Brachytherapy boost (BT-boost) or stereotactic body radiation therapy boost (SBRT-boost) for high-risk prostate cancer (HR-PCa).

Systematic review for the treatment of high-risk prostate cancer (HR-PCa, D'Amico classification risk system) with external body radiation therapy (EBRT)+brachytherapy-boost (BT-boost) or with EBRT+stereotactic body RT-boost (SBRT-boost). In March 2020, 391 English citations on PubMed matched with search terms "high risk prostate cancer boost". Respectively 9 and 48 prospective and retrospective studies were on BT-boost and 7 retrospective studies were on SBRT-boost. Two SBRT-boost trials were prospective. Only one study (ASCENDE-RT) directly compared the gold standard treatment [dose-escalation (DE)-EBRT+androgen deprivation treatment (ADT)] versus EBRT+ADT+BT-boost. Biochemical control rates at 9 years were 83% in the experimental arm versus 63% in the standard arm. Cumulative incidence of late grade 3 urinary toxicity in the experimental arm and in the standard arm was respectively 18% and 5%. Two recent studies with HR-PCa (National Cancer Database) demonstrated better overall survival with BT-boost (low dose rate LDR or high dose rate HDR) compared with DE-EBRT. These recent findings demonstrate the superiority of EBRT+BT-boost+ADT versus DE-EBRT+ADT for HR-PCa. It seems that EBRT+BT-boost+ADT could now be considered as a gold standard treatment for HR-PCa. HDR or LDR are options. SBRT-boost represents an attractive alternative, but the absence of randomised trials does not allow us to conclude for HR-PCa. Prospective randomised international phase III trials or meta-analyses could improve the level of evidence of SBRT-boost for HR-PCa.

The development of a clinically useful tool for predicting the development of psychological disorder following injury.

OBJECTIVES: To identify factors significantly associated with post-traumatic stress disorder (PTSD), anxiety, and depression at 3 months post-injury; to develop a generic model to predict the occurrence of PTSD, anxiety, and depression at 3 months post-injury; and to validate this model in a test data set of patients. DESIGN: Prospective cohort study. METHODS: Participants were 823 patients attending an emergency department (ED) following accidental injury. Baseline questionnaires were completed, with 1 and 3 months postal follow-ups. Predictor variables demonstrating significant associations with two of the three outcome measures (3-month HAD anxiety and depression scores and PTSD symptoms) were included in multivariate regression models for each outcome. Non-significant predictor variables were removed until all remaining independent variables made the most significant contribution to each of the three models. Models were validated using a test dataset. RESULTS: Previous history of mental health problems, neuroticism score and having PTSD symptoms at 1 month predicted adverse outcomes at 3 months. When used on the test datasets, the areas under the receiver operating curve (ROC) curve for the models predicting outcomes at 3 months were: PTSD=0.91 (sensitivity=88.5%); anxiety=0.87 (sensitivity=93.7%); and depression=0.87 (sensitivity=96.7%). CONCLUSIONS: The final model performed moderately well across the three outcomes and may be useful clinically as a generic rule-out tool to identify those who will not require follow up, watchful waiting or intervention.

Risk factors for psychological distress following injury.

OBJECTIVES: To identify predictors of psychological morbidity among injured patients admitted to an Emergency Department (ED). DESIGN: A prospective cohort study. PARTICIPANTS: Participants were consecutive male ED attenders. 210 (97.7%) patients consented to participate. At one month, 128 (61.0%) responded, at six months, 114 (54.3%), at eighteen months 96 (45.7%). MAIN OUTCOME MEASURES: Measures immediately following injury were the Hospital Anxiety and Depression Scale, the Eysenck Personality Questionnaire and the McGill pain questionnaire. Recovery at one month was recorded using the SF-36 Health Survey, COPE scale, Perceived Stress Scale and Revised Impact of Events Scale. At six and eighteen months outcome was measured using the General Health Questionnaire (28 items) and Revised Impact of Events Scale. Multivariate analysis identified pre-morbid, accident-related and recovery factors influencing outcome at six and eighteen months. RESULTS: The strongest predictors of outcome were initial levels of anxiety and depression, prior history of mental health problems, early PTSD symptoms and involvement in litigation. These factors predicted between 40-60% of the variance at six months (p<0.001), and 50-60% of the variance in psychological distress at eighteen months (p<0.001). CONCLUSION: Factors identifying individuals at-risk from psychological distress following injury include those related to the immediate response and the recovery phases of injury. Further development is needed to convert identified predictors into a comprehensive screening tool for clinical use.

Elevated C-reactive protein constitutes an independent predictor of advanced carotid plaques in dyslipidemic subjects.

Inflammation plays a key role in the physiopathology of atherosclerosis. C-reactive protein (CRP) has been found to predict cardiac events in healthy subjects and in patients with coronary heart disease. However, the relationship between CRP and subclinical atherosclerosis is not well established. We examined the potential relationship between CRP and common carotid artery intima-media thickness and carotid plaques in dyslipidemic subjects. Dyslipidemic patients (n=1051) were recruited for the study. All patients had a complete clinical examination and systematically underwent ultrasonographic evaluation of the extracranial carotid arteries on a duplex system. The serum concentration of CRP was measured by using a sensitive immunoradiometric assay. In a univariate model, a strong positive relationship was found between CRP and the severity of carotid stenosis (P<0.0001). In multivariate analysis, the association between CRP and the degree of carotid atherosclerosis remained significant for advanced plaques (P=0.0007) in male subjects only. Significant correlations were found between CRP and body mass index (P<0.0001) and between CRP and other markers associated with the metabolic syndrome. In this large dyslipidemic population, elevated CRP is an independent predictor of advanced carotid plaques in male subjects. Body mass index and other markers of the metabolic syndrome (HDL cholesterol, triglycerides, diabetes, and high blood pressure) are significant determinants of CRP levels in this population.

Evaluation of alternative computer input devices used by people with disabilities.

The aim of this study was to evaluate a range of alternative computer input devices suitable for people with disabilities and to provide comparative data that will enable health care professionals and users to make informed choices when selecting products. Our focus was on the potential advantages and disadvantages of individual product features as they related to the abilities and needs of different users. A sample of 14 alternative keyboards and pointing devices commonly used by people with disabilities were appraised by 35 disabled adults. A multi-disciplinary panel of independent assessors also appraised the products. We identified key factors regarding the set-up, personal acceptability, ease of use, design features, compatibility and potential limitations of each device. We found that difficulties in accessing computers could sometimes be reduced or overcome by adjusting the existing workstation and customizing computer settings rather than through additional technology. However, successful computer access often requires a combined approach, as a single piece of equipment will rarely provide a complete solution. If alternative computer input devices are necessary, it is likely that the hardware settings will need customizing.

Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism.

T(4) levels are determinant of several components of the fibrinolytic system. However, relationships between hypothyroidism and alteration of fibrinolytic capacity are not well established, and published data remain conflicting. As the impact of hypothyroidism on both degradation and synthesis of proteins may vary according to the severity of the disease, we measured fibrinolytic activity across varying states of hypothyroidism. We measured fibrinogen, D-dimers (DDI), alpha(2)-antiplasmin activity, tissue plasminogen activator antigen (t-PA Ag), plasminogen, plasminogen activator inhibitor antigen (PAI-1 Ag), and factor XII (FXII) of the coagulation. We prospectively included 76 middle-aged female subjects: 25 controls, 24 patients displaying moderate hypothyroidism (TSH, 10--50 mU/L), and 27 patients with severe hypothyroidism (TSH, >50 mU/L). Blood pressure, body mass index, smoking habits, total cholesterol as well as high and low density lipoprotein subfractions, triglyceride, fasting glycemia, and insulinemia were recorded. We found a different pattern of fibrinolytic abnormalities according to the severity of hypothyroidism. Compared with controls, patients with moderate hypothyroidism displayed a decreased fibrinolytic activity, as reflected by lower DDI levels, higher alpha(2)-antiplasmin activities, and higher levels of t-PA and PAI-1 Ag. In sharp contrast, patients with severe hypothyroidism exhibited higher DDI levels, lower alpha(2)-antiplasmin activities, and lower t-PA and PAI-1 Ag levels. These results were not accounted for by confounding factors such as age, smoking, and components of the insulin resistance syndrome. Free T(4) was significantly associated with fibrinogen, alpha(2)-antiplasmin, PAI-1 Ag, total cholesterol, and triglyceride and was negatively associated with DDI. The main hypotheses underlying the mechanisms by which thyroid status may affect the fibrinolytic system remain to be established. In conclusion, patients with moderate hypothyroidism, who were consistently shown to be at high risk for cardiovascular disease, have decreased fibrinolytic activity. Subjects with severe hypothyroidism have a tendency toward increased fibrinolytic activity, and these modifications may participate to the bleeding tendency observed in such patients.

Presence of somatostatin receptors negatively coupled to adenylate cyclase in ectopic growth hormone-releasing hormone- and alpha-subunit-secreting tumors from acromegalic patients responsive to octreotide.

The functional study of SRIH receptors was performed in ectopic GHRH-secreting tumors from two patients with acromegaly; patient 1 presented with multiple endocrine neoplasia type 1 with GHRH- and insulin-secreting pancreatic tumors, and patient 2 presented with a multihormone-secreting carcinoid tumor (including GHRH and alpha-subunit secretion, as demonstrated by clinical and immunohistochemical studies). In both cases, plasma GH levels were responsive to octreotide. In patient 2, plasma GHRH and alpha-subunit levels were responsive to octreotide. In vitro perifusion studies of a tumor fragment from patient 1 also showed inhibition of GHRH secretion by SRIH. A high density of specific SRIH-binding sites was visualized by autoradiography in GHRH tumors from both patients. SRIH specific binding was much higher in the GHRH tumors (6.6-8.4 fmol/surface unit) than in the insulinoma (1.9 fmol/surface unit). The binding inhibition constant (IC50) was in the nanomolar range (0.9-3 nmol/L) in the GHRH tumors. SRIH-14 inhibited forskolin-stimulated adenylate cyclase in the GHRH tumors from both patients, but not in the insulinoma. The functional SRIH receptors negatively coupled to adenylate cyclase present in ectopic GHRH-secreting tumors mediate the inhibitory effect of octreotide on GHRH secretion and on previously underrecognized ectopic alpha-subunit secretion from carcinoid tumors.

Indications and limits of ultrasound-guided cytology in the management of nonpalpable thyroid nodules.

Although ultrasound (US)-guided fine needle aspiration biopsy (FNAB) is widely prescribed in nonpalpable thyroid nodules, the goal of this study was to define precisely the indications and limits of US-FNAB in a series of 450 nonpalpable nodules. Among 94 surgically controlled cases, 20 (8 infracentimetric and 12 centimetric or supracentimetric) carcinomas were diagnosed. The diagnosis of malignancy was successfully made by US-FNAB in 16 of 20 carcinomas, 3 were missed because of insufficient cytological material, and 1 was misdiagnosed. US-FNAB sensitivity and specificity were 94% and 63%, respectively. A logistic model indicated that nodule size (P < 0.6) was not associated with histological diagnosis, but that solid hypoechoic features were more likely to be malignant (P < 0.0003), with US sensitivity and specificity for malignancy of 80% and 70%, respectively. Logistic regression indicated that adequate cytological material significantly increased with nodule size (P < 0.0001). This result outlined the limits of US-FNAB in small nodules. Hence, indication of US-FNAB appears judicious in centimetric or supracentimetric nodules or in solid and hypoechoic ones. Such a management would allow the discovery of 15 of 20 carcinomas and would avoid 16% of unnecessary biopsies.

A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length.

Our study aims to provide a comprehensive view of the endocrine features in Kennedy's disease (KD). Twenty-two men with KD underwent detailed endocrine investigations. Clinical signs of partial androgen resistance were present in more than 80% of the patients, with gynecomastia being the most prominent. Gynecomastia was postpubertal but appeared before muscular weakness in most cases. Thirteen patients had alteration of testicular exocrine function. Hormonal profile of partial androgen resistance was present in 86% of the patients, with an elevated testosterone level in 68%. Androgen insensitivity seems to appear later in life in KD, similar to the development of neurological signs. Although we confirm the previously reported correlation between the CAG repeat length and the early onset of the neurological disease, we describe a significant correlation between repeat length and the age of onset of gynecomastia as well as biological indexes of androgen insensitivity. This is supported by numerous in vitro data correlating variations in the CAG tract with androgen receptor activity; the longer the CAG repeats, the weaker the receptor transactivation. Ours is the first study to show such a clear and prominent pattern of androgen insensitivity in KD. In clinical practice, KD patients are often misdiagnosed as having amyotrophic lateral sclerosis. Careful examination of the endocrine component could avoid such a deleterious misdiagnosis.

Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas.

Data for patients with bone metastases (BMs) of differentiated thyroid carcinoma (DTC) were retrospectively studied to identify factors associated with survival. We especially studied the impact of therapies. Among the 1977 patients followed for DTC in our department from 1958 to 1999, 109 (77 females and 32 males; age range, 20--87 yr) presented BMS: All patients except 1 underwent total thyroidectomy, followed by radioiodine therapy (> or =3.7 gigabecquerels) in 95 cases. Survival rates at 5 and 10 yr were 41% and 15%, respectively. Univariate analyses indicated that a young age at BM discovery (P < 0.005) and the discovery of BM as a revealing symptom of DTC (P < 0.05) were features significantly associated with improved survival as well as radioiodine therapy (P < 10(-4)) and BM complete surgery (P < 0.02). Using multivariate analysis, the detection of BMs as a revealing symptom of thyroid carcinoma (P < 0.0005), the absence of metastasis appearance in other organs than bones during the follow-up (P < 0.03), the cumulative dose of radioiodine therapy (P < 0.0001), and complete BM surgery in young patients (P < 0.04) appeared as independent prognostic features associated with an improved survival.

Efficacy and safety of ciprofibrate in hyperlipoproteinaemias.

Ciprofibrate is an effective treatment for three main types of atherogenic hyperlipoproteinaemia: type IIa hypercholesterolaemia, type IIb combined hyperlipidaemia, and type IV hypertriglyceridaemia. In type IIa hypercholesterolaemia, administration of 100 mg/day of ciprofibrate, to approximately 3000 patients, decreased total cholesterol (TC), triglycerides, apolipoprotein B (apo B) and low-density lipoprotein (LDL) cholesterol. Levels of apolipoproteins in high-density lipoprotein (HDL) cholesterol and apolipoprotein AI (apo A-I) were increased. Administration of the same dose of ciprofibrate, to approximately 3500 patients with type IIb combined hyperlipidaemia, had a marked cholesterol- and triglyceride-lowering effect, in addition to producing a decrease in LDL cholesterol and apo B, and an increase in apo A-I. TC levels were also decreased in type IV hypertriglyceridaemia following administration of 100 mg/day of ciprofibrate to 800 patients. The decrease in TC levels was attributable to a decrease in triglyceride levels and an increase in HDL cholesterol levels. The pharmacokinetics, mechanism of action and safety of ciprofibrate treatment are also discussed.

Cysteine is a cardiovascular risk factor in hyperlipidemic patients.

Several studies have reported that moderate hyperhomocysteinemia is related to an increased risk for atherosclerosis, but few data are available with regard to any other thiol compound having a potential vascular toxicity. Therefore, we measured both total cysteine and homocysteine plasma levels in patients with hyperlipidemia (242 males and 147 females, 41-65 years old). Homocysteine was higher in males than in females, 13.2+/-4.1 versus 11.1+/-3.4 micromol/l (P<0.0001). The mean cysteine level was 243.3+/-45.7 micromol/l in the whole study population. The subjects were split in two groups, symptomatic patients with cardiovascular disease (n = 106) and asymptomatic subjects (n = 283). Blood pressure, smoking status, total cholesterol, LDL-cholesterol and triglycerides did not statistically differ between groups, but the mean HDL-cholesterol level was lower in symptomatic patients (1.24+/-0.38 versus 1.42+/-0.41, P<0.0001). Cysteine levels were higher in patients with cardiovascular disease than in asymptomatic patients, respectively 254.7+/-47.7 versus 239.1+/-44.3 micromol/l (P = 0.003). A similar result was found for homocysteine, respectively 13.1+/-4.3 versus 12.2+/-3.9 micromol/l (P = 0.05). To analyse whether cysteine levels were related to atherosclerosis independently of age, adjusted levels were compared between asymptomatic patients with normal carotid arteries (n = 176), carotid atherosclerosis (n = 107) and symptomatic patients (n = 106). Age adjusted cysteine levels differed significantly between groups (P = 0.027) while the P-value was of borderline significance for homocysteine (P = 0.09). Odds ratios for having symptomatic cardiovascular disease were 1.81 (95% CI, 1.02-3.21) and 2.05 (95% CI, 1.16-3.60) for the mid and highest tertiles of cysteine using the lowest as the reference. After adjustment in a multivariate model including age, sex, and creatinine, the odds ratio for disease remained significant between the highest tertile versus the lowest (OR = 1.89). Adjusted odds ratios were found to be weaker when homocysteine tertiles were compared. Our data suggest that plasma total cysteine is a risk factor for atherosclerosis in hyperlipidemic patients.

Relationship of circulating C-reactive protein levels to thyroid status and cardiovascular risk in hyperlipidemic euthyroid subjects: low free thyroxine is associated with elevated hsCRP.

The mechanism(s) by which low circulating levels of thyroid hormones may lead to development of premature atherosclerosis remain to be established. These mechanisms include indirect effects of thyroid hormones on cardiovascular risk factors such as plasma lipoproteins, homocysteine and fibrinogen. High-sensitivity C-reactive protein (hsCRP) has been identified as an independent predictor of cardiovascular events. We presently investigated the relationship between hsCRP and free thyroxine (FT4) levels in a large population of euthyroid hyperlipidemic patients (n=429, mean age: 47.1 years, 28% of current smokers). None of these subjects presented a recent history of infection or inflammatory disease and those taking drugs known to influence thyroid or hsCRP were excluded. Serum FT4 levels were measured by radioimmunoassay and CRP, by a high-sensitivity immunoassay. In the population of non-smokers, plasma FT4 levels were negatively and significantly correlated with those of hsCRP (r=-0.13, P=0.02). Significant correlations between FT4 levels and age (r=-0.16, P=0.003), glycemia (r=-0.14, P=0.01), and fibrinogen (r=-0.18, P=0.001) were equally observed. Upon division of the population on the basis of FT4 tertiles, the mean level of hsCRP was significantly higher in non-smoker patients with the lowest FT4 tertile as compared to those displaying the highest FT4 level (3.04mg/l versus 1.77mg/l, respectively, P<0.05). No correlation between FT4 levels and CRP was found in smokers.In conclusion, we demonstrate that hsC-reactive protein is significantly negatively correlated with free thyroxine levels in non-smoker hyperlipidemic patients, suggesting that low thyroxine levels in euthyroid hyperlipidemic subjects constitute a new biomarker of elevated cardiovascular risk.

Homocysteine and lipid lowering agents. A comparison between atorvastatin and fenofibrate in patients with mixed hyperlipidemia.

BACKGROUND: Hyperhomocysteinemia is a risk factor for cardiovascular disease. Elevation in homocysteine levels has recently been demonstrated during lipid lowering treatment with fibrates. We compared the effect of a statin and a fibrate (atorvastatin and fenofibrate) on plasma levels of homocysteine and other thiol compounds in hyperlipidemic patients. METHOD AND RESULTS: The study was of open randomized, parallel design with a preliminary screening phase, and a 6 week placebo period. After the placebo period, patients were allocated randomly to atorvastatin or fenofibrate for a 6 month period. Plasma thiols were assayed by high pressure liquid chromatography with fluorescence detection. There were 29 patients in the fenofibrate group and 24 in the atorvastatin group. Fenofibrate induced a significant increase in both homocysteine and cysteine plasma levels (+35.8 and +18%, respectively, P<0.0001); by contrast, cysteinylglycine remained stable. There were no significant changes in any thiol compounds in the atorvastatin group. Both treatments induced a significant decrease in uric acid, although fenofibrate was noticeably more effective than atorvastatin (-22.8 and -6.4%, respectively). Fenofibrate induced a non-significant increase in creatinine (12%) while atorvastatin reduced it (4.7%, NS). CONCLUSION: Our study confirms that the induction of elevations in plasma homocysteine and cysteine levels are a distinct feature of the pleiotropic effects of fibrates. Further studies are needed not only to investigate the potential deleterious effects of this modification, but also to define the specific mechanism which underlies such fibrate-mediated action.

The replacement of arginine by cysteine at residue 151 in apolipoprotein A-I produces a phenotype similar to that of apolipoprotein A-IMilano.

Rare nonsynonymous mutations in the apolipoprotein A-I (apo A-I) gene are associated with low HDL-cholesterol levels. Despite the inverse correlation of high density lipoprotein (HDL)-cholesterol levels with the risk of coronary heart disease (CHD) in the population, reduced circulating concentrations of HDL do not necessarily predispose to premature CHD. One apo A-I defect was even reported to cause longevity. We describe a French patient who presented with very low serum HDL-cholesterol levels (10 mg/dl). Sequence analysis of the apo A-I gene identified a heterozygous mutation in the apo A-I gene which causes a cysteine for arginine replacement at residue 151. Family members with the mutation displayed 50% lower levels of plasma HDL-cholesterol and of apo A-I than unaffected members. Plasma activity of lecithin:cholesterol acyl transferase (LCAT) was significantly lower in apo A-I(R151C) heterozygotes than in controls. Furthermore, we found that as for apo A-IMilano (R173C), apo A-I(R151C) forms heterodimers with apo A-II. Moreover, HDL particles were abnormal in both lipid composition and size distribution. Despite these quantitative and qualitative differences in HDL, neither the history of the family over three generations nor the examination of the patient, gave any indication of premature occurrence of atherosclerosis or CHD. We conclude that apo A-I(R151C) causes a phenocopy of apo A-IMilano (R173C), an apo A-I variant which is assumed to cause longevity and which is considered as a potentially anti-atherogenic agent.

Metabolism of apolipoproteins AI and AII in subjects carrying similar apoAI mutations, apoAI Milano and apoAI Paris.

ApoAI Milano (AI(M)) and apoAI Paris (AI(P)) are mutant forms of apoAI in which cysteine is substituted for arginine at residues 173 and 151 respectively leading to the formation of homodimers and heterodimers with apoAII. Heterozygous subjects with these mutants are characterized by low levels of plasma HDL cholesterol and apoAI. The present study analyzed the metabolism of the different complexes of apoAI in three subjects, two AI(M) and one AI(P), using a primed-constant infusion of trideuterated leucine. In AI(M) carriers, the mutant form was almost equally distributed in AI(M) dimer, AI(M):AII heterodimer and the monomer, whereas, in the AI(P) subject, the mutant apoAI was essentially in the apoAI(P):AII complex. Normal apoAI was low in the AI(M) subjects (20 and 16 mg/dl) but very low in the AI(P) subject (0.3 mg/dl). In the AI(M) subjects, the low levels of apoAI were due to a rapid catabolism with a normal synthetic rate. However, the apoAI kinetics were heterogeneous with a rapid catabolism of the AI(M):AII complex (FCR of 0.430 and 0.401 day(-1)) and the AI(M) monomer (FCR of 0.570 and 0.406 day(-1)) whereas the AI(M) dimer was catabolized slowly (FCR of 0.114 and 0. 118 day(-1)). In contrast, AI(P) was catabolized relatively slowly with a FCR of 0.263, 0.182 and 0.258 day(-1) for AI(P) homodimer, apoAI(P):AII heterodimer and AI(P) monomer. In the three subjects, normal apoAI was catabolized quickly, with an FCR of 0.805 and 0.601 day(-1) in AI(M) carriers and 0.526 day(-1) in the AI(P) carrier. Therefore, the low level of apoAI in the AI(P) carrier is caused by a low production rate of apoAI, particularly of normal apoAI. In conclusion, apoAI is kinetically heterogeneous in AI(M) and in AI(P) subjects. Moreover, the two mutations lead to significant differences in the kinetic behavior of mutant apoAI depending on its inclusion in its complexes.

Characterization of two HDL subfractions and LpA-I, LpA-I:A-II distribution profiles and clinical characteristics of hyperalphalipoproteinemic subjects without cholesterol ester transfer protein deficiency.

The aims of the present study were (i) to characterize the HDL2, HDL3 and the LpA-I, LpA-I:A-II distribution, (ii) to investigate the prevalence of atherosclerotic lesions and (iii) to assess the activity of cholesteryl ester transfer protein (CETP) in 29 hyperalphalipoproteinemic (HALP) patients (HDL-C=90+/-11 mg/dl) with combined hypercholesterolemia (LDL-C=180+/-16 mg/dl). According to the HDL2/HDL3 and LpA-I/LpA-I:A-II ratios, two HALP profiles (A and B) were defined: in 22 patients (HALP profile A) these ratios were increased compared to the normolipidemic control subjects (1.19+/-0.11 versus 0.53+/-0.19, P < 0.001 and 1.01+/-0.2 versus 0.51+/-0.25, P < 0.001, respectively) and in seven patients (HALP profile B) these ratios were within the normal range (0.64+/-0.20 and 0.69+/-0.2, respectively). The atherosclerotic lesions were assessed by ultrasonography of the carotid arteries. Amongst patients with HALP profile A, 17 were free from lesions, five had intimal wall thickening and none displayed plaques, whereas for patients within the HALP profile B, only one was free from lesions, two had intimal wall thickening and four displayed plaques. CETP activities (348+/-116 versus 371+/-75%/ml/h) and CETP concentrations (2.4+/-0.5 versus 2.5+/-0.6 microg/ml) were similar in HALP profiles A and B, however these values were both higher than in control subjects (190+/-40%/ml/h, P < 0.001 and 1.8+/-0.3 microg/ml, P < 0.001, respectively). Hence the hyperalphalipoproteinemic profiles (A and B) described here were not related to CETP deficiency. In conclusion, the HALP profile A was characterized by both increased HDL2/HDL3 and LpA-I/LpA-I:A-II ratios and was associated with a low prevalence of atherosclerosis, whereas the HALP profile B, characterized by HDL2/HDL3 and LpA-I/LpA-I:A-II ratios within the normal range, was less cardioprotective.

Relation between plasminogen activator inhibitor-1 and hepatic enzyme concentrations in hyperlipidemic patients.

Plasminogen activator inhibitor type-1 (PAI-1) is a key determinant of the fibrinolytic capacity. Its activity correlates with most of the characteristic features of insulin resistance syndrome, i.e. obesity, high blood pressure and hyperlipidemia. We measured plasma PAI-1 antigen levels in 131 asymptomatic men (aged 44.2 +/- 11 years) who had been referred for hyperlipidemia. Those taking medication and those with a secondary hyperlipidemia were excluded. We confirmed the correlation between PAI-1 levels and the following variables: body mass index, blood pressure, triglyceride concentration, and blood glucose and insulin levels before and after an oral glucose tolerance test. We also found a significant and independent correlation between PAI-1 and the concentration of the hepatic enzymes glutamyl transferase, alanine aminotransferase and aspartate aminotransferase. Mild liver abnormalities (presumably steatosis) may thus be one of the factors accounting for high plasma PAI-1 levels in hyperlipidemic patients.

Relationship between thyroid hormones and plasma D-dimer levels.

High serum levels of cholesterol and triglycerides are risk factors for coronary heart disease and are strongly related to several haemostatic parameters. Thyroid disorders are a frequent feature in hyperlipidemic patients and are also associated with a variety of haemostatic abnormalities. Therefore, we analysed the relationships between free T4 (fT4) levels and Factor VII and VIII activities (FVIIc and FVIIc), D-Dimers (DDI) and Plasminogen Activator Inhibitor type 1 (PAI-1), in a group of 472 healthy patients referred for hyperlipidemia. Fourty patients were found to have primary hypothyroidism. A negative correlation was found in the whole study population between fT4 and DDI (p = 0.0001, r = -0.21) and the same results were found after exclusion of the patients with fT4 below the normal range (p = 0.0007, r = -0.17). In a multivariate regression analysis, the relationship between DDI and fT4 was independent of age, Body Mass Index (BMI), gender and total cholesterol. Less impressive correlation coefficients were found with FVIIc (r = -0.10), FVIIIc (r = -0.09) and PAI-1 (r = -0.09). These results suggest that fT4 may play a physiological role in the regulation of the haemostatic equilibrium in hyperlipidemic patients and that low levels of fT4 are associated with a hypercoagulable state.

Usefulness in predicting coronary artery disease by ultrasonic evaluation of the carotid arteries in asymptomatic hypercholesterolemic patients with positive exercise stress tests.

A positive exercise electrocardiogram (ECG) is not infrequent occurrence in asymptomatic hypercholesterolemic patients, but the number of false-positive tests may be relatively high (50%). Therefore, the ability of a positive stress ECG to predict coronary artery lesions is low even in populations with > or =1 cardiovascular risk factors. To increase the diagnostic value of exercise tests for screening asymptomatic individuals, we analyzed whether combined clinical parameters with carotid echography would accurately predict coronary atherosclerotic lesions by coronary angiography in asymptomatic hypercholesterolemic patients with a positive exercise ECG. Seventy-six asymptomatic patients (between 35 and 65 years of age) with hypercholesterolemia (total plasma cholesterol >6.5 mmol/L or 250 mg/dl) and a positive stress ECG were referred for carotid B-mode echography and coronary angiography. Carotid echography data were divided into 2 categories: (1) absence of any atherosclerotic plaque, or (2) presence of > or =1 arterial plaques. Coronary stenosis assessed by coronary angiography was considered to correspond to a > or =50% reduction of coronary lumen diameter. Forty-three patients (57%) displayed coronary lesions; most (38; 88%) had carotid plaque. Multivariate analysis showed that the presence of carotid plaque was significantly associated with coronary stenosis (odds ratio 15.2; confidence interval 5.0 to 54.5). In subgroups characterized by high frequency of false-positive exercise electrocardiographic tests (women and patients with a 10-year predicted risk of coronary artery disease [CAD] <15%), none of the patients without carotid plaque exhibited coronary lesions. Echographic evaluation of carotid plaque (plaque vs no plaque) significantly improved the diagnostic specificity of exercise electrocardiography. We conclude that the combination of clinical, electrical, and echographic data facilitates cost-effective noninvasive detection of CAD in asymptomatic hypercholesterolemic patients.