Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry.

Winged helix transcription factors play important roles in cellular differentiation and cell-specific gene expression. To define the role of the winged helix factor hepatocyte nuclear factor/forkhead homologue (HFH)-4, a targeted mutation was created in the mouse hfh-4 gene. No expression of HFH-4 was detected in hfh-4(-)/- mice by RNA blot analysis, in situ hybridization, or RT-PCR. hfh-4(-)/- mice were noted to have abnormalities of organ situs consistent with random determination of left-right asymmetry. In addition, a complete absence of cilia was noted in hfh-4(-)/- mice. The hfh-4 gene is thus essential for nonrandom determination of left-right asymmetry and development of ciliated cells. Homozygous mutant mice also exhibited prenatal and postnatal growth failure, perinatal lethality and, in some cases, hydrocephalus. RT-PCR revealed an absence of left-right dynein (lrd) expression in the embryonic lungs of hfh-4(-)/- mice, suggesting that HFH-4 may act by regulating expression of members of the dynein family of genes. The abnormalities in ciliary development and organ situs in hfh-4(-)/- mice are similar to those observed in human congenital syndromes such as Kartagener syndrome. Targeted mutation of hfh-4 thus provides a model for elucidating the mechanisms regulating ciliary development and determination of left-right asymmetry.

Relation between aortic dicrotic notch pressure and mean aortic pressure in adults.

It has recently been suggested that mean arterial pressure provides a reliable estimate of dicrotic notch pressure in infants and children. The aim of the present study was twofold: (1) to investigate the relation existing between aortic dicrotic notch pressure and both the steady and pulsed component of aortic pressure in adults (i.e., mean and pulse aortic pressures, respectively); and (2) to evaluate mean aortic pressure as an estimate of aortic dicrotic notch pressure. High-fidelity pressure recordings were obtained at the aortic root level in 17 men (52 +/- 13 years). Pressure data were analyzed at rest over 10 consecutive beats in each patient, and, in 6 patients, during the Valsalva maneuver (over 22 to 50 consecutive beats). At rest, dicrotic notch pressure was greater than mean pressure (109.0 +/- 17.9 vs 99.6 +/- 12.5 mm Hg, p = 0.0001). Dicrotic notch pressure was positively related to mean pressure (r = 0.93) and to pulse pressure (r' = 0.77), but not to patient's heart rate, cardiac output, or total estimated arterial compliance. There was a spontaneous beat-to-beat relation between dicrotic notch and mean pressures (1) at rest in 16 of 17 patients (mean r = 0.85), and (2) in all patients undergoing the Valsalva maneuver (mean r = 0.97). During the maneuver, intravascular mean pressure ranged from 59 to 171 mm Hg. Dicrotic notch pressure was positively related to mean pressure (r = 0.98) and to pulse pressure (r' = 0.44). Both at rest and during the Valsalva maneuver, mean pressure underestimated dicrotic notch pressure, and the higher the dicrotic notch pressure, the more negative the percent error (each p = 0.0001). In conclusion, aortic dicrotic notch pressure was mainly related to the steady component of aortic pressure. The mean aortic pressure slightly but significantly underestimated aortic dicrotic notch pressure, and thus should be used with greater caution in adults than in young patients as an estimate of end-systolic pressure.

A comparison between systolic aortic root pressure and finger blood pressure.

BACKGROUND: Digital photoplethysmography is used to assess hemodynamic variability and baroreflex sensitivity. Numerous studies have critically evaluated the accuracy of the photoplethysmographic device against peripheral pressure. The aim of our study was to compare finger blood and aortic root pressure. METHODS: We prospectively compared simultaneous recordings of systolic pressure at the aortic root and finger level over three consecutive respiratory cycles in 15 patients (56+/-11 years) undergoing routine cardiac catheterization. Data were obtained at baseline, during deep breathing maneuver (0.1 Hz), and after left ventricular cineangiography. RESULTS: At baseline, systolic finger pressure overestimated systolic aortic pressure (145.2+/-22.5 vs 115.0+/-20.1 mm Hg; p<0.001). The pressure difference (30.2+/-17.0 mm Hg) was not influenced by systolic aortic pressure. There was no relationship between pressure difference and the main determinants of the pulse wave amplification phenomenon. There was a beat-to-beat relationship between finger and aortic pressure in 14 of 15 subjects (slope ranging from 0.37 to 1.70; ordinate: from -56 to +98 mm Hg). During the deep breathing maneuver and after left ventricular cineangiography, finger pressure still overestimated aortic pressure by 32.3+/-15.0 mm Hg and 38.3 13.9 mm Hg, respectively (each p<0.001). There was a beat-to-beat relationship between systolic aortic root pressure (IAoBP) and systolic finger (FBP) in 13 of 15 patients, with major scattering of both slopes and ordinates. Throughout the study, there was no predictable relationship between the level of IAoBP and pressure bias. CONCLUSIONS: As expected, FBP was almost always higher than IAoBP. Importantly, the differences in systolic pressure did not correlate with known determinants of the pulse wave amplification phenomenon. The device must be used cautiously if one wants to noninvasively track spontaneous or induced changes in IAoBP.

Left ventricular function during weaning of patients with chronic obstructive pulmonary disease.

OBJECTIVE: Determine the evolution of left ventricular ejection fraction during weaning. DESIGN: Prospective study. SETTING: Intensive care unit of a university teaching hospital. PATIENTS AND PARTICIPANTS: 12 consecutive mechanically ventilated patients, without documented coronary artery disease, suffering from acute exacerbation of chronic obstructive pulmonary disease and able to be weaned. MEASUREMENTS AND RESULTS: Left ventricular ejection fraction was determined during mechanical ventilation, inspiratory pressure support (10 cmH2O) and spontaneous ventilation with constant inspiratory oxygen fraction using technetium 99m radionuclide angiography. Spontaneous ventilation induced a significant decrease in left ventricular ejection fraction from 54.5 +/- 12.4 to 47.0 +/- 13% (p < 0.01). Inspiratory pressure support induced a slight but non-significant decrease in left ventricular ejection fraction from 55.0 +/- 12.1 to 50.3 +/- 12.4%. Left ventricular ejection fraction was homogeneously reduced by spontaneous ventilation without patent regional wall motion abnormalities of the left ventricle. Myocardial 201thallium imaging performed 15 min after weaning showed a normal perfusion in the left ventricle anterior and posterior free wall. CONCLUSION: Weaning of patients suffering from chronic obstructive pulmonary disease without coronary artery disease induced a significant reduction in left ventricular ejection fraction. The non significant decrease in left ventricular ejection fraction observed with inspiratory pressure support suggested that our results might be explained by a weaning induced increase in afterload.

Pulse pressure response to the strain of the valsalva maneuver in humans with preserved systolic function.

Arterial pulse pressure response during the strain phase of the Valsalva maneuver has been proposed as a clinical tool for the diagnosis of left heart failure, whereas responses of subjects with preserved systolic function have been poorly documented. We studied the relationship between the aortic pulse amplitude ratio (i.e., minimum/maximum pulse pressure) during the strain phase of the Valsalva maneuver and cardiac hemodynamics at baseline in 20 adults (42 +/- 14 yr) undergoing routine right and left heart catheterization. They were normal subjects (n = 5) and patients with various forms of cardiac diseases (n = 15), and all had a left ventricular ejection fraction >/=40%. High-fidelity pressures were recorded in the right atrium and the left ventricle at baseline and at the aortic root throughout the Valsalva maneuver. Aortic pulse amplitude ratio 1) did not correlate with baseline left ventricular end-diastolic pressure, cardiac index (thermodilution), or left ventricular ejection fraction (cineangiography) and 2) was positively related to total arterial compliance (area method) (r = 0.59) and to basal mean right atrial pressure (r = 0.57) (each P < 0.01). Aortic pulse pressure responses to the strain were not related to heart rate responses during the maneuver. In subjects with preserved systolic function, the aortic pulse amplitude ratio during the strain phase of the Valsalva maneuver relates to baseline total arterial compliance and right heart filling pressures but not to left ventricular function.

[Fortuitous discovery of the association of true and false aneurysm of the left ventricle after cardiogenic shock]. / Découverte fortuite de l'association d'un vrai et d'un faux anévrysme du ventricule gauche au décours d'un choc cardiogénique.

The authors report the fortuitous diagnosis of a true and a false left ventricular aneurysm in a 77 year old man with severe ischaemic heart disease and calcific aortic stenosis, admitted for cardiogenic shock. The association of these two forms of aneurysm is very rare. Clinical and paraclinical diagnosis is difficult. Conventional left ventriculography is the investigation of reference but the diagnosis has been facilitated by Technetium 99 cardiac scintigraphy and color Doppler echocardiography. Surgery may be considered in cases of true aneurysm especially in patients with left ventricular failure, but the indication is formal in cases of false aneurysm.

[Coronary spasm and diffuse coronary vasoconstriction responsible for transient left ventricular insufficiency]. / Spasmes coronaires et vasoconstriction coronaire diffuse responsables d'une insuffisance ventriculaire gauche transitoire.

A 52 year old patient presenting with spontaneous anginal chest pain for 4 days was admitted to hospital for a more intense and prolonged chest pain associated with signs of left ventricular failure (gallop, pulmonary crepitations, hypoxemia). Coronary angiography showed marked septal hypokinesia and spontaneous localised spasm of the left anterior descending and marginal arteries with a variable degree of luminal narrowing of the other segments of these two arteries and of the right coronary artery. These changes regressed after intracoronary injection of molsidomine. The signs of left ventricular failure disappeared in 48 hours. The wall motion abnormality, monitored by 2D echocardiography, regressed slowly over 3 days. On the other hand, the electrocardiogram, which showed anterior wall subendocardial ischaemia with prolongation of the QTc interval during the spasm, remained abnormal for a long time. Therefore, in the absence of organic heart disease, coronary spasms associated with vasoconstriction can induce a sufficiently severe and durable alteration of left ventricular function to create clinical signs of cardiac failure and profound and prolonged ST-T wave changes on the electrocardiogram.

[Arrhythmogenic right ventricular dysplasia]. / Nouveautés dans la dysplasie ventriculaire droite arythmogène.

Congestive cardiac failure could be as important as cardiac arrhythmias in the natural history of arrhythmogenic right ventricular dysplasia. This can be related to the progressive replacement of myocardium by fat and fibrosis of the right ventricle. The left ventricle may also be involved by the same disease process. Moreover, inflammation can be superimposed on ARVD, resulting in a wide spectrum of clinical presentation which can mimick idiopathic dilated cardiomyopathy. Right ventricular cardiac failure has been controlled by anterior dynamic cardiomyoplasty.

[Relationship between end-systolic aortic pressure and mean aortic pressure in adults]. / Relation entre la pression aortique télésystolique et la pression aortique moyenne chez l'adulte.

The mean blood pressure is an accurate estimate of the end-systolic aortic pressure in children. The aim of this study was: 1) to assess the relationship between the pressure at the incisura (PIAo) and the mean (MAoP) and pulse (PAoP) pressures of the supravalvular aorta in adults: and 2) to evaluate MAoP as an estimate of PIAo in adults. High fidelity pressure recordings were carried out in the supravalvular aorta in 17 men. The pressures were measured at rest in 10 consecutive beats and. In 6 subjects, during a Valsalva manoeuvre. At rest, PIAo was greater than the MAoP (109 +/- 17.9 versus 99.6 +/- 12.5 mmHg, p = 0.0001). There was a positive linear correlation between PIAo and MAoP (r = 0.93) and between PIAo and PAoP (r' = 0.77) whereas no correlation was observed between PIAo and heart rate, cardiac output or estimated total systemic arterial compliance. A beat-to-beat relationship was observed between PIAo and MAOP: 1) at rest in 16 of the 17 subjects and 2) in each subject who performed a Valsalva manoeuvre. Both at rest and during Valsalva, MAOP underestimated PIAo significantly, especially when PIAo was increased (p = 0.0001). The authors conclude that end-systolic supraaortic pressure is mainly related to the mean component of aortic pressure. MAOP slightly but constantly underestimated PIAo and this should lead to caution in assimilating MAOP to end-systolic aortic pressure in adults, especially in subjects with very high aortic pressures.

[Hypertrophic myocardiopathy with isolated obstruction of the right ventricle]. / Myocardiopathie hypertrophique avec obstruction isolée du ventricule droit.

The authors report one case of biventricular hypertrophic cardiomyopathy in a 23 year old female patient with severe localized obstruction of the right ventricle (105 mm Hg gradient, almost complete angiographic disappearance of the middle and apical portions of the right ventricle during systole). Echocardiography, hemodynamic findings, and angiography demonstrated nonobstructive involvement of the left ventricle. Among other family members, only her father was noted to have minimal hypertrophic cardiomyopathy. A favorable response to therapy was obtained over 14 months with 320 mg of propranolol given daily (disappearance of palpitations and ventricular tachycardia which had previously been noted on a continuous 24 hour recording before treatment). Other very rare similar cases in the literature are analyzed. It is not possible to distinguish these cases from those with predominantly left ventricular involvement by clinical and radiological findings alone. However, the ECG can often demonstrate right ventricular involvement (right ventricular hypertrophy and/or right bundle branch block). Lastly, it appears that biventricular hypertrophic cardiomyopathies in young patients can initially be localized to only the right ventricle.

Facilitating changes in exercise behavior: effect of structured statements of intention on perceived barriers to action.

Two groups of worksite employees (58 in a control, 53 in an experimental group) underwent three 90-min. educational sessions designed to increase participation in exercise. At the end of the third session, experimental subjects were asked to complete a structured statement of exercise intention which addressed the major barrier to exercise. Two weeks following the program, chi-squared analysis showed that the two groups were proportionately different in changes in frequency and intensity of exercise such that the experimental group in both cases showed greater changes than the control. Experimental subjects showed a twofold increase in frequency and intensity of exercise over the control group. Pearson r indicated a statistically significant association between the completeness of structured statements of intention and an increase in frequency of exercise. We conclude that structured statements of intention are useful for distinguishing between contrived barriers to exercise (excuses) and actual barriers that require practical solutions.

Role of both actin-myosin cross bridges and NO-cGMP pathway modulators in the contraction and relaxation of human placental stem villi.

INTRODUCTION: Human placental stem villi (PSV) present contractile properties. We studied the role of actin-myosin cross bridges (CBs) and the effects of NO-cGMP pathway modulators in the PSV contraction and relaxation. METHODS: In vitro contractile properties were investigated in 71 PSV from term human placentas studied according to their long axis. Contraction was induced by both KCl and electrical tetanic stimulation. Relaxation was induced by inhibiting the CB cycle with either 2,3-butanedione monoxime (BDM) or blebbistatin (BLE) and by activating the NO-cGMP pathway with isosorbide dinitrate (ISDN), sildenafil (SIL) or ISDN + SIL. RESULTS: PSV tension slowly increased by 140% of the basal tone after KCl exposure and by 85% after tetanus. The addition of BDM, BLE, ISDN, SIL and ISDN + SIL induced a relaxation of PSV, the overall time course of relaxation (in s) was respectively (means ± SD) 3412 ± 1904, 14,250 ± 3095*, 3813 ± 1383, 2883 ± 1188 and 2440 ± 477; significantly longer in BLE compared with BDM, ISDN, SIL and ISDN + SIL:*p < 0.001). the overall time course of relaxation (in s) was respectively (means ± SD) 3412 ± 1904, 14,250 ± 3095*, 3813 ± 1383, 2883 ± 1188 and 2440 ± 477; significantly longer in BLE compared with BDM, ISDN, SIL and ISDN + SIL:*p < 0.001). These relaxation kinetics were particularly slow. Other relaxation parametres, i.e., maximum lengthening, -peak dT/dt, and resting tension, did not differ between these 5 subgroups. DISCUSSION AND CONCLUSION: Isolated human PSV were able to contract after both KCl exposure and tetanus. This increase in contractility was reversed by inhibiting the CB cycle with BDM or BLE and by stimulating the NO-cGMP pathway with ISDN or SIL. The association ISDN + SIL did not potentiate the relaxing processes.

Increased entropy production in diaphragm muscle of PPAR alpha knockout mice.

Peroxisome proliferator activated receptor alpha (PPAR alpha) regulates fatty acid beta-oxidation (FAO) and plays a central role in the metabolic and energetic homeostasis of striated muscles. The thermodynamic consequences of the absence of PPAR alpha were investigated in diaphragm muscle of PPAR alpha knockout mice (KO). Statistical mechanics provides a powerful tool for determining entropy production, which quantifies irreversible chemical processes generated by myosin molecular motors and which is the product of thermodynamic force A/T (chemical affinity A and temperature T) and thermodynamic flow (myosin crossbridge (CB) cycle velocity upsilon). The behavior of both wild type (WT) and KO diaphragm was shown to be near-equilibrium and in a stationary state, but KO was farther from equilibrium than WT. In KO diaphragm, a substantial decrease in contractile function was associated with an increase in both A/T and upsilon and with profound histological injuries such as contraction band necrosis. There were no changes in PPAR delta and gamma expression levels or myosin heavy chain (MHC) patterns. In KO diaphragm, a marked increase in entropy production (A/T x upsilon) accounted for major thermodynamic dysfunction and a dramatic increase in irreversible chemical processes during the myosin CB cycle.

Statistical mechanics of myosin molecular motors in skeletal muscles.

Statistical mechanics provides the link between microscopic properties of matter and its bulk properties. The grand canonical ensemble formalism was applied to contracting rat skeletal muscles, the soleus (SOL, n = 30) and the extensor digitalis longus (EDL, n = 30). Huxley's equations were used to calculate force (pi) per single crossbridge (CB), probabilities of six steps of the CB cycle, and peak muscle efficiency (Eff(max)). SOL and EDL were shown to be in near-equilibrium (CB cycle affinity 2.5 kJ/mol) and stationary state (linearity between CB cycle affinity and myosin ATPase rate). The molecular partition function (z) was higher in EDL (1.126+/-0.005) than in SOL (1.050+/-0.003). Both pi and Eff(max) were lower in EDL (8.3+/-0.1 pN and 38.1+/-0.2%, respectively) than in SOL (9.2+/-0.1 pN and 42.3+/-0.2%, respectively). The most populated step of the CB cycle was the last detached state (D3) (probability P(D3): 0.890+/-0.004 in EDL and 0.953+/-0.002 in SOL). In each muscle group, both pi and Eff(max) linearly decreased with z and statistical entropy and increased with P(D3). We concluded that statistical mechanics and Huxley's formalism provided a powerful combination for establishing an analytical link between chemomechanical properties of CBs, molecular partition function and statistical entropy.

Percutaneous brachial approach using the femoral artery sheath for left heart catheterization and selective coronary angiography.

A percutaneous method via the brachial artery for left heart catheterization and selective coronary angiography is described. The technique uses the sheath intended for the femoral artery, continuously infused and introduced following a particular technique. The procedure was performed with minimal complications over 18 months, with multipurpose "Schoonmaker" or preshaped catheters, in all the patients (37) in whom the femoral approach was contraindicated or failed. When a catheterization must be performed from the arm, this method, without cutdown and arteriotomy and allowing a good distal flow during the procedure, appears to have some advantages over the classical Sones technique or the percutaneous arterial axillary approach.

Percutaneous brachial approach for transluminal coronary angioplasty.

Transluminal coronary angioplasty from the arm is performed generally with cutdown and brachial arteriotomy. We describe a brachial percutaneous technique for coronary angioplasty, almost similar to the femoral one, with a special focus on the prevention of induced vasoconstriction. Our preliminary results are satisfactory and without complications: 13 procedures in 11 patients have been performed over a 30 month period, with the sheaths left in place for 4-6 h after the procedure. This method could be an easy alternative to the Sones technique for operators who are essentially familiar with the femoral percutaneous arterial approach.

[Acute human and experimental poisoning with diethylene glycol]. / Intoxication aiguë humaine et expérimentale par le diéthylène-glycol.

Although acute poisoning with ethylene glycol (EG) used in antifreeze mixtures is well known in man, only a few reports have described acute intoxication with diethylene glycol (DEG) and only one has mentioned oxaluria. Furthermore, there is no experimental evidence that DEG is metabolized into oxalate. The ability of ethanol infusions to prevent hepatic oxidation of DEG has not been proved. Moreover, failure of this treatment has been reported by some authors. In order to resolve such questions, Wistar male adult rats possessing a hepatic alcohol deshydrogenase were given a single oral dose of 15 ml/kg-1 DEG. Rats were either untreated or treated with hydration alone or associated with bicarbonate or ethanol. Urinary output, urinary oxalate excretion, acid-base balance in peripheral blood and renal histology were studied. Acute poisoning induced metabolic acidosis, polyuria, hyperoxaluria with renal tubular necrosis and a 66% mortality. Massive hydration improved acidosis and prognosis, but mortality and renal lesions were avoided only when bicarbonate or ethanol were added. Only ethanol significantly decreased oxaluria. In acute DEG poisoning, both the mechanism and the treatment appear to be the same as in acute EG intoxication.