Biomedical subjects

A Ciucci

Publications and source records attributed to A Ciucci.

At least 19 recordsLinked to original sources

PubMed2006

Cardiac myxoma cells exhibit embryonic endocardial stem cell features.

The origin of myxoma, the most frequent tumour of the heart, remains uncertain. Previous phenotypic characterizations have shown heterogeneous results and the most recent hypothesis suggests that cardiac myxoma originates from a primitive pluripotential cardiogenic cell. We investigated the expression of actin isoforms in 30 left atrial myxomas by immunohistochemistry and in eight consecutive tumours by RT-PCR. alpha-Smooth muscle actin (alpha-SMA) protein and/or transcripts were detected in all cases, whereas alpha-cardiac actin was observed in few cases and alpha-skeletal actin was always absent. Besides classical features, vessel-like structures were characterized by cells expressing CD34 and, less frequently, alpha-SMA. Confocal microscopy showed focal co-expression of CD34 and alpha-SMA in myxoma cells, suggesting a gradual loss of stem endothelial markers and the acquisition of myocytic antigens. In order to confirm this hypothesis, early cardiac differentiation markers were also investigated. RT-PCR documented the presence of transcripts for Sox9 (100%), Notch1 (87.5%), NFATc1 (37.5%), Smad6, metalloproteinases 1 and 2 alone or in variable combinations and the absence of ErbB3 and WT1. Myxoma cells maintained phenotypic heterogeneity in vitro, including the expression of alpha-SMA and the presence of stress fibres. These findings document in cardiac myxoma cells phenotypic markers of the embryonic endothelial-to-mesenchymal transformation that precedes terminal differentiation of endocardial cushions, supporting the hypothesis that cardiac myxoma cells may derive from adult developmental remnants.

Actins↗

PubMed2006

Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes.

OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.

Aged↗

PubMed2005

[Cardiac tumors].

Primary cardiac tumors are rare and their subdivision often difficult because of their unknown origin. In the most recent classification, cardiac tumors are divided into benign (about 75% and malignant neoplasms in relationship to their tissue differentiation (rhabdomyoma, haemangioma, etc.) or uncertain aetiology (myxoma, papillary fibroelastoma). Primary malignant tumors are maimly represented by sarcomas. The most frequent tumor is cardiac myxoma, which by itself represents about 50% of all primary cardiac neoplasms. Although non-invasive technologies as trans-esophageal ecocardiography allow the detection and exact localization of cardiac mass, clinical diagnosis is often tardive. This is due, besides the intrinsic rarity, to two main factors: first, the tumor is often asymptomatic (incidental autopic finding) or; alternatively, it may show aspecif symptoms mimicking heart failure or other pathologies. In this article, clinicopathological features of main primary cardiac tumors are presented. Investigation of the histogenesis of some of these neoplasms is still a primary field of research.

Adult↗

PubMed2004

Cellular retinol-binding protein-1 expression in endometrial stromal cells: physiopathological and diagnostic implications.

AIMS: Cellular retinol-binding protein-1 (CRBP-1) contributes to the maintenance of the differentiated state of the endometrium through retinol bioavailability regulation. The aim was to analyse CRBP-1 expression in endometrial stromal cells at eutopic and ectopic sites in different physiopathological conditions. METHODS AND RESULTS: Antibodies to CRBP-1, CD10 and alpha-smooth muscle actin were applied to proliferative (n = 10), secretory (n = 9) and atrophic (n = 7) endometrium, decidua (n = 4), adenomyosis (n = 5), endometriosis (n = 10), endometrial polyps (n = 9), simple endometrial hyperplasia (n = 6), well-differentiated endometrioid carcinoma (n = 6) and submucosal leiomyomas (n = 5). In some cases, Western blotting and reverse transcription-polymerase chain reaction were also applied. CRBP-1 was expressed by eutopic and ectopic endometrial stromal cells more markedly during the late secretory phase and in decidua of pregnancy. CRBP-1 expression was low in the stroma of atrophic endometrium and absent in myometrium, leiomyomas and cervical stroma. CD10 immunoreactivity was weak in atrophic endometrium and in decidua. CONCLUSIONS: CRBP-1 expression characterizes endometrial stromal cells at eutopic and ectopic sites and appears to be more specific than CD10. The level of CRBP-1 varies in intensity according to hormonal variations, reaching its maximum in predecidua and decidua. Thus, immunodetection of CRBP-1 may help to elucidate the physiopathological changes which occur in endometrial stroma and can also be applied as an adjuvant stromal marker.

Adult↗

PubMed2004

Unusual cardiac tumour with perivascular myoid differentiation: a case report.

A previously healthy 70 year old woman was admitted for fatigue and dyspnoea on exertion and cough. A two dimensional echocardiography revealed a mass in the right atrium, which obstructed filling and infiltrated the cardiac chamber wall. Postsurgical histological examination revealed an unusual tumour with prevalent myoid glomangiopericytoma-type and haemangiopericytoma-like patterns. Mitosis and necrosis were absent. A computed tomography scan excluded the presence of metastasis to distant organs or, conversely, metastatic involvement of the heart. Therefore, a diagnosis of tumour with perivascular myoid differentiation was made. This new entity, recently described in soft tissues, can easily recur. Its recognition helps to differentiate from metastasis and other primitive cardiac tumours sharing some morphological features but a different clinical behaviour, with consequent improvement to the management of patient care.

Aged↗

PubMed2001

IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells.

Insulin-like growth factor binding proteins (IGFBPs) are important local factors in the development of proliferative diabetic retinopathy. We investigated the effects of IGF-I and increased glucose concentrations on the release of IGFBPs and the growth of human retinal endothelial cells (HRECs). HRECs secrete IGFBPs-2 to -5. IGF-I stimulated thymidine incorporation and modified the pattern of IGFBPs, decreasing the inhibitory IGFBP-4 through down-regulation of its mRNA, and increasing IGFBP-5 which, per se, was able to modulate HREC growth, exerting post-transcriptional control. Studies using an antibody (alpha IR3) against the IGF-I receptor, and compounds with low affinity for IGFBPs, such as insulin and des(1-3)IGF-I, showed that an interaction between IGF-I and IGFBP-5 was necessary to detach this IGFBP from its binding sites. The dose of IGF-I that significantly decreased the IGFBP-4/IGFBP-5 ratio was the same that stimulated HREC growth. Chronic exposure to high concentrations of glucose was able to reduce HREC mitogenesis, interacting with the IGF system through a decrease in the stimulatory IGFBPs-2, -3 and -5, leaving the concentration of the inhibitory IGFBP-4 constant. These results extend our previous observations in endothelial cells and suggest that the IGFBP-4/IGFBP-5 ratio regulates IGF-I-induced growth of HRECs, whereas a general decrease in IGFBPs (except for IGFBP-4) was the anti-proliferative effect of chronic exposure to high glucose concentrations.

Analysis of Variance↗

PubMed2001

Apoptotic events in a human ovarian cancer cell line exposed to anthracyclines.

Cytotoxic drugs commonly used in cancer therapy promote tumor cell death by inducing apoptosis, but the cell death pathway(s) is likely dependent on the mechanism of drug action. In the present study, we investigated the mechanisms of cell death induced by doxorubicin (DXR) and the novel disaccharide anthracycline MEN 10755, in a human ovarian cancer cell line (A2780). Exposure to either anthracycline induced the up-regulation of several genes known to promote cell cycle arrest and DNA repair (WAF1/p21, GADD45) or apoptosis (bax, Fas). Although the expression of Fas was increased, an antagonistic anti-Fas antibody ZB4 did not inhibit anthracycline-induced apoptosis, suggesting that the stimulation of the Fas receptor did not play a critical role in the induction of apoptosis in this cell line. We also observed that neither MEN 10755 nor DXR were able to induce apoptosis in A2780 cells deprived of the nucleus but retaining an intact mitochondrial function (cytoplasts) and that apoptosis induced by either anthracycline was inhibited by cycloheximide, indicating that it is an active process requiring new protein synthesis. Both the caspases inhibitors, ZVAD-fmk and DEVD-cho, inhibited at similar extent apoptosis induced by either DXR or MEN 10755, suggesting an involvement of caspase-3 in this response. We conclude that, in a tumor cell line of epithelial origin, the apoptosis following exposure to anthracyclines is an active process requiring protein synthesis and drug interaction with nuclear structures. The pathway was Fas-independent but likely involved bax and caspase-3 as effectors of the cascade culminating in apoptosis.

Annexins↗

PubMed2000

Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea-pigs.

We have evaluated the potential protective activity of nepadutant, a selective tachykinin NK2 receptor antagonist, in a model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. The injury was quantified visually by using a macroscopic injury score, and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of nepadutant (0.3-10 mg/kg s.c., 1 h before acetic acid) markedly reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early phase of the injury. Single administration of nepadutant (3 mg/kg s.c.) reduced the macroscopic score and myeloperoxidase activity at the top (24 h) of inflammation. Repeated administration (3 mg/kg s.c. three times during 24 h) or co-administration of the tachykinin NK1 receptor antagonist MEN 11467 (3 mg/kg s.c.) did not enhance the antiulcer effect obtained with the single treatment with nepadutant. These data suggest the involvement of tachykinin NK2 receptors in the first phases of inflammation induced by acetic acid.

Acetic Acid↗

PubMed2000

Comparison of capillary electrophoresis with HPLC for diagnosis of factitious hypoglycemia.

BACKGROUND: The diagnosis of "factitious hypoglycemia" is essentially based on the disclosure of hypoglycemic agents in blood or urine. The aim of this study was to evaluate the performance of capillary electrophoresis (CE) as a quantitative method for determination of chlorpropamide, tolbutamide, glipizide, gliclazide, and glibenclamide in serum. METHODS: Serum samples (1 mL), with internal standard added, were purified by solid-phase extraction on OASIS(TM) HLB cartridges (Waters), dried under reduced pressure, and reconstituted with 30-60 microL of acetonitrile:H(2)O. Analysis was carried out by micellar electrokinetic capillary chromatography in 5 mmol/L borate, 5 mmol/L phosphate, 75 mmol/L sodium cholate, pH 8.5, containing 25 mL/L methanol. Separation was accomplished in a 20 cm x 50 microm (i.d.) silica capillary at 25 degrees C and a constant voltage of +10 kV. Pharmacokinetics of gliclazide (80-mg tablet) in a diabetic patient were assayed by both HPLC and CE. Two hypoglycemic patients positive by HPLC analysis for unreported gliclazide and tolbutamide overdose were also screened by CE. RESULTS: Separation of six drugs (including the internal standard) was accomplished in 5 min plus 5 min rinsing. The between-day CV of the ratio of the areas of the sulfonylurea drugs to internal standard was <1% (n = 10). Linearity (r(2) > or =0.998) and recovery (> or =80%) were good for all sulfonylurea drugs tested. Pharmacokinetic curves for gliclazide by CE and HPLC were superimposable. CE analysis confirmed the HPLC diagnosis of surreptitious abuse of gliclazide and tolbutamide. CONCLUSION: CE is a useful tool in the clinical chemistry and toxicology laboratory for drug monitoring and pharmacokinetic investigations.

Adult↗

PubMed1999

Value of a simple echocardiographic linear predictor of left ventricular mass in systemic hypertension.

The need for calculations limits the clinical use of left ventricular (LV) mass. Because LV mass is strictly dependent on wall thickness for every given value of LV external dimension, we tested the clinical value of the sum of LV external dimension plus ventricular septal thickness plus posterior wall thickness as predictors of standard LV mass. We studied 295 healthy normotensive subjects and 1,686 subjects with systemic hypertension, followed up for 1 to 9 years. In the normotensive group, the predictor of LV mass showed a very close association with standard LV mass according to an allometric model (LV mass [g] = 0.230 x LV mass predictor [cm]3.01), with 99.7% of LV mass variability explained by the model. Also, in the hypertensive group, the LV mass predictor showed a very close allometric relation to standard LV mass (R2 = 0.998). During follow-up there were 154 cardiovascular morbid events and 50 deaths from all causes. The risk of cardiovascular morbid events and that of death increased to a similar extent with LV mass normalized by body surface area, height or height2.7, as well as with the LV mass predictor. The risk estimates for cardiovascular morbidity and all-cause mortality provided by models including either LV mass predictor or LV mass uncorrected or corrected by height, body surface area, or height2.7 did not show any statistical differences between the different models. In conclusion, the sum of LV external dimension plus ventricular septum thickness plus posterior wall thickness, easily measurable from the M-mode echocardiographic tracing, very closely predicts standard LV mass in adult hypertensive subjects. The prognostic value of this measure does not differ from that of standard LV mass.

Adult↗

PubMed1999

Circulating insulin and insulin growth factor-1 are independent determinants of left ventricular mass and geometry in essential hypertension.

BACKGROUND: It is unclear whether insulin and insulin-like growth factor-1 (IGF-1) are independent determinants of left ventricular (LV) mass in essential hypertension. METHODS AND RESULTS: We studied 101 never-treated nondiabetic subjects with essential hypertension. All had 24-hour noninvasive ambulatory blood pressure (ABP) monitoring and a 75-g oral glucose tolerance test. We determined fasting glucose, insulin, and IGF-1 and postload glucose and insulin 2 hours after glucose. Insulin resistance was estimated by the homeostasis model assessment (HOMA(IR)) formula. LV mass showed an association with body mass index (BMI) (r=0.47; P<0.01), postload insulin (r=0.54; P<0.01), HOMA(IR) (r=0.39; P<0.01), and IGF-1 (r=0. 43; P<0.01) and a weaker association with average 24-hour systolic and diastolic ABPs (r=0.29 and r=0.26; P<0.05) and basal insulin (r=0.31; P<0.05). Relative wall thickness was positively related to IGF-1 (r=0.39; P<0.01) but not to fasting or 2-hour postload insulin, HOMA(IR), and glucose. In a multiple regression analysis, the final LV mass model (R(2)=0.64) included IGF-1, postload insulin, average 24-hour systolic ABP, sex, and BMI. IGF-1 and postload insulin accounted for >40% of variability of LV mass. The final model (R(2)=0.36) for relative wall thickness included IGF-1 (16% total explained variability), average 24-hour systolic ABP, sex, BMI, and age but not insulin and HOMA(IR). CONCLUSIONS: These data indicate that insulin and IGF-1 are powerful independent determinants of LV mass and geometry in untreated subjects with essential hypertension and normal glucose tolerance.

Adult↗

PubMed1999

Human glomerular endothelial cells IGFBPs are regulated by IGF-I and TGF-beta1.

The release of insulin-like growth factor binding proteins (IGFBPs) and their regulation in human glomerular endothelial cells (GENC) was characterised. GENC produce IGFBP-4, IGFBP-2 and IGFBP-3 and express mRNA for IGFBP-2 to IGFBP-5. Due to the fact that IGF-I and TGF-beta1 modulate glomerular hypertrophy, their action on IGFBP release and GENC growth was studied. IGF-I increased IGFBP-3, IGFBP-2 and decreased IGFBP-4, while TGF-beta1 decreased IGFBP-3 and apparently increased IGFBP-4. All of the IGFBPs, except the TGF-beta1-regulated IGFBP-4, were modulated at mRNA level. IGF-I stimulated GENC proliferation, while TGF-beta1 inhibited their growth. It was demonstrated that an IGFBP-3 antibody reduced GENC proliferation. However, rhIGFBP-3 alone had no effect on GENC, but after 48 h pre-incubation the IGF-I stimulated GENC growth was increased, suggesting that IGFBP-3 could modulate the IGF-I induced GENC proliferation. It was concluded that the stimulatory IGFBP-3 and the inhibitory IGFBP-4 could regulate GENC growth, although the IGFBP-3 seems to have a predominant effect in this control.

Cell Division↗

PubMed1999

Effect of MEN 11467, a new tachykinin NK1 receptor antagonist, in acute rectocolitis induced by acetic acid in guinea-pigs.

The aim of this study was to evaluate the effect of MEN 11467 (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N{N-(p-tolylacetyl)-N-(meth yl)-D-3(2-Naphthyl)alanyl}diaminocyclohexane), a new potent tachykinin NK1 receptor antagonist, in an experimental model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. This effect was compared to that of mesalazine (5-amino-2-hydroxybenzoic acid). The injury was quantified visually by using a macroscopic injury score and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of MEN 11467 (0.3-10 mg/kg s.c., I h before acetic acid) reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early acute phase of the injury (death at 2.5 h). Mesalazine (100 mg/kg p.o., 1 h before) reduced the macroscopic score but not the plasma protein extravasation. Repeated administration of MEN 11467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5% acetic acid) reduced the macroscopic score and myeloperoxidase activity but not the plasma protein extravasation induced in the late phase of acute injury (death at 24 h). At this time mesalazine markedly reduced the macroscopic score, myeloperoxidase activity and plasma protein extravasation induced by 7.5% acetic acid. These results suggest a greater involvement of tachykinin NK1 receptors in the early phase than in the late phase of colonic inflammation in response to chemical injury.

Acetic Acid↗

PubMed1999

Calcium antagonists and cardiovascular risk in patients with hypertension and Type 2 diabetes mellitus: evidence from the PIUMA Study. Progetto Ipertensione Umbria Monitoraggio Ambulatoriale.

We conducted a retrospective analysis of all subjects with essential hypertension and Type 2 diabetes mellitus enrolled in the PIUMA (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale) registry, in order to evaluate whether the use of calcium antagonists is associated with an increase in cardiovascular risk in these subjects. One hundred and sixty-four consecutive subjects with no previous cardiovascular morbid events and coexistence of essential hypertension and Type 2 diabetes mellitus were studied before therapy and followed for up to 12 years (mean 5). There were periodical contacts with family doctors and patients in order to ascertain the occurrence of major cardiovascular events. The use of calcium antagonists that preceded the event was considered for classification. None of the patients was lost to follow-up. At entry, the patients who were subsequently given calcium antagonists (n=50) had a higher clinical (174/98 vs 161/92 mmHg, both p<0.01) and 24-hr ambulatory blood pressure (150/90 vs 141/84 mmHg, both p<0.01) than those who were not. During follow-up there were 53 major cardiovascular morbid events (6.46 per 100 person-years). The rate of total cardiovascular events [5.6 vs 6.8 events per 100 person-years, relative risk 0.88 (95% CI: 0.47-1.61)] and that of cardiac events [4.0 vs 3.3 events per 100 person-years, relative risk 1.33 (95% CI: 0.62-2.89)] did not differ between users of calcium antagonists and non-users. The use of angiotensin converting enzyme inhibitors (n=66) was unrelated to the risk of cardiovascular events (relative risk 1.24, 95% CI: 0.71-2.16). In a Cox multivariate analysis, only age (p=0.002) and 24-hr pulse pressure (p=0.04) were independent predictors of cardiovascular events. In conclusion, this cohort study does not support the hypothesis that use of calcium antagonists is associated with an excess risk of adverse cardiovascular events in uncomplicated subjects with essential hypertension and Type 2 diabetes mellitus.

Aged↗

PubMed1998

Prognostic value of a new electrocardiographic method for diagnosis of left ventricular hypertrophy in essential hypertension.

OBJECTIVES: We tested the prognostic value of a new electrocardiographic (ECG) method (Perugia score) for diagnosis of left ventricular hypertrophy (LVH) in essential hypertension and compared it with five standard methods (Cornell voltage, Framingham criterion, Romhilt-Estes point score, left ventricular strain, Sokolow-Lyon voltage). BACKGROUND: Several standard ECG methods for assessment of LVH are used in the clinical setting, but a comparative prognostic assessment is lacking. METHODS: A total of 1,717 white hypertensive subjects (mean age 52 years; 51% men) were prospectively followed up for up to 10 years (mean 3.3). RESULTS: At entry, the prevalence of LVH was 17.8% (Perugia score), 9.1% (Cornell), 3.9% (Framingham), 5.2% (Romhilt-Estes), 6.4% (strain) and 13.1% (Sokolow-Lyon). During follow-up there were 159 major cardiovascular morbid events (33 fatal). The event rate was higher in the subjects with than in those without LVH (all p < 0.001) according to all methods except the Sokolow-Lyon method. By multivariate analysis, an independent association between LVH and cardiovascular disease risk was maintained by the Perugia score (hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.5 to 2.8) and the Framingham (HR 1.91, 95% CI 1.1 to 3.2), Romhilt-Estes (HR 2.63, 95% CI 1.7 to 4.1) and strain methods (HR 2.11, 95% CI 1.4 to 3.2). The Perugia score showed the highest population-attributable risk for cardiovascular events, accounting for 15.6% of all cases, whereas the Framingham, Romhilt-Estes and strain methods accounted for 3.0%, 7.4% and 6.8% of all events, respectively. LVH diagnosed by the Perugia score was also associated with an increased risk of cardiovascular mortality (HR 4.21, 95% CI 2.1 to 8.7), with a population-attributable risk of 37.0%. CONCLUSIONS: The Perugia score carried the highest population-attributable risk for cardiovascular morbidity and mortality compared with classic methods for detection of LVH. Traditional interpretation of standard electrocardiography maintains an important role for cardiovascular risk stratification in essential hypertension.

Age Factors↗

PubMed1998

Lack of association between blood pressure variability and left ventricular mass in essential hypertension.

Blood pressure (BP) variability could induce detrimental effects on left ventricular (LV) structure in hypertension. We investigated the association between short-term BP variability, assessed with 24-h noninvasive ambulatory BP monitoring, and LV mass at echocardiography in 1822 untreated subjects (953 men, 869 women) with essential hypertension (EH). The standard deviation (SD) of daytime and night-time systolic BP (SBP, r = 0.13/0.10; both P < .001), but not of diastolic BP, showed a weak correlation with LV mass. Because the SD of daytime SBP showed a direct association with average 24-h SBP (r = 0.27), subjects were ranked into quartiles of the distribution of 24-h SBP. For each quartile, the subjects with SD of daytime (and night-time) SBP below or above the median were classified at low or high BP variability. In both genders, subjects with high daytime SBP variability were older than those at low variability (both P < .01). Within each quartile, LV mass did not differ between the groups at low v those at high SBP variability. Overall, age-adjusted LV mass index was 115 and 115 g/m2 in men at low and high daytime SBP variability (P = .84), and 116 and 114 g/m2 in men at low and high nighttime SBP variability (P = .31). The corresponding values in women were 98 and 99 g/m2 (P = .53) and 98 and 99 g/m2 (P = .64). In conclusion, when the effects of age, gender, and average 24-h BP are taken into account, short-term BP variability assessed with noninvasive monitoring is unrelated to LV mass in subjects with EH.

Aging↗

PubMed1998

Point mutation increases a form of the NK1 receptor with high affinity for neurokinin A and B and septide.

1. The binding modalities of substance P and neurokinin A on the wild type and Gly166 to-Cys mutant NK1 receptors expressed on CHO cells were investigated in homologous and heterologous binding experiments using both radiolabelled substance P and neurokinin A. 2. On the wild type NK1 receptor NKA displaces radiolabelled substance P with very low apparent affinity, despite its high-affinity binding constant (determined in homologous binding experiments). The Gly166 to-Cys substitution in the NK1 tachykinin receptor greatly enhances the apparent affinity of neurokinin A in competition for radiolabelled substance P, but it does not change the binding constant of neurokinin A. The mutation, thereby, eliminates the discrepancy between the low apparent affinity and the high binding constant of neurokinin A. 3. On the wild type receptor the binding capacity of neurokinin A is significantly smaller than that of substance P. In contrast, the two tachykinins bind to approximately the same number of sites on the mutant receptor. 4. Simultaneous mass action law analysis of binding data in which multiple radioligands were employed in parallel demonstrated that a one-site model was unable to accommodate all the experimental data, whereas a two-site model provided a dramatically better description. 5. These two receptor-sites display equally high affinity for substance P, while neurokinin A strongly discriminates between a high and a low affinity component. The binding affinities of neurokinin A are not affected by the mutation, which instead specifically alters the distribution between receptor sites in favour of a high affinity neurokinin A binding form. 6. The low apparent affinity and binding capacity of neurokinin A on the wild type receptor results from neurokinin A binding with high affinity only to a fraction of the sites labelled by substance P. The mutation increases the proportion of this site, and consequently enhances the apparent affinity and binding capacity of neurokinin A. 7. The binding modalities of septide-like ligands (i.e. neurokinin B, SP(6-11), SP-methyl ester) are affected similarly to neurokinin A and are better resolved into two sites. The mutation leaves the affinity of these ligands for the two receptor forms unchanged, but increases the fraction of high-affinity sites. On the other hand, the binding of non-peptide and peptide antagonists (SR140.333 and FK888) behaved similarly to substance P with a single high affinity site that is unaffected by the mutation. 8. These findings may suggest that the NK1 receptor exists in two different forms with similar affinity for substance P and NK1 antagonists, but with a high and a low affinity for neurokinin A and septide-like ligands. Hence, the Gly166 in the NK1 receptor would seem to control the distribution between a pan-reactive form and a substance P-selective form of the receptor.

Animals↗

PubMed1998

Adverse prognostic value of a blunted circadian rhythm of heart rate in essential hypertension.

BACKGROUND: Previous studies revealed a direct association between resting heart rate and risk of mortality in essential hypertension. However, resting heart rate is a highly variable measure since it is affected by the alerting reaction to the visit. OBJECTIVE: To investigate whether the heart rate values recorded during the 24 h of ambulatory blood pressure monitoring are independent predictors of survival of uncomplicated subjects with essential hypertension. METHODS: We followed up 1942 initially untreated and uncomplicated subjects with essential hypertension (mean age 51.7 years, 52% men) for an average of 3.6 years (range 0-10 years). All subjects underwent baseline procedures including 24 h non-invasive blood pressure monitoring with simultaneous assessment of heart rate, one reading every 15 min for 24 h. MAIN OUTCOME MEASURES: All-cause mortality and cardiovascular morbidity. RESULTS: During follow-up there were 74 deaths from all causes (1.06 per 100 person-years) and 182 total (fatal plus non-fatal) cardiovascular morbid events (2.66 per 100 person-years). Clinic, average 24 h, daytime and night-time heart rates exhibited no association with total mortality. However, the subjects who subsequently died had had a blunted reduction of heart rate on going from day to night during the baseline examination. After adjustment for age (P < 0.001), diabetes (P < 0.001) and average 24 h systolic blood pressure (SBP, P= 0.002) in a Cox model, for each 10% less reduction in the heart rate from day to night the relative risk of mortality was 1.30 (95% confidence interval 1.02-1.65, P = 0.04). Rates of death were 0.38, 0.71, 0.94 and 2.0 per 100 person-years among subjects in the four quartiles of the distribution of the percentage reduction in heart rate from day to night The baseline day-night changes in the heart rate exhibited an inverse correlation to age and to clinic and ambulatory SBP and a direct association with the day-night changes in blood pressure. The degree of reduction of heart rate from day to night also had an independent inverse association with total cardiovascular morbidity after adjustment for age, diabetes and left ventricular hypertrophy, but this association did not remain significant when average 24 h SBP and the degree of day-night reduction in SBP were entered into the equation. CONCLUSIONS: A flattened diurnal rhythm of heart rate in uncomplicated subjects with essential hypertension is a marker of risk for subsequent all-cause mortality and this association persists after adjustment for several risk factors. For assessing these subjects, a limited and uniformly distributed period of ambulatory heart rate recording during the 24 h is clinically valuable.

Adult↗