Budd-Chiari syndrome in a patient heterozygous for the G20210A mutation of the prothrombin gene.
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Adult↗
Biomedical subjects
F Franchi
Publications and source records attributed to F Franchi.
[The dispersion of ventricular repolarization diagnosed by Holter: limitations and possibilities].
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Electrocardiography, Ambulatory↗
Activation of the protein C pathway in hereditary thrombophilia.
Levels of free activated protein C are a measure of the activation of the protein C pathway in vivo. The aim of this study was to establish if the protein C pathway is triggered in familial thrombophilia and if activated protein C levels correlate with type of defect or symptoms. We measured activated protein C in 133 patients with a deficiency of antithrombin (n = 31), protein C (n = 24) or protein S (n = 27) or with resistance to activated protein C (n = 51). Levels of activated protein C were evaluated also in 97 healthy individuals. Results indicate that the levels of activated protein C are higher in patients who have experienced a thrombotic event than in patients who have not and that 71% of patients with levels of activated protein C above the normal reference range had had a venous thromboembolic event. We conclude that the protein C pathway is triggered in patients with thrombophilia and that in symptomatic patients, activated protein C levels are increased and may reflect heightened coagulation activation and scavenging through the protein C pathway.
Adult↗
Homozygous G20210A prothrombin gene mutation without thromboembolic events: a case report.
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3' Untranslated Regions↗
The transition G to A at position 20210 in the 3'-untranslated region of the prothrombin gene is not associated with cerebral ischemia.
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Adult↗
Resistance to activated protein C in unselected patients with arterial and venous thrombosis.
Four hundred and ninety-three consecutive patients referred for arterial or venous thrombosis were screened for congenital and acquired abnormalities of blood coagulation predisposing to thrombosis, and were compared to 341 age- and sex-matched controls. The aim of the study was to determine the prevalence and clinical characteristics of resistance to activated protein C (APC), a defect shown to have different prevalences in different ethnic groups and to be associated with an increased risk of thrombosis. Seventy-three (15%) patients had both APC resistance and the 1691 G to A factor V gene mutation, compared to 6/341 (2%) controls. Seven patients had antithrombin deficiency (1.4%), 11 had protein C deficiency (2.2%), and 4 had protein S deficiency (0.8%). The relative risk of thrombosis in APC-resistant patients was 9.4. Resistance to APC was associated mainly with venous thrombosis, the most frequent being deep-vein thrombosis of the lower limbs. Fifty-eight percent of APC-resistant patients had an associated risk factor at the first thrombotic event: pregnancy and oral contraceptive intake were associated with the first thrombotic episode in 35% and 30% of women, respectively. APC resistance is the most frequent defect of blood coagulation in the general population and in the unselected thrombotic population studied by us.
Adult↗
A phase I trial of 5-day chronomodulated infusion of 5-fluorouracil and 1-folinic acid in patients with metastatic colorectal cancer.
The aim of this phase I study was to establish the maximum tolerated dose (MTD) of 5-fluorouracil (5-FU), administered as a 5-day chronomodulated infusion in combination with 1-folinic acid (FA) to ambulatory metastatic colorectal cancer patients. Consecutive cohorts of 6 patients were given 5-FU and FA infusions from 10.00 p.m. to 10.00 a.m. with peak delivery at 4.00 a.m. by means of a multichannel programmable pump. The FA dose was always the same (150 mg/m2/d). For the first cohort, the 5-FU dose level was 600 mg/m2/d at the first course, escalated by 100 mg/m2 for each subsequent cohort. Intrapatient dose was also escalated by 100 mg/m2 if toxicity was less than grade 2. The courses were repeated every 3 weeks. Thirty-four patients (17 previously treated) received a total of 154 courses. Dose-limiting toxicity consisted of stomatitis and diarrhoea. No significant haematological, cutaneous or cardiac toxicity was encountered. The MTD of 5-FU was reached at the fourth level (first course at 900 mg/m2/d equal to 4500 mg/m2/course) with 5-FU increased to 1100 mg/m2/d (5500 mg/m2/course) in 4 patients. The received 5-FU dose intensity (DI) over the first 3 courses at this level was 1318 mg/m2/week. Thirty-three patients were assessed for response. An objective response was achieved in 1 out of the 13 previously-treated and in 8 out of the 20 previously-untreated patients. The chronomodulated infusion of 5-FU at a dose of 900 mg/m2/d, together with FA at 150 mg/m2/d for 5 days, was safely delivered to out-patients with metastatic colorectal cancer. The low toxic profile and activity of this regimen in previously untreated patients deserves further exploration for the treatment of 5-FU-sensitive tumours.
Adenocarcinoma↗
Parallel increase in carotid, brachial and left ventricular cross-sectional areas in arterial hypertension.
Few data have been published about the relation between the vessels geometry and development of left ventricular (LV) hypertrophy in patients with arterial hypertension. The aim of this study is to describe arterial and LV geometry changes due to mild-to-moderate arterial hypertension in an untreated hypertensive population. In 95 untreated patients with mild-to-moderate hypertension and 23 age- and sex-matched healthy normotensives, we measured the end-diastolic diameter and wall thickness of the left ventricle and the internal diameter and intimal-medial thickness (IMT) of carotid and brachial arteries. From these data, the cross-sectional areas (CSAs) of arterial and myocardial walls were calculated. Hypertensive patients were further subdivided on the basis of the presence of LV hypertrophy defined according to Devereux et al as anatomical LV mass >125 g/m. In hypertensive patients with hypertrophy, carotid and brachial CSAs increased, without significant changes in thickness/diameter ratio (arterial 'enlargement'), while the left ventricle developed 'concentric' hypertrophy. Arterial and LV CSAs showed a significant direct correlation with systolic blood pressure (BP). However, when data were corrected for BP, the correlation between the increase in arterial and LV CSAs became much improved than for the raw data. In conclusion patients with untreated mild-to-moderate hypertension, both carotid and brachial arterial walls showed an enlargement that was proportional to the development of LV hypertrophy. These results suggest that the effects of arterial hypertension on carotid, brachial and LV wall geometry have a common modulation.
Adult↗
Autonomic regulation of heart rate and QT interval in nonalcoholic cirrhosis with ascites.
BACKGROUND/AIMS: Autonomic neuropathy, as indicated by alterations in standard cardiovascular tests, is frequently encountered in cirrhosis. We investigated the autonomic modulation of the heart in nonalcoholic cirrhosis with ascites by evaluating the 24-hour heart rate variability (HRV), a powerful noninvasive tool to assess the sympathovagal balance of the heart. METHODS: Low (LF) and high frequency (HF) components and their ratio, and time domain indexes of HRV were evaluated in 24-hour, daytime and nighttime periods in 12 patients and 12 healthy subjects, together with the conventional and dynamic QT interval. RESULTS: Cirrhotic patients had values of the mean RR interval and frequency domain indexes in the whole 24-hour period similar to those of healthy subjects, despite higher than normal plasma norepinephrine levels. Patients also showed lower LF and higher HF values than controls during the day, a reduction in time domain indexes, and no circadian rhythm of frequency domain indexes. QT parameters were similar in the 2 groups, but patients had a blunted QT rhythm and a reduced QT variability. CONCLUSIONS: Patients with nonalcoholic cirrhosis and ascites have an impaired autonomic regulation of the heart, which involves both the sympathetic and the parasympathetic branches of the autonomic nervous system.
Aged↗
Beyond 5-fluorouracil monochemotherapy in colorectal cancer--it is time.
Over the last 40 years the treatment of colorectal cancer has not achieved the same progress as treatment for other types of tumors. Fluorouracil, with the various modulations, still remains the most effective treatment. This article summarizes the protocols in which fluorouracil is combined with other agents in order to obtain the best results. Researchers in this field need to reach a new consensus on the evaluation of colorectal cancer response to different protocols in order to obtain more precise data on the activity of new anticancer regimens.
Antimetabolites, Antineoplastic↗
The role of hypoxic stop-flow perfusion and high dose chemotherapy in the treatment of regionally advanced colorectal cancer.
The primary or secondary forms of colorectal cancers involving local structures or spreading in the abdomen or pelvic area without extra-regional metastases are identified as regionally advanced colorectal cancers (RACRC). They are unresectable and thus radiotherapy and chemotherapy are the fundamental treatment methods. However, these regimens have failed to check the diffusion of tumor satisfactorily in most forms of RACRC. The abdominal and pelvic regions can be isolated from corporal circulation by temporary occlusion of the aorta and cava and perfused with high doses of chemotherapeutic drugs. The hypoxic abdominal or pelvic stop-flow method for delivering high-dose antiblastic agents to these body districts to avoid toxicity by chemofiltration has been suggested. This study examines the possibility of using this method to treat various forms of RACRC.
Abdominal Neoplasms↗
Modulation of 5-fluorouracil in mice using uridine diphosphoglucose.
Uridine diphosphoglucose (UDPG) is a precursor of uridine that can be used as a rescuing agent from 5-fluorouracil (5FU) toxicity. Four doses of UDPG (2000 mg/kg i.p. or p.o. at 2, 6, 24, and 30 h after 5FU bolus) allowed the escalation of a weekly bolus of 5FU from 100 mg/kg (5FU100) to 150 mg/kg (5FU150) in healthy and tumor-bearing BALB/c, C57/BI, and CD8F1 (BALB/c x DBA/8) mice. 5FU150 without rescuing agents is not tolerated by the animals. When followed by UDPG, on the contrary, it is possible to increase the dose of 5FU even when it is modulated by leucovorin. Toxicity was the same for 5FU100 and 5FU150 + UDPG, and the nadir values (expressed as a percentage of pretreatment values) were 83 and 85% for weight, 45 and 45% for hematocrit, and 45 and 61% for leukocytes, respectively. Platelets were not affected by treatment. A protective effect was also shown for the gastrointestinal tract. The enzymes thymidine kinase, maltase, and sucrase were measured in the intestinal mucosa at different times after 5FU treatment with or without UDPG rescue. Even if the nadir values in enzyme activities were similar in mice receiving or not receiving UDPG, the pattern of recovery showed that cell repopulation was more rapid in the group treated with UDPG. 5FU150 + UDPG had enhanced antitumor activity against CD8F1 mammary carcinoma and against the resistant tumor Colon 26 (tumor doubling time 1.9 days for controls, 8.5 days for 5FU100, 13.7 days for 5FU150 + UDPG, and 15.9 days for 5FU150 + leucovorin + UDPG). We demonstrated that UDPG administered at 2, 24, and 30 h after 5FU100 does not reduce the antitumor activity of 5FU in two sensitive tumors (Colon 38 and Colon 26-10). In conclusion, UDPG is a promising rescuing agent for 5FU; it reduces the toxic side effects and increases the therapeutic index.
Animals↗
Resistance to activated protein C mimicking dysfunctional protein C: diagnostic approach.
It has been reported that resistance to activated protein C interferes with functional plasma-based coagulation assays of protein C, mimicking a type II deficiency. In this study we confirm and extend these findings. In our laboratory approximately 25% of patients with resistance to activated protein C have an apparent type II protein C deficiency. It is important for rapid and accurate diagnosis to be able to confirm or exclude a dysfunction of protein C associated with resistance. We therefore propose a new coagulation assay that requires first absorption of protein C from plasma, activation with a snake venom and measurement of its anticoagulant activity. This assay is quick, reproducible and can be automated. It is also insensitive to the presence of resistance to activated protein C and allows detection of all types of protein C deficiency. This is important when screening for inherited causes of thrombophilia since more than one defect might be present and interference from resistance to activated protein C is common.
Drug Resistance↗
The same molecular mechanism at the maternal meiosis I produces mono- and dicentric 8p duplications.
We studied 16 cases of 8p duplications, with a karyotype 46,XX or XY,dup(8p), associated with mental retardation, facial dysmorphisms, and brain defects. We demonstrate that these 8p rearrangements can be either dicentric (6 cases) with the second centromere at the tip of the short arm or monocentric (10 cases). The distal 8p23 region, from D8S349 to the telomere, including the defensin 1 locus, is deleted in all the cases. The region spanning from D8S252 to D8S265, at the proximal 8p23 region, is present in single copy, and the remaining part of the abnormal 8 short arm is duplicated in the dicentric cases and partially duplicated in the monocentric ones. The distal edge of the duplication always spans up to D8S552 (8p23.1), while its proximal edge includes the centromere in the dicentric cases and varies from case to case in the monocentric ones. The analysis of DNA polymorphisms indicates that the rearrangement is consistently of maternal origin. In the deleted region, only paternal alleles were present in the patient. In the duplicated region, besides one paternal allele, some loci showed two different maternal alleles, while others, which were duplicated by FISH analysis, showed only one maternal allele. We hypothesize that, at maternal meiosis I, there was abnormal pairing of chromosomes 8 followed by anomalous crossover at the regions delimited by D8S552 and D8S35 and by D8S252 and D8S349, which presumably contain inverted repeated sequences. The resulting dicentric chromosome, 8qter-8p23.1(D8S552)::8p23.1-(D8S35)-8q ter, due to the presence of two centromeres, breaks at anaphase I, generating an inverted duplicated 8p, dicentric if the breakage occurs at the centromere or monocentric if it occurs between centromeres.
Abnormalities, Multiple↗
Systemic hemodynamics and renal function during brain natriuretic peptide infusion in patients with essential hypertension.
We assessed the cardiovascular and renal effects of human brain natriuretic peptide (BNP) infused at a dose inducing an increase in plasma BNP to pathophysiologic levels, in eight hypertensive patients in a randomized, placebo-controlled, cross-over study. Left ventricular performance, cardiac output (echocardiography), heart rate, arterial pressure, glomerular filtration rate (GFR; creatinine clearance), sodium excretion, intrarenal sodium handling (lithium clearance method), and urine flow rate were measured in the infusion and postinfusion periods (1 h each), together with plasma BNP and the urinary excretion rate of cGMP. Plasma BNP levels increased from 2.90 +/- 0.74 to 36.43 +/- 5.51 pmol/L (P < .01) at the end of the infusion and were still elevated at the end of the postinfusion period (7.03 +/- 1.41 pmol/L, P < .05). The urinary excretion of cGMP was also significantly higher during BNP infusion. Left ventricular performance, cardiac output, arterial pressure, and peripheral vascular resistance were not affected by BNP. Peptide infusion induced a significant increase in GFR (placebo, 115 +/- 24; BNP, 147 +/- 19 mL/min), sodium excretion (placebo, 129 +/- 40; BNP, 243 +/- 60 mumol/min), and urine flow rate. All these effects were observed also in the postinfusion period. The natriuretic effect of BNP was attributable to both an increase in filtered sodium load and a reduction of distal sodium reabsorption. These results suggest that BNP may contribute to maintain renal function and sodium excretion in patients with essential hypertension.
Adult↗
Antitumour activity, toxicity and inhibition of thymidylate synthase of prolonged administration of 5-fluorouracil in mice.
Continuous infusions of 5-fluorouracil (5-FU) are increasingly used in the treatment of cancer. Their optimal use, however, has still to be determined since the availability of suitable animal models is limited. We studied continuous infusions in mice using subcutaneously implanted pellets that release 5-FU over a period of 3 weeks. At the maximum tolerated dose (MTD) (based on the systemic toxicity in healthy animals) we assessed the antitumour activity, haematological toxicity, inhibition of thymidylate synthase (TS) in tumours and the concentration of 5-FU in plasma during the 3-week period. We also studied the addition of leucovorin in different schedules. The dose-limiting toxicity was weight loss, and at the MTD of 10 mg of 5-FU released in 21 days per mouse myelosuppression was tolerable (nadir for leucocytes and thrombocytes was approximately 40% of pretreatment levels). In several independent experiments using the 5-FU-resistant Colon 26 tumour, a good antitumour activity was observed during the first part of the infusion, but thereafter the growth of the tumours resumed; the overall effect of continuous infusions was thus comparable to that of bolus injections. Coadministration of leucovorin did not enhance the therapeutic results; depending on the schedule used, it proved ineffective or only increased toxicity. Similar results were obtained with head and neck squamous cell carcinomas and with the 5-FU-sensitive tumour Colon 38. In Colon 26 tumours the TS activity (FdUMP-binding assay) initially decreased to 20-30% of controls and returned to normal after 11 days. In the catalytic TS assay a slight inhibition was observed for the continuous infusion, followed after 11 days by a marked (4-fold) increase in activity. 5-FU plasma levels varied from 0.1 to 1 microM following a circadian rhythm (with a peak at 6 h after light onset), and were maintained during the entire period. Subcutaneously implanted pellets represent a suitable model to study prolonged administration of 5-FU in mice and to evaluate the effect of modulating agents in laboratory animals before transferring data obtained in vitro to the clinic.
Animals↗
Cardiovascular function during brain natriuretic peptide infusion in man.
To investigate the cardiovascular effects of pathophysiological levels of brain natriuretic peptide (BNP), 7 healthy subjects were submitted to equilibrium radionuclide angiocardiography in baseline conditions and during BNP infusion at increasing doses (4, 8, 10 and 12 pmol/kg.min for 20 min each). BNP induced a progressive, significant reduction in left ventricular end diastolic volume, stroke volume and end systolic volume and an increase in ejection fraction and heart rate. Cardiac output, arterial pressure and peripheral vascular resistance were unchanged. Activation of the sympathetic nervous system, as indicated by the significant increase in plasma norepinephrine levels, probably played a contributory role in the maintenance of cardiovascular homeostasis. These results indicate that BNP, at pathophysiological plasma concentrations, influences cardiovascular homeostasis in man.
Adult↗
Cardiovascular effects of brain natriuretic peptide in essential hypertension.
We evaluated the cardiovascular effects of pathophysiological plasma levels of brain natriuretic peptide in seven patients with mild to moderate essential hypertension by performing equilibrium radionuclide angiocardiography at baseline and during brain natriuretic peptide infusion at increasing doses (4, 8, 10, and 12 pmol/kg per minute for 20 minutes each). Brain natriuretic peptide induced a progressive reduction of left ventricular end-diastolic volume (from 107.5 +/- 10.3 to 89.0 +/- 11.0 mL at the end of all infusion periods) and end-systolic volume, whereas stroke volume did not show any significant change (from 64.9 +/- 5.9 to 62.7 +/- 7.8 mL). Cardiac output, arterial pressure, and peripheral vascular resistance did not change significantly. The lack of effects on systemic hemodynamics was probably due to compensatory activation of the sympathetic nervous system, as indicated by the significant increase in plasma norepinephrine levels (from 1.75 +/- 0.18 to 2.19 +/- 0.21 nmol/L), heart rate (from 68 +/- 6 to 81 +/- 6 beats per minute), peak ejection rate, and peak filling rate. These results indicate that brain natriuretic peptide, at the pathophysiological plasma concentrations reached in this study, influences cardiovascular homeostasis mainly by reducing cardiac preload.
Aged↗