Search

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10−9). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism. © 2021 UICC

Angiotensin II (Ang II) action on vascular smooth muscle cells is not limited to contraction, but includes long term effects such as hypertrophy and hyperplasia. This implies a complex pattern of gene modulation, which remains largely unknown. We used the mRNA differential display method to screen rat aortic smooth muscle cells cultured with or without Ang II. We demonstrated that Ang II induces the expression of calponin, a 34-kD protein, which has been shown to regulate smooth muscle cell contraction and to be a marker of smooth muscle cell differentiation. We demonstrated this induction both at gene and protein level in vascular smooth muscle cells. Calponin mRNA was dose-dependently induced by Ang II, with an effect still evident at 5 x 10(-9)M, and it did not require active protein synthesis, since cycloheximide treatment did not suppress this induction. Calponin gene expression was maximal at 3 h, while protein expression was maximal at 8 h. Calponin expression was completely abolished by the AT1 receptor antagonist, losartan, at 1 x 10(-6)M. Our data demonstrate that Ang II increases calponin gene expression and protein level in rat aortic smooth muscle cells in vitro.

Background Unstable angina is most frequently caused by coronary thrombosis, with or without plaque fissure, but the mechanisms underlying these events are still speculative. Since cytomegalovirus (CMV) antigens and DNA encoding CMV major immediate-early (MIE) gene have been detected in atherosclerotic arterial walls, the active replication of CMV may be responsible for plaque instability. Therefore the expression of CMV MIE gene mRNA, an early marker of viral replication, was assessed in coronary atherectomy specimens from patients with stable or unstable angina. Methods and Results Twenty patients with unstable angina (12 men and 8 women; mean age, 62 years; range, 44 to 89 years) and 20 patients with stable angina (16 men and 4 women; mean age, 62 years; range, 43 to 81 years) who underwent successful directional coronary atherectomy were enrolled in the study. The efficiency of mRNA extraction, transcription, and amplification from each coronary atherectomy specimen was assessed by performance of reverse transcription and thermal cycling amplification of a 548-bp human β-actin cDNA segment. After Southern blotting and hybridization with a specific probe, all specimens but one showed a positive hybridization signal. The negative sample was excluded from the study. Reverse transcription and thermal cycling amplification of a 145-bp CMV cDNA segment of the MIE gene were then carried out. After Southern blotting and hybridization with a specific probe, none of the specimens showed a positive hybridization signal. Plasmid pACYC 184 containing the Xba I–inserted MIE gene cDNA was used as a positive control: as few as 10 molecules of the plasmid per reaction were detectable after amplification. Conclusions Our results do not support the hypothesis that, in patients with unstable angina, replication of CMV in coronary atherosclerotic plaques is a major cause of plaque instability. These findings suggest that the research for the causes of unstable angina should be directed toward processes other than CMV replication.

Ang II (angiotensin II) has multiple effects on vascular smooth muscle cells through the modulation of different classes of genes. Using the mRNA differential-display method to investigate gene expression in rat aortic smooth muscle cells in culture in response to 3 h of Ang II stimulation, we observed that Ang II down-regulated the expression of a member of the family of transmembrane receptors for Wnt proteins that was identified as Fzd2 [Fzd (frizzled)-2 receptor]. Fzds are a class of highly conserved genes playing a fundamental role in the developmental processes. In vitro, time course experiments demonstrated that Ang II induced a significant increase (P

Objectives It has been shown that angiotensin II (Ang II) induces the expression of calponin, a 34 kD actin-binding protein, in vascular smooth muscle cells in vitro. The aim of this study was to investigate whether Ang II can modulate calponin gene expression in rat aorta in vivo. Design Aortic calponin gene expression was studied after chronic exogenous Ang II administration and in Goldblatt hypertension. Methods To investigate the effect of Ang II administration, Sprague Dawley rats were treated for 6 days with a continuous infusion of Ang II (200 ng/kg per min) or saline by osmotic minipumps. The effect of endogenous Ang II on aortic calponin mRNA expression was studied in Goldblatt hypertensive rats with (2K1C model), or without (1K1C model) activation of the renin-angiotensin system. In particular, calponin gene expression in 2K1C rats was studied both at 1 week (2K1C-HR, high renin) and 4 weeks after the onset of hypertension, when plasma renin activity (PRA) was returned to normal values (2K1C-NR, normal renin). Systolic blood pressure (SBP) was measured twice a week. At the end of the experimental period, PRA was measured by radioimmunoassay, and aortic calponin gene expression was measured by Northern hybridization. Results SBP was significantly higher (P < 0.01), whereas PRA was suppressed (P < 0.01), in Ang II versus saline-treated rats. Northern hybridization showed that the aortic calponin gene expression significantly increased (2.5-fold) in Ang II-treated rats (P = 0.01). In Goldblatt hypertensive rats, SBP was significantly higher in 2K1C-HR (P < 0.01), 2K1C-NR (P < 0.01) and 1K1C (P < 0.01) rats compared with the corresponding sham-treated rats. Activation of the renin-angiotensin system was present only in 2K1C-HR rats (P < 0.01), and Northern analysis showed that aortic calponin mRNA expression was significantly increased (2.2-fold) in this group of rats only (P < 0.01). Conclusions Our data demonstrate that both exogenous and endogenous Ang II increase calponin gene expression in aortic smooth muscle cells, independently of the hemodynamic effect of Ang II. (C) 2001 Lippincott Williams & Wilkins.

A growing amount of data supports the role of inflammation in the pathophysiology of atherosclerotic diseases but the cellular source of cytokines has not been clearly identified. Cytokines could be produced by inflammatory cells, activated endothelial and smooth muscle cells, and by the tissue exposed to recurrent ischemia. Accordingly, we evaluated whether hypoperfusion induces gene expression of interleukin (IL)-1beta and IL-6 in the skeletal muscle of patients with peripheral arterial disease and critical limb ischemia.Skeletal muscle biopsies were obtained, during a femoral-distal bypass, from normoperfused (control) and hypoperfused skeletal muscles in 8 patients. Gene expression was assessed by semiquantitative reverse transcriptase-polymerase chain reaction, using glyceraldehyde-phosphate-deydrogenase mRNA levels as a normalization factor.In the hypoperfused biopsies, the level of IL-1beta gene expression was significantly higher in all but 2 patients (mean upregulation8.8 fold, p = 0.043), and the level of IL-6 gene expression was significantly higher in all but 1 patient (mean upregulation23.7 fold, p = 0.031).We report that IL-1beta and IL-6 gene expression is markedly upregulated in hypoperfused skeletal muscle of patients with critical lower limb ischemia. To our knowledge this is the first report of a local activation of the inflammatory cascade at the level of hypoperfused skeletal muscle. This activation, which could worsen symptoms and tissue viability and be involved in the pathophysiology of reperfusion injury, might be considered as a therapeutic target. It remains to be investigated whether our results may also apply to coronary artery disease.

The presence of inflammatory infiltrates in unstable coronary plaques suggests that inflammatory processes may contribute to the pathogenesis of these syndromes. In patients with unstable angina, coronary atherosclerotic plaques are characterized by the presence of macrophages, and to a lesser extent, T-lymphocytes, at the immediate site of either plaque rupture or superficial erosion; moreover, the rupture-related inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption. These observations are confirmed by clinical studies demonstrating activated circulating neutrophils, lymphocytes and monocytes, and increased concentrations of pro-inflammatory cytokines, such as interleukin (IL) 1 and 6, and of acute phase reactants in patients with unstable angina and myocardial infarction. In particular elevated levels of C-reactive protein are associated with an increased risk of in-hospital and 1 to 2 years new coronary events in patients with unstable angina, but are also associated with an increased long-term risk of death and myocardial infarction in apparently normal subjects. Thus, accumulating evidence suggests that inflammation may cause local endothelial activation and, possibly, plaque fissure, leading to unstable angina and infarction. Although no information is yet available on the causes of inflammation and on its localization, these novel lines of research may open the way to a different approach to the patient with acute coronary syndromes.

The importance of genetics to the pathogenesis of myocardial infarction is suggested by the frequent familial clustering of premature disease. Yet, studies associating myocardial infarction with gene polymorphisms of vascular proteins (angiotensinogen, angiotensin converting enzyme, angiotensin II type 1 receptor, endothelial nitric oxide synthase) and haemostatic factors (fibrinogen, coagulation factors II, V, VII and XIII, plasminogen activator inhibitor-1, tissue-type plasminogen activator, platelet glycoproteins IIb/IIIa, Ia/IIa and Ib-IX-V, or methylenetetrahydrofolate reductase) have revealed conflicting results. This is hardly surprising, given: 1) the multigenic nature of myocardial infarction, whereby single polymorphisms are bound to play at best only a limited role in the global risk of disease; 2) the multiple pathogenetic mechanisms of infarction (e.g., atheromatous obstruction, plaque rupture, thrombosis, vasospasm), each of which is likely influenced by a number of genes and by several environmental factors. The simultaneous investigation of a set of polymorphisms--and of their interactions with environmental factors--in extremely homogeneous sets of patients should offer a better understanding of the contribution of specific genes to the risk of myocardial infarction.

One of the most potent pro-inflammatory mediators is the early-acting cytokine interleukin (IL)-1, whose actions are regulated by the structurally related IL-1 receptor antagonist (IL-1 Ra). IL-1 Ra is a competitive IL-1 inhibitor and a powerful anti-inflammatory agent. Several autoimmune and inflammatory diseases have been associated with an allelic polymorphism of the IL-1 Ra gene.We investigated the frequency of allele 2 of an intron 2 polymorphism of the IL-1 Ra gene in 115 consecutive patients with ischemic heart disease -74 of which had a previous myocardial infarction (48 +/- 11 years), 21 chronic stable angina (54 +/- 10 years), and 20 unstable angina (54 +/- 9 years)--and in 80 healthy controls, matched for age and sex to patients with myocardial infarction (47 +/- 10 years). An 86 base pair variable tandem repeat in intron 2 of the IL-1 Ra gene was determined by a polymerase chain reaction-based method.The frequency of allele 2 was 15% in controls (carriage rate 25%) and 17% in ischemic heart disease patients (carriage rate 28%; p = 0.70). The allele 2 frequency did not differ significantly among the three patient groups. Among patients with myocardial infarction, the allele 2 frequency tended to be higher in patients with myocardial infarction40 years compared to thoseor = 40 years (20 vs 11%, p = 0.20, OR 1.85, 95% CI 0.70-4.90), and in patients with C-reactive protein levelsor = 3 mg/l compared to those with values3 mg/l (31 vs 16%, p = 0.15, OR 2.38, 95% CI 0.64-9.25).These data do not show a clear-cut association between the allele 2 of this IL-1 Ra gene polymorphism and ischemic heart disease. Among patients with myocardial infarction, the increased allele 2 frequency in those of younger age and with higher levels of C-reactive protein merits further investigation.

To evaluate the scientific output of Italy compared to other countries in clinical and basic research, the twelve top ranking journals according to the impact factor in each group were considered. A total impact factor score of one country was the sum of the impact factor of all articles attributed to a certain country in all journals. Italy ranked sixth in clinical research but only ninth in basic research. According to our analysis, the Italian scientific output in the biomedical field is comparable to that of other countries. Further financial analysis of the correlation between research funding and scientific output could allow a more productive allocation of resources.

In this article, the clinical, angiographic, and postmortem features of unstable angina are reviewed and its pathogenesis is discussed. Coronary plaque inflammation may play a key role in the pathogenesis of unstable angina and the evidence for this assertion is examined. Finally, the therapeutic implications of the involvement of inflammation in acute coronary syndromes are outlined.

Background. The radial artery was first used as a coronary graft by Carpentier and associates in 1973 but, due to the disappointing results, it was abandoned. In 1992 its revival coincided with the widespread use of calcium-channel blockers in cardiovascular surgery, in the belief they could prevent spasm. Methods. From January 1993 to October 1995 we operated on 109 patients for myocardial revascularization employing the radial artery with two different surgical techniques: in 95 patients (group 1) it was "pretreated" by opening its fascia after a gentle hydrostatic dilation and then anastomosed to the aorta; in 14 patients (group 2) it was branched to another conduit. We had two operative deaths (1.82%). Results. At a mean interval of 532.42 days 105 patients are still alive, 2 (1.86%) having died of abdominal tumors. Fifty-six patients (52.33%) underwent angiography at a mean interval of 334.42 days: the patency of the radial artery was 88.88% in group 1 and 62.50% in group 2. Indications and contraindications are discussed. Conclusions. The radial artery is an easily manageable conduit whose early patency is very promising, although a longer follow-up is mandatory.

Background Although a major role of coronary thrombosis in the pathogenesis of unstable angina has been demonstrated, the results of a series of studies have suggested that activation of the hemostatic system may not be confined to ischemic episodes. The purpose of this study was to investigate the temporal relation between ischemic episodes and activation of the coagulation system in unstable angina. Methods and Results Thrombin–antithrombin III (TAT) and prothrombin fragment 1+2 (F 1+2 ) levels were measured in 13 patients during spontaneous ischemic episodes (time 0, 5, and 15 minutes and 1 hour) to evaluate the time course of the activation of the coagulation system associated with the development of ischemia (protocol A). TAT and F 1+2 levels were also measured in 28 patients with unstable angina on admission to hospital (every 6 hours for 24 hours and daily for 3 days) to assess their temporal relation with ischemic episodes (protocol B). In protocol A, TAT and F 1+2 levels were elevated in 10 of 13 patients (77%) in at least 1 sample. The median value of TAT showed a peak at 5 minutes and returned to baseline within 15 minutes ( P 1+2 showed no significant changes, possibly because of its longer half-life, which tends to dampen sudden bursts of thrombin production. In protocol B, activation of the clotting system was found in 10 of 33 samples (30%) temporally related to ischemia and also in 23 of 150 (15%, P =.07) of those not temporally related to ischemia. Conclusions Our study demonstrates that patients with active unstable angina develop frequent bursts of thrombin production not necessarily associated with ischemic episodes and that, conversely, some ischemic episodes are not associated with evidence of thrombin activation.

Background: Lipopolysaccharide (endotoxin) has been shown to increase the expression of plasminogen activator inhibitor type-1 (PAI-1) in the vessel wall. Endotoxin is known to increase PAI-1 production in endothelial cells, but its action on smooth muscle cells (SMCs) is presently not clear. In this study we determined the effect of endotoxin on PAI-1 and tissue plasminogen activator (t-PA) production by aortic SMCs in vivo in two animal species, and in culture. Methods: The aortas of Sprague Dawley rats and of New Zealand White rabbits were rapidly excised after parenteral administration of endotoxin. Total RNA was extracted from the aortic media, and PAI-1 and t-PA mRNA levels were quantified after Northern blotting. In addition, cultured rat aortic SMCs were treated with endotoxin. PAI activity in the conditioned medium was determined with a spectrophotometric assay, and total RNA was extracted from the cells and analyzed. Results: A rapid and strong induction in the aortic media of PAI-1 mRNA was observed by endotoxin in both rat (50 mg/kg) and rabbit (1 mg/kg). t-PA mRNA was barely detectable and was not increased by endotoxin. Studies in cultured SMCs showed low expression of PAI-1 mRNA under serum-free conditions and little PAI activity in the cell-conditioned medium. Endotoxin did not increase the levels of PAI-1 mRNA nor PAI activity under serum-free conditions. The effect of endotoxin (10 mg/ml) in the presence of 10% (v/v) newborn calf serum on PAI-1 mRNA was negligible; PAI activity, however, increased by 50.3 ± 7.3% compared with controls. mRNA levels of t-PA and low-density lipoprotein/receptor-related protein/α2-macroglobulin receptor also increased after endotoxin administration. PAI activity was identified as PAI-1 by immunoblotting. Fibrin zymography showed that t-PA was present only in complex with PAI-1. Conclusions: A strong increase in PAI-1 gene expression by endotoxin was observed in aortic SMCs in vivo but not in culture. This suggests that the effect of endotoxin on SMCs is indirect. The fibrinolytic/proteolytic potential of the SMCs in the vessel wall is likely to have important implications for the migration of cells during vessel wall remodeling, such as neointima formation, during tumor cell metastasis, and for the fate of intramural thrombi. © Kluwer Academic Publishers. Chemicals/CAS: alpha 2 macroglobulin, 95568-41-5; fibrin, 9001-31-4; plasminogen activator inhibitor 1, 140208-23-7; RNA, 63231-63-0; tissue plasminogen activator, 105913-11-9

Until a few years ago coronary atherosclerosis was thought to be a slowly progressive disease eventually leading to total coronary occlusion and myocardial infarction. Recent angiographic studies have shown, instead, that mild or moderate coronary stenoses have the highest risk of causing acute coronary syndromes when complicated by thrombus formation which, in turn, appears to be due to a complex interaction between the atherosclerotic background and acute ischemic stimuli. The tendency of the atherosclerotic background to develop thrombosis may be different in different patients, as indicated by the observation that the risk factor profile of patients who present with chronic coronary syndromes is different from that of patients who present with acute syndromes. The acute ischemic stimuli so far identified are: a sudden local thrombogenic stimulus; a transient systemic increase in systemic pro-coagulant activity; a transient increase in proximal and/or distal coronary tone. The recent observation of inflammatory cells activation, including T-lymphocytes, in patients with acute ischemic syndromes raises the intriguing possibility that a specific antigenic stimulus may play an important pathogenetic role.

Sudden limitations in coronary flow account for the majority of cases of UA. Measurement of TAT in peripheral blood represent a reliable marker of an ongoing thrombotic process. The aim of the study was to assess the reliability of frequent blood sampling (Phase A) and to correlate TAT fluctuation to clinical symptoms of ischemia in patients with UA (Phase B). We included into the study 6 normal volunteers (Phase A) and 31 patients with unstable angina admitted to our Coronary Care Unit within 24 hours from the last ischemic episode (Phase B). In both groups the blood was collected every 6 hours for 24 hours and then every day for 2 days. After venipuncture the blood was immediately collected in CTAD tubes placed in melting ice and centrifuged at 2000 g and 4°C for 20 minutes, plasma aliquots of 500 μl were snap-frozen and stored at −80°C. The aliquots were assayed for TAT complexes using a commercially available ELISA assay. TAT levels in normas remained stable and below pathologic levels during the study and no significant increase was observed with repeated venipuncture. In 11 out of 31 patients (35%) no episode of TAT increase was observed, in 20 (65%) at least 1 episode was observed. Five patients without episodes of TAT increase did not have any ischemic event during the hospitalization, but all patients with episodic elevation had recurrent ischemia during the study (p < 0.005). Our data demonstrate that sampling by clear venipuncture do not cause itself an activation of the haemostatic system and suggest that frequent sampling might be important for better understanding the pathophysiology of UA.

BACKGROUND The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase plasminogen activator inhibitor type 1 (PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several steps of its intracellular signaling pathway. METHODS AND RESULTS The expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in cultured rat VSM cells was studied. Northern blot analysis demonstrated a severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with 300 nmol/L Ang II. A similar response for TPA mRNA was observed. This induction did not require the synthesis of an intermediate protein or peptide because it was not affected by cycloheximide. In the cell-conditioned supernatant, the net result was an increase in PAI-1 activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang II-induced increase in PAI activity was dose related, with a maximal effect at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L (n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L Ang II. In basal conditions, fibrin overlay zymography demonstrated the presence of free TPA. After stimulation with Ang II, lysis caused by the in situ dissociation of TPA was also present in the region of the TPA/PAI-1 complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar to that obtained with equivalent doses of Ang II. Captopril (5 micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE), completely prevented the Ang I effect, demonstrating that VSM cells display an ACE-like activity. CONCLUSIONS Recent research has demonstrated the existence of a localized vascular renin-angiotensin system. The finding that Ang II can potentially modulate the plasminogen activation in the arterial wall has important biological and therapeutical implications for the evolution of arterial wall thrombi and the migration of cells through the vessel wall in the genesis of atherosclerotic lesions. We speculate that the reduction in thrombotic events observed in patients with a previous myocardial infarction and in high-renin, hypertensive patients treated with ACE inhibitors could be due at least in part to the decreased production of PAI-1 by VSM cells caused by these agents.

Vascular smooth muscle (VSM) cell migration and proliferation play a major role in the development of atherosclerotic lesions, graft occlusion, and restenosis after angioplasty. Cell migration implies the digestion of the surrounding extracellular matrix. Cell-associated proteolysis has been extensively studied in neoplastic and inflammatory cells, but very little is known about the proteolytic properties of VSM. We have evaluated the ability of rat cultured VSM cells to solubilize [3H]amino acid-labeled extracellular matrices produced by bovine VSM. When plated at a density of 30,000 cells per well in 24 multiwell plates, VSM cells were able to solubilize 63.3 +/- 7.0% of the extracellular matrix after 10 days in culture. Extracellular matrix digestion occurred also when the cells were cultured in plasminogen-depleted serum but was higher in the presence of 10 micrograms/ml purified plasminogen (net percent digestion after the subtraction of the appropriate control, 8.6 +/- 3.0% versus 21.2 +/- 3.5% after 3 days in culture, p less than 0.005, respectively). The involvement of other enzymes in addition to plasmin is confirmed by the ability of VSM cells to degrade extracellular matrices from which the plasmin-sensitive component was removed with plasmin pretreatment. Rat VSM cells were able to solubilize 52.3 +/- 2.0% of this residual extracellular matrix-associated radioactivity after 6 days in culture versus 26.1 +/- 1.5% in the control dishes (p less than 0.01, n = 5). Cell contact was required for extracellular matrix degradation: cell-conditioned medium did not have any effect on extracellular matrix digestion.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the reliability of the Del Mar Avionics indirect blood pressure (BP) monitoring system 15 hypertensive patients were concomitantly studied with the intraarterial Oxford system. During daytime a statistically significant correlation was found between the BP values obtained with the two systems. On the contrary during the night this correlation in most cases was not significant. However the histograms of the between-method differences were similar during the day and the night, showing that the Del Mar Avionics Pressurometer (P) performs equally well throughout the 24 hours. It is concluded that the P is reliable for continuous indirect BP monitoring and suitable for the evaluation of the efficacy of antihypertensive treatments.

To investigate the prevalence and nature of ventricular arrhythmias in athletes, 40 well trained healthy endurance athletes (20 cyclists and 20 runners) and 40 healthy sedentary subjects as controls were studied. Twenty four-hour continuous ECG monitoring showed a higher, even though not significant prevalence of ventricular ectopy in athletes (70% vs 55%). Complex forms of ventricular ectopy were also more prevalent in the athletes than in the controls (25% vs 5%; p less than 0.05). A prolongation of both measured QT interval and QT corrected for heart rate was observed at the ECG. Echocardiograms showed higher dimensional indices in the athletes, while functional indices were similar in athletes and controls. No correlation was found between any ECG or echocardiographic finding and the grade of ventricular arrhythmia. The comparison between the cyclists and the runners did not show any significant difference in the prevalence of ventricular arrhythmias or in the QT interval duration.

1 Labetalol was administered by intravenous infusion or by the combination of intravenous bolus injection plus infusion to 15 patients with severe essential hypertension and to one with phaeochromocytoma. 2 With the infusion alone the reduction of arterial pressure was slow to develop and limited in degree, but with the combination of the bolus injection plus the infusion the reduction in pressure was more prompt, more pronounced and longer lasting. Apart from an uncomplicated syncopal attack in one patient, no serious side--effects were encountered. 3 Subsequent treatment with oral labetalol usually required the addition of a diuretic to control the blood pressure probably due to sodium and fluid retention during treatment with labetalol alone.

The effects of bilateral glomectomy on arterial blood pressure and heart rate and the response to the pressor tests were studied in a women of 37. Arterial pressure and ECG were recorded by the continuous unrestricted Oxford method. Hypotension, increased blood pressure variability and tachycardia rapidly developed 2 days after surgery, indicating sympathetic hyperactivity and/or deactivation of vagal tone. Wide blood pressure fluctuations were present on standing and abnormal blood pressure responses to head up tilting and to the Valsalva maneuver were observed reflecting a less prompt and precise control of blood pressure. Treatment with propranolol reduced tachycardia and blood pressure variability. After 5 and 17 months of this therapy propranolol was withheld for 36 h. Tachycardia was still present and blood pressure fluctuations were recorded on assuming the upright posture. However, the heart rate and pressure response to the Valsalva maneuver were normal after 17 months, indicating an improvement of the reflex control of blood pressure.

Aim of the present study was to verify whether average blood pressure continuously recorded throughout the day correlates with the degree of target organ damage more closely than casual pressure in hypertensive patients. The study was conducted in 102 subjects with borderline, moderate and severe hypertension. Our results confirm a closer relationship between cardiovascular complications and recorder blood pressure than casual pressure possibly because the latter less perfectly reflects the patients usual pressures which are generally lower. However our results further demonstrate that blood pressure variability also contributes to the degree of target organ damage since for equal average day-time pressures a greater severity of cardiovascular complications was observed in patients with the highest blood pressure variability and the highest peaks of pressure. These findings should be carefully considered when evaluating the effect of antihypertensive drugs.

Blood pressure signals recorded continuously in ambulatory patients using the Oxford system were analyzed by an IBM 37o computer in order to obtain beat by beat systolic and diastolic blood pressure along 24 hour blood pressure recordings. The analogical-digital conversion of the signal and the analysis of the sphygmogram are presented and discussed. Synthesis of the several thousands data obtained in 24 hour recordings and plotting of the data for clinical purposes and pharmacological studies are also reported.

In this study, the Pressurometer III (Del Mar Avionics) was used to monitor blood pressure on two occasions in 17 ambulatory hypertensive patients. In 9 patients a placebo was administered between the first and the second monitoring. In the remaining 8 patients, placebo administration was discontinued prior to the first monitoring period.

In A7r5 vascular smooth muscle cells, the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) caused a marked increase in the rate of unidirectional Ca2+ influx and a 63 +/- 9% increase in net 30-min 45Ca2+ uptake. Maximal TPA-stimulated 45Ca2+ uptake occurred at concentrations less than or equal to 3 nM and was equivalent to the maximal uptake stimulated by 55 mM KCl or 1 microM Bay k 8644. TPA-stimulated Ca2+ uptake was not additive to KCl- or Bay k 8644-stimulated uptake, and was inhibited by verapamil (100 microM), nitrendipine (1 microM), or high concentrations of Bay k 8644 (greater than or equal to 10 microM). The biologically inactive phorbol ester 12-O-tetradecanoyl phorbol-13-acetate methyl ether (10 nM) had no effect on 45Ca2+ uptake. TPA caused a 43 +/- 12% increase in Ca2+ efflux in 30 min, and exposure to TPA (10 nM) for 5 and 30 min caused no significant change in net cellular Ca2+ content as determined by radioisotopic equilibration or atomic absorption spectroscopy. TPA caused no apparent change in intracellular free Ca2+ concentration as determined with quin 2. Thus, in A7r5 cells, TPA causes a marked increase in Ca2+ influx through channels with the pharmacological characteristics of dihydropyridine-sensitive, voltage-dependent channels. This TPA-stimulated Ca2+ uptake is associated with increased Ca2+ efflux and no significant change in net cellular Ca2+ content or intracellular free Ca2+ concentration.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tissue remodeling processes. TIMP-1 is the main native inhibitor of MMPs and it contributes to the development of tissue fibrosis. It is known that ANG II plays a fundamental role in vascular remodeling. In this study, we investigated whether ANG II modulates TIMP-1 expression in rat aortic smooth muscle cells. In vitro, ANG II induces TIMP-1 mRNA expression in a dose-dependent manner. The maximal increase in TIMP-1 expression was present after 3 h of ANG II stimulation. The ANG II increase in TIMP-1 expression was mediated by the ANG type 1 receptors because it was blocked by losartan. The increase in TIMP-1 expression was present after the first ANG II treatment, whereas repeated treatments (3 and 5 times) did not modify TIMP-1 expression. In vivo, exogenous ANG II was administered to Sprague-Dawley rats (200 ng · kg−1· min−1sc) for 6 and 25 days. Control rats received physiological saline. After treatment, systolic blood pressure was significantly higher ( P < 0.01), whereas plasma renin activity was suppressed ( P < 0.01), in ANG II-treated rats. ANG II increased TIMP-1 expression in the aorta of ANG II-treated rats both at the mRNA ( P < 0.05) and protein levels as evaluated by Western blotting ( P < 0.05) and/or immunohistochemistry. Neither histological modifications at the vascular wall nor differences in collagen content in the tunica media were present in both the ANG II- and saline-treated groups. Our data demonstrate that ANG II increases TIMP-1 expression in rat aortic smooth muscle cells. In vivo, both short- and long-term chronic ANG II treatments increase TIMP-1 expression in the rat aorta. TIMP-1 induction by ANG II in aortic smooth muscle cells occurs in the absence of histological changes at the vascular wall.

To the Editor. —We read with interest the article by Chrysant et al in the MarchArchives(1983;143:437-441). We also recently observed the development of acute reversible renal failure in a patient. Report of a Case. —A 30-year-old woman had high-grade bilateral renal artery stenosis. She was judged inoperable in December 1976, and she was treated conservatively for four years with 10 mg of minoxidil three times a day, 40 mg of propranolol hydrochloride three times a day, 10 mg of amiloride hydrochloride, and 50 mg/day of hydrochlorothiazide. With this drug regimen her BP ranged between 140 to 160 mm Hg (systolic) and 85 to 95 mm Hg (diastolic) and renal function test results were in the normal range. In January 1983, because of severe hirsutism, the minoxidil dosage was tapered to 2.5 mg three times a day, and therapy with captopril (25 mg twice a day) was added. Seven