[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.

[Early detection in prostate cancer and shared decision making]. / Früherkennung des Prostata- karzinoms und partizipative Entscheidungsfindung (Shared Decision Making).

Screening of prostate cancer with PSA is a challenge for the aid to decision. Beside the rather mediocre characteristics of the screening test, there the additional problem of the peculiar biology of this cancer, with its late development and its ability to remain latent for a prolonged period. On the other hand, the treatment (surgery, irradiation) is associated with important side-effects: impotence and urinary leakage. Several studies, which appear to be a form of aid to information than aid to shared decision, have been carried out to analyse the effect of various modes of information on the behaviour of potential candidates to screening of prostate cancer, with the following results: better knowledge of the problem, lower rate of acceptance of PSA testing and trend towards watchful waiting rather than surgery in case of discovery of cancer.

[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.

[Application of evidence based medicine to the individual patient: the role of decision analysis]. / Application de la médecine factuelle au patient individuel: la place de l'analyse décisionnelle.

INTRODUCTION: The objective of evidence based medicine (EBM) is to contribute to medical decision making by providing the best possible information in terms of validity and relevance. This allows evaluation in a specific manner of the benefits and risks of a decision. METHODS: The limitations and hazards of this approach are discussed in relation to a clinical case where the diagnosis of pulmonary embolism was under consideration. The individual details and the limited availability of some technical procedures illustrate the need to adapt the data of EBM to the circumstances. The choice between two diagnostic tests (d-dimers and ultrasound of the legs) and their optimal timing is analysed with integration of the consequences for the patient of the treatments proposed. This allows discussion of the concept of utility and the use of sensitivity analysis. CONCLUSIONS: If EBM is the cornerstone of rational and explicit practise it should also allow for the constraints of real life. Decision analysis, which depends on the same critical demands as EBM but can also take account of the individual features of each patient and test the robustness of a decision, gives a unique opportunity reconcile rigorous reasoning with individualisation of management.

Role of echocardiography in the evaluation of syncope: a prospective study.

OBJECTIVE: To study the role of echocardiography in the stepwise evaluation of syncope. DESIGN: A prospective observational study with an 18 month follow up. SETTING: University teaching hospital providing primary and tertiary care. SUBJECTS: 650 consecutive patients with syncope and clinical suspicion of an obstructive valvar lesion, or with syncope not explained by history, physical examination, or a 12 lead ECG, who underwent bidimensional Doppler transthoracic echocardiography. MAIN OUTCOME MEASURES: The causes of syncope were assigned using published diagnostic criteria. Echocardiography was considered diagnostic when confirming a suspected diagnosis, or when revealing occult cardiac disease explaining the syncope. RESULTS: A systolic murmur was identified in 61 of the 650 patients (9%). Severe aortic stenosis was suspected in 20 of these and was confirmed by echocardiography in eight. Follow up excluded further cases of aortic stenosis. In patients with unexplained syncope (n = 155), routine echocardiography showed no abnormalities that established the cause of the syncope. Echocardiography was normal or non-relevant in all patients with a negative cardiac history and a normal ECG (n = 67). In patients with a positive cardiac history or an abnormal ECG (n = 88), echocardiography showed systolic dysfunction (left ventricular ejection fraction < or = 40%) in 24 (27%) and minor non-relevant findings in the remaining 64. Arrhythmias were diagnosed in 12 of the 24 patients with systolic dysfunction (50%), and in 12 of the 64 remaining patients (19%) (p < 0.01). CONCLUSIONS: Echocardiography was most useful for assessing the severity of the underlying cardiac disease and for risk stratification in patients with unexplained syncope but with a positive cardiac history or an abnormal ECG.

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.

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.

Predicting adverse outcome in patients with acute pulmonary embolism: a risk score.

Reliable prediction of adverse outcomes in acute pulmonary embolism may help choose between in-hospital and ambulatory treatment. We aimed to identify predictors of adverse events in patients with pulmonary embolism and to generate a simple risk score for use in clinical settings. We prospectively followed 296 consecutive patients with pulmonary embolism admitted through the emergency ward. Logistic regression was used to predict death, recurrent thromboembolic event, or major bleeding at 3 months. Thirty patients (10.1%) had one or more adverse events during the 3-month follow-up period: 25 patients (8.4%) died, thromboembolic events recurred in 10 patients (3.4%), and major bleeding occurred in 5 patients (1.7%). Factors associated with an adverse outcome in multivariate analysis were cancer, heart failure, previous deep vein thrombosis, systolic blood pressure <100 mmHg, arterial PaO2 <8 kPa, and presence of deep vein thrombosis on ultrasound. A risk score was calculated by adding 2 points for cancer and hypotension, and 1 point each for the other predictors. A score of 2 best identified patients at risk of an adverse outcome in a receiver operating characteristic curve analysis. Of 180 low-risk patients (67.2%) (score < or =2), only 4 experienced an adverse outcome (2.2%), compared to 23 (26.1%) of 88 high-risk patients (score > or =3). A simple risk score based on easily available variables can accurately identify patients with pulmonary embolism at low risk of an adverse outcome. Such a score may be useful for selecting patients with pulmonary embolism eligible for outpatient care.

[Evidence-based medicine: an approach without any weakness?]. / Evidence-based medicine: une approche au-dessus de toute faiblesse?

Evidence-based medicine is a methodological approach giving access to the best information derived from clinical research for an individual patient. It requires the formulation of a question, a strategy to search for the best information, the selection of the latter, its critical appraisal and its application to the patient. The qualities, but also the limitations of this approach are discussed.

Reactive oxygen metabolites increase mitochondrial calcium in endothelial cells: implication of the Ca2+/Na+ exchanger.

In endothelial cells, a bolus of hydrogen peroxide (H2O2) or oxygen metabolites generated by hypoxanthine-xanthine oxidase (HX-XO) increased the mitochondrial calcium concentration [Ca2+]m. Both agents caused a biphasic increase in [Ca2+]m which was preceded by a rise in cytosolic free calcium concentration [Ca2+]c (18 and 6 seconds for H2O2 and HX-XO, respectively). The peak and plateau elevations of [Ca2+] were consistently higher in the mitochondrial matrix than in the cytosol. In Ca2+-free/EGTA medium, the plateau phase of elevated [Ca2+] evoked by H2O2 due to capacitative Ca2+ influx was abolished in the cytosol, but was maintained in the mitochondria. In contrast to H2O2 and HX-XO, ATP which binds the P2Y purinoceptors induced an increase in [Ca2+]m that was similar to that of [Ca2+]c. When cells were first stimulated with inositol 1,4, 5-trisphosphate-generating agonists or the Ca2+-ATPase inhibitor cyclopiazonic acid (CPA), subsequent addition of H2O2 did not affect [Ca2+]c, but still caused an elevation of [Ca2+]m. Moreover, the specific inhibitor of the mitochondrial Ca2+/Na+ exchanger, 7-chloro-3,5-dihydro-5-phenyl-1H-4.1-benzothiazepine-2-on (CGP37157), did not potentiate the effects of H2O2 and HX-XO on [Ca2+]m, while causing a marked increase in the peak [Ca2+]m and a significant attenuation of the rate of [Ca2+]m efflux upon addition of histamine or CPA. In permeabilized cells, H2O2 mimicked the effects of CGP37157 causing an increase in the basal level of matrix free Ca2+ and decreased efflux. Dissipation of the electrochemical proton gradient by carbonylcyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), and blocade of the Ca2+ uptake by ruthenium red prevented [Ca2+]m increases evoked by H2O2. These results demonstrate that the H2O2-induced elevation in [Ca2+]m results from a transfer of Ca2+ secondary to increased [Ca2+]c, and an inhibition of the Ca2+/Na+ electroneutral exchanger of the mitochondria.

Hydrogen peroxide-induced DNA damage is independent of nuclear calcium but dependent on redox-active ions.

In cells undergoing oxidative stress, DNA damage may result from attack by .OH radicals produced by the Fenton reaction, and/or by nucleases activated by nuclear calcium. In the present study, the participation of these two mechanisms was investigated in HeLa cells. Nuclear-targeted aequorin was used for selectively monitoring Ca2+ concentrations within the nuclei ([Ca2+]n), in conjunction with the cell-permeant calcium chelator bis-(o-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid acetoxymethyl ester (BAPTA/AM), the lipid-soluble broad-spectrum metal chelator with low affinity for Ca2+ and Mg2+ N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), and the high-affinity iron/copper chelator 1, 10-phenanthroline (PHE). In Ca2+-containing medium, H2O2 induced extensive DNA strand breaks and an increase in [Ca2+]n that was almost identical to that observed in the cytosol ([Ca2+]c). In cells bathed in Ca2+-free/EGTA medium, in which the increases in [Ca2+]n and [Ca2+]c due to H2O2 were significantly reduced, similar levels of DNA fragmentation also occurred. In cells preloaded with BAPTA/AM or TPEN, the small increase of [Ca2+]n normally elicited by H2O2 in Ca2+-free medium was completely buffered, and DNA damage was largely prevented. On the other hand, pretreatment with PHE did not affect the calcium response in the nuclei, but completely prevented DNA strand breakage induced by H2O2. Re-addition of 100 microM CuSO4 and 100 microM FeSO4 to TPEN- and PHE-treated cells prior to H2O2 challenge reversed the effect of TPEN and PHE, whereas 1 mM was necessary to negate the effect of BAPTA/AM. The levels of DNA strand breakage observed, however, did not correlate with the amounts of 8-hydroxy 2'-deoxyguanosine (8-OHdG): H2O2 did not produce 8-OHdG, whereas PHE alone slightly increased 8-OHdG levels. CuSO4 and FeSO4 enhanced the effects of PHE, particularly in the presence of H2O2. Exposure of cells to a mixture of CuSO4/FeSO4 also resulted in a significant increase in 8-OHdG levels, which was prevented in cells preloaded with BAPTA/AM. Similar results were obtained in a cell-free system using isolated calf thymus DNA exposed to CuSO4/FeSO4, regardless of whether H2O2 was present or not. These results suggest that BAPTA/AM prevents H2O2-induced DNA damage by acting as an iron/copper chelator. These data also indicate that caution must be exercised in using Ca2+ chelating agents as evidence for a role in cellular Ca2+ levels in experimental conditions in which transition-metal-ion-mediated oxidant production is also occurring.

Predictors of inappropriate hospital days in a department of internal medicine.

BACKGROUND: This study aimed to identify predictors of inappropriate hospital days in a department of internal medicine, as a basis for quality improvement interventions. METHODS: The appropriateness of 5665 hospital days contributed by 500 patients admitted to the Department of Internal Medicine, Geneva University Hospitals, Switzerland, was assessed by means of the Appropriateness Evaluation Protocol. Predictor variables included patient's age and sex, manner of admission and discharge, and characteristics of hospital days (weekend, holiday, sequence). RESULTS: Overall, 15% of hospital admissions and 28% of hospital days were rated as inappropriate. In multivariate models, inappropriate hospital days were more frequent among patients whose admission was inappropriate (odds ratio [OR] = 5.3, 95% CI: 3.1-8.4) and among older patients (80-95 years: OR = 3.6, 95% CI: 1.7-7.0, versus <50 years). The likelihood of inappropriateness also increased with each subsequent hospital day, culminating on the day of discharge, regardless of the total length of stay. CONCLUSIONS: This study identified both the admission and the discharge processes as important sources of inappropriate hospital use in a department of internal medicine. The oldest patients were also at high risk of remaining in the hospital inappropriately. Surprisingly, long hospital stays did not generate a higher proportion of inappropriate days than short hospital stays. This information proved useful in developing interventions to improve the hospitalization process.

Preventing stroke recurrence in patients with patent foramen ovale: antithrombotic therapy, foramen closure, or therapeutic abstention? A decision analytic perspective.

Emphasis on the role of patent foramen ovale as a potential risk factor for ischemic paradoxical stroke has recently increased. Current therapeutic options for secondary stroke prevention include long-term antithrombotic therapies and invasive closure of the defect, but selective indications have not been evaluated. Therefore we developed a Markov-based decision analysis model for a hypothetical cohort of patients 55 years of age with presumed paradoxical embolism, measuring for each therapy the risks of stroke recurrence, treatment-related complications, and death after 5 years and the quality-adjusted life-years. Over a wide range of stroke risk recurrence (0.8% per year to 7% per year), the gain provided by closure of the defect exceeded the one obtained by other therapeutic options. When the risk exceeded 0.8% per year and 1.4% per year, respectively, this was also verified for anticoagulation and antiplatelet therapies compared with therapeutic abstention. Therapeutic abstention was the preferred strategy under 0.8% per year. Sensitivity analyses identified key parameters influencing the choice of therapy. These included estimates of stroke recurrence, bleeding rates, surgery-related case fatality rates, and age. Considering the risks of treatment and the devastating consequences of a recurrent stroke, our model suggests that if the estimated risk of paradoxical stroke recurrence is > 0.8% per year, therapeutic abstention becomes the worst option. Above this threshold secondary stroke prevention with anticoagulation therapy or surgical closure of the defect is the preferred strategy, and assessment of both the risk of stroke recurrence and the risk related to therapeutic options should guide individual therapeutic decision making.

Should there be systematic screening of coronary heart disease in asymptomatic patients with risk factors alone? A decision analysis approach.

The problem of choosing between detection of asymptomatic coronary heart disease (CHD) in patients at risk and primary prevention was assessed in a decision analysis model. Most of the relevant data were derived from the WOSCOP study, which evaluated the effects of statins in asymptomatic hypercholesterolaemic subjects. This study is considered to be a model of primary prevention measurement. Over a 5-year period, 10% of control subjects had events related to CHD, with a 20% mortality rate which was reduced by 33% under statin administration. A decision tree was used to compare these two sets of data (controls and treated patients) with those of a third option in which an exercise test, 201Tl scintigraphy and, in certain cases, coronary arteriography were used to detect and treat CHD at an asymptomatic stage. The test characteristics and outcomes correspond as closely as possible to previously reported data, concerning what can be expected in this particular situation. Over a wide range of CHD probabilities, screening appeared to be better than primary prevention. This result is robust since it was not modified by sensitivity analysis for most of the data. A sharp decrease in the sensitivity of the first two tests and a marked increase in the effectiveness of primary prevention would alter the decision in favour of primary prevention, whereas an increased death rate from CHD and higher CHD probability would favour the utility of screening. As the cost-effectiveness of screening compares favourably with that of primary prevention, it may be useful to assess the validity of this model in a prospective controlled study.

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.