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This case report describes of a pharmacokinetic drug–drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic non-small cell lung cancer with MET exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvir/velpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb edema and class III NYHA dyspnea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug–drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) and/or P-gp (voxilaprevir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 and/or P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).

Background: Cardiac metastases from thyroid cancers are uncommon with a poor prognosis. There is a lack of long-term follow-up studies. Cases: We report 2 cases of cardiac metastasis from medullary thyroid cancer (MTC). Both patients presented limited metastatic disease apart from a cardiac metastasis. The initial diagnosis was challenging and was facilitated by functional imaging with an immuno-PET-CT using an anti-CEA bispecific antibody and a 68Ga-labeled peptide. Both patients were treated with the multitarget kinase inhibitor vandetanib with prolonged stability. The first patient was alive at the last follow-up, 14 years after the diagnosis of cardiac metastasis. The second patient required surgical excision of the cardiac mass because of disease progression under vandetanib. Conclusion: These cases illustrate long-term survival and effectiveness of clinical management of 2 patients who developed cardiac metastases from MTC, in the current era of personalized medicine with targeted therapy.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Learning Objectives After completing this course, the reader will be able to: Describe the profile of severe toxicities in patients treated with sorafenib.Summarize the pharmacokinetics of sorafenib-induced toxicities.Identify predictive factors for early and delayed toxicities in patients treated with sorafenib. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background. Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity. Methods. We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography. Results. For 83 patients (median age, 62 years; range, 21–84 years), median sorafenib 12-hour area under the curve (AUC0–12) was 52.8 mg · h/L (range: 11.8–199.6). A total of 51 patients (61%) experienced grade 3–4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC0–12 preceding grade 3–4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC0–12 on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin reactions significantly decreased over time. Conclusion. Sorafenib AUC0–12 decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression.

Sorafenib is a novel oral bis-aryl urea compound originally developed as an inhibitor of RAF kinase for its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-1/2/3, Flt-3 and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Sorafenib has been approved for the treatment of metastatic renal cell carcinoma as well as hepatocellular cancer. Despite its inherent selectivity, sorafenib can cause unusual adverse events whose the management represents a challenge for oncologists.Relevant literature was identified using a Pubmed search of articles published up to June 2009. Search terms included 'sorafenib' and 'toxicity'. Original articles were reviewed and relevant citations from these articles were also considered.The clinical aspect of sorafenib-induced adverse events and the molecular basis behind this toxicity are discussed. Finally, recommendations for the management of these adverse events are proposed.Although not life-threatening, toxicity of sorafenib can severely impact the physical, psychological and social well-being of patients. The management of this unusual toxicity highlights the particular need of new pluridisciplinarities linking oncologist, cardiologist and dermatologist.

Objective To assess the prevalence of primary cardiac complications in a large population of patients with systemic sclerosis (SSc), using recently developed echocardiographic techniques. Methods We prospectively studied 100 consecutive patients (mean ± SD age 54 ± 14 years; 86 women) presenting with SSc without pulmonary arterial hypertension or clinical manifestations of heart failure. All patients underwent standard echocardiography, along with measurements of longitudinal velocities by tissue Doppler imaging (TDI) to assess left ventricular (LV) and right ventricular (RV) contractility and LV diastolic function. Results were compared with those in 26 age- and sex-matched healthy controls. Results Patients with SSc had a wider mean left atrial diameter and impaired relaxation compared with the controls. A trend was observed toward a smaller LV ejection fraction (EF) in the patients (mean ± SD 64.9 ± 0.6%) than in the controls (67.2 ± 0.7%), as well as higher pulmonary artery pressure (mean ± SD 33.3 ± 0.6 mm Hg versus 30.8 ± 1.0 mm Hg). LVEF was

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

We report a case of severe mitral stenosis caused by Libman-Sacks endocarditis, as an initial manifestation of systemic lupus erythematosus (SLE) in a 20-year-old woman. Cardiac magnetic resonance imaging (MRI) demonstrated a thickening of the mitral valve with basal endocardial thickening exhibiting defect on first-pass perfusion short-axis acquisition and delayed enhancement in keeping with extensive fibrous endocarditis. The patient underwent successful mechanical mitral valve replacement. This case illustrates that MRI is useful in diagnosing this recognised but uncommon cardiac complication of SLE and excluding differential diagnosis such as valve tumour and infective endocarditis with perivalvular abscesses.

ObjectiveCongenital cardiovascular malformations and aortic dilatation are frequent in patients with Turner syndrome (TS). The objective of this study was to investigate the cardiovascular findings and management in a large cohort of patients, including children and adults.Design/methodsWe recruited 336 patients with TS from a network of tertiary centers. We reviewed their files, checking for cardiovascular events, cardiac valve abnormalities, and aortic diameters indexed to body surface area (BSA) from magnetic resonance imaging (n=110) or echocardiography (n=300).ResultsInformative cardiovascular data were available for only 233 patients. Vascular surgery was reported in 7.4% of the cohort. The first cause of surgery was aortic coarctation, detected in 6.9% at a median age of 9.5 (range: 0–60) years. Bicuspid aortic valve (BAV) was detected in 21% at a median age of 20 years (25th–75th percentiles: 15–30). At least one aortic diameter exceeded 32 mm in 12% of the cohort. This was detected at a median age of 19 (7–30) years. When indexed to BSA, at least one aortic diameter exceeded 20 mm/m2 in 39% of the cohort.ConclusionOur study shows that cardiovascular monitoring for TS patients is currently insufficient in France. BAV is present at birth, but often remains undiagnosed until later in life. Therefore, improved management in cardiovascular monitoring is required and a more systematic approach should be taken.

Background. Hypertension is a common toxicity of bevacizumab, but the frequency of assessment of blood pressure and standardized grading remain to be defined. This study aimed to describe the incidence of bevacizumab-induced hypertension and factors associated with its development, then to retrospectively assess its relation with activity. Patients and methods. One hundred nineteen patients with advanced or metastatic non-small cell lung cancer, colorectal cancer, or ovarian cancer receiving bevacizumab (2.5 mg/kg per week) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0, and the European Society of Hypertension (ESH) criteria. Results. Home-based measurements detected significantly more cases of hypertension than in-clinic measurements did, according to the ESH criteria (54.6% versus 24.4%; p < .001) or the NCI-CTC (42.9% versus 22.7%; p = .0015). Very early hypertension (within 42 days, according to the ESH criteria) but not hypertension (occurring at any time during treatment period) was predictive of response (p = .0011 and p = .26, respectively). Conclusions. Our preliminary results indicate that home-based measurement and grading according to the ESH criteria represents a reliable method to detect bevacizumab-induced hypertension. Whether hypertension is a biomarker of bevacizumab activity remains to be determined in a prospective study.

Background Hypertension is a common toxicity of anti-VEGF agents, but its optimal treatment remains to define. This study aimed to describe the efficacy and tolerability of amlodipine, a calcium channel blocker, in patients with metastatic malignancies treated with bevacizumab, a humanized monoclonal antibody to VEGF. Patients and methods One hundred and eighty-seven patients with advanced or metastatic NSCLC, colorectal or ovarian cancer receiving bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines. Patients received amlodipine 5 mg daily for grade ≥2 bevacizumab-induced hypertension. Results Twenty-six patients received amlodipine 5 mg daily for de novo hypertension (group A), and another 10 patients received amlodipine for exacerbation of previously existing hypertension (group B). Hypertension was controlled within 7 days under amlodipine in 23/26 (88.5%, 95%CI: 76.2–100) patients in group A, and 8/10 (80%, 95%CI: 55.2–100) patients in group B, with a favourable toxicity profile. Conclusions Amlodipine 5 mg daily appears safe and efficient for the treatment of hypertension in patients receiving bevacizumab at a dose-intensity of 2.5 mg/kg/week. Further prospective studies are warranted to confirm these results.

Following the death in France by acute aortic dissection of two women with Turner syndrome who were pregnant following oocyte donation, the Director of the French Biomedicine Agency (Agence de la biomedecine) sent a letter to the President of the French College of Obstetricians and Gynaecologists (FCOG). He requested the College's expertise in reviewing point-by-point the cases and risk factors and in determining whether there are grounds to propose additional measures complementary to the recommendations made by the Haute autorite de sante or French National Authority for Health (HAS) in 2008 in terms of indication and monitoring of patients. A joint practice committee of the FCOG, the French Cardiologic Society, the French Chest and Cardiovascular Surgery Society, the French Society of Anaesthesia and Intensive Care, the French Endocrine Society, the French study group for oocyte donation, and the Biomedicine Agency defined the exact questions to be put to the experts, chose these experts, followed them up and drafted the synthesis of recommendations resulting from their work. The questions concerned the check-up before pregnancy of Turner patients, contraindication and acceptance of pregnancy, information for the patients, and recommendations for antenatal care, delivery and postnatal follow-up.

Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function. Such hyperresponsiveness is best explained by cholinergic vasodilation of blood vessels in the small airways, with extravasation of plasma due to high left ventricular filling pressure. Because this vasodilation may be prevented by the inhalation of the vasoconstrictor agent methoxamine, we studied the effect of methoxamine on exercise performance in patients with chronic left ventricular dysfunction.We studied 19 patients with a mean left ventricular ejection fraction of 22 +/- 4 percent and moderate exertional dyspnea. In the first part of the study, we performed treadmill exercise tests in 10 patients (group 1) at a constant maximal workload to assess the effects of 10 mg of inhaled methoxamine on the duration of exercise (a measure of endurance). In the second part of the study, we used a graded exercise protocol in nine additional patients (group 2) to assess the effects of inhaled methoxamine on maximal exercise capacity and oxygen consumption. Both studies were carried out after the patients inhaled methoxamine or placebo given according to a randomized, double-blind, crossover design.In group 1, the mean (+/- SD) duration of exercise increased from 293 +/- 136 seconds after the inhalation of placebo to 612 +/- 257 seconds after the inhalation of methoxamine (P = 0.001). In group 2, exercise time (a measure of maximal exercise capacity) increased from 526 +/- 236 seconds after placebo administration to 578 +/- 255 seconds after methoxamine (P = 0.006), and peak oxygen consumption increased from 18.5 +/- 6.0 to 20.0 +/- 6.0 ml per minute per kilogram of body weight (P = 0.03).The inhalation of methoxamine enhanced exercise performance in patients with chronic left ventricular dysfunction. However, the improvement in the duration of exercise at a constant workload (endurance) was much more than the improvement in maximal exercise capacity assessed with a progressive workload. These data suggest that exercise-induced vasodilation of airway vessels may contribute to exertional dyspnea in such patients. Whether or not inhaled methoxamine can provide long-term benefit in patients with heart failure will require further study.

Objective To evaluate N-terminal pro–brain natriuretic peptide (NT-proBNP) as a marker of early pulmonary artery hypertension (PAH) and to study changes in the levels of this marker following treatment with dihydropyridine-type calcium-channel blocker (DTCCB) in patients with systemic sclerosis (SSc). Methods We evaluated 40 consecutive SSc patients who had been hospitalized for followup care (mean ± SD age 56 ± 11 years and mean ± SD duration of cutaneous disease 9 ± 9 years; 27 with limited cutaneous and 13 with diffuse cutaneous disease) but who had no clinical symptoms of heart failure and had a normal left ventricular ejection fraction. At baseline, 10 patients had PAH, defined as a systolic pulmonary artery pressure (sPAP) >40 mm Hg, as measured by echocardiography. Levels of NT-proBNP were determined at baseline (after discontinuation of DTCCB treatment for 72 hours), after taking 3 doses of DTCCB following treatment reinitiation (assessment 1), and after 6–9 months of continuous DTCCB treatment (assessment 2) in the 20 patients who attended regular appointments (including the 10 patients with PAH at baseline). Results At baseline, 13 patients had high NT-proBNP values for their ages. High NT-proBNP levels identified patients with PAH with a sensitivity of 90%, a specificity of 90.3%, a positive predictive value of 69.2%, and a negative predictive value of 96%. The NT-proBNP level correlated with the sPAP (r = 0.44; P = 0.006). By assessment 1, the number of patients with PAH and high levels of NT-proBNP had decreased from 9 of 10 to 2 of 10 (P = 0.02). This decrease was partially sustained at assessment 2 (4 of 10 patients; P = 0.06). Conclusion NT-proBNP is a useful biologic marker that can be used to diagnose early PAH in SSc patients without clinical heart failure. Measurement of NT-proBNP may be valuable for the evaluation of treatment with DTCCB and vasodilators in patients with PAH.

Background: An accurate diagnosis of patent foramen ovale (PFO) and atrial septal aneurysm (ASA) may be of decisional importance in the management of patients with ischemic stroke. Very few studies have been devoted to observer agreement in the diagnosis of these atrial septum abnormalities using contrast transesophageal echocardiography, which is considered as the method of choice for the diagnosis. The aim of this study was to assess interobserver and intraobserver variability in the diagnosis of PFO and ASA with contrast echocardiography. Methods: Three sonographers independently reviewed 100 contrast studies stored on videotape on 2 occasions each. The interobserver and intraobserver variability was assessed by calculating κ statistics. Results: The overall interobserver and intraobserver κ values for the assessment of degree of shunting through a PFO were 0.77 (first and second reading) and 0.82, respectively. The best κ statistics were obtained when no and small shunts (less than 10 microbubbles) were pooled and compared with larger shunts. For the diagnosis of ASA, the overall interobserver κ value was 0.45 for the first reading and 0.71 for the second reading, whereas the overall intraobserver κ value was 0.74. Conclusion: Interobserver and intraobserver agreements for the diagnosis of PFO and ASA by transesophageal echocardiography are not perfect and need to be improved, particularly for ASA. This variability has to be taken into account when deciding on a potential risky treatment to prevent recurrent strokes. (J Am Soc Echocardiogr 2002;15:441-6.)

170 Background: Older age is a cause of disparity in cancer treatment decision and treatment guidelines for patients with comorbidities, polypharmacy, denutrition or psycho-social frailty are needed. A pre-therapeutic multidimensional assessment might improve the complex patient management. We developed an experimental program of integrated medicine called ARIANE. We report 18 months activity of this outpatient setting evaluation, its feasibility and impact on treatment decision-making. Methods: Complex patients with predefined cancer treatment strategy entered into the program. A one-day evaluation combined consultations of cardiologist, geriatrician, diabetologist, anesthetist, pharmacist, pain specialist, dietician, psychologist and social worker. Evaluation of performance status, EKG, ejection fraction, ASA score, diabetes, social vulnerability and malnutrition was performed including a geriatric assessment, which focused on items like comorbidity (CIRS-G), dependance (ADL, IADL), fails (Up and Go Test), cognitive impairment (MMSE, Clock Drawing Test) and depression (GDS scale). A pharmacist assessed the risk of drug-drug interactions. Results: Eighty-seven pts, median age 81 years (range 25-94), 76% male, 51% PS 0-1, 77% grade 3 or 4 comorbidity were included. Genito-urinary, lung cancers and sarcoma represented 77% of pts. Eighty-two percent of pts were assessed by at least ≥ 7 participants. Identified factors of vulnerability were polypharmacy (n=65; 75%; >3 drugs), social distress or severe malnutrition (both n=21; 24%), depression (n=17; 19.5%) and cognitive impairment (n=13; 15%). We identified drug interaction in 18 pts (27%). The risk assessment resulted in anticancer treatment changes in 47/87 patients (54%): protocol adaptation (n=19/87; 22%), less aggressive treatment (n=15/87; 17.2%), or more intensive therapy (n=13/87; 15%). Conclusions: A one-day multidisciplinary risk assessment is an answer to the complexity of unfit cancer patients and improves the safety of anticancer treatments.

Study objectives: In dyspneic patients without left ventricular enlargement, it may be difficult to differentiate between obstructive lung disease and diastolic heart failure. Determination of plasma brain natriuretic peptide (BNP) levels, known to increase with ventricular stretch, may be of clinical relevance in this situation. We compared the discriminant power of BNP blood levels and of echocardiography in patients with either chronic obstructive lung disease or diastolic heart failure. Patients: Twenty-six New York Heart Association class III dyspneic patients with normal left ventricular systolic function were enrolled: 17 patients with chronic obstructive lung disease and 9 patients with unequivocal diastolic heart failure. Results: Echocardiographic data were unable to accurately differentiate between the two groups, whereas BNP levels were significantly and markedly higher in patients with diastolic heart failure when compared to those with obstructive lung disease (224 240 pg/mL vs 14 12 pg/mL, p < 0.0001). Conclusions: These preliminary results warrant a prospective, large-scale evaluation of the value of BNP assay for determining diastolic dysfunction, a common cause of dyspnea in elderly patients, and differentiating it from other diagnoses such as obstructive lung disease. (CHEST 2001; 120:2047–2050)

Patent foramen ovale and atrial septal aneurysm have been identified as potential risk factors for stroke, but information about their effect on the risk of recurrent stroke is limited. We studied the risks of recurrent cerebrovascular events associated with these cardiac abnormalities.A total of 581 patients (age, 18 to 55 years) who had had an ischemic stroke of unknown origin within the preceding three months were consecutively enrolled at 30 neurology departments. All patients received aspirin (300 mg per day) for secondary prevention.After four years, the risk of recurrent stroke was 2.3 percent (95 percent confidence interval, 0.3 to 4.3 percent) among the patients with patent foramen ovale alone, 15.2 percent (95 percent confidence interval, 1.8 to 28.6 percent) among the patients with both patent foramen ovale and atrial septal aneurysm, and 4.2 percent (95 percent confidence interval, 1.8 to 6.6 percent) among the patients with neither of these cardiac abnormalities. There were no recurrences among the patients with an atrial septal aneurysm alone. The presence of both cardiac abnormalities was a significant predictor of an increased risk of recurrent stroke (hazard ratio for the comparison with the absence of these abnormalities, 4.17; 95 percent confidence interval, 1.47 to 11.84), whereas isolated patent foramen ovale, whether small or large, was not.Patients with both patent foramen ovale and atrial septal aneurysm who have had a stroke constitute a subgroup at substantial risk for recurrent stroke, and preventive strategies other than aspirin should be considered.

Pathophysiological mechanisms of ischaemic strokes occurring in patients with Rendu-Osler-Weber (ROW) disease remain unclear. We report on the case of a patient with ROW disease and pulmonary arteriovenous fistula thrombosis who suffered from recurrent strokes. In January 2005, a 38 year old woman was referred for the first time to our hospital for an ischaemic stroke fifteen days after undergoing a medically induced abortion. She reported recurrent epistaxis during her two pregnancies (1993 and 1994) and two familial cases of Rendu-Osler-Weber (ROW) disease. She also had experienced two episodes of ischaemic stroke (January 1996 and December 1997). Stroke workup had only revealed a patent foramen ovale with atrial septal aneurysm, which had been surgically closed after the second stroke. She had been receiving aspirin since closure of the foramen ovale. Eight years after the procedure, she presented with a new ischaemic stroke in the right middle …

An association between atrial septal aneurysm and embolic events has been suggested. Atrial septal aneurysm has been shown to be associated with patent foramen ovale and, in some reports, with mitral valve prolapse. These two latter cardiac disorders have been identified as potential risk factors for ischemic stroke. The aim of this prospective study was to assess the role of atrial septal aneurysm as an independent risk factor for stroke, especially for cryptogenic stroke. We studied the prevalence of atrial septal aneurysm, patent foramen ovale, and mitral valve prolapse in 100 consecutive patients < 55 years of age with ischemic stroke who underwent extensive etiological investigations. We compared these results with those in a control group of 50 consecutive patients. The diagnosis of atrial septal aneurysm and patent foramen ovale relied on transesophageal echocardiography with a contrast study and that of mitral valve prolapse, on two-dimensional transthoracic echocardiography. Stepwise logistic regression analysis showed that atrial septal aneurysm (odds ratio, 4.3; 95% confidence interval, 1.3 to 14.6; P = .01) and patent foramen ovale (odds ratio, 3.9; 95% confidence interval, 1.5 to 10; P = .003) but not mitral valve prolapse were significantly associated with the diagnosis of cryptogenic stroke. The stroke odds of a patient with both atrial septal aneurysm and patent foramen ovale were 33.3 times (95% confidence interval, 4.1 to 270) the stroke odds of a patient with neither of these cardiac disorders. For a patient with atrial septal aneurysm of > 10-mm excursion, the stroke odds were approximately 8 times the stroke odds of a patient with atrial septal aneurysm of < 10 mm. This study shows that atrial septal aneurysm and patent foramen ovale are both significantly associated with cryptogenic stroke and that their association has a marked synergistic effect. Atrial septal aneurysms of > 10-mm excursion are associated with a higher risk of stroke.

Background and Purpose: A patent foramen ovale has been reported to be significantly more frequent in young stroke patients than in matched control subjects, and paradoxical embolism has been suggested as the main mechanism of stroke in-this situation. The present study was designed to test this hypothesis. Methods: Sixty-eight consecutive patients under 55 years of age presenting with an ischemic stroke had an extensive workup, including transesophageal echocardiography with contrast. We compared the prevalence of criteria for the diagnosis of paradoxical embolism in patients with and without a patent foramen ovale. Results: A patent foramen ovale was found in 32 patients (47%). A Valsalva-provoking activity was present at stroke onset in six patients with a patent foramen ovale and in eight patients with no patent foramen ovale (X(sup 2)=0.1, nonsignificant). Clinical/radiological features suggestive of an embolic mechanism were not more frequent in patients with a patent foramen ovale. Clinical evidence of deep vein thrombosis was present in one patient with a patent foramen ovale and in none of the others. No occult venous thrombosis was found in a subgroup of patients with a patent foramen ovale and no definite cause for stroke who underwent venography (n=13). Conclusions. Our results do not support the hypothesis that paradoxical embolism is the primary mechanism of stroke in patients with a patent foramen ovale. (Stroke 1993;24:31-34) KEY WORDS e cerebral ischemia e embolism foramen ovale, patent

Resistance to gas flow of an airway is a function of both airway smooth muscle tone and thickness of the airway wall internal to the outer ring of airway smooth muscle. Schematically, the increase in airway resistance caused by shortening of airway smooth muscle may be potentiated by a concomitant increase in airway wall thickness caused by vasodilation of the bronchial vessels and/or microvascular leakage. Conversely, bronchial vasoconstriction may limit to some extent the increase in resistance to gas flow caused by airway smooth muscle shortening and/or congestion and edema of the airway wall. Many endogenous paracrine mediators, putatively involved in asthma and bronchial hyperresponsiveness, have both bronchomotor and vascular effects. The overall effects on resistance to airflow of endogenous or exogenous agents depend not only upon pre-existing airway smooth muscle tone and pre-existing condition of bronchial vessels but also upon two factors that facilitate microvascular leakage, namely, inflammation of the airway wall and outflow pressure of the bronchial circulation, which is close to left atrial pressure.

1943 wurde die Stauung und das Odem der Bronchialwand bei Patienten mit Linksherzversagen beschrieben. Experimentell hervorgerufene Lungenstauung bewirkt bei Tieren eine bronchiale Hyperreaktivitat auf Histamin und Methacholin. Dieser Effekt wird durch Bronchialverengung und gesteigerte vagale Reflexmechanismen erklart. Bei Normalpersonen konnen Manover, die eine leichte Lungenstauung bewirken, ebenfalls eine bronchiale Hyperreaktivitat auf Methacholin hervorrufen. Bei Patienten mit einer schlechten Pumpfunktion des linken Ventrikels oder mit Mitralklappenerkrankung, nicht aber bei Kontrollpatienten mit normaler Linksventrikelfunktion ist eine masige bis schwere bronchiale Hyperreaktivitat auf Methacholin die Regel. Die methacholininduzierte bronchiale Obstruktion bei diesen Patienten kann durch eine Inhalation eines α-adrenergischen Vasoconstrictors, namlich Methoxamin, verhindert werden, welches uber eine Stimulation der postganglionaren α-Rezeptoren wirkt. Das last vermuten, das eine Vasodilatation der nutritiven Gefase der Atemwege zur bronchialen Hyperreaktivitat fuhrt, aber nur bei abnorm erhohtem pulmonalvenosen Druck. Dies kann am besten durch den begleitenden erweiternden Effekt von Methacholin auf die Atemwegsgefase und den kontraktilen Effekt auf die Atemwegsmuskulatur erklart werden. Der letztere kann auf einen direkten Methacholineffekt zuruckgefuhrt werden, in gleichem Mase aber auch auf kontraktile Effekte von extravasalen Mediatoren oder auf einen gesteigerten Vagustonus, welcher durch eine Stimulation der afferenten Nervenendigungen in der Bronchialwand zustande kommt. Die Rolle und die moglichen therapeutischen Implikationen der bronchialen Hyperreaktivitat beim Asthma cardiale und bei der kardialen Dyspnoe sind gegenwartig Gegenstand weiterer Untersuchungen.

To elucidate the pathogenesis of bronchospasm in congestive heart failure, we studied 23 patients with chronic impairment of left ventricular function due to coronary artery disease or dilated cardiomyopathy. In 21 of them we found marked bronchial hyperresponsiveness to methacholine. The mean dose (+/- SD) of methacholine that elicited a 20 percent decrease in the forced expiratory volume in one second (FEV1) was 421 +/- 298 micrograms, nearly the same as in patients with symptomatic asthma. In contrast, there was no bronchial response to methacholine in 9 of 10 patients who had coronary artery disease but normal left ventricular function. Administration of the bronchodilator albuterol led to a partial (43 percent) reversal of the methacholine-induced bronchial obstruction. In 12 patients, pretreatment with the alpha-adrenergic agonist methoxamine (10 mg by inhalation), a potent vasoconstrictor, fully prevented the methacholine-induced decrease in FEV1. The protective effect of methoxamine was blocked by the alpha-adrenergic antagonist phentolamine in all six patients who received this agent. We conclude that bronchial hyperresponsiveness to cholinergic agonists is frequent in patients with impaired left ventricular function and may contribute to the wheezy dyspnea commonly observed in such patients. The bronchoconstriction may be mediated at least in part by dilatation of the bronchial vessels.

Systemic alkalosis was used to detect coronary spasm in 237 patients with infrequent, resting, angina-compatible chest pain. The provocative test was performed without previous coronary arteriography but only in patients with negative submaximal exercise test results. Rapid infusion of alkaline solution followed by maximal hyperventilation raised arterial pH above the 7.65 value necessary for diagnostic significance in 196 (83%) patients. In 24 (12%) of these patients the provocative test induced significant ischemic ST segment changes. In all patients with a positive response, coronary artery disease, which was predominantly vasospastic (19 patients) or atheromatous with a vasospastic contribution (five patients), was demonstrated by coronary arteriography followed, if necessary, by ergot derivative injection. Chest pain and ECG changes were always reversed within 5 minutes by intravenous nitroglycerin. Coronary arteriography was not performed in all patients with a negative response; therefore, the sensitivity of the procedure could not be assessed. However, 36 patients with a negative response to hyperventilation underwent coronary arteriography; 33 (92%) had normal arteriograms and a negative response to ergot derivatives. Hyperventilation appears to be a safe and specific diagnostic procedure in a subset of patients in whom the probability of coronary artery disease may not be judged sufficient to warrant coronary arteriography as a primary diagnostic approach.

Aging people are more subject to pain than others. On a daily basis the pain is a real invasion of their body and mind. The elderly and in particular those suffering from dementia, with their very particular issues, express this pain through verbal and non-verbal communication. Thus, the psychomotor therapist, by investing in the therapeutic relationship, revalorizes a fragmented body. The therapeutic touch approach, which we will develop in this dissertation, allows the reinvestment of the suffering body.; Le vieillissement est sujet à l’augmentation des douleurs, réels envahissements de soi au quotidien. La personne âgée et en particulier atteinte de démence, avec ses enjeux tout particuliers, exprime cette douleur, par le biais de la communication verbale et non verbale. Ainsi, le psychomotricien, en investissant la relation thérapeutique, revalorise un corps morcelé. L’approche du toucher thérapeutique, que nous développerons dans ce mémoire, permet le réinvestissement du corps souffrant.

La vieillesse et la démence de type Alzheimer provoquent des troubles tant au niveau psychique, corporel qu'affectif. Malgré la pathologie, les mouvements du sujet atteint de démence restent présents mais ils se trouvent bien souvent perturbés par la pathologie. C'est ainsi que l'on assiste à des troubles des représentations du corps. Elles ont, avec les troubles psycho-comportements, un impact direct sur les mouvements du sujet. Incohérents, troublants, surprenants, ils restent néanmoins les seuls indices permettant de communiquer avec l'individu. Au-delà de communiquer, le mouvement va permettre de déceler l'état affectif de la personne grâce à l'expressivité qu'elle dégage. Au travers du tonus, des comportements, des attitudes, le psychomotricien sollicite les émotions et la mémoire émotionnelle du sujet le reliant ainsi à son histoire et à une certaine conscience de soi.