[Risk scores for the development of venous thromboembolism in ambulatory patients and in patients hospitalized for acute medical disease]. / Les scores de risque de développement de maladie veineuse thromboembolique. Dans la population ambulatoire et chez les patients hospitalisés pour affection médicale aiguë.

The recognition of an increased risk of VTE following surgery has initiated a similar investigation in: 1) Ambulatory subjects. In this group, the Qthrombosis score has identified 8 to 11 risk factors. The incidence of VTE is of the order of 0,15%/year. 2) The patients admitted to hospital for an acute medical disease. Nine scores are available for analysis. Results are difficult to interpret because of confusing factors: the inclusion of symptomatic VTE only or both symptomatic and asymptomatic VTE; the uncontrolled prescription of thromboprophylaxis. VTE incidence over 3 months varies between 15 and 0,5%, but is around 1% in the most recent studies. New studies, with a more rigorous methodological approach, are needed.

[The diagnostic scores for deep venous thrombosis]. / Les scores diagnostiques pour la thrombose veineuse profonde.

Seven diagnostic scores for the deep venous thrombosis (DVT) of lower limbs are analyzed and compared. Two features make this exer- cise difficult: the problem of distal DVT and of their proximal extension and the status of patients, whether out- or in-patients. The most popular score is the Wells score (1997), modi- fied in 2003. It includes one subjective ele- ment based on clinical judgment. The Primary Care score 12005), less known, has similar pro- perties, but uses only objective data. The pre- sent trend is to associate clinical scores with the dosage of D-Dimers to rule out with a good sensitivity the probability of TVP. For the upper limb DVT, the Constans score (2008) is available, which can also be coupled with D-Dimers testing (Kleinjan).

[The diagnostic and the exclusion scores for pulmonary embolism]. / Les scores diagnostiques pour 1'embolie pulmonaire et les scores d'exclusion de l'embolie pulmonaire.

Several clinical scores for the diagnosis of pulmonary embolism (PE) have been published. The most popular ones are the Wells score and the revised Geneva score; simplified versions exist for these two scores; they have been validated. Both scores have common properties, but there is a major difference for the Wells score, namely the inclusion of a feature based on clinical judgment. These two scores in combination with D-dimers measurement have been used to rule out PE. An important improvement in this process has recently taken place with the use of an adjustable, age-dependent threshold for DD for patients over 50 years.

[Clinical scores for the venous thromboembolic disease: an aid for the diagnosis and the treatment?]. / Scores cliniques dans La maladie veineuse thromboembolique: une aide dans la décision diagnostique et thérapeutique?

The venous thromboembolic disease includes a wide range of conditions from well defined medical entities (pulmonary embolism, deep venous thrombosis), their diagnosis and prognosis, as well as the risk of developping a venous thromboembolic disease in association with hospitalisation for acute medical illness and with cancer. The assessment of the risk of treatment with anticoagulants is also itaken into account. For all these medical situations, numerous (approximately 50) clinical scores have been reported. They will be presented and critically analysed in the next series of 6 articles.

Radioautographic demonstration of 5-hydroxytryptamine- 3 H uptake by pulmonary endothelial cells.

The lung is able to rapidly remove 5-hydroxytryptamme (5-HT) from the circulation by a Na(+)-dependent transport mechanism. In order to identify the sites of uptake, radioautographic studies were done on rat lungs which had been isolated and perfused with 5-HT-(3)H and 0 5 mM iproniazid, a monoamine oxidase inhibitor. In control experiments 10(-4)M imipramine was added to the perfusate to inhibit the membrane transport of 5-HT At the light microscope level, silver grains were seen concentrated near capillaries and in the endothelium of large vessels From electron microscope radioautographs a semiquantitative grain count was made and 90% of the silver grains were observed over capillary endothelial cells. The grains were found over the nucleus and cytoplasm of the cell and shewed no preferential association with any particular cytoplasmic inclusion bodies, organelles, or vesicles Other cell types were unlabeled except for a few mast cells, certain vascular smooth muscle cells, and one nerve ending. This radioautographic demonstration of the cell type responsible for the rapid removal of 5-HT from the lung circulation clearly establishes the existence of a new metabolic role for pulmonary endothelial cells.

Diabetogenic action of streptozotocin: relationship of dose to metabolic response.

The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.

Effects of culture conditions and hyperoxia on antioxidant enzymes in pig pulmonary artery and aortic endothelium.

Because hyperoxia induces early injury to lung endothelial cells and since tolerance to hyperoxia is correlated with increased lung antioxidant enzyme activity, we measured superoxide dismutase, catalase and glutathione peroxidase in both fresh isolates and primary cultures of endothelial cells from pig pulmonary artery and aorta. Cultured endothelial cells were studied at confluency and up to 5 days thereafter under control or hyperoxic conditions. In both types of confluent cell, total and cyanide-insensitive superoxide dismutase increased when compared to fresh cells. The most conspicuous postconfluency change in both types of endothelial cell was a marked decrease in glutathione peroxidase, which could be prevented by the addition of selenomethionine to culture media. A 5-day exposure to hyperoxia resulted in a 2-fold increase in cyanide-insensitive superoxide dismutase in both aortic and pulmonary artery endothelial cells. In view of a similar decrease in DNA in both types of cells despite some differences in enzyme levels, oxygen cytotoxicity could not be related to a particular antioxidant enzyme profile.

Differential effects of hyperoxia and hydrogen peroxide on thymidine kinase and adenosine kinase activities of cultured endothelial cells.

To compare the respective sensitivity of two nucleoside kinases, adenosine kinase and thymidine kinase, to oxidative stress, we measured these enzyme activities in cultured aortic endothelial cells exposed for 48 h to various O2 concentrations, and in cell extracts treated with H2O2 or the enzyme system hypoxanthine-xanthine oxidase. Adenosine kinase activity was not significantly influenced by the exposure to hyperoxia, nor by treatment with the enzyme system hypoxanthine-xanthine oxidase or with H2O2. On the other hand, there was a dose-dependent inhibitory effect on thymidine kinase activity resulting from exposure to various O2 concentrations or from treatment with various amounts of xanthine oxidase. Incubation of cell extracts in the presence of H2O2 also resulted in a significant reduction of thymidine kinase activity. These results indicate that thymidine kinase exhibits a selective sensitivity to the toxic effect of O2 concentrations and of O2 intermediates such as H2O2.

Cultured human alveolar macrophages from smokers with lung cancer: resolution of factors that stimulate fibroblast proliferation, production of collagenase, or prostaglandin E2.

Marked connective tissue remodelling involves both destruction and repair in inflammatory lung diseases. Throughout the remodelling event, it was reasoned that alveolar macrophages may release substances similar to those produced by blood monocyte-macrophages that affect fibroblast functions, ie, the interleukin 1 family of monokines (or cytokines). We have examined human alveolar macrophage cultures obtained after bronchoalveolar lavage of freshly excised lungs from heavy smokers with bronchial carcinoma. Crude culture media contained fibroblast proliferative activity and collagenase- and PGE2- production-stimulating activity. The main peak of these biological activities was located around approximately 18 kilodaltons (kD) on gel filtration chromatography. Resolution of this peak by high performance liquid chromatography showed the presence of three distinct peaks, with quantitative and qualitative differences in biological activities. This suggests the presence of heterogeneous factors.

Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score.

OBJECTIVE: To develop a simple standardized clinical score to stratify emergency ward patients with clinically suspected pulmonary embolism (PE) into groups with a high, intermediate, or low probability of PE to improve and simplify the diagnostic approach. METHODS: Analysis of a database of 1090 consecutive patients admitted to the emergency ward for suspected PE in whom diagnosis of PE was ruled in or out by a standard diagnostic algorithm. Logistic regression was used to predict clinical parameters associated with PE. RESULTS: A total of 296 (27%) of 1090 patients were found to have PE. The optimal estimate of clinical probability was based on 8 variables: recent surgery, previous thromboembolic event, older age, hypocapnia, hypoxemia, tachycardia, band atelectasis, or elevation of a hemidiaphragm on chest x-ray film. A probability score was calculated by adding points assigned to these variables. A cutoff score of 4 best identified patients with low probability of PE. A total of 486 patients (49%) had a low clinical probability of PE (score /=9). CONCLUSIONS: This clinical score, based on easily available and objective variables, provides a standardized assessment of the clinical probability of PE. Applying this score to emergency ward patients suspected of having PE could allow a more effective diagnostic process.

Diagnosis of pulmonary embolism by a decision analysis-based strategy including clinical probability, D-dimer levels, and ultrasonography: a management study.

BACKGROUND: Assessment of the clinical probability of pulmonary emboli sm, plasma D-dimer measurement, and lower-limb venous compression ultrasonography have all been advocated in the workup of suspected pulmonary embolism, to minimize the requirement for pulmonary angiography in patients with nondiagnostic lung scans. However, their contribution has not been assessed prospectively. METHODS: Three hundred eight consecutive patients who came to the emergency department with suspected pulmonary embolism were managed according to a diagnostic protocol that included clinical probability assessment, lung scan, and sequential noninvasive tests: plasma D-dimer measurement by enzyme-linked immunosorbent assay (a concentration <500 microgram/L ruled out pulmonary embolism) and lower-limb B-mode venous compression ultrasonography (a positive finding was diagnostic of venous thromboembolism). Patients without pulmonary embolism according to the diagnostic workup did not receive anticoagulant treatment. The safety of this approach was assessed by a 6-month follow-up. RESULTS: of the 308 patients, 106 (34%) had a diagnostic lung scan (normal in 43 and high probability in 63). For the remaining 202 patients, noninvasive workup was diagnostic in 125 (62%). Pulmonary embolism was ruled out by a low clinical probability and a nondiagnostic scan in 48 patients and a D-dimer level less than 500 microgram/L in 53; pulmonary embolism was established by a high clinical probability and a nondiagnostic scan in seven patients and by a finding of a deep vein thrombosis on ultrasonography in 17. Therefore, only 77 of these 202 patients underwent pulmonary angiography (negative in 55; positive in 22). At 6-month follow-up (completed for 99.4% of the study population), only two of the 199 patients in whom the diagnostic protocol had ruled out pulmonary embolism (1.0% [95% confidence interval, 0.1 to 3.6]) had a thromboembolic event (pulmonary embolism, one; deep vein thrombosis, one). CONCLUSIONS: This decision analysis strategy yielded a definitive noninvasive diagnosis in 62% of patients with a nondiagnostic scan and appears to be safe.

Risk factors for a medically inappropriate admission to a Department of Internal Medicine.

OBJECTIVE: To identify patient- and admission-related risk factors for a medically inappropriate admission to a department of internal medicine. METHODS: Cross-sectional study of a systematic sample of 500 admissions to the department of internal medicine of an urban teaching hospital. The appropriateness of each admission and reasons for inappropriate admissions were assessed using the Appropriateness Evaluation Protocol. Risk factors included the time (day of week and holidays) and manner (through emergency department or direct admission) of admission, patient age and sex, health status of patient and spouse, living arrangements, formal home care services, and informal support from family or friends. RESULTS: Overall, 76 (15.2%) hospital admissions were rated as medically inappropriate by the Appropriateness Evaluation Protocol. In multivariate analysis, the likelihood of an inappropriate admission was increased by better physical functioning of the patient (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1-2.1 [for 1 SD in Physical Functioning scores]), lower mental health status of the patient's spouse (OR, 2.6; 95% CI, 1.3-5.6), receipt of informal help from family or friends (OR, 3.3; 95% CI, 1.5-7.2), and hospitalization by one's physician (OR, 3.6; 95% CI, 1.7-7.5). Receiving formal adult home care was not associated with inappropriateness of hospitalization. CONCLUSIONS: Inappropriate admissions to internal medicine wards are determined by a mix of factors, including the patient's health and social environment. In addition, the private practitioners' discretionary ability to hospitalize their patients directly may also favor medically inappropriate admissions.

Cost-effectiveness of noninvasive diagnostic aids in suspected pulmonary embolism.

BACKGROUND: Noninvasive instruments such as plasma D-dimer measurement (DD) and lower-limb compression ultrasonography (US) are being increasingly advocated to reduce the number of necessary angiograms in patients having suspected pulmonary embolism (PE) and a nondiagnostic lung scan. We therefore designed a decision analysis model (1) to evaluate the cost-effectiveness of combining these noninvasive diagnostic aids with lung scan and angiography in the diagnosis of PE and (2) to determine the optimal sequence and combination of tests taking into account the clinical probability of PE. METHODS: We performed a cost-effectiveness analysis based on literature data, including data from a management study in our institution. Six diagnostic strategies were compared with the reference, ie, lung scan followed when nondiagnostic (low or intermediate probability) by angiography. In all strategies, PE was ruled out by a normal or near-normal scan, a negative DD (plasma level below 500 micrograms/L), or a negative angiogram. Pulmonary embolism was diagnosed and anticoagulant treatment was undertaken in the presence of a high-probability lung scan, deep vein thrombosis showed by US, or a positive angiogram. In case of a nondiagnostic scan (low or intermediate probability), patients could be either treated or not treated, or undergo other tests, according to the selected strategy. RESULTS: Under baseline conditions (prevalence of PE, 35%), strategies combining DD and US with lung scan, angiography being done only in case of an inconclusive noninvasive workup (DD level > 500 micrograms/L, normal US, and nondiagnostic lung scan), were most cost-effective. This approach yielded a 9% incremental cost reduction and a 37% to 47% decrease in the number of necessary angiograms compared with the reference strategy (scan +/- angiography). For patients with a low clinical probability of PE (< or = 20%), withholding treatment from those with a low-probability lung scan without performing an angiogram proved safe and highly cost-effective (30% cost reduction), provided US showed no deep vein thrombosis. CONCLUSION: The DD test and US are cost-effective in the diagnostic workup of PE, whether performed after or before lung scan, thus allowing centers devoid of lung scanning and/or angiography facilities to screen patients with suspected PE and avoid costly referrals. In patients with a low clinical probability, a low-probability lung scan, and a normal US, treatment may be withheld without resorting to angiography.

Using clinical evaluation and lung scan to rule out suspected pulmonary embolism: Is it a valid option in patients with normal results of lower-limb venous compression ultrasonography?

BACKGROUND: In patients with a low clinical probability of pulmonary embolism (PE) and a nondiagnostic lung scan, the prevalence of PE is theoretically very low. We assessed the safety and usefulness of this association for ruling out PE. METHODS: We analyzed data from 2 consecutive cohort management studies performed in 2 university hospitals (Geneva University Hospital, Geneva, Switzerland, and Hospital Saint-Luc, Montreal, Quebec), which enrolled 1034 consecutive patients who came to the emergency department with clinically suspected PE. All patients were submitted to a sequential diagnostic protocol of lung scan, D-dimer testing, lower-limb venous compression ultrasonography (US), and pulmonary angiography in case of inconclusive results of noninvasive workup. RESULTS: The prevalence of PE was 27.6%. Empirical assessment was accurate for identifying patients with a low likelihood of PE (8.2% prevalence of PE in the low clinical probability category). One hundred eighty patients had a low clinical probability of PE and a nondiagnostic lung scan. Among these patients, US showed deep vein thrombosis in 5. Hence, PE could be ruled out by a low clinical probability, a nondiagnostic lung scan, and a normal US in 175 patients (21.5%). The 3-month thromboembolic risk in these patients was low (1.7%; 95% confidence interval, 0.4%-4.9%). CONCLUSIONS: Anticoagulant treatment could be safely withheld in patients with a low clinical probability of PE and a nondiagnostic lung scan, provided that the US is normal. This combination of findings avoided pulmonary angiography in 21.5% of patients with suspected PE in this series.

[The PROVE IT-TIMI-22 study or the biter being bit]. / L'étude PROVE IT-TIMI-22, ou l'arroseur arrosé.

The importance of statins in secondary prevention is well established since the 4S, CARE and LIPID studies, their indications being now applied to even normocholesterolemic patients. To date, it is still unclear which statin to choose, and at what dose. A recent study entitled "PROVE IT-TIMI-22" has compared 80 mg of atorvastatin/day to 40 mg of pravastatin/day in early secondary prevention. It appears that the intensive treatment with atorvastatin has been more effective on the LDL-cholesterol levels and has had a more favourable effect on the clinical evolution based on a composite score. We herein propose a critical review of this study and recommend a somewhat cautious attitude before giving high doses of atorvastatin in the secondary prevention of all the patients with coronary heart disease.

[Osteonecrosis of the jaws and bisphosphonates]. / Ostéonécrose des maxillaires et bisphosphonates.

Widely prescribed, bisphosphonates inhibit bone resorption. They are not metabolised and have long half-lives. Two cases of osteonecrosis of the jaws have recently been attributed to bisphosphonates at the University Hospital of Geneva. The recent literature reveals more than a hundred similar cases throughout the world. Bone exposure appears spontaneously or after dental care. Treatment of the osteonecrosis is controversial and cure very difficult. This pathology is usually seen in patients on chemotherapy, steroids and i.v. bisphosphonates, but is sometimes seen with low-dose p.o. bisphosphonates. In view of the strong association between bisphosphonate therapy and osteonecrosis of the jaw, specialists have recommended dental and oral evaluation during bisphosphonate therapy as well as for several years after drug discontinuation.

Modulation of the DNA binding activity of transcription factors CREP, NFkappaB and HSF by H2O2 and TNF alpha. Differences between in vivo and in vitro effects.

Human endothelial cells exposed to H2O2 showed reduced CREP DNA binding activity, enhanced HSF activation, and no induction of NFkappaB binding activity. Interestingly, H2O2 was able to induce NFkappaB subunit p65 translocation in the nucleus. In contrast, cells exposed to TNF alpha showed enhanced CREP binding activity, activation of NFkappaB and no induction of HSE-HSF complex. Addition of H2O2, diamide and iodoacetic acid to the binding reaction mixture markedly reduced the DNA binding ability of the three transcription factors. Thus free sulfhydryls were important in DNA binding activity of CREP, NFkappaB and HSF, and the lack of induction of NFkappaB by H2O2 in intact cells was likely caused by oxidation on a thiol, and not by a deficiency in the activation pathway.

Role of oxygen free radicals in cancer development.

In aerobic life, oxidative stress arises from both endogenous and exogenous sources. Despite antioxidant defence mechanisms, cell damage from oxygen free radicals (OFR) is ubiquitous. OFR-related lesions that do not cause cell death can stimulate the development of cancer. This review discusses the effects of oxidative stress at the different stages of carcinogenesis. Mutagenesis through oxidative DNA damage is widely hypothesised to be a frequent event in the normal human cell. A large body of evidence suggests important roles of OFR in the expansion of tumour clones and the acquisition of malignant properties. In view of these facts, OFR may be considered as an important class of carcinogens. Therefore, the ineffectiveness of preventive antioxidant treatments, as documented in several recent clinical trials, is surprising. However, the difficulties of antioxidant intervention are explained by the complexity of both free radical chemistry and cancer development. Thus, reducing the avoidable endogenous and exogenous causes of oxidative stress is, for the present, the safest option. In the near future, new insights in the action of tumour suppressor genes and the DNA repair mechanisms may lead the way to additional tools against carcinogenesis from OFR.

Prospective evaluation of patients with syncope: a population-based study.

PURPOSE: To determine the diagnostic yield of a standardized sequential evaluation of patients with syncope in a primary care teaching hospital. PATIENTS AND METHODS: All consecutive patients who presented to the emergency department with syncope as a chief complaint were enrolled. Their evaluation included initial and routine clinical examination, including carotid sinus massage, as well as electrocardiography and basic laboratory testing. Targeted tests, such as echocardiography, were used when a specific entity was suspected clinically. Other cardiovascular tests (24-hour Holter monitoring, ambulatory loop recorder ECG, upright tilt test, and signal-averaged electrocardiography) were performed in patients with unexplained syncope after the initial steps. Electrophysiologic studies were performed in selected patients only as clinically appropriate. Follow-up information on recurrence and mortality were obtained every 6 months for as long as 18 months for 94% (n = 611) of the patients. RESULTS: After the initial clinical evaluation, a suspected cause of syncope was found in 69% (n = 446) of the 650 patients, including neurocardiogenic syncope (n = 234, 36%), orthostatic hypotension (n = 156, 24%), arrhythmia (n = 24, 4%), and other diseases (n = 32, 5%). Of the 67 patients who underwent targeted tests, suspected diagnoses were confirmed in 49 (73%) patients: aortic stenosis (n = 8, 1%), pulmonary embolism (n = 8, 1%), seizures/stroke (n = 30, 5%), and other diseases (n = 3). Extensive cardiovascular workups, which were performed in 122 of the 155 patients in whom syncope remained unexplained after clinical assessment, provided a suspected cause of syncope in only 30 (25%) patients, including arrhythmias in 18 (60%), all of whom had abnormal baseline ECGs. The 18-month mortality was 9% (n = 55, including 8 patients with sudden death); syncope recurred in 15% (n = 95) of the patients. CONCLUSION: The diagnostic yield of a standardized clinical evaluation of syncope was 76%, greater than reported previously in unselected patients. Electrocardiogram-based risk stratification was useful in guiding the use of specialized cardiovascular tests.