A multidisciplinary guided practical on type I diabetes engaging students in inquiry-based learning.

In the present article, we describe a 3-day experimental workshop on type I diabetes aimed at helping high school students to understand how fundamental research on glycemia regulation contributes to the development of scientific knowledge and therapeutic strategies. The workshop engaged students in open-ended investigations and guided experiments. Each class was divided into three or four groups, with each group working with a trained doctoral student or postdoctoral fellow. During an initial questioning phase, students observed slides depicting the glycemia of individuals in various situations. Students identified hyperglycemic individuals relative to the average glycemia of the displayed population. Students were asked to devise a treatment for these diabetics. They quickly realized that they couldn't experiment on patients and understood the need for laboratory models. Each group gave ideas of experiments to perform. We then explained, taking into account their propositions, the protocols students could execute to address one of the following questions: Which criteria must an animal model of diabetes fulfill? How do pancreatic cells maintain glycemia? Is there a way to produce an insulin protein similar to the one released by human pancreatic cells? We used two different evaluation metrics of the workshop: a questionnaire filled out by the students before and after the workshop and a poster produced by students at the end of the workshop. We found that this educational approach successfully improved student awareness and understanding of the scientific reasoning and research process.

Hands-on experiments on glycemia regulation and type 1 diabetes.

In the present article, we describe a 3-day experimental workshop on glycemia regulation and type 1 diabetes that engages students in open-ended investigations and guided experiments leading to results that are not already known to them. After an initial questioning phase during which students observe PowerPoint slides depicting the glycemia (blood glucose levels) of individuals in various situations, students design, execute, and interpret experiments to address one of the following questions: 1) Which criteria must an animal model of diabetes fulfill? 2) How do pancreatic cells maintain glycemia constant? and 3) Is there a way to produce an insulin protein similar to the one released by human pancreatic cells? Students then 1) measure glycemia and glycosuria in control mice and in a mouse model of type 1 diabetes (Alloxan-treated mice), 2) measure the release of insulin by pancreatic ß-cells (INS-1 cell line) in response to different concentrations of glucose in the extracellular medium, and 3) transfect Chinese hamster ovary cells with a plasmid coding for green fluorescent protein, observe green fluorescent protein fluorescence of some of the transfected Chinese hamster ovary cells under the microscope, and observe the characteristics of human insulin protein and its three-dimensional conformation using RASMOL software. At the end of the experimental session, students make posters and present their work to researchers. Back at school, they may also present their work to their colleagues.

KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570.

Mutation of KIT receptor tyrosine kinase at residue D816 results in ligand-independent constitutive kinase activity. This mutation occurs in most patients with mastocytosis, a myeloproliferative neoplasm, and is detected at lower frequencies in acute myeloid leukemia and in germ cell tumors. Other KIT mutations occur in gastrointestinal stromal tumors (GIST) and mucosal melanoma. KIT is considered as a bona fide therapeutic target as c-kit mutations are driving oncogenes in these pathologies. However, several evidences suggest that KIT-D816V mutant is not as aggressive as other KIT mutants. Here, we show that an intracellular docking site in the juxtamembrane region of KIT maintains a negative regulation on KIT-D816V transforming potential. Sixteen signaling proteins were shown to interact with this motif. We further demonstrate that mutation of this site results in signaling modifications, altered gene expression profile and increased transforming activity of KIT-D816V mutant. This result was unexpected as mutations of the homologous sites on wild-type (WT) KIT, or on the related oncogenic FLT3-ITD receptor, impair their function. Our results support the hypothesis that, KIT-D816V mutation is a mild oncogenic event that is sufficient to confer partial transforming properties, but requires additional mutations to acquire its full transforming potential.

Loss of AF6/afadin, a marker of poor outcome in breast cancer, induces cell migration, invasiveness and tumor growth.

Afadin/AF6, an F-actin-binding protein, is ubiquitously expressed in epithelia and has a key role during development, through its regulatory role in cell-cell junction organization. Afadin loss of expression in 15% of breast carcinoma is associated with adverse prognosis and increased risk of metastatic relapse. To determine the role of afadin in breast cancer, we studied the functional consequences of afadin protein extinction using in vitro and in vivo models. Three different breast cancer cell lines representative of the major molecular subtypes were stably repressed for afadin expression (knockdown of afadin (afadin KD)) using RNA interference. Collective and individual migrations as well as Matrigel invasion were markedly increased in afadin KD cells. Heregulin-ß1 (HRG-ß1)-induced migration and invasion were increased by twofold in afadin KD cells. Conversely, ectopic expression of afadin in the afadin-negative T47D cell line inhibited spontaneous and HRG-ß1-induced migrations. RAS/MAPK and SRC kinase pathways were activated in afadin KD cells. Activation levels positively correlated with migration and invasion strength. Use of MEK1/2 (U0126) and SRC kinases (SU6656) inhibitors reduced afadin-dependent migration and invasion. Afadin extinction in the SK-BR-3 cell line markedly accelerated tumor growth development in mouse mammary gland and lung metastasis formation. These results may explain why the loss of afadin expression in tumors correlates with high tumor size and poor metastasis-free survival in patients.

FES kinases are required for oncogenic FLT3 signaling.

The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.

Permanent Genetic Resources added to the Molecular Ecology Resources Database 1 February 2010-31 March 2010.

This article documents the addition of 228 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Anser cygnoides, Apodemus flavicollis, Athene noctua, Cercis canadensis, Glis glis, Gubernatrix cristata, Haliotis tuberculata, Helianthus maximiliani, Laricobius nigrinus, Laricobius rubidus, Neoheligmonella granjoni, Nephrops norvegicus, Oenanthe javanica, Paramuricea clavata, Pyrrhura orcesi and Samanea saman. These loci were cross-tested on the following species: Apodemus sylvaticus, Laricobius laticollis and Laricobius osakensis (a proposed new species currently being described).

MBC / UNAIDS / SPC Pacific Islands AIDS / STD strategic planning. Project update.

PIP: This article presents an update of the Pacific Islands AIDS/sexually transmitted disease (STD) Strategic Planning Project. It also provides specific stories on the strategic planning experiences and achievements of four countries namely New Caledonia, Kiribati, Solomon Islands, and Nauru. The project began in 1998 when 17 Pacific Island countries participated in a workshop where each country developed an action plan which contained the following common elements: 1) a plan on how to integrate the strategic planning process into existing structures for HIV/AIDS activities; 2) strategies to gain political and other organizational support into HIV/AIDS and STD planning; 3) a summary of the factors contributing to HIV and STD risk; and 4) a review of what has been done to address these problems. In 1999, these plans were put into action. Each country was challenged at the planning and execution of situational analysis and response review. A project review conducted in June 1999 resulted in a decision to hold individual country workshops in the future which will allow more participants and facilitators to concentrate their efforts on developing an individual strategic plan for each country.^ieng

[Rotablator and endoprosthesis on the left main coronary trunk]. / Rotablator et endoprothèse sur tronc commun de la coronaire gauche.

A 78 year old woman with unstable angina due to significant stenosis of the left main coronary artery and occlusion of the right coronary artery was treated medically for 29 months because of a surgical contraindication. Resistance to drug therapy led to referral for complex angioplasty of the left main, left anterior descending and left circumflex arteries, successively by rotablator and balloon angioplasty. An immediate elastic recoil on the left main coronary artery led to implantation of a Palma-Schatz stent. There were no complications and the patient is asymptomatic twenty months later.

[Thromboembolic disease in patients aged 80 and over. Diagnostic and therapeutic strategies]. / La maladie thromboembolique chez la personne âgée de 80 ans et plus. Stratégies diagnostiques et thérpeutiques.

The aim of this retrospective study of 50 deep vein thromboses (DVT) of the lower limbs in patients aged 80 and over (35 women, including 2 with bilateral DVT and 13 men), mean age 83.37 +/- 2.72, hospitalised in a department of cardiology, was to assess the diagnostic value of ultrasound investigations, clinical parameters and results of treatment of thrombo-embolic disease in this age group. High DVT were found in 76 per cent of cases and pulmonary embolism occurred in 52.1 per cent of cases, its incidence increasing with age. One third of DVT were asymptomatic and presented as pulmonary embolism, the predominant clinical feature being edema in the absence of other signs. The existence of atrial fibrillation was associated in 90 per cent of cases with a pulmonary embolism. Venous Echo-Doppler is also the key investigation in the diagnosis of thrombo-embolic disease. Cardiac Echo-Doppler seems particularly useful in the diagnosis of pulmonary embolism when more than 40 per cent of the vascular bed is cut off. Thrombolytic treatment remains possible after the age of 80 in life-threatening situations. Overall hospital mortality remains high (10.4 per cent) and appears to be due chiefly to the onset of a pulmonary embolism which is not thrombolyzed since considered insufficiently serious or occurring in a situation in which fibrinolysis is theoretically contra-indicated.

[Relations between antihypertensive and vascular effects of nitrendipine]. / Relations entre les effets antihypertenseurs et vasculaires de la nitrendipine.

We have realized an unicentric prospective study to assess the effects of Nitrendipine on carotid circulation and arterial blood pressure (BP) in essential, permanent, uncomplicated arterial hypertension. This randomized, double blind versus placebo trial concerned 21 mild to moderate hypertensive patients (pts) (WHO advices) aged from 35 to 65 years. After a 15 days washout, the pts were randomized in two groups: 11 pts received a 20 mg Nitrendipine tablet once a day and 10 pts received a placebo. BP control and ultrasonic carotid flowmetry were performed at J0 and J30. At J30, BP was normalized for 55% of pts under NT (versus 30% for placebo). This result correspond to a very significative decrease for systolic and diastolic BP and differential BP (Dif BP) without reflex tachycardia, under Nitrendipine, opposite to placebo. Ultrasonic carotid flowmetry variations are not significative excepting common carotid vasodilation under Nitrendipine. Under Nitrendipine, at J30, 5 pts show a decrease of a least 15% of the cerebral vascular resistances (responding patients); and 6 pts do not show any significative decrease of cerebral vascular resistances. For the responding pts, arteriolar vasodilation is then correlated to the decrease of BP and Dif BP, to the increase of carotid blood flow and to the arterial vasodilation; while there is no significative decrease of BP for non responding pts. It suggests an improvement of arterial compliance by a direct action on the arterial wall. Furthermore, inspite of a drop in diastolic parietal tension, there is not any group showing reflex tachycardia. Thus, antihypertensive efficacy of Nitrendipine seem to be principally subordinated to the improvement of arterial compliance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pheochromocytoma and hyperthyroidism caused by amiodarone]. / Phéochromocytome et hyperthyroïdie à l'amiodarone.

The authors report, in a 66 y. old patient, a case of pheochromocytoma, interesting in that its initial clinical picture is one of amiodarone-induced hyperthyroidism with orthostatic hypotension, and a persisting severe weight loss in spite of the improvement of the thyroid work-up is the indication of an adrenal tumor discovered on tomodensitometry. The accidental combination of these two endocrine diseases delays the already unusual manifestation of this pheochromocytoma and emphasizes the role of radiographic (tomodensitometry) and/or isotopic (MIBG) imaging in the "discovery" of these tumors.

[Latent congenital mitral insufficiency caused by an isolated mitral cleft. Diagnosis by two-dimensional echocardiography and pulsed Doppler]. / Insuffisance mitrale congénitale silencieuse due à une fente mitrale isolée. Diagnostic par échocardiographie bidimensionnelle et Doppler pulsé.

In this paper, the authors report the case of an 8-year-old boy with an isolated slit in his mitral valve, and who did not have a heart murmur detectable either by auscultation or by phonocardiography and who had no symptoms of heart failure. Two-dimensional echocardiography, with a left parasternal direction, in a transversal view revealed the presence of this abnormality of the endocardial leaflets accompanied by an accessory chorda tendina, and this procedure confirmed the absence of hemodynamic percussion. Doppler ultrasonography detected an abnormal turbulent systolic blood flow immediately behind the mitral valve, suggesting a minimal to moderate degree latent regurgitation. Two-dimensional echocardiography together with the Doppler ultrasound makes possible the diagnosis of an isolated slit of the mitral valve by non-invasive technique and the detection of concomitant latent mitral valve regurgitation, especially when the left atrium is not dilated and if the patient does not have low cardiac output.

[Effect of ventricular and sequential cardiac stimulation on carotid output]. / Effet de la stimulation cardiaque ventriculaire et séquentielle sur le débit carotidien.

12 patients (10 men and 2 women), of 59 +/- 10.5 years of age, including 4 with a patent cardiomyopathy and 7 with a cardiothoracic index higher than 0.52, presenting a permanent and complete atrio-ventricular block and fitted with a two-chambers cardiac stimulator, underwent a carotid output study by Doppler-sonography. The objective of this study was to determine the factors which could influence the carotid output: synchronous atrial systole, frequency of the electro-stimulated rhythm, atrio-ventricular delay in sequential mode, cardiomyopathy, increase of the cardiothoracic index, age and body area. It appears that the carotid output, for an identical stimulation frequency, is significantly higher in sequential mode than in one-chamber ventricular electrostimulation (p less than 0.05 at 70 c/min, p less than 0.01 at 80 c/min and p less than 0.001 at 90 c/min) and this is even more marked in case of cardiomyopathy (p less than 0.01 versus p less than 0.05). On the contrary, an elevated cardiothoracic index does not alter the nature of the results. An accelerated electrostimulated rhythm discloses an increase of the carotid output (p = 0.01) up to a threshold frequency of 70 c/min in the entire population and of 60 c/min in case of cardiomyopathy. Beyond that, the carotid output decreases. Sequential stimulation does not prevent this decrease from 80 c/min (p = 0.001). The carotid output is significantly lower (p less than 0.01) with an atrio-ventricular delay of 115 ms than with a delay of 165 ms. The carotid output decreases in direct ratio to age (p = 0.01) but the gradient of the regression axis is lower in sequential mode.(ABSTRACT TRUNCATED AT 250 WORDS)

[Echocardiography and connective tissue diseases]. / Echocardiographie et maladies du tissu conjonctif.

The aim of this study is to show the clinical value of the echocardiography in the heritable disorders of connective tissue, within a series of 10 cases, from 7,500 echocardiograms reviewed between 1978 and 1985. Echocardiography visualized an aneurysm of the ascending aorta in three patients, a dilatation of the pulmonary artery in one case, a mitral valve prolapse in six patients associated with an aortic and tricuspid valve prolapse in two cases, and a tricuspid valve prolapse and aortic regurgitation in one case. In two patients, an aortic valve prolapse was isolated. Other echocardiographic features were intracardiac calcifications (4 cases), septal hypertrophy (2 cases) and an incompetent foramen ovale (2 cases). Echocardiographic examination must be performed in all connective tissue diseases because cardiovascular complications are responsible for the vast majority of deaths. Conversely, all the patients with valvular prolapse, dilatation of the great vessels, aneurysm of the sinuses of Valsalva or congenital heart defects type incompetent foramen ovale should be suspected of connective tissue disorders. Such diagnosis is crucial when a surgical intervention is being considered because of the fragility of the tissues.

[Marfan's or Marfan-like syndrome: value of echocardiography]. / Syndromes de Marfan ou marfanoïdes: intérêt de l'échocardiographie.

The purpose of this study of 6 cases of Marfan's or Marfan-like syndrome detected in 7077 echocardiographic examinations was to investigate the clinical value of echocardiography. The mean age of the patients was 40 years, and 4 of them (66 p. 100) were female. The diagnosis was based on the 4 criteria of Marfan's syndrome in 1 case, on 3 criteria in 2 cases and on 2 criteria in 3 cases. Four patients were known to have a previous cardiac murmur. Auscultation revealed a systolic murmur of mitral regurgitation in 3 cases (associated with a diastolic murmur of aortic regurgitation in 2 of them), a diastolic murmur of aortic regurgitation in 3 cases and a systolic murmur due to calcified bicuspid aortic valve in 1 case. ECG recorded a normal rhythm in 4 cases, atrial fibrillation in 2 cases of mitral regurgitation, and left ventricular hypertrophy in 3 cases. Chest X-ray showed cardiomegaly in 3 patients and severe kyphoscoliosis in one. Echocardiography visualized dilatation of the ascending aorta, severe (60 mm) in 1 case, in 3 patients; dilatation of the pulmonary artery in 1 patient; pansystolic mitral valve prolapse in 3 patients (associated with aortic and tricuspid valve prolapse in 2 of them after the disease had progressed); isolated aortic valve prolapse due to bicuspid valve in 2 patients; intracardiac calcifications in 3 patients; subaortic septal hypertrophy in 1 patient and calcified incompetent foramen ovale in 1 patient. Aortography performed in 3 patients disclosed an aneurysm of Valsalva's sinuses in 1 case and a mild aortic insufficiency in 2 cases. Two patients underwent cardiac catheterization for severe mitral regurgitation due to mitral valve prolapse requiring valve replacement, which was successfully done. Thus, echocardiography may provide an early diagnosis of Marfan's syndrome, since cardiovascular abnormalities are frequent in infancy. It also ensures a close follow-up of the disorders and it is useful in deciding whether treatment should be medical or surgical. It may detect formes frustes in a family with Marfan's syndrome, and it may define a borderline group of patients: those with Marfan-like syndrome. In these patients the cardiovascular lesions are more preponderant and appear later than in the classical Marfan's syndrome; they are often difficult to differentiate from the lesions of Barlow's syndrome.

[Aneurysm or false aneurysm of the interauricular septum disclosed by 2 cerebral embolisms]. / Anévrysme ou faux anévrysme du septum interauriculaire, révélé par deux embolies cérébrales.

The authors report a case of solitary aneurysm of the interatrial septum documented by ultrasonography and angiography and revealed by two transient cerebral ischaemic accidents unexplainable by other causes. At surgery, performed later, the interatrial septum was redundant, and Botallo's foramen was about 17 millimetres in diameter, but no sacciform cavity was found. The reasons for the discrepancy between imaging techniques and operative findings and the mechanism of systemic embolism are discussed.

[Effects of nifedipine on carotid blood flow and baroreflex response in essential arterial hypertension. Preliminary results]. / Effet de la nifédipine sur le débit carotidien et la réponse baroréflexe, au cours de l'hypertension artérielle essentielle. Résultats préliminaires.

The objective of this prospective study was to evaluate the effect of nifedipine administered at usual daily doses of 30 to 40 mg on the carotid flow in arterial hypertension. The study included 15 patients (8 men and 7 women), 50 to 79 (mean 59.5) years old suffering from long-standing, fixed essential hypertension becoming instable under central antihypertensive drug therapy. For calculating the carotid blood flow, vascular echotomography combined with Doppler ultrasonography and spectral analysis (Duplex probe) determining the vascular section and flow velocity were used. Arterial pressure using a mercury tonometer, flow velocity, common carotid artery diameter, carotid blood flow, Pourcelot's index, parietal tension and heart rate were measured before treatment and at the 8th day of nifedipine administration. It could be shown that the drug produced a significantly (p less than 0.001) increased carotid blood flow, in spite of a marked (p less than 0.001) decrease in systolic (p less than 0.001) and diastolic (p less than 0.005) blood pressure. The increase in carotid blood flow was directly related to the increase in flow velocity (p less than 0.001) and in the diameter of common carotid artery (p less than 0.01) and was associated with a significant decrease in the Pourcelot's index. Analysis of two groups of patients isolated from the total group according to the elevation of carotid blood flow, showed that the degree of hypotensive effect of nifedipine is negatively correlated with the baroreflex response determined by the variation of parietal tension.(ABSTRACT TRUNCATED AT 250 WORDS)

[Atypical echocardiographic aspects of cardiac amylosis]. / Aspects échographiques atypiques de l'amylose cardiaque.

Echographic abnormalities of cardiac amylosis are now well known and quite useful to the diagnosis. Forms that are morphologically atypical are rare. From three observations (2 hypertrophic, asymmetrical and obstructive forms, and 1 hypertrophic and dilated form) and a review from the literature, we study the nosological, diagnostic and therapeutic problems presented by these atypical echographic of cardiac amylosis.

[Ultrasonic detection of arteriosclerosis of the main arterial trunks in the coronary patient]. / Athérosclérose des gros troncs artériels chez le coronarien, dépistage ultrasonore.

Ultrasonic investigations of the peripheral vessels (continuous Doppler with spectral analysis, echotomography) were performed to evaluate atherosclerosis of the main arteries (abdominal aorta, cervical arteries, lower limb arteries) in 50 coronary patients and 40 control subjects. In the main, our results support those of previously published series (epidemiological and autopsy studies): Atherosclerosis of the main arterial vessels is significantly more common (p less than 0.01) in coronary patients than in control subjects: carotid lesions: 70% (including 10% with severe stenosis) compared to 32% (no severe stenosis); aortic lesions: 50% (including 20% with severe stenosis) compared to 17.5% (7.5% severe stenosis); lower limb arteries: 58% (including 16% severe stenosis) compared to 12.5% (no severe stenosis). The difference of incidences of associations of atherosclerosed vessels between the two groups was significant (p less than 0.01): no peripheral vascular disease was detected in 57.5% of controls compared to only 12% of coronary patients; more than one territory diseased in 15% of controls compared to 58% of coronary patients. The severity of these lesions correlated with the presence of the three major cardiovascular risk factors which were studied (hypertension, smoking, hypercholesterolaemia) and was significantly higher (p less than 0.01) in coronary patients (38% had more than one major risk factor and only 10% had none) than in controls (47% had no risk factors and 6% had more than one). In addition, the preferential sites of atherosclerosis were also confirmed.(ABSTRACT TRUNCATED AT 250 WORDS)