotropin secretion in women.

The effect of ghrelin on gonadotropin secretion has been equivocal. Recent data have shown an inhibitory effect of repeated injections of ghrelin on nocturnal LH and FSH secretion in women. The aim of this study was to investigate the effect of submaximal doses of ghrelin on the diurnal secretion of gonadotropins. Ten normally cycling women received 2 consecutive dosages of ghrelin (0.15 µg/kg and 0.30 µg/kg) intravenously in the early and late follicular phases of the cycle. Saline was injected in the preceding cycle. Blood samples in relation to ghrelin or saline administration (time 0 and 90 min) were taken at -15, 0, 30, 90, 120, 150, and 180 min. Serum estradiol concentrations were significantly higher in the late than in the early follicular phase. Following ghrelin administration, serum LH and FSH levels decreased significantly, in relation to the saline injection, in the late (p<0.01), although FSH values showed a within the group decrease also in the early follicular phase (p<0.05). The study suggests a differential action of ghrelin on diurnal gonadotropin secretion throughout the follicular phase of the cycle.

Baseline insulin-like growth factor-I plasma levels, systemic inflammation, weight loss and clinical outcome in metastatic non-small cell lung cancer patients.

BACKGROUND: Cancer patients frequently suffer from weight loss and systemic inflammation in the context of advanced disease, which is related to adverse outcome. Insulin-like growth factor (IGF)-I is an anabolic molecule implicated in the maintenance of muscle mass and cancer growth. We investigated potential correlations of IGF-I with an inflammatory and weight loss status and with clinical outcome. METHODS: Baseline IGF-I plasma levels were measured in 77 patients (66 males, median age 65.5 ± 10.6 years), diagnosed with metastatic non-small cell lung cancer, and were correlated with serum albumin and C-reactive protein (CRP) levels, weight loss history, treatment response and overall survival. RESULTS: IGF-I correlated with age (p = 0.01), histologic subtype (p = 0.019), albumin (p < 0.001) and CRP (p < 0.001). In univariate analysis, gender (p = 0.005), smoking status (p = 0.012), albumin (p = 0.034) and IGF-I (p = 0.017) were related to time to progression, while IGF-I (p = 0.003), gender (p = 0.049) and smoking status (p = 0.003) retained their significance in multivariate analysis. Age (p = 0.005), gender (p = 0.029), weight loss (p = 0.009), performance status (p < 0.001), number of metastatic sites (p = 0.004), albumin (p = 0.008), CRP (p = 0.022) and IGF-I (p = 0.042) were associated with overall survival, although only gender (p = 0.013), weight loss (p = 0.027), performance status (p = 0.015) and number of metastatic sites (p = 0.021) emerged as independent prognostic factors. CONCLUSION: IGF-I correlates with systemic inflammation and seems to play an independent predictive role in metastatic non-small cell lung cancer.

Effect of ghrelin and metoclopramide on prolactin secretion in normal women.

BACKGROUND: Administration of ghrelin to women stimulates the secretion of PRL but the mechanism is not known. AIM: The aim of the study was to investigate the effect of the dopamine receptor blocker, metoclopramide, on ghrelin-induced PRL release. SUBJECTS AND METHODS: Ten healthy normally cycling women were studied in the midluteal phase of 4 menstrual cycles. A single dose of normal saline (cycle 1), ghrelin (1 µg/kg) (cycle 2), metoclopramide (20 mg) (cycle 3), and ghrelin plus metoclopramide (cycle 4) was given to the women iv. Blood samples in relation to the iv injection (time 0) were taken at -15, 0, 15, 30, 45, 60, 75, 90, and 120 min. The response of PRL and GH was assessed. RESULTS: Following ghrelin administration (cycles 2 and 4), plasma ghrelin and serum PRL and GH levels increased rapidly, peaking at 30 min (p<0.001). PRL was also increased after the injection of metoclopramide (p<0.001, cycle 3), but the increase was much greater than after the administration of ghrelin. The combination of ghrelin and metoclopramide stimulated PRL secretion to the same extent with metoclopramide alone. No changes in GH and PRL levels were seen after saline injection. CONCLUSIONS: These results demonstrate that the stimulating effect of ghrelin on PRL secretion is not additive with that of metoclopramide, although a dose range study might provide further information.

Effect of ghrelin and thyrotropin-releasing hormone on prolactin secretion in normal women.

It is known that ghrelin stimulates the secretion of prolactin in women. The aim of this study was to examine the effect of exogenous thyrotropin-releasing hormone (TRH) on ghrelin-induced prolactin release. Ten healthy normally cycling women were studied in four menstrual cycles. The women were injected intravenously in late follicular phase (follicle size 16-17 mm) with a single dose of normal saline (cycle 1), ghrelin (1 microg/kg) (cycle 2), thyrotropin-releasing hormone (200 microg) (cycle 3), and ghrelin plus thyrotropin-releasing hormone (cycle 4). Blood samples in relation to saline or drugs injection (time 0) were taken at -15, 0, 15, 30, 45, 60, 75, 90, and 120 min. The prolactin and growth hormone responses were assessed. After ghrelin administration (cycles 2 and 4), plasma ghrelin, serum prolactin, and growth hormone levels increased rapidly, peaking at 15-30 min (p<0.001). The injection of thyrotropin-releasing hormone (cycle 3) stimulated prolactin secretion markedly (p<0.001), but reduced growth hormone levels significantly (p<0.05). Ghrelin induced a smaller prolactin increase than thyrotropin-releasing hormone (p<0.05). The combination of ghrelin and thyrotropin-releasing hormone induced a similar increase in prolactin levels as with thyrotropin-releasing hormone alone. No changes in growth hormone and prolactin levels were seen after saline injection. These results demonstrate that the stimulating effect of ghrelin on prolactin secretion is not additive with that of thyrotropin-releasing hormone.

Current and potential roles of ghrelin in clinical practice.

Ghrelin is a novel GH-releasing peptide, which has been identified as an endogenous ligand for GH-secretagogue receptor. Ghrelin is mainly secreted by the stomach and plays a critical role in a variety of physiological processes including endocrine, metabolic, cardiovascular, immunological, and other actions. Ghrelin stimulates food intake via hypothalamic neurons and causes a positive energy balance and body weight gain by decreasing fat utilization and promoting adiposity. Given the multiple effects of ghrelin, its potential clinical applications have been evaluated in various conditions. Preliminary trials have shown that it may prove valuable in the management of disease-induced cachexia. Ghrelin may improve the wasting syndrome through GH-dependent or GH-independent effects. Moreover, ghrelin may play a role in the management of disorders of gut motility and obesity. Finally, other potential clinical applications of ghrelin include the treatment of patients with diabetes mellitus, infections, rheumatological diseases or GH deficiency and the diagnosis of this hormonal disorder.

Impact of dopamine transporter single photon emission computed tomography imaging using I-123 ioflupane on diagnoses of patients with parkinsonian syndromes.

To assess the impact of I-123 ioflupane single photon emission computed tomography (SPECT) imaging on classifying patients with striatal dopaminergic deficits. Sixty-one patients with an initial diagnosis of parkinsonism or uncertain tremor disorder were screened and followed-up for one year. All patients were re-examined by two neurologists at our centre and were classified as having neurodegenerative or non-neurodegenerative disorders. Patients underwent I-123 ioflupane SPECT imaging. SPECT studies were blindly evaluated and classified as normal or abnormal (indicative of neurodegenerative disorders). The overall agreement of the SPECT imaging results with the initial classification was 65.6% (kappa=0.229, p=0.074) but was 90.2% (kappa=0.782, p<0.001) with the classification of the neurologists at our centre. I-123 ioflupane SPECT imaging is a valuable method in the evaluation of patients presenting clinically with uncertain parkinsonian syndromes or for whom diagnostic doubt exists.

PET Counting Response Variability Depending on Tumor Location, Activity, and Patient Obesity: A Feasibility Study of Solitary Pulmonary Nodule Using Monte Carlo.

We aim to investigate the counting response variations of positron emission tomography (PET) scanners with different detector configurations in the presence of solitary pulmonary nodule (SPN). Using experimentally validated Monte Carlo simulations, the counting performance of four different scanner models with varying tumor activity, location, and patient obesity is represented using a noise equivalent count rate (NECR). NECR is a well-established quantitative metric which has positive correlation with clinically perceived image quality. The combined effect of tumor displacement and increased activity shows a linear ascending trend for NECR with slope ranges of (12.5-18.2)*10-3 (kBq/cm3)-1 for three-ring (3R) scanners and (15.3-21.5)*10-3 (kBq/cm3)-1 for four-ring (4R). The trend for the combined effect of tumor displacement and patient obesity is exponential decay with 3R configurations weakly dependent on the patient obesity if the tumor is located at the center of the field of view with exponent's range of (6.6-33.8)*10-2cm-1. The dependence is stronger for 4R scanners (9.6-38.5)*10-2cm-1. The analysis indicates that quantitative PET data from the same SPN patient possibly examined in different time points (e.g., during staging or for the evaluation of treatment response) are affected by the different detector configurations and need to be normalized with patient weight, activity, and tumor location to reduce unwanted bias of the diagnosis. This paper provides also with a proof of concept for the ability of properly tuned simulations to provide additional insights into the counting response variability especially in tumor types where often borderline decisions have to be made regarding their characterization.

Blood ghrelin, adiponectin and resistin levels during controlled ovarian stimulation in IVF cycles.

The aim of the present study was to investigate changes of blood ghrelin, adiponectin and resistin levels in IVF/ICSI-ET cycles. Twenty women were stimulated with recombinant FSH in a GnRH agonist short protocol for IVF/ICSI. Blood samples were taken on cycle day 2 before the commencement of injections, on cycle day 6 and on the days of HCG injection, oocyte pick up (OPU), embryo transfer (ET) as well as 7 and 12 days post-ET. Serum E2 levels increased during the stimulation, peaking on the HCG day and declined thereafter (p<0.001). Serum progesterone levels started to increase on the OPU day, peaking on the ET day (p<0.001) and decreased on days 7 and 12 post-ET. Plasma ghrelin remained unchanged during the whole cycle. Serum adiponectin levels remained stable during the stimulation period until the ET day and decreased on days 7 and 12 post-ET (p<0.001). Serum resistin levels increased until the ET day (p<0.05), remained unchanged on day 7 post-ET and decreased on day 12 post-ET (p<0.05). The present study shows for the first time that ghrelin levels did not change significantly during IVF/ICSI-ET cycles. Resistin levels increased during the stimulation period while adiponectin levels remained stable decreasing during the luteal phase.

Ghrelin suppresses the GnRH-induced preovulatory gonadotropin surge in dairy heifers.

Ghrelin, a known growth hormone (GH) secretagogue, alters gonadotropin secretion in many species. Our objectives were to study the effects of ghrelin, on GH, LH, FSH secretion, and on luteal function of the ensuing estrous cycle in cattle. The estrous cycles of eight heifers were synchronized with progesteron releasing intravaginal device, and ovulation was induced with GnRH. Eight animals were treated with 1.5 µg kg(-1) bovine ghrelin (group Ghr, n = 4) or saline (group C, n = 4). Starting with the first ghrelin injection, 13 blood samples were collected over a 4-hour period for the determination of ghrelin, GH, LH, and FSH concentration. Progesterone levels were measured in samples collected every other day after estrus expression. Data were analyzed by repeated measures of ANOVA followed by Bonferroni post hoc testing and t test. In group Ghr, ghrelin concentration increased significantly 15 minutes after the first injection and remained in elevated levels until the 90th minute after the last injection. At the time of third ghrelin injection, GH was significantly higher in the Ghr group compared with C (17.1 ± 1.3 vs. 2.6 ± 0.3 ng mL(-1), P < 0.0001). Similar differences were found for the next three samples collected 15, 30, and 60 minutes later; no difference was evident after 90 minutes. In group Ghr, the area under the curve for LH and FSH were significantly reduced compared with the ones of group C (266 ± 10.3 vs. 331.9 ± 7.3, P = 0.007 and 102.3 ± 2.0 vs. 134.9 ± 5.5, P < 0.005 for LH and FSH respectively). At particular time points the concentration of the two gonadotrophins in group Ghr was significantly lower than those of group C (15, 30, 45, 75, and 90 and 60, 75, 90, 120, and 150 minutes after GnRH administration for LH and FSH respectively). The duration of the following estrous cycle was shorter (P = 0.004) in group Ghr (19.0 ± 0.4 days) compared with C (21.8 ± 0.5 days). In days 4, 6, 8, 10, and 14, progesterone concentration was lower (P < 0.05) in group Ghr compared with C; similarly the progesterone area under the curve for group Ghr (113.1 ± 4.8) was suppressed (P = 0.007) compared with that of C (141 ± 4.8). These results imply that ghrelin acts on pituitary causing impaired response to the GnRH stimulus, and it is likely to affect luteinization of the cellular compartment of the preovulatory follicle, and/or to suppress steroidogenetic activity of the luteal cells.

[Myocardial perfusion scintigraphy using 99mTC-tetrofosmin: a comparison with coronary angiography]. / Myokard-Perfusionsszintigraphie mit 99mTc-Tetrofosmin: Ein Vergleich mit der koronaren Angiographie.

AIM: Coronary angiography is still the most reliable method for the detection of coronary artery disease. In this study we compared to this method the accuracy of 99mTc-Tetrofosmin myocardial SPECT. METHOD: Fifty two patients (38 male and 14 female) were studied with stress-rest 99mTc-Tetrofosmin myocardial SPECT. Two independent observers evaluated the uptake of the radiotracer using a score from 0 to 4. All patients underwent coronary angiography and the results were compared to SPECT findings. We considered as hemodynamic significant any obstruction greater than 50% and as ischemic any myocardial region with radiotracer uptake less than 4 at stress. RESULTS: There was good segmental correspondence between tetrofosmin scintigram and angiography. Sensitivity 72.2-91.1%, specificity 80.0-88.2%, ppv 76.4-88.5% and npv 83.3-85.7%, depending on the obstructed vessel. CONCLUSION: 99mTc-Tetrofosmin myocardial SPECT is a reliable alternative for the detection of CAD.

Tc-99m tetrofosmin myocardial perfusion imaging before and six months after percutaneous transluminal coronary angioplasty.

The role of Tc-99m tetrofosmin single-photon emission tomography (SPECT) in the evaluation of myocardial perfusion before and 6 months after successful percutaneous transluminal coronary angioplasty (PTCA) was assessed in 41 consecutive patients (32 men and 9 women). Twenty-five patients had one-vessel disease, 14 had two-vessel disease, and 2 had three-vessel disease. Thirty-six patients had dilation of one vessel and five patients dilation of two stenosed vessels, with a total of 46 dilated vessels. All patients underwent coronary angiography both before PTCA and 6 months after revascularization. Restenosis was angiographically demonstrated in 16 (39%) patients and 16 (34.8%) vessels. Tc-99m tetrofosmin myocardial SPECT was 81.3% sensitive and 88% specific for the detection of restenosis in the group of patients with a positive predictive value of 81.3% and a negative predictive value of 88%. Sensitivity, specificity, positive predictive value, and negative predictive value were 81.3%, 90%, 76.5%, and 89.7%, respectively, for restenosis detection in specific vessels. It was concluded that most patients who underwent successful PTCA (34 of 41, or 82.9%) had significant (P < 0.001) improvement in their scan image 6 months after the angioplasty, and that Tc-99m tetrofosmin myocardial SPECT is an excellent tool to follow these patients because it can detect restenosis accurately and noninvasively.

Elimination half-life of anti-Müllerian hormone.

CONTEXT: Anti-Müllerian hormone (AMH) is a glycoprotein that is secreted by the granulosa cells in the human ovary. In the postpubertal female, circulating AMH reflects the number of follicles within the ovary. It is mandatory to know the serum elimination half-life (t(1/2)) of AMH to study in vivo short-term changes of the hormone. OBJECTIVE: Our objective was to determine the kinetics of decay of AMH in the human female. PATIENTS, DESIGN, AND SETTING: Premenopausal women undergoing total abdominal hysterectomy plus bilateral salpingo-oophorectomy participated in this cohort study (n = 21) at an academic tertiary referral center. INTERVENTIONS: Serum samples were obtained immediately before surgery and in 12-h intervals thereafter for 8 d. MAIN OUTCOME MEASURE: AMH elimination was calculated, applying a one-compartment model with first-order kinetics. RESULTS: Mean preoperative AMH levels were 0.67 ng/ml (range, 0.1-1.78 ng/ml) and dropped to 0.08 ng/ml within 84 h after surgery. The AMH decay followed first-order kinetics. The mean terminal t(1/2) of AMH was calculated as 27.6 ± 0.8 h. CONCLUSION: AMH elimination reaches approximately 84% after 3 d, approximately 91% after 4 d, approximately 95% after 5 d, and can be considered complete after 8 d.

Alzheimer's disease: spect and pet tracers for beta-amyloid imaging.

The definite diagnosis of Alzheimer's disease (AD) is based on the detection of beta amyloid (Aß) plaques and neurofibrillary tangles (NFTs) - which are the pathological hallmarks of the disease- in the postmortem brains. Although regional Cerebral Blood Flow (rCBF) and Cerebral Glucose Metabolism (CGM) abnormalities have already been studied in AD patients with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), the development of specific imaging agents for direct mapping of Aß plaques in the living brain, is a great challenge. Aß probes could significantly contribute to the early diagnosis of AD, the elucidation of the underlying neuropathological processes and the evaluation of anti-amyloid therapies which are currently under investigation. The development of SPECT and PET tracers for Aß imaging represents an active area in radiopharmaceutical design. A substantial number of potential Aß imaging radioligands have been designed and used in-vitro. They are either monoclonal antibodies to Aß and radiolabeled Aß peptides, or derivatives of histopathological stains such as Congo red (CR), chrysamine-G (CG) and Thioflavin T (TT). Though, only few of them, that display high binding affinity to Aß as well as sufficient brain penetration, have been used primarily in in-vivo studies and to a smaller degree on human subjects. Since Aß plaques are not homogenous and contain multiple binding sites that can accommodate structurally diverse compounds, they offer flexibility in designing various different probes, as potential amyloid imaging agents.