Hypereosinophilic syndrome with characteristic left ventricular thrombus demonstrated by contrast echocardiography.

Hypereosinophilic syndrome (HES) is a rare condition characterised by idiopathic eosinophilia with organ system involvement. The condition is far more common in males, with a typical onset in the third to sixth decade. Cardiac damage may result in the formation of a characteristic apical thrombus readily visualised on two-dimensional echocardiography. Cardiac involvement portends a less favourable prognosis as it can be complicated by acute embolic events and progressive development of restrictive cardiomyopathy, valvular dysfunction, and heart failure. In this case report, we describe a middle-aged gentleman with HES and characteristic apical thrombus identified on contrast echocardiography. Although the use of contrast agents for assessment of left ventricular thrombus is documented in the literature,1 this case illustrates the application of contrast echocardiography in the evaluation of eosinophilia. (Neth Heart J 2009;17:169-70.).

Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice.

Many neurodegenerative diseases are associated with the abnormal sequestration of disease-specific proteins in the brain, but the events that initiate this process remain unclear. To determine whether the deposition of the beta-amyloid peptide (Abeta), a key pathological feature of Alzheimer's disease (AD), can be induced in vivo, we infused dilute supernatants of autopsy-derived neocortical homogenates from Alzheimer's patients unilaterally into the hippocampus and neocortex of 3-month-old beta-amyloid precursor protein (betaAPP)-transgenic mice. Up to 4 weeks after the infusion there was no Abeta-deposition in the brain; however, after 5 months, the AD-tissue-injected hemisphere of the transgenic mice had developed profuse Abeta-immunoreactive senile plaques and vascular deposits, some of which were birefringent with Congo Red. There was limited deposition of diffuse Abeta also in the brains of betaAPP-transgenic mice infused with tissue from an age-matched, non-AD brain with mild beta-amyloidosis, but none in mice receiving extract from a young control case. Abeta deposits also were not found in either vehicle-injected or uninjected transgenic mice or in any nontransgenic mice. The results show that cerebral beta-amyloid can be seeded in vivo by a single inoculation of dilute AD brain extract, demonstrating a key pathogenic commonality between beta-amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo beta-amyloidogenesis in the brain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.

Permeation of Na+ through a delayed rectifier K+ channel in chick dorsal root ganglion neurons.

In whole-cell patch clamp recordings from chick dorsal root ganglion neurons, removal of intracellular K+ resulted in the appearance of a large, voltage-dependent inward tail current (Icat). Icat was not Ca2+ dependent and was not blocked by Cd2+, but was blocked by Ba2+. The reversal potential for Icat shifted with the Nernst potential for [Na+]. The channel responsible for Icat had a cation permeability sequence of Na+ >> Li+ >> TMA+ > NMG+ (PX/PNa = 1:0.33:0.1:0) and was impermeable to Cl-. Addition of high intracellular concentrations of K+, Cs+, or Rb+ prevented the occurrence of Icat. Inhibition of Icat by intracellular K+ was voltage dependent, with an IC50 that ranged from 3.0-8.9 mM at membrane potentials between -50 and -110 mV. This voltage-dependent shift in IC50 (e-fold per 52 mV) is consistent with a single cation binding site approximately 50% of the distance into the membrane field. Icat displayed anomolous mole fraction behavior with respect to Na+ and K+; Icat was inhibited by 5 mM extracellular K+ in the presence of 160 mM Na+ and potentiated by equimolar substitution of 80 mM K+ for Na+. The percent inhibition produced by both extracellular and intracellular K+ at 5 mM was identical. Reversal potential measurements revealed that K+ was 65-105 times more permeant than Na+ through the Icat channel. Icat exhibited the same voltage and time dependence of inactivation, the same voltage dependence of activation, and the same macroscopic conductance as the delayed rectifier K+ current in these neurons. We conclude that Icat is a Na+ current that passes through a delayed rectifier K+ channel when intracellular K+ is reduced to below 30 mM. At intracellular K+ concentrations between 1 and 30 mM, PK/PNa remained constant while the conductance at -50 mV varied from 80 to 0% of maximum. These data suggest that the high selectivity of these channels for K+ over Na+ is due to the inability of Na+ to compete with K+ for an intracellular binding site, rather than a barrier that excludes Na+ from entry into the channel or a barrier such as a selectivity filter that prevents Na+ ions from passing through the channel.

Myocardial stunning in hypertrophic cardiomyopathy: recovery predicted by single photon emission computed tomographic thallium-201 scintigraphy.

A young woman with hypertrophic cardiomyopathy confirmed by echocardiography and cardiac catheterization presented with chest pain and features of a large left ventricular aneurysm. The initial diagnosis was myocardial ischemia with either an evolving or an ancient myocardial infarction. Subsequently, verapamil therapy was associated with complete resolution of the extensive left ventricular wall motion abnormalities, normalization of left ventricular ejection fraction and a minimal myocardial infarction. Normal thallium uptake on single photon emission computed tomographic scintigraphy early in the hospital course predicted myocardial viability in the region of the aneurysm. Thus, orally administered verapamil may reverse spontaneous extensive myocardial ischemia in hypertrophic cardiomyopathy and possibly limit the extent of myocardial infarction in such circumstances.

Continuous ICV infusion of scopolamine impairs sustained attention of rhesus monkeys.

Systemic administration of anticholinergic agents impairs cognitive performance in animals and man. The anticholinergic, scopolamine, has profound effects on peripheral and central cholinergic function, making interpretation of its effects on cognitive performance difficult. To circumvent this problem, scopolamine was administered directly to the central nervous system of rhesus monkeys using a subcutaneously implanted infusion pump connected to a cannulae directed toward the right lateral ventricle. Intracerebroventricular (ICV) infusion of scopolamine (0.004, 0.012, 12.5, and 40.0 micrograms/kg/h) produced a dose-dependent decrease in the number of responses on a continuous performance task. Response decrements produced by scopolamine were seen mainly during the last half of the test session and at short stimulus durations. These data suggest that scopolamine produces a deficit in sustained attention or slowing of information processing that is mediated through direct central cholinergic blockade in the rhesus monkey.

PD 142676 (CI 1002), a novel anticholinesterase and muscarinic antagonist.

Inhibition of brain acetylcholinesterase (AChE) can provide relief from the cognitive loss associated with Alzheimer's disease (AD). However, unwanted peripheral side effects often limit the usefulness of the available anticholinesterases. Recently, we identified a dihydroquinazoline compound, PD 142676 (CI 1002) that is a potent anticholinesterase and a functional muscarinic antagonist at higher concentrations. Peripherally, PD 142676, unlike other anticholinesterases, inhibits gastrointestinal motility in rats, an effect consistent with its muscarinic antagonist properties. Centrally, the compound acts as a cholinomimetic. In rats, PD 142676 decreases core body temperature. It also increases neocortical arousal, as measured by quantitative electroencephalography, and cortical acetylcholine levels, measured by in vivo microdialysis. The compound improves the performance of C57/B10j mice in a water maze task and of aged rhesus monkeys in a delayed match-to-sample task involving short-term memory. The combined effect of AChE inhibition and muscarinic antagonism distinguishes PD 142676 from other anticholinesterases, and may be useful in treating the cognitive dysfunction of AD and produce fewer peripheral side effects.

Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist.

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

Validation of instantaneous pressure gradients measured by continuous-wave Doppler in experimentally induced aortic stenosis.

The relation between catheter-measured and Doppler-derived aortic pressure gradients was examined in 8 open-chest dogs. A snare was placed around the proximal ascending aorta and adjusted to provide a wide range of gradient to left ventricular (LV) outflow. A continuous-wave Doppler transducer was placed above the level of the obstruction and angled to optimize the audio and spectral signals. Pressure tip transducer catheters recorded LV and ascending aortic pressures simultaneously with the Doppler signal. In 120 randomly selected sinus beats, Doppler-derived maximal gradient correlated well with maximal instantaneous catheter gradient from 4 to 179 mm Hg (r = 0.99). Mean gradients also were closely related (r = 0.98). For gradients above 100 mm Hg, the correlation remained good (r = 0.98), but for gradients below 50 mm Hg, the correlation was not as precise (r = 0.81). All 120 cycles were digitized at 10-ms intervals to examine the correspondence between the Doppler and catheter data throughout systole. For the 2,742 pairs of points so obtained, the correlation was excellent (r = 0.95). The close relation between Doppler-derived pressure gradient and that measured simultaneously by catheterization provides further validation of the use of continuous-wave Doppler in the assessment of aortic stenosis, not only at maximal gradient, but throughout the period of LV ejection.

Transient atrioventricular block after open-heart surgery for congenital heart disease.

The records of 22 patients with transient atrioventricular (AV) block after open-heart surgery for congenital heart disease from 1972 to 1978 were reviewed to determine the natural history of this entity. Preoperatively, no patient had AV block; 3 had right bundle branch block (BBB), 1 had left BBB and 5 had nonspecific intraventricular conduction delay. Complete AV block developed in 20 patients and Mobitz II AV block in 2. Transient AV block occurred intraoperatively in 14 patients and within 48 hours postoperatively in 8; AV block persisted for greater than or equal to 48 hours postoperatively in all patients, for a mean of 7.3 days (range 2 to 28). During a follow-up of 5.5 years (range 2.5 to 10), late AV block developed in 2 patients. None of the 18 patients whose escape QRS complex morphology during AV block was similar to the final QRS complex during normal sinus rhythm or atrial fibrillation with AV conduction had late AV block, whereas 2 of the 4 in whom it differed did (p less than 0.01). There was no difference in the escape rate between the 2 groups. Thus, late development of high-grade AV block is infrequent among patients with transient postoperative AV block. An escape QRS complex during postoperative AV block that differs from the QRS complex seen on recovery of normal sinus rhythm or atrial fibrillation with anterograde conduction may identify those at high risk of late AV block.

Two-dimensional echocardiographically guided pericardiocentesis: experience in 117 consecutive patients.

Pericardiocentesis guided by 2-dimensional echocardiography has been used at the Mayo Clinic since April 1980. The 2-dimensional examination localizes the pericardial fluid. Particular note is made of the place on the body wall closest to the fluid. An entry track that permits puncture of the pericardial sac without damage to any vital structure is then selected for the pericardiocentesis needle. Between April 1980 and March 1984, 132 consecutive pericardiocenteses in 117 patients were done by this technique. The volume of fluid obtained ranged from 75 to 1,700 ml (mean 650). Seventy percent of the taps were done for therapy, 21% for diagnosis, and 9% for both therapy and diagnosis. A Teflon-sheathed "intracath" needle was used to complete 80% of the pericardiocenteses. In the other 20%, a large catheter was secondarily introduced and connected to a closed drainage system. There were no deaths related to the procedure. One symptomatic pneumothorax occurred. There were 3 minor complications. Two-dimensional echocardiographic imaging of the heart and pericardial fluid permits a safe and effective means of performing pericardiocentesis.

Position-dependent ventricular tachycardia related to a peripherally inserted central catheter.

Recently, peripherally inserted central venous catheters (PICCs) have been widely used for venous access. Advantages of a PICC over centrally inserted central catheters include the virtual elimination of the risk of pneumothorax, hemothorax, and arterial puncture, along with a reduced risk of bleeding. However, the PICC has associated risks. We present 2 cases of body position-dependent ventricular tachycardia related to PICCs. These events occurred in patients with no prior history of cardiac arrhythmia and were corrected by repositioning of the PICC. They serve to identify a potentially serious cardiac complication of the PICC that, to our knowledge, has not been described previously.

Cardiopulmonary metastatic lesions of osteosarcoma and associated cerebral infarction.

Osteogenic sarcoma frequently disseminates by hematogenous routes. A 32-year-old patient underwent evaluation for an acute cerebral infarction. Cardiac auscultation disclosed an abnormal diastolic sound. Echocardiographic examination revealed a large left atrial mass, which was found at thoracotomy to be metastatic osteogenic sarcoma. Cerebral computed tomographic scans at the time of initial examination and 3 months later demonstrated new cerebral lesions consistent with metastatic growths. The abrupt cerebral infarction, other clinical findings, and results of diagnostic studies strongly suggested that the acute cerebrovascular event was the result of metastatic cerebral embolization from the tumor material found in the thorax. Cerebral infarction is an unusual and catastrophic complication of thoracic metastatic lesions of osteogenic sarcoma.

Electrocardiographic and echocardiographic changes associated with malignant catatonia.

We describe a case of malignant catatonia manifested by catatonic symptoms, fever, hemodynamic instability, and acute neurologic decline that was associated with electrocardiographic and echocardiographic abnormalities similar to those noted in patients with other central nervous system processes. The patient's electrocardiographic and echocardiographic abnormalities resolved after successful electroconvulsive therapy for the underlying neuropsychiatric disorder. The theoretic, physiologic, and clinical significances of this case are discussed.

Doppler echocardiography: theory, instrumentation, technique, and application.

A Doppler examination is a valuable adjunct to a complete echocardiographic examination. It has the capability of measuring normal and abnormal velocities of blood flow noninvasively. For the first time, this procedure allows noninvasive quantitation of stenotic gradients, intracardiac pressures, and blood flow as well as semiquantitative assessment of regurgitant lesions. With this procedure, the operator must progress through a learning curve in order to gain a complete understanding of the examination techniques, the limitations of the instruments, and the Doppler physics principles before applications can be made to clinical practice. Evaluation of other aspects of Doppler echocardiography, such as color-flow mapping and assessment of diastolic events, portends great promise for the role of this procedure in the future.

Doppler color flow imaging: a new technique for visualization and characterization of the blood flow jet in mitral stenosis.

We used Doppler color flow imaging, a new noninvasive technique for mapping of intracardiac blood flow, to visualize and characterize the blood flow jet in 42 patients with mitral stenosis. Color flow imaging provides information about the direction of blood flow, its velocity, and the presence of turbulence. Although we found various jet configurations, most frequently the jet was centrally and apically directed and had a "candle flame" appearance (a central blue zone surrounded by hues of yellow and orange). The blood flow jet can be used to guide the positioning of the continuous-wave Doppler beam parallel to the blood flow; thus, the accuracy of the Doppler data can be enhanced. This new technology has promising potential for other clinical applications in cardiology.

Noninvasive measurement of cardiac output by continuous-wave Doppler echocardiography: initial experience and review of the literature.

Doppler echocardiographic measurement of the velocity of blood flow in the ascending aorta is a noninvasive method for determining cardiac output in the critically ill patient. Fifty-four patients in the medical intensive care unit (35 men and 19 women, age range 41 to 91 years) in whom a Swan-Ganz catheter had been inserted underwent measurement of cardiac output with use of a commercially available continuous-wave Doppler echocardiographic instrument. The aortic root diameter was measured by A-mode echocardiography. An additional 26 patients (17 men and 9 women, age range 20 to 83 years) who had undergone an open-heart surgical procedure and had hemodynamic monitoring in the postoperative period also underwent Doppler measurement of cardiac output. In these patients, the aortic root diameter was measured directly intraoperatively. Cardiac output was also determined by thermodilution in both groups. An adequate A-mode study was possible in 83% of the medical patients but only 27% of the surgical patients. Doppler signals were adequate in 84% of the medical patients and 92% of the surgical patients. The correlation between thermodilution and Doppler-derived cardiac output was good in both the medical (r = 0.94, SEE = 0.78, P less than 0.001) and the surgical (r = 0.85, SEE = 0.78, P less than 0.001) group. Doppler echocardiography is a promising noninvasive method for determining cardiac output in critically ill patients.

Combining tacrine with milameline reverses a scopolamine-induced impairment of continuous performance in rhesus monkeys.

RATIONALE: Cholinomimetic therapy in Alzheimer's disease (AD) has been hampered by narrow efficacious dose ranges and dose-limiting side effects. These limitations highlight the need for an alternative therapeutic approach for the symptomatic treatment of AD. OBJECTIVES: To determine in rhesus monkeys if combined treatment with the acetylcholinesterase inhibitor tacrine (Cognex) and the muscarinic agonist milameline improve behavioral efficacy in a scopolamine-reversal task without potentiating adverse side effects. METHODS: Behavioral performance of rhesus monkeys was measured using a continuous performance task. The effects of tacrine and milameline, separately or in combination, were determined following administration of an impairing dose of the anticholinergic scopolamine. In addition, tacrine and milameline were given similarly in the absence of scopolamine to determine the presence of adverse side effects. RESULTS: Tacrine and milameline, separately or in combination, reversed the scopolamine-induced decrease in responses on a continuous performance task. Administered in combination, tacrine and milameline significantly improved performance on this task at lower doses and across a broader dose range than when given separately. In the absence of scopolamine, combined treatment did not potentiate the appearance of side effects or produce adverse events significantly different from those observed with either compound alone. CONCLUSIONS: Tacrine and milameline given in combination broadened the range of doses significantly reversing a scopolamine-induced impairment without potentiating adverse side effects.

Paraneoplastic digital thrombosis: a case report.

Persistent digital ischemia is an uncommon paraneoplastic syndrome. We describe a 71-year-old man whose only manifestation of an underlying adenocarcinoma was digital ischemia. His symptoms responded dramatically to bilateral dorsal sympathectomies. A thorough search for the mechanism producing the ischemia failed to provide an explanation. We assume that unknown neurohumoral factors produced by the tumor were responsible.

Reliable assessment of perfusivity and diffusivity from diffusion imaging of the body.

Diffusion-weighted MRI of the body has the potential to provide important new insights into physiological and microstructural properties. The intra-voxel incoherent motion (IVIM) model relates the observed DW-MRI signal decay to parameters that reflect perfusivity (D*) and its volume fraction (f), and diffusivity (D). However, the commonly used voxel-wise fitting of the IVIM model leads to parameter estimates with poor precision, which has hampered their practical usage. In this work, we increase the estimates' precision by introducing a model of spatial homogeneity, through which we obtain estimates of model parameters for all of the voxels at once, instead of solving for each voxel independently. Furthermore, we introduce an efficient iterative solver which utilizes a model-based bootstrap estimate of the distribution of residuals and a binary graph cut to generate optimal model parameter updates. Simulation experiments show that our approach reduces the relative root mean square error of the estimated parameters by 80% for the D* parameter and by 50% for the f and D parameters. We demonstrated the clinical impact of our model in distinguishing between enhancing and nonenhancing ileum segments in 24 Crohn's disease patients. Our model detected the enhanced segments with 91%/92% sensitivity/specificity which is better than the 81%/85% obtained by the voxel-independent approach.