Effect of acute and chronic vitamin D administration on systemic renin angiotensin system in essential hypertensives and controls.

AIM: To investigate the systemic renin-angiotensin system (RAS) in essential hypertensives (EH) and controls (C) after short- and long-term vitamin D receptor activation. DESIGN: Ten consecutive EH (under controlled low-salt diet) and 10 C underwent calcitriol administration (0.25 µg bid) for 1 week (Group A). Eighteen consecutive EH under angiotensin II receptor antagonist therapy received a single oral dose of 300,000 IU of cholecalciferol and were followed up for 8 weeks (Group B). METHODS: In basal conditions and at the end of the study (1 week in Group A and 8 weeks in Group B), plasma renin activity (PRA), plasma active renin, aldosterone, and angiotensin II were evaluated, as well as blood pressure, plasma 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH. RESULTS: In Group A, plasma 25(OH)D levels in EH and C were below the normal range, although lower levels were found in the former. No association between basal plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS components was observed either in the whole group or in the two subgroups. Calcitriol administration did not affect any RAS parameter either in EH or in C. In Group B, cholecalciferol significantly increased 25(OH)D and 1,25(OH)2D levels without interfering with the angiotensin II receptor antagonist-induced increase in RAS components. No correlation was found between plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS parameters before and after cholecalciferol administration. CONCLUSIONS: The present data suggest that, in our experimental conditions, vitamin D receptor activation is unable to influence systemic RAS activity.

Cardiovascular changes in patients with primary aldosteronism after surgical or medical treatment.

BACKGROUND: Data on the cardiovascular middle-term follow-up of patients with primary aldosteronism (PA) are scanty. AIM: To detect the cardiovascular effects of surgery in patients with aldosterone (ALD)-producing adenoma (APA) and of pharmacotherapy in those with bilateral adrenal hyperplasia (BAH), a prospective study involving 60 consecutive patients with PA was performed. MATERIAL/ METHODS: Clinical, biochemical, and cardiovascular assessment was obtained before and after (31.5±4.4 months) surgery or proper medical treatment (32.1±5.0 months) in 19 and 41 patients, respectively. RESULTS: As expected, plasma ALD normalized in all operated patients, while in the other group it did not change. Systolic and diastolic blood pressure decreased (p<0.001) after both treatments. However, absolute and percentage reduction was significantly more pronounced (p<0.01) in operated than in non-operated patients. Left ventricular (LV) mass showed significant reduction after surgery (LV mass g/m(2), p<0.0007; LV mass g/m(2.7), p<0.01), but no change after medical treatment, so that the differences between absolute and percentage values at follow- up were statistically significant (p<0.01) between groups. Basal LV mass/m(2.7) was positively associated with age (p<0.009), body mass index (p<0.0008), drug number (p<0.03), and ALD/plasma renin activity ratio (p<0.01). Allocating the patients according to plasma ALD and cardiac parameters, patients who presented ALD reduction during the study also had a decrement in cardiac mass (p<0.04). CONCLUSIONS: Our data indicate that in patients with PA the removal of ALD excess by surgery in APA is effective in reducing blood pressure and in improving cardiac parameters, while anti-hypertensive therapy in BAH shows less positive impact on cardiovascular system.

Malignant extra-adrenal pheochromocytoma caused by an SDHB intronic variation leading to a 54-bp deletion in exon 4.

In the last few years several papers have reported on the association between mutations of the genes encoding the structural (SDHC, SDHD) and catalytic (SDHB) subunits of succinate dehydrogenase and the occurrence of hereditary pheochromocytomas/paragangliomas (Pheo/PGL) syndromes. We diagnosed a malignant extraadrenal Pheo in a 38-yr-old man with abdominal lesions; many areas of increased uptake at octreoscan scintigraphy in the skeleton indicated metastatic disease. We then approached genetic analysis through the screening of the SDHB, SDHC, and SDHD genes. Here we report a heterozygous G>A transversion at position +1 of intron 4 of SDHB gene. To clarify this mutation we performed cDNA analysis by RT-PCR and we assume that the splice site mutation in intron 4 abolishes the consensus splice donor sequence leading to an in-frame deletion of 18 amino acid. This finding indicates once again that SDHB mutations could predispose to malignant Pheo.

Cardiac remodeling in patients with primary aldosteronism.

OBJECTIVE: To evaluate the morpho-functional changes of the myocardium in patients with primary aldosteronism (PA). DESIGN: An observational study in a university referral center for blood pressure diseases. PATIENTS: Twenty- three patients with PA, 24 patients with essential hypertension (EH), and 15 normotensive controls (C) underwent conventional echocardiography with integrated backscatter (IBS) and tissue Doppler imaging (TDI) analysis. The corrected IBS (C-IBS) values and the systo-diastolic variation of IBS (CV-IBS) were performed at both interventricular septum and the posterior wall levels. TDI myocardial systolic (Sm), early diastolic (Em), and late diastolic (Am) velocities of both left ventricular walls were also determined. RESULTS: In PA patients, septal and posterior wall CV-IBS were significantly lower than C (p<0.0001) and EH patients (p<0.001). In EH, CV-IBS was significantly lower than C (p<0.001). Patients with PA exhibited lower Sm, lower Em, and higher Am, and a subsequently reduced Em/Am ratio than C (p<0.001 for all) and EH (p<0.01 for all) at interventricular septum and lateral wall levels. In the latter, Sm, Em, and Em/Am ratio were lower and Am was higher than C (p<0.001 for all). In PA and EH patients, CV-IBS at both septum (r=-0.66, p<0.001) and posterior wall levels (r=-0.67, p<0.001) and Sm peak of both septum (r=-0.52, p<0.001) and lateral wall (r=-0.55, p<0.001) were inversely related to plasma aldosterone. CONCLUSIONS: Patients with PA showed myocardial wall remodeling characterized by increased myocardial fibrosis and early left ventricular systodiastolic function abnormalities.

Awareness of medical radiation exposure among patients: A patient survey as a first step for effective communication of ionizing radiation risks.

INTRODUCTION: The European Directive 2013/59/EURATOM requires patient radiation dose information to be included in the medical report of radiological procedures. To provide effective communication to the patient, it is necessary to first assess the patient's level of knowledge regarding medical exposure. The goal of this work is to survey patients' current knowledge level of both medical exposure to ionizing radiation and professional disciplines and communication means used by patients to garner information. MATERIAL AND METHODS: A questionnaire was designed comprised of thirteen questions: 737 patients participated in the survey. The data were analysed based on population age, education, and number of radiological procedures received in the three years prior to survey. RESULTS: A majority of respondents (56.4%) did not know which modality uses ionizing radiation. 74.7% had never discussed with healthcare professionals the risk concerning their medical radiological procedures. 70.1% were not aware of the professionals that have expertise to discuss the use of ionizing radiation for medical purposes, and 84.7% believe it is important to have the radiation dose information stated in the medical report. CONCLUSION: Patients agree with new regulations that it is important to know the radiation level related to the medical exposure, but there is little awareness in terms of which modalities use X-Rays and the professionals and channels that can help them to better understand the exposure information. To plan effective communication, it is essential to devise methods and adequate resources for key professionals (medical physicists, radiologists, referring physicians) to convey correct and effective information.

SDH mutations in patients affected by paraganglioma syndromes: a personal experience.

Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest-derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL. Haplotype analysis showed the presence of a founder effect. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumors, variably associated or not with PGLs or PHEOs. A novel missense SDHD variant, T112I, was also found in one of our families. A new missense G106D mutation, involving a highly conserved amino acid, was found in two sisters affected by bilateral glomus tumors. A P81L mutation associated with abdominal and head and neck PGL was detected in three families. A G12S variant of the SDHD gene was found in one patient affected by a PHEO. The finding of this variant in 3 of 100 control subjects suggests that it is a polymorphism and not a mutation. A novel IVS2-1G>T variant was found at intron 2 of SDHD gene in one patient affected by a glomus tumor. All the tumors associated with SDHD mutations were benign. Conversely, the only mutation we found in SDHB gene (IVS3+1G>A) was associated with a malignant PHEO.

Unusual association of adrenal pheochromocytoma and para-aortic neurofibroma in pregnancy.

The association of pheochromocytoma (PHEO) and pregnancy is uncommon and life threatening for both the fetus and the mother. Early diagnosis and treatment is essential to decrease maternal and fetal mortality and to differentiate the disease from the more common pre-eclampsia. While medical treatment should be started immediately after diagnosis, the timing of surgical treatment is still debated. We describe the case of a 27-yr-old woman in the 18th week of pregnancy who showed a biochemical pattern typical of PHEO and, by imaging studies, 2 tumors with the same characteristics: the first localized on the right adrenal gland, the second at the right renal hilum. The patient underwent surgery because of suspicion of malignant PHEO with local metastasis, while histology revealed a rare association of a solitary PHEO and para-aortic neurofibroma, both tumors embryologically deriving from a common cell precursor.

In vivo cytoreduction studies and cell sorting--enhanced tumor-cell detection in high-risk neuroblastoma patients: implications for leukapheresis strategies.

PURPOSE: To improve autologous leukapheresis strategies in high-risk neuroblastoma (NB) patients with extensive bone marrow involvement at diagnosis. PATIENTS AND METHODS: Anti-G(D2) immunocytochemistry (sensitivity, 1 in 10(5) to 10(6) leukocytes) was used to evaluate blood and bone marrow disease at diagnosis and during the recovery phase of the first six chemotherapy cycles in 57 patients with stage 4 NB and bone marrow disease at diagnosis. A total of 42 leukapheresis samples from the same patients were evaluated with immunocytology, and in 24 of these patients, an anti-G(D2) immunomagnetic enrichment step was used to enhance tumor-cell detection. RESULTS: Tumor cytoreduction was much faster in blood compared with bone marrow (3.2 logs after the first cycle and 2.1 logs after the first two cycles, respectively). Bone marrow disease was often detectable throughout induction, with a trend to plateau after the fourth cycle. By direct anti-G(D2) immunocytology, a positive leukapheresis sample was obtained in 7% of patients after either the fifth or sixth cycle; when NB cell immunomagnetic enrichment was applied, 25% of patients had a positive leukapheresis sample (sensitivity, 1 in 10(7) to 10(8) leukocytes). CONCLUSION: Standard chemotherapy seems to deliver most of its in vivo purging effect within the first four cycles. In patients with overt marrow disease at diagnosis, postponing hematopoietic stem-cell collection beyond this point may not be justified. Tumor-cell clearance in blood seems to be quite rapid, and earlier collections via peripheral-blood leukapheresis might be feasible. Immunomagnetically enhanced NB cell detection can be highly sensitive and can indicate whether ex vivo purging should be considered.

Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension.

OBJECTIVES: We sought to evaluate whether fasting hyperhomocystinemia reduces endothelial function by oxidative stress in normotensive subjects and hypertensive patients. BACKGROUND: Subjects with hyperhomocystinemia have endothelial dysfunction. METHODS: In 23 normotensive subjects and 28 hypertensive patients, classified into normohomocystinemic and hyperhomocystinemic groups according to homocysteine plasma levels (< 8.7 and >14.6 micromol/l, respectively), we studied forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.15 to 15 microg/100 ml tissue per min) or sodium nitroprusside (1 to 4 microg/100 ml per min), an endothelium-dependent and -independent vasodilator, respectively. Acetylcholine was repeated with N(G)-monomethyl-L-arginine (L-NMMA; 100 microg/100 ml per min), vitamin C (8 mg/100 ml per min) and L-NMMA plus vitamin C. RESULTS: Normotensive hyperhomocystinemic patients showed a blunted response to acetylcholine and a lower inhibiting effect of L-NMMA on acetylcholine, as compared with normohomocystinemic patients. Although vitamin C was ineffective in normohomocystinemic subjects, it increased the response to acetylcholine and restored the inhibiting effect of L-NMMA on acetylcholine in hyperhomocystinemic patients. Hypertensive hyperhomocystinemic patients showed a reduced response to acetylcholine, as compared with normohomocystinemic subjects. In both subgroups, L-NMMA failed to blunt the response to acetylcholine. The potentiating effect of vitamin C on acetylcholine was greater in hyperhomocystinemic patients than in normohomocystinemic subjects, although it restored the inhibitory effect of L-NMMA on acetylcholine-induced vasodilation to the same extent in both groups. Hyperhomocystinemia did not change the response to sodium nitroprusside. CONCLUSIONS: In normotensive subjects and hypertensive patients, hyperhomocystinemia impairs endothelium-dependent vasodilation. It could be related to oxidant activity.

Imaging of somatostatin receptors by indium-111-pentetreotide correlates with quantitative determination of somatostatin receptor type 2 gene expression in neuroblastoma tumors.

We reported previously that the relative level of gene expression for sst2, a subtype of somatostatin receptors, was positively related to patient outcome in the childhood tumor neuroblastoma (NB). Because sst2 binds with high-affinity octreotide and its scintigraphic derivative, 111In-pentetreotide, we tested the hypothesis of whether NB tumor imaging with 111In-pentetreotide gives similar information to ex vivo measurement of sst2 expression. We, therefore, studied simultaneously nine NB tumors with 111In-pentetreotide single photon emission computed tomography and competitive reverse transcription-PCR for sst2, along with other prognostic markers. To quantitate the relative abundance of 111In-pentetreotide binding to NB tumors, we developed a simple semiquantitative method, based on the mathematical analysis of 111In-pentetreotide association to cancer cell receptors at different time points (4 and 24 h). We indeed found that the ratio between the activity in a manually extracted region of interest from pathological (ROIT) and background (ROINT) area was increasing between early and late acquisition only in affected tissues. The rate of this pathological increase was quite different among patients and significantly (P < 0.01) related to the abundance of sst2 gene expression, as measured by competitive reverse transcription-PCR on ex vivo tumor samples. Because we demonstrated that in 26 NB patients the density of sst2 is strongly related to survival (P < 0.0005) and apparently independent from N-myc oncogene amplification (P < 0.05), we propose that NB tumor imaging with 111In-pentetreotide may have not only a diagnostic but also a prognostic value.

Menopause is associated with endothelial dysfunction in women.

To evaluate the effect of endogenous estrogens on endothelial function in humans, we examined whether menopause is associated with impairment in endothelium-dependent vasodilation in normotensive and essential hypertensive women. In 73 normotensive subjects (37 women, 36 men) and 73 hypertensive patients (36 women, 37 men), we studied endothelial function by measuring forearm blood flow modifications (strain-gauge plethysmography) induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 micrograms/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1,2, and 4 micrograms/100 mL per minute), an endothelium-independent vasodilator. Women younger than 45 years had normal menstrual cycles. In essential hypertensive patients, responses to acetylcholine but not to sodium nitroprusside were significantly (P < .001) reduced compared with responses in normotensive subjects. Moreover, in both groups, vasodilation to acetylcholine showed a marked negative correlation with advancing age (normotensive subjects: r = -.88, P < .001; hypertensive patients: r = -.87, P < .001). In contrast, vasodilation to sodium nitroprusside showed a less evident negative correlation with advancing age (normotensive subjects: r = -46, P < .01; hypertensive patients: r = -.48, P < .01). However, in normally menstruating normotensive women, no endothelial dysfunction was observed, and age-related impairment in endothelium-dependent vasodilation was evident only after menopause. In normally menstruating hypertensive women, aging was associated with endothelial dysfunction although the deterioration of endothelium-dependent vasodilation was less marked than that in men. In contrast, after menopause, the age-related endothelial dysfunction in hypertensive women was similar to that observed in men. Finally, no sex-related difference in the response to sodium nitroprusside was observed in either normotensive subjects or essential hypertensive patients. Age-related endothelial dysfunction is attenuated in premenopausal normotensive and hypertensive women compared with men, whereas no sex-induced difference is observed after menopause, suggesting a protective effect of endogenous estrogens on endothelial function.

Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women.

Acute exogenous estrogen administration enhances endothelial function in postmenopausal women. To evaluate the effect of endogenous estrogen on endothelium-dependent vasodilation, in 10 fertile normotensive women (age range 45 to 51 years) we studied the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, 1.5 micrograms.100 mL-1.min-1), an endothelium-dependent vasodilator, or sodium nitroprusside (1, 2, 4 micrograms.100 mL-1.min-1), an endothelium-independent vasodilator, in basal conditions and within 1 month after ovariectomy. As control subjects, 10 matched healthy women were also evaluated. In basal condition, vasodilation to acetylcholine and sodium nitroprusside was similar in patients and control subjects. Ovariectomy was followed by endogenous estrogen deprivation (from 71.6 +/- 31.3 to < 12 pg/mL) and was associated with a significant (P < .01) reduction in acetylcholine-induced vasodilation compared with baseline (maximum percent increase in forearm blood flow: baseline 568.2 +/- 47.1%; ovariectomy 309.5 +/- 37.4%); the response to sodium nitroprusside was unaffected by ovariectomy (maximum percent increase in forearm blood flow: baseline 526.4 +/- 36.5%; ovariectomy 454.7 +/- 47.2%; P = NS). In 6 of 10 patients, the study was repeated after 3 months of estrogen replacement therapy (17 beta-estradiol, 50 micrograms/d by transdermal patches). Exogenous estrogen restored acetylcholine-induced vasodilation (maximum percent increase in forearm blood flow: 548.9 +/- 43.1%; P < .01 versus ovariectomy), which was no longer different from baseline, whereas the response to sodium nitroprusside was not affected (maximum percent increase in forearm blood flow: 480.2 +/- 39.3%; P = NS). These results suggest a protective role of endogenous estrogen on endothelium-dependent vasodilation in the forearm vascular bed of normotensive women.

Endothelial dysfunction in hypertension is independent from the etiology and from vascular structure.

The aim of our study was to evaluate the relationships between endothelial function, small resistance artery structure, and blood pressure in patients with primary or secondary hypertension. Sixty subjects were included in the study: 9 patients with pheochromocytoma, 10 with primary aldosteronism, 17 with renovascular hypertension, and 13 with essential hypertension with 11 normotensive subjects who served as controls. Clinic and 24-hour ambulatory blood pressure (ABPM) were evaluated. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on a micromyograph and the media/lumen ratio was calculated. A dose-response curve to acetylcholine was performed at cumulative concentrations from 10(-9) to 10(-5) mol/L. The vasodilator response to acetylcholine was similarly impaired in the four groups of hypertensive patients (ANOVA P<.05 versus normotensive controls), without any significant difference among them. In subcutaneous small arteries of patients with either primary aldosteronism or renovascular hypertension, a marked increase in media:lumen ratio was observed, while in patients with pheochromocytoma, the extent of vascular structural alterations was similar to that observed in essential hypertension. No significant correlation between media-lumen ratio or clinic blood pressure and maximum acetylcholine-induced vasodilatation was observed. On the contrary, a significant, albeit not very close, correlation between ABPM values and maximum acetylcholine-induced vasodilatation was observed (r=34, P<.05 with 24-hour systolic blood pressure, r=0.36, P<.05 with 24-hour diastolic blood pressure). In conclusion, endothelial dysfunction seems to be independent from the degree of vascular structural alterations and from the etiology of hypertension, and it is probably more linked to the hemodynamic load.

Endogenous androgens and carotid intimal-medial thickness in women.

The influence of endogenous androgens on atherosclerotic disease in women is unknown. In this study involving 101 pre- and post-menopausal females, we evaluated the relationship between serum androgen levels and both carotid artery intimal-medial thickness (IMT) and major cardiovascular risk factors. In addition to evaluation of blood pressure, body mass index, and waist-to-hip ratio, serum dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), total testosterone (TTS), free testosterone (FTS), insulin, cholesterol (total and high density lipoproteins), triglycerides, and glucose were measured. All women underwent carotid ultrasonography. Spearman correlation coefficients showed that serum DHEA-S and A levels were negatively related (P < 0.03-0.0004) to several IMT measures. Higher tertiles of DHEA-S, A, and FTS corresponded to significantly lower measures of carotid thickness. DHEA-S, and all androgens were inversely related to age (P < 0.03 or less), showing no unfavorable association with major cardiovascular risk factors. In contrast, serum DHEA-S was negatively associated with WHR (P < 0.02), while A was negatively associated with body mass index (P < 0.02). Stepwise multiple regression analysis indicated that A and FTS showed an inverse association with IMT measures (P < 0.05-0.001). In conclusion, our data indicate that in women serum DHEA-S and androgens decline with age and that normal hormonal levels are not associated with major cardiovascular risk factors. They also show that higher DHEA-S and androgen concentrations are related to lower carotid wall thickness; for A this association is independent of cardiovascular risk factors. Our results suggest that, in the physiological range, DHEA-S and androgens in women are correlated with lower risk of carotid artery atherosclerosis.

Angiogenesis in human normal and pathologic adrenal cortex.

The angiogenic phenotype of 13 normal adrenal glands (N), 13 aldosterone-producing adenomas (APA), 12 cortisol-producing adenomas (CPA), 13 nonfunctioning adrenal cortical adenomas (NFA), and 13 adrenal cortical carcinomas (CA) was investigated. Intratumoral vascular density was explored by CD34, a marker of endothelial cells, and the angiogenic status was investigated by vascular endothelial growth factor (VEGF) expression, an important angiogenic factor expressed by tumoral cells. Vascular density, quantified as the number of vessels per square millimeter, was significantly lower (P < 0.0001) in CA (110.3 +/- 27.8) than in N (336.6 +/- 14.5), APA (322.8 +/- 19.1), CPA (288.5 +/- 14.3), and NFA (274.2 +/- 19.8). VEGF expression, calculated as the percentage of positive cells, was significantly greater (P < 0.0001) in CA (85.3 +/- 2.1) than in APA (56.5 +/- 7.5), CPA (38.5 +/- 7.0), N (33.1 +/- 6.1), and NFA (0.76 +/- 0.6). In APA, a negative relation between CD34 and plasma renin activity (P < 0.0002) and a positive association between CD34 and aldosterone levels (P < 0.05) was found. In conclusion, the angiogenic phenotype of CA is characterized by VEGF overexpression but low vascularization, a finding suggesting a dissociation between angiogenic potential and neoangiogenic capabilities of these tumors. The lack of VEGF expression in NFA and the close association between angiogenesis and functional status in APA also suggest a possible influence of the angiogenic phenotype on hormonal secretion of these endocrine tumors.

Quantitative determination of sst2 gene expression in neuroblastoma tumor predicts patient outcome.

Neuroblastoma (NB) is the most common pediatric neuroendocrine tumor, and it is characterized by a quite variable clinical course. We previously found a great variability in the expression of somatostatin receptor type 2 (sst2) in several human NB cell lines and primary tumors. In this report we investigated whether expression of sst2 is somehow related to clinical outcome. We performed a retrospective study on 54 patients with a maximum follow-up of 100 months. The concentration of specific messenger ribonucleic acid (mRNA) for sst2 was measured by competitive RT-PCR and validated, in a small subset of samples, by quantitative imaging of gene (in situ hybridization) and protein (immunohistochemistry) expression. We found that sst2 mRNA was variably expressed in all NB tumors (range, 2.5 x 10(5) to 8 x 10(9) molecules/microg RNA) with a relevant reduction in the more advanced stage (P < 0.01). Analysis of Kaplan-Meier curves indicated that sst2 expression is positively related to the overall (P < 0.0001) and event-free (P < 0.0001) survival. Expression of sst2 was negatively related to tumor stage (P < 0.02) and MYCN amplification (P < 0.001), a poor prognostic factor. However, the prognostic information derived from sst2 is apparently independent from MYCN amplification, as assessed by stratifying sst2 values according to MYCN. In addition, the expression of sst2 was the only significant prognostic factor (P < 0.02) when it was included in a multivariate model containing other well known prognostic factors such as age, stage, and MYCN amplification. Hence, we propose that sst2 expression represents a new prognostic marker for NB. The main clinical value of a quantitative measure of sst2 lies in its ability to detect patients at low risk, independently from other prognostic factor, including MYCN amplification.

Hyperglycemia and prognosis of acute myocardial infarction in patients without diabetes mellitus.

The present study assessed the prognostic value of hyperglycemia--a common feature in the early phase of acute myocardial infarction (AMI)--in 330 nondiabetic patients. Seventy-nine known diabetics and 10 (3%) unknown diabetics--diagnosed before discharge by stable glycosylated hemoglobin greater than 6.9% and by oral glucose tolerance testing--were excluded. Thirty-three (10%) patients died. The mortality rate was higher in women, in patients with anterior AMI, in older patients (greater than 65 years) and in the presence of heart failure. It was highest in patients with cardiogenic shock (24/36 vs 9/294; p less than 0.0001). Admission plasma glucose was significantly higher in nonsurvivors than in survivors (163 +/- 60 vs 114 +/- 36 mg/dl; p less than 0.0001). Mortality rate increased with increasing admission plasma glucose: 3% in normoglycemic patients (less than or equal to 120 mg/dl) versus 15% in patients with borderline plasma glucose (121 to 180 mg/dl) versus 43% in hyperglycemic patients (greater than 180 mg/dl) (p less than 0.0001). Multiple regression (stepwise) analysis identified cardiogenic shock, infarct site and age as the major determinants of mortality, while admission plasma glucose failed to reach full statistical significance (p = 0.067). Hyperglycemia was related to all 3 of these independent prognostic factors; when age and infarct site were accounted for, hyperglycemia was significantly associated with heart failure only and this association was characterized by a remarkable mortality rate. In nondiabetic patients with AMI, hyperglycemia is a correlate of heart failure and, therefore, an important factor of prognosis.

The inter-relationship between insulin resistance and hypertension.

Insulin resistance and compensatory hyperinsulinaemia commonly occur in patients with untreated essential hypertension. The coexistence of insulin resistance and hypertension can be viewed as a cause-effect relationship (insulin resistance as a cause of hypertension or vice versa) or as a noncausal association. Insulin can increase blood pressure via several mechanisms: increased renal sodium reabsorption, activation of the sympathetic nervous system, alteration of transmembrane ion transport, and hypertrophy of resistance vessels. Conversely, hypertension can cause insulin resistance by altering the delivery of insulin and glucose to skeletal muscle cells, resulting in impaired glucose uptake. For example, hypertension can impair vasodilation of skeletal muscle as a result of vascular structural changes and rarefaction, and increased response to vasoconstrictor stimuli. Also, the prevalence of muscle type 2b fibres (fast twitch fibres) may contribute to the development of insulin resistance. The common pathogenetic mechanism for both insulin resistance and hypertension could be activation of the sympathetic nervous system. This results in vasoconstriction, and may contribute to the genesis of vascular structural changes and increase the number of fast twitch fibres. Finally, hypertension and insulin resistance can be viewed as a noncausal association, according to the following hypotheses: 1) they may represent 2 independent consequences of the same metabolic disorder (intracellular free calcium accumulation), or 2) insulin resistance is a genetic marker and/or a pathogenetic mechanism of multiple metabolic abnormalities frequently associated with hypertension.

Influence of endogenous androgens on carotid wall in postmenopausal women.

OBJECTIVE: There is increasing evidence of a direct association between normal androgen levels and reduced cardiovascular morbidity and mortality in women. After menopause the influence of estrogens declines, whereas that of androgens increases. Therefore, we investigated the effects of androgens on atherosclerosis in postmenopausal women, by using carotid artery intimal-medial thickness as a marker of vascular damage. DESIGN: Blood pressure, body mass index, waist-to-hip ratio, serum dehydroepiandrosterone sulfate, androstenedione, total and free testosterone, estrone, insulin, lipid profile, and glucose were evaluated in 44 women in stable physiological menopause. All subjects underwent carotid ultrasound (Biosound 2000 II s.a. high-resolution unit). RESULTS: Spearman correlation coefficients indicated that serum androstenedione and free testosterone were negatively associated with several carotid intimal-medial thickness measures with correlation coefficients (r) ranging from 0.477 to 0.397 (p < 0.01-0.04). Moreover, age-adjusted androstenedione and free testosterone highest tertiles showed intimal-medial thickness values significantly (p < 0.03-0.05) lower than the other tertiles. There was a favorable association between hormones and the most important cardiovascular risk factors. This association, however, did not reach statistical significance. Stepwise multiple regression analysis showed that the inverse relationships between the hormones (androstenedione and free testosterone) and several intimal-medial thickness measures were maintained (F: 4.15-6.07, p < 0.05-0.02) after adjustment for major cardiovascular risk factors. CONCLUSIONS: Our data demonstrate that in postmenopausal women endogenous steroid precursors and androgens are inversely related to carotid intimal-medial thickness, an established marker of atherosclerosis. In addition, these hormones show favorable associations with cardiovascular risk factors. Therefore, our study suggests that, after menopause, normal androgen levels may benefit the carotid artery wall.

G-CSF serum pharmacokinetics during peripheral blood progenitor cell mobilization: neutrophil count-adjusted dosage might potentially improve mobilization and be more cost-effective.

The optimal dosing schedule of G-CSF for peripheral blood progenitor cell (PBPC) mobilization is still under investigation although many centers use 10 microg/kg/day in a single subcutaneous dose. However, G-CSF clearance increases with increasing absolute neutrophil count (ANC). Hence a G-CSF dosage adjusted to ANC might be a reasonable approach. We measured G-CSF trough serum levels by sandwich ELISA assay at different ANCs in eight patients undergoing treatment with filgrastim at 10 microg/kg/day in a single subcutaneous dose. A total of 26 samples were analyzed, and a strong correlation between increasing ANC and decreasing G-CSF levels was found by linear regression analysis (P < 0.0003, r2 = 0.4199). For ANC values above 5000/microl the trough serum levels, ie 24 h after administration, were consistently below the level that provides maximal clonogenic precursor stimulation in vitro (10 ng/ml). Serial serum G-CSF measurements performed in three patients at 0, 3, 6, 9 and 24 h after G-CSF administration, showed a reduction of the area under the curve (AUC) with increasing ANC. For an ANC of 20000/microl or greater, the G-CSF serum level fell under the maximal in vitro stimulation threshold of 10 ng/ml within 12 h. This preliminary pharmacokinetic data seems to suggest that an ANC-adjusted G-CSF dosing schedule might improve the design of PBPC mobilization regimens.