Modifiable and non-modifiable risk factors affecting walking recovery after hip fracture.

UNLABELLED: Modifiable and non-modifiable predictors of mobility recovery were analyzed on a sample of 774 hip fracture patients according to pre-fracture abilities. Overall predictors were mostly non-modifiable factors related to frailty of patients with the exception of 25-hydroxyvitamin D concentration which significantly affected walking recovery, especially in patients with higher pre-fracture performance. INTRODUCTION: This study aims to investigate mobility changes after hip fracture with the aim of identifying modifiable and non-modifiable predictors of mobility recovery according to different pre-fracture abilities. METHODS: This is a prospective inception cohort study of consecutive older patients, admitted with a fragility hip fracture in three Hospitals of Emilia Romagna (Italy). A sample of 774 patients alive at the sixth month was divided into three groups according to pre-fracture ambulation ability (group 1: mobile outdoors; group 2: mobile indoors; and group 3: mobile with help). The relationship between baseline characteristics of patients and the odds of walking recovery was analyzed using multivariate regression analysis. RESULTS: Mortality differed significantly among the three groups and was the highest in patients needing help to walk. Among the survivors, only 50.3 % of patients recovered walking ability. In a multivariate analysis, independent risk factors were different among the three groups. In group 1, older age, comorbidities, the use of walking devices before fracture, and low albumin level acted as negative factors while male gender, a pre-fracture high functional status, and higher 25-hydroxyvitamin D levels increased the probability of full recovery. In group 2, only pre-fracture functional status and 25-hydroxyvitamin D concentration were related to the recovery of walking ability. Pre-fracture functional status was also the only significant predictor for patients in group 3. CONCLUSIONS: Several baseline characteristics of patients are related to the likelihood of recovering walking ability after hip fracture. The 25-hydroxyvitamin D level seems to be the only relevant modifiable factor even if the effectiveness of its supplementation has yet to be demonstrated.

Rationale, design and methods of CTCA-PRORECAD (Computed Tomography Coronary Angiography Prognostic Registry for Coronary Artery Disease): a multicentre and multivendor registry.

PURPOSE: This study was done to assess the prognostic value of computed tomography coronary angiography (CTCA) in a large multicentre population of patients with suspected coronary artery disease (CAD) and, in particular, its incremental value compared with traditional methods for risk stratification. MATERIALS AND METHODS: This is a retrospective observational study that began in January 2003 conducted on patients with suspected CAD assessed with CTCA on the basis of symptoms (chest pain, dyspnoea) and/or abnormal or equivocal stress test and/or a high cardiovascular risk profile. The participating centres will provide data obtained with CTCA performed with 16-slice or higher equipment. Exclusion criteria are renal insufficiency, allergy to iodinated contrast material, pregnancy and previous myocardial infarction or revascularisation (percutaneous coronary intervention and/or coronary artery bypass graft). All patients are stratified by means of clinical assessment and/or data retrieved from a clinical database. Risk factors considered are hypertension, dyslipidaemia, diabetes mellitus, smoking, family history and obesity. Symptoms are classified as absent, typical chest pain, atypical chest pain and dyspnoea. Primary endpoints are death, major adverse cardiovascular events (cardiac death, unstable angina requiring hospitalisation, acute myocardial infarction) and shifting of cardiovascular risk category on the basis of coronary plaque burden. The secondary endpoint is coronary revascularisation. Telephone interviews and/or clinical databases are used for the follow-up. The study will be conducted on a population >1,000 patients. CONCLUSIONS: The information collected from the Prognostic Registry for Coronary Artery Disease (PRORECAD) will provide insight into the prognostic value of CTCA in addition to demographic and clinical features. The results will allow for better use and interpretation of CTCA for prognostic purposes.

Computed tomography coronary angiography in the selection of outlier patients: a feasibility report.

PURPOSE: This study evaluated criteria, presence and distribution of outlier patients by means of computed tomography coronary angiography (CTCA) in a large institutional database. MATERIAL AND METHODS: From a population of 2,881 consecutive patients (1,842 men, mean age 62 ± 13 years) in sinus rhythm who underwent CTCA, we extracted data on patients with suspected coronary artery disease (CAD). We selected patient outliers in the fifth and sixth decades of life with the following criteria: ≥ 3 risk factors and absence of CAD, zero to one risk factors and ≥ 5 diseased coronary segments. Diabetes was excluded from risk factors because of the different impact on CAD. RESULTS: The patient population consisted of 2,432 individuals with suspected CAD (1,495 men, age 62 ± 13 years). The prevalence of obstructive CAD (≥ 50% lumen reduction at CTCA) was 36% (863/2,432). Patients with normal coronary arteries accounted for 34% of the total (837/2,432; 431 men, age 55 ± 14 years). Of these, 210 were in the fifth and 231 in the 6th decade (men 196, women 245); those with ≥ 3 risk factors accounted for 4.2% of the total (102/2,432; men 42, women 60). Patients with ≥ 5 diseased coronary segments accounted for 28% of the total (686/2,432; 510 men, age 68 ± 10 years). Of these, 115 were in the fifth and 270 in the sixth decade (men 309, women 76); those with zero to one risk factors accounted for 3.0% (73/2,432; men 66, women 7). CONCLUSIONS: CTCA is a reliable noninvasive diagnostic modality that can be used to identify outlier patients. This will enable dedicated trials aimed at characterising biomarkers and genomics of protective and nonprotective factors against CAD and its complications.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data on the comparison between male and female population.

PURPOSE: This study was undertaken to evaluate the diagnostic accuracy of computed tomography coronary angiography (CTCA) for detecting significant coronary artery stenosis (≥50% lumen reduction) compared with conventional coronary angiography (CAG) in a male and female population. MATERIAL AND METHODS: A total of 1,372 patients (882 men, 490 women; mean age 59.3 ± 11.9 years) in sinus rhythm imaged with CTCA (64-slice technology) and CAG were enrolled. Diagnostic accuracy and likelihood ratios (LR+ and LR-) of CTCA were assessed against CAG for the male and female populations. RESULTS: The prevalence of obstructive disease was 53% (men 58%; women 43%). CAG demonstrated the absence of significant coronary artery disease (CAD) in 47% (men 42%; women 56%), single-vessel disease in 25% (men 36%; women 22%) and multivessel disease in 29% (men 32%; women 23%) of patients. In the per-patient analysis, sensitivity, specificity and positive (PPV) and negative (NPV) predictive values of CTCA were 99% (men 98%; women 100%), 92% (men 92%; women 92%), 94% (men 95%; women 90%) and 99% (men 98%; women 100%), respectively. The per-patient likelihood ratios (LR) in the total population (LR+=12.4 and LR-=0.011), the male (LR+=12.9 and LR-=0.016) and female (LR =11.9 and LR-=0) populations were very good. We observed no significant differences in diagnostic accuracy between male and female populations. CONCLUSIONS: CTCA is a reliable diagnostic modality with high sensitivity and NPV in the female population.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data on the impact of calcium score.

PURPOSE: This study evaluated the diagnostic accuracy of computed tomography coronary angiography (CTCA) for detecting significant coronary artery stenosis (≥50% lumen reduction) at different coronary calcium score (CACS) values with conventional coronary angiography (CAG) as the reference standard. MATERIAL AND METHODS: A total of 1,500 patients (928 men, mean age 58.2±12.5 years) in sinus rhythm who underwent CTCA (64-slice technology) and CAG were enrolled. Diagnostic accuracy and likelihood ratios (LR) of CTCA were evaluated against CAG for the total population and in different CACS classes (0; 1-10; 11-100; 101-400; 401-1,000; >1,000). RESULTS: The prevalence of obstructive disease was 51% (23.5% single vessel; 27.5% multivessel; progressive increase from 17.9% to 94% through the CACS classes). In the per-patient analysis, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CTCA were 99%, 92%, 94% and 99%, respectively. Per-patient analysis showed a worse PPV of CTCA (76-77%) in classes with low CACS (1-10/11-100). Per-patient LR were higher in classes with extreme CACS values (0 = LR+ 18.3 and LR- = 0.0; c1,000 = LR+ 17.0 and LR- = 0.0) with values always >7 for LR+ and <0.033 for LR- for all CACS classes. CONCLUSIONS: CTCA is a reliable diagnostic modality, with high sensitivity and NPV regardless of CACS.

Prognostic value of computed tomography coronary angiography in patients with chest pain of suspected cardiac origin.

PURPOSE: The authors sought to determine the prognostic value of computed tomography coronary angiography (CTCA) in patients with acute chest pain (ACP). MATERIALS AND METHODS: A total of 145 consecutive patients (75 men; 64±12 years) with ACP were referred from the Emergency Department for CTCA, which was performed with a standard protocol using a 64-slice scanner. Patients were stratified according to the Morise clinical score (low, intermediate, high) and to the CTCA findings [absence of coronary artery disease (CAD), nonobstructive CAD, obstructive CAD]. Patients were followed up for the occurrence of major events: cardiac death, nonfatal myocardial infarction, unstable angina and revascularisation. RESULTS: One hundred and twenty-seven (87.6%) patients were without a history of CAD, and 18 (12.4%) patients had a history of CAD. Obstructive CAD (>50% luminal narrowing) was detected in 35 (24%) patients; nonobstructive CAD (≤ 50% luminal narrowing) in 62 (43%) and absence of CAD in 48 (33%) patients. During a mean follow-up of 20 ± 3 months, 20 events occurred (four hard events). Sixteen events (three hard events) occurred in patients without a history of CAD, and four events (one hard event) occurred in patients with a history of CAD. In patients with absence of CAD as detected by CTCA, the rate of events was 0%. At multivariate analysis, hypercholesterolaemia and obstructive CAD were significant predictors of events (p<0.05). CONCLUSIONS: An excellent prognosis was observed in patients with ACP and normal CTCA. CTCA shows the potential for optimal stratification of patients with ACP.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data in NSTEMI acute coronary syndrome and influence of gender and risk factors.

PURPOSE: This study sought to evaluate the diagnostic accuracy of computed tomography coronary angiography (CTCA) for detecting significant coronary artery stenosis (≥50% lumen reduction) compared with conventional coronary angiography (CAG) in non-ST-elevation myocardial infarction-acute coronary syndrome (NSTEMI-ACS) and in subgroups selected by gender and number of risk factors (RF). MATERIALS AND METHODS: We selected from a population of 1,500 patients in a multicentre registry with NSTEMI-ACS who had undergone CTCA and CAG, (n=237; 187 men, mean age 63±10 years). Diagnostic accuracy and likelihood ratios (LR) of CTCA were assessed against CAG in the total population and subgroups (men, women: 0 RF = absence of RF, 1-2 RF = presence of one or two RF, >2 RF = presence of more than two RF). RESULTS: The prevalence of obstructive disease was 53%. In the per-patient analysis, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CTCA were 100% (men 100%; women 100%; 0 RF 100%; 1-2 RF 100%; >2 RF 100%), 95% (men 98%; women 50%; 0 RF NA% (NA, not assessable); 1-2 RF 96%; >2 RF 96%), 95% (men 98%; women 91%; 0 RF 91%; 1-2 RF 96%; >2 RF 96%), 100% (men 100%; women 100%; 0 RF NV%; 1-2 RF 100%; >2 RF 100%), respectively. The per-segment analysis showed a reduction in PPV (ranging between 56% and 67%). The per-patient LR+ ranged between 18 and 27, whereas LR-were always 0. We observed no significant differences in diagnostic accuracy between subgroups. CONCLUSIONS: CTCA is a reliable diagnostic modality with high sensitivity and NPV in NSTEMI-ACS patients who are not candidates for early revascularisation, regardless of gender and number of risk factors.

Computed tomography coronary angiography in asymptomatic patients.

PURPOSE: This study assessed the accuracy of computed tomography coronary angiography (CT-CA) for detecting significant coronary artery disease (CAD; ≥50% lumen reduction) in intermediate/high-risk asymptomatic patients. MATERIALS AND METHODS: A total of 183 consecutive asymptomatic individuals (92 men; mean age 54±11 years) with more than one major risk factor (obesity, hypertension, diabetes, hypercholesterolaemia, family history, smoking) and an inconclusive or nonfeasible noninvasive stress test result (stress electrocardiography, stress echocardiography, nuclear stress scintigraphy) underwent CT-CA in an outpatient setting. All patients underwent conventional coronary angiography (CAG) within 4 weeks. Data from CT-CA were compared with CAG regarding the presence of significant CAD (≥50% lumen reduction). RESULTS: Mean calcium score was 177±432, mean heart rate during the CT-CA scan was 58±8 bpm and the prevalence (per-patient) of obstructive CAD was 19%. CT-CA showed single-vessel CAD in 9% of patients, two-vessel CAD in 9% and three-vessel CAD in 0%. Per-patient sensitivity, specificity, positive predictive value and negative predictive value of CT-CA were 100% (90-100), 98% (96-99), 97% (85-99), 100% (97-100), respectively. Positive and negative likelihood ratios were 151 and 0, respectively. CONCLUSIONS: CT-CA is an excellent noninvasive imaging modality for excluding significant CAD in intermediate/ high-risk asymptomatic patients with inconclusive or nonfeasible noninvasive stress test.

Prognostic value of Morise clinical score, calcium score and computed tomography coronary angiography in patients with suspected or known coronary artery disease.

PURPOSE: Our aim was to determine the prognostic value of computed tomography coronary angiography (CTCA), coronary artery calcium scoring (CACS) and Morise clinical score in patients with known or suspected coronary artery disease (CAD). MATERIALS AND METHODS: A total of 722 patients (480 men; 62.7±10.9 years) who were referred for further cardiac evaluation underwent CACS and contrast-enhanced CTCA to evaluate the presence and severity of CAD. Of these, 511 (71%) patients were without previous history of CAD. Patients were stratified according to the Morise clinical score (low, intermediate, high), to CACS (0-10, 11-100, 101-400, 401-1,000, >1,000) and to CTCA (absence of CAD, nonsignificant CAD, obstructive CAD). Patients were followed up for the occurrence of major events: cardiac death, nonfatal myocardial infarction, unstable angina and revascularisation. RESULTS: Significant CAD (>50% luminal narrowing) was detected in 260 (36%) patients; nonsignificant CAD (<50% luminal narrowing) in 250 (35%) and absence of CAD in 212 (29%). During a mean follow-up of 20±4 months, 116 events (21 hard) occurred. In patients with normal coronary arteries on CTCA, the major event rate was 0% vs. 1.7% in patients with nonsignificant CAD and 7.3% in patients with significant CAD (p<0.0001). Three hard events (14%) occurred in patients with CACS≤100 and two (9.5%) in patients with intermediate Morise score; one revascularisation was observed in a patient with low Morise score. At multivariate analysis, diabetes, obstructive CAD and CACS >1,000 were significant predictors of events (p<0.05). CONCLUSIONS: An excellent prognosis was noted in patients with a normal CTCA (0% event rate). CACS ≤100 and low-intermediate Morise score did not exclude the possibility of events at follow-up.

Low dose CT of the heart: a quantum leap into a new era of cardiovascular imaging.

In 10 years, computed tomography coronary angiography (CTCA) has shifted from an investigational tool to clinical reality. Even though CT technologies are very advanced and widely available, a large body of evidence supporting the clinical role of CTCA is missing. The reason is that the speed of technological development has outpaced the ability of the scientific community to demonstrate the clinical utility of the technique. In addition, with each new CT generation, there is a further broadening of actual and potential applications. In this review we examine the state of the art on CTCA. In particular, we focus on issues concerning technological development, radiation dose, implementation, training and organisation.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data and review of multicentre trials.

PURPOSE: This study was undertaken to evaluate the diagnostic accuracy of computed tomography coronary angiography (CT-CA) for the detection of significant coronary artery stenosis (> or =50% lumen reduction) compared with conventional coronary angiography (CCA) in a registry and to review major multicentre trials. MATERIALS AND METHODS: A total of 1,372 patients (882 men, 490 women; mean age 59.3+/-11.9 years) in sinus rhythm were studied with CT-CA (64-slice technology) and CCA. The diagnostic accuracy of CT-CA was evaluated against quantitative CCA as a reference standard for coronary artery stenosis. Positive and negative likelihood ratios and inter- and intraobserver agreement were calculated. RESULTS: The prevalence of disease was 53%. CCA demonstrated the absence of significant coronary artery disease in 46.6% (639/1372), single-vessel disease in 24.7% (337/1372) and multivessel disease in 28.9% (396/1372) of patients. In per-patient analysis sensitivity, specificity and positive and negative predictive value of CT-CA were 99% [confidence interval (CI) 97-99], 92% (CI 89-94), 94% (CI 91-95) and 99% (CI 97-99), respectively. Per-patient and per-segment likelihood ratios (LR+=12.4 and LR-=0.011; LR+=18.3 and LR-=0.064, respectively), were good. Inter- and intraobserver variability was 0.78 and 0.85, respectively. CONCLUSIONS: CT-CA is a reliable diagnostic modality both in terms of sensitivity and negative predictive value. Differences in trial results are also due to the different parameters used for patient inclusion.

Prevalence of myocardial bridging and correlation with coronary atherosclerosis studied with 64-slice CT coronary angiography.

PURPOSE: This study aimed to assess the prevalence and characteristics of myocardial bridging in patients who underwent multislice computed tomography coronary angiography (MSCT-CA) and to evaluate the correlation between bridged coronary segments and atherosclerosis. MATERIALS AND METHODS: A total of 277 patients (mean age 60+/-11 years) we consecutively examined with 64-slice MSCT-CA for suspected or known coronary atherosclerosis were retrospectively reviewed for myocardial bridging. Segments proximal and distal to the bridging were evaluated for atherosclerotic plaque, as were the remaining coronary segments. RESULTS: Myocardial bridging was present in 82 patients (30%, mean age 59+/-12). Bridges were of variable length (<1 cm 58%; 1-2 cm 32%; >2 cm 10%) and depth (superficial 69%, intramyocardial 31%) and frequently localised in the mid-distal segment of the left anterior descending artery (95%). Myocardial bridging cannot be considered a significant risk factor for coronary atherosclerosis (odds ratio 0.49) compared with traditional cardiovascular risk factors. Coronary segments proximal to the bridge showed no atherosclerotic disease (33%), positive remodelling (27%), <50% stenosis (20%) or >50% stenosis (20%). We identified 12 noncalcified, 32 mixed and 17 calcified plaques. The distal segments were significantly less affected (p<0.0001). CONCLUSIONS: MSCT-CA is a reliable, noninvasive method that is able to depict myocardial bridging and associated atherosclerotic plaque in the proximal segments.

Clinical applications of multi-detector computed tomography coronary angiography.

Cardiac computed tomography (CT) is a fast developing technique. In 10 years it developed from investigative tool into a clinical reality. The technology drive has been the key to success for this technique which is to date the only non invasive clinical tool for coronary angiographic assessment. Technical background is quite complex and the newer solutions are aiming at reducing the scan time and the radiation dose while improving temporal resolution, contrast resolution and ultimately image quality. The key technical development has been in the late 1990, the introduction of ECG triggering/gating techniques. Spatial resolution has also been improved reaching sub-millimeter performance. The latest innovations provide fast coverage with >64 slice detectors, high spatial resolution with 0.5 mm slice thickness, high temporal resolution with <100 ms in hardware, and higher contrast resolution with the forthcoming dual-energy solutions. Recently, also dose issues have been exploited and current state of the art technology are able to perform cardiac CT with 1-2 mSv. These improvements put cardiac CT as the most promising clinical tool for the non invasive assessment of coronary arteries.

Prevalence of coronary artery intramyocardial course in a large population of clinical patients detected by multislice computed tomography coronary angiography.

BACKGROUND: Intramyocardial course, an inborn coronary anomaly, is defined as a segment of a major epicardial coronary artery that runs intramurally through the myocardium; in particular, we distinguish myocardial bridging, in which the vessel returns to an epicardial position after the muscle bridge, and intramyocardial course, which is described as a vessel running and ending in the myocardium. PURPOSE: To evaluate the prevalence of myocardial bridging and intramyocardial course of coronary arteries as defined by multidetector computed tomography (MDCT) angiography. MATERIAL AND METHODS: The study population consisted of 242 consecutive patients (211 men, 31 women; mean age 59+/-6 years) with atypical chest pain admitted to our hospital between December 2004 and September 2006. All MDCT examinations were performed using a 16-detector-row scanner (Aquilion 16 CFX; Toshiba Medical System, Tokyo, Japan). Patients with heart rate above 65 bpm received 50 mg atenolol orally for 3 days prior to the MDCT scan, or they increased their usual therapy with beta-blockers, in order to obtain a prescan heart rate <60 bpm. Curved multiplanar and 3D volume reconstructions were performed to explore coronary anatomy. RESULTS: In 235 patients, the CT scan was successful and images were appropriate for evaluation. The prevalence of myocardial bridging and intramyocardial course of coronary arteries was 18.7% (47 cases) in our patient population. In 30 segments (63.8%), the vessels ran and ended in the myocardium. In the remaining 17 segments (36.2%), the vessels returned to an epicardial position after the muscle bridge. We found no difference in the prevalence of this inborn coronary anomaly when comparing different clinical characteristics of the study population (sex, age, body-mass index [BMI], etc.). The mean length of the subepicardial artery was 7 mm (range 5-12 mm), and the mean depth in the diastolic phase was 1.9 mm (range 1.2-2.3 mm). There was no significant difference of diameter in these segments between the different R-R phases examined. CONCLUSION: Our study is in agreement with major angiographic literature reporting a prevalence of myocardial bridging and intramyocardial course between 0.5% and 33%. MDCT technology represents a useful, noninvasive imaging method to assess and evaluate the location, depth, and length of this anatomical variation.

Granulosa cell-derived insulin-like growth factor (IGF) binding proteins are inhibitory to IGF-I hormonal action. Evidence derived from the use of a truncated IGF-I analogue.

An increasing body of information now suggests that insulin-like growth factor (IGF) binding proteins (BPs) may serve as antigonadotropins at the level of the ovary. It is the objective of the present communication to evaluate the functional role of endogenous (granulosa cell-derived) IGFBPs by exploiting the unique properties of des(1-3)IGF-I, a naturally occurring IGF-I analogue characterized as a weak ligand of IGFBPs but not of type I IGF receptors. Given IGFBP-replete circumstances, des(1-3)IGF-I proved more potent (10-fold) than its intact counterpart in promoting the follicle stimulating hormone (FSH)-stimulated accumulation of progesterone by cultured rat granulosa cells. In contrast, des(1-3)IGF-I proved virtually equipotent to the unmodified principle under IGFBP-deplete circumstances. Taken together, these findings are in keeping with the notion and that the apparently enhanced potency of des(1-3)IGF-I (under IGFBP-replete conditions) is due to its diminished affinity for endogenously generated IGFBPs and that rat granulosa cell-derived IGFBPs are inhibitory to IGF (and thus inevitably to gonadotropin) hormonal action. Accordingly, the reported ability of gonadotropins to attenuate IGFBP release by granulosa cells may be designed to enhance the bioavailability of endogenously generated IGFs in the best interest of ovarian steroidogenesis.

A kinase-mediated regulation of granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs): disparate response sensitivities of distinct IGFBP species.

Rat granulosa cell-derived insulin-like growth factor (IGF) binding proteins (BPs) have been found subject to biphasic dose-dependent regulation by FSH under in vitro circumstances. Since cAMP may play an intermediary role in FSH hormonal action, we have undertaken to characterize the A kinase-mediated regulation of the elaboration of IGFBPs by cultured rat granulosa cells. Treatment with increasing concentrations of prostaglandin E2 or choleragen, both established cAMP-generating agonists, produced biphasic dose-dependent regulation of the release of the major 28-29 kilodalton (kDa) IGFBP species while promoting the release of their minor 24 (and 19) kDa counterparts. Similar effects were noted for other cAMP-generating agonists including vasoactive intestinal peptide and forskolin (a potent activator of adenylate cyclase). Moreover, concomitant treatment with a functionally inert low dose (10(-7) M) of forskolin, substantially potentiated the FSH (10 ng/ml)-mediated inhibition of the elaboration of the 28-29 kDa IGFBPs. Application of decreasing dilutions of the invasive adenylate cyclase toxin of bordetella pertussis (but not of an inactive mutant strain) yielded monophasic dose-dependent modulation of the release of the 28-29 kDa IGFBPs while effecting biphasic regulation of the 24 kDa moiety. Concurrent treatment with 1-methyl-3-isobutylxanthine (a potent inhibitor of cAMP phosphodiesterase activity) at the 10(-4) M level resulted in profound (P < 0.05) inhibition of the (low dose) FSH (3 ng/ml)-supported accumulation of the major 28-29 kDa IGFBP species, an effect associated with modest (2.5-fold) induction (P < 0.05) of the minor 24 kDa IGFBP moiety. Lastly, provision of increasing concentrations of nondegradable lipophilic analogs of cAMP (i.e. (Bu)2cAMP and 8-bromoadenosine cAMP resulted in biphasic dose-dependent modulation of the release of the major 28-29 kDa IGFBP doublet while producing an increase in the accumulation of the minor 24 kDa IGFBP species. Taken together, these observations suggest that the ability of low dose FSH to stimulate and of high dose FSH to inhibit the elaboration of the 28-29 kDa IGFBP species may entail activation of the A-kinase transduction pathway. Similar conclusions appear to apply for the ability of FSH to regulate (albeit at a lower response sensitivity level) the biphasic elaboration of the 24 kDa IGFBP moiety. As such, these observations point out the disparate response sensitivities of distinct IGFBP species, thereby suggesting a novel potent mechanism through which FSH may determine the relative distribution pattern of granulosa cell-derived IGFBPs and the consequent overall IGF responsiveness of this cell type.

Endothelin-1 as a luteinization inhibitor: inhibition of rat granulosa cell progesterone accumulation via selective modulation of key steroidogenic steps affecting both progesterone formation and degradation.

Endothelin (ET)-1, is a 21 amino acid vasoactive peptide subject to regulation by cellular oxygen tension. However, an increasing body of information now suggests that ET-1 is a multifunctional peptidergic regulator the actions of which are not limited to the vascular system. Although ET-1 has been shown to inhibit the gonadotropin-supported accumulation of progesterone by cultured granulosa cells, the precise cellular mechanism(s) involved remain unknown. It was therefore the objective of this study to examine in greater detail the effects of ET-1 on progestin economy in cultured granulosa cells from immature rats. Treatment with ET-1 was inhibitory to the FSH-supported accumulation of progesterone in a dose-dependent manner, an action characterized by a median inhibitory dose of 2 x 10(-11) M and a maximal inhibitory effect of 90%. This inhibitory action of ET-1 was reversible following extensive washing and could not be accounted for by a decrease in the viable cell mass. Evaluation of the activities of progesterone-forming enzymes revealed ET-1 to be a potent (P < 0.01) inhibitor of cholesterol side-chain cleavage and 3 beta-hydroxysteroid dehydrogenase (HSD)/isomerase (76.1 +/- 1.2% and 47.3 +/- 8.6% inhibition, respectively). Cellular radiolabeling with [3H]pregnenolone confirmed an ET-1-induced inhibition of the FSH-supported accumulation of radiolabeled progesterone. However, this effect was concomitant with enhancement of the accumulation of more distal metabolites, i.e. 20 alpha-dihydroprogesterone, 5 alpha-pregnane-3 alpha, 20 alpha-diol, and 5 alpha-pregnane-3 alpha-ol-20-one. Analysis of the FSH-supported activities of the progesterone-degrading enzymes revealed ET-1 as a potent (P < 0.05) stimulator of 20 alpha-HSD and 5 alpha-reductase (3.6 +/- 1.0 and 1.7 +/- 0.3-fold, stimulation respectively). In contrast, no significant changes were observed in 3 alpha-HSD activity. Taken together, our findings demonstrate that the ET-1 induced inhibition of gonadotropin-supported progesterone accumulation constitutes a complex phenomenon wherein ET-1 inhibits the activities of steroidogenic enzymes concerned with progesterone formation while enhancing the activities of enzymes concerned with progesterone degradation. We speculate that ET-1, possibly of intraovarian origin, acts as a luteinization-inhibitor to suppress premature luteinization at a time when continued preovulatory expression of ET-1 (in the intact but not ruptured follicle) may be contingent upon relative intrafollicular hypoxia.

Interleukin-1 stimulates ovarian prostaglandin biosynthesis: evidence for heterologous contact-independent cell-cell interaction.

An increasing body of information now suggests the existence of a complete intraovarian IL-1 system replete with ligands, receptor, and receptor antagonist. Since IL-1 is an established mediator of inflammation and since ovulation may constitute an inflammatory-like reaction, consideration may be given to the possibility that IL-1 may play an intermediary role in the ovulatory process. To further assess the above hypothesis, we have set out to determine whether IL-1 is capable of promoting ovarian prostaglandin biosynthesis, an established component of the ovulatory cascade. Cultured whole ovarian dispersates from immature (25 day old) rats constitutively elaborated major prostaglandin species (PGE2 greater than PGF2 alpha) in a cell density-dependent fashion. Treatment with IL-1 produced dose-dependent increments in prostaglandin (PGE2 greater than PGF2 alpha) accumulation as compared with untreated controls. Comparable cellular densities of untreated or IL-1 beta-treated whole ovarian dispersates elaborated substantially more PGE2 as compared with isolated granulosa or theca-interstitial cell preparations suggesting a requirement for cell-cell interaction. Indeed, cell contact-dependent reconstitution experiments involving isolated granulosa and theca-interstitial cells at a projected physiologic ratio of 4:1 revealed synergistic interactions in the elaboration of PGE2 under both basal and IL-1 beta-treated circumstances. Identical results were obtained for cell contact-independent heterologous (but not homologous) coculture experiments. Taken together, our present findings reveal optimal basal and IL-1-stimulated ovarian prostaglandin (PGE2 greater than PGF2 alpha) biosynthesis to require heterologous, contact-independent, presumably humorally-mediated, cell-cell interaction. These observations along with the demonstration of the gonadotropin-dependent preovulatory induction of ovarian IL-1 beta gene expression provide strong support for the view that IL-1 may be the centerpiece of an intraovarian regulatory loop concerned with the promotion of the preovulatory cascade.

Rat ovarian insulin-like growth factor binding protein-3: a growth hormone-dependent theca-interstitial cell-derived antigonadotropin.

To further the identification and characterization of insulin-like growth factor binding proteins at the level of the immature rat ovary, we have set out to study the ovarian expression, cellular localization, and hormonal regulation of the insulin-like growth factor binding protein (IGFBP)-3. To this end, use was made of a solution hybridization/RNAse protection assay wherein ovarian total RNA from immature (21-23 days old) female rats was hybridized with a 343 bases-long [32P]-labeled rat IGFBP-3 riboprobe. As in liver, a single protected fragment (315 bases-long) corresponding to IGFBP-3 transcripts was identified in whole ovarian material. Cellular localization studies revealed the IGFBP-3 gene to be exclusively expressed in the theca-interstitial rather than the granulosa cell compartment. To confirm presence and cellular distribution of the IGFBP-3 protein, media conditioned by cultured granulosa cells, theca-interstitial cells, and whole ovarian dispersates were subjected to Western Ligand Blotting. Importantly, media conditioned by cultured theca-interstitial (but not granulosa) cells displayed an IGFBP the size of rat IGFBP-3 (46kDa) as determined by comigration with a rat serum standard. A similarly-sized band was apparent in media conditioned by cultured whole ovarian dispersates reflecting in all likelihood the contribution of the theca-interstitial cell component. Significantly, deglycosylation of media conditioned by cultured theca-interstitial cells revealed the glycosylated nature of the 46kDa IGFBP species as judged by the apparent reduction in its molecular size to 35kDa. Similar alterations were noted in corresponding rat serum samples. Hypophysectomy of immature rats resulted in a modest but statistically insignificant decrease in the relative (densitometrically-quantified) abundance of ovarian IGFBP-3 transcripts, an effect further augmented by the systemic provision of either FSH or diethylstilbestrol (DES). In contrast, systemic treatment of hypophysectomized rats with GH produced a marked (3.2-fold) increase (P less than 0.05) in the steady state levels of ovarian (as well as hepatic) IGFBP-3 transcripts. However, the concurrent provision of either FSH or DES resulted in substantial (P less than 0.05) attenuation (78 and 57% inhibition, respectively) of the upregulatory GH effect. These findings document the highly compartmentalized expression of the IGFBP-3 gene at the level of the immature rat ovary, implicate the theca-interstitial cell as the sole source of its generation, reveal its pituitary dependence, and disclose its diametrically-opposed (indeed antagonistic) regulation by FSH (or estrogens) and GH.(ABSTRACT TRUNCATED AT 400 WORDS)

The relation of antemortem characteristics to cardiovascular findings at necropsy--The Framingham Study.

The relation of premorbid cardiovascular risk attributes routinely measures at regular biennial examinations to cardiac necropsy findings using a special autopsy protocol was examined among 127 decedents of the Framingham cohort. Necropsy findings analyzed were: heart weight, left ventricular (LV) muscle thickness, percent luminal insufficiency of the coronary arteries, and percent intimal involvement with atherosclerosis. Clinical data analyzed included weight, height, blood pressure and serum cholesterol measured 1, 5, and 9 years prior to death. Systolic blood pressure, but not diastolic, correlated strongly with heart weight and LV muscle thickness in both sexes, and with atherosclerotic involvement in women, but not men. Serum cholesterol 1, 5, and 9 years antemortem all correlated positively with the degree of luminal insufficiency in men, while in women only cholesterol 9 years before death correlated significantly. In multivariate analysis only systolic pressure in women correlated independently with left ventricular muscle thickness and relative weight was the only independent correlate of heart weight. Only age was an independent significant correlate of the extent of coronary atherosclerosis in women. For men, coronary atherosclerotic involvement was independently correlated with only the serum cholesterol and measures of obesity were the major predictors of heart size. The degree of coronary pathology also correlated positively with heart weight in men and LV muscle thickness in women. In general clinical data measured just prior to death did not correlate as well with pathological findings as did earlier measurements.