Brain MRI findings in neurologically asymptomatic patients with infective endocarditis.

BACKGROUND AND PURPOSE: Neurologic complications in infective endocarditis are frequent and affect patient prognosis negatively. Additionally, detection of asymptomatic lesions by MR imaging could help early management of this condition. The objective of our study was to describe MR imaging characteristics of cerebral lesions in a neurologically asymptomatic population with infective endocarditis. MATERIALS AND METHODS: One hundred nine patients at the acute phase of a definite or possible infective endocarditis according to the Duke modified criteria and without neurologic manifestations according to the NIHSS were prospectively included. Each patient underwent cerebral MR imaging and MRA within 7 days of admission. RESULTS: MR imaging showed abnormalities in 78 patients (71.5%). Acute ischemic lesions (40 patients, 37%) and cerebral microbleeds (62 patients, 57%) were the most frequent lesions. Eight patients had an acute SAH, 3 patients had brain microabscesses, 3 had a small cortical hemorrhage, and 3 had a mycotic aneurysm. Acute ischemic lesions mostly appeared as multiple small infarcts disseminated in watershed territories (25/40, 62.5%) and as lesions of different ages (21/40, 52.5%). Cerebral microbleeds were preferentially distributed in cortical areas (362/539 cerebral microbleeds, 67%). No significant correlation was found among lesions, in particular between acute ischemia and cerebral microbleeds. CONCLUSIONS: Occult cerebral lesions, in particular cerebral microbleeds and acute ischemic lesions, are frequent in infective endocarditis. The MR imaging pattern of acute small infarcts of different ages predominating in watershed territories and cortical cerebral microbleeds may represent a surrogate imaging marker of infective endocarditis.

Early stroke risk and ABCD2 score performance in tissue- vs time-defined TIA: a multicenter study.

OBJECTIVES: Stroke risk immediately after TIA defined by time-based criteria is high, and prognostic scores (ABCD2 and ABCD3-I) have been developed to assist management. The American Stroke Association has proposed changing the criteria for the distinction between TIA and stroke from time-based to tissue-based. Research using these definitions is lacking. In a multicenter observational cohort study, we have investigated prognosis and performance of the ABCD2 score in TIA, subcategorized as tissue-positive or tissue-negative on diffusion-weighted imaging (DWI) or CT imaging according to the newly proposed criteria. METHODS: Twelve centers provided data on ABCD2 scores, DWI or CT brain imaging, and follow-up in cohorts of patients with TIA diagnosed by time-based criteria. Stroke rates at 7 and 90 days were studied in relation to tissue-positive or tissue-negative subcategorization, according to the presence or absence of brain infarction. The predictive power of the ABCD2 score was determined using area under receiver operator characteristic curve (AUC) analyses. RESULTS: A total of 4,574 patients were included. Among DWI patients (n = 3,206), recurrent stroke rates at 7 days were 7.1%(95% confidence interval 5.5-9.1) after tissue-positive and 0.4% (0.2-0.7) after tissue-negative events (p diff < 0.0001). Corresponding rates in CT-imaged patients were 12.8% (9.3-17.4) and 3.0% (2.0-4.2), respectively (p diff < 0.0001). The ABCD2 score had predictive value in tissue-positive and tissue-negative events (AUC = 0.68 [95% confidence interval 0.63-0.73] and 0.73 [0.67-0.80], respectively; p sig < 0.0001 for both results, p diff = 0.17). Tissue-positive events with low ABCD2 scores and tissue-negative events with high ABCD2 scores had similar stroke risks, especially after a 90-day follow-up. CONCLUSIONS: Our findings support the concept of a tissue-based definition of TIA and stroke, at least on prognostic grounds.

Aseptic meningitis and ischaemic stroke in Fabry disease.

BACKGROUND: Fabry disease (OMIM 301 500) is an X-linked lysosomal storage disease. Neurological symptoms in Fabry disease mainly include stroke, acroparesthesia, cranial nerve palsies and autonomic dysfunction. We report on aseptic meningitis in Fabry patients. METHODS: Clinical analysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, treatment and outcome data were analysed in three cases of meningitis associated with Fabry disease. FINDINGS: Mean age at meningitis onset was 26.6 (24-28) years. Headache was present in all cases and fever in two cases. Meningitis was always diagnosed before Fabry disease. A familial history of Fabry disease was present in two cases. Non-neurological symptoms caused by Fabry disease were present in all cases. All patients also suffered stroke and sensorineural hearing loss. Cerebrospinal fluid (CSF) analysis showed pleocytosis (mean, 36; range: 8-76 cells/mm(3)) and a high protein level (mean, 63; range, 47-70 mg/dl). C-reactive protein blood levels and erythrocyte sedimentation rate were raised. Diagnosis was assessed by low alpha-galactosidase A dosage and/or gene mutation analysis in all cases. All patients were treated with enzyme replacement therapy (ERT). In two cases, lumbar puncture was repeatedly performed and there was no normalisation of CSF under ERT alone, at 9 and 24 months of follow-up, respectively. One patient who suffered intracranial hypertension was treated efficiently with steroids, associated with azathioprine. The fact that Fabry disease could be an auto-inflammatory disorder is discussed. INTERPRETATION: Fabry disease may cause aseptic meningitis.

[Feasibility of percutaneous exclusion of the left atrial appendage: results of 11 cases]. / Faisabilité de l'exclusion percutanée de l'auricule gauche. A propos de 11 cas.

Atrial fibrillation is associated with a risk of cerebral embolism, the only proven effective prevention of which is anticoagulant therapy. There is no known alternative in cases with contra-indications to this treatment. Percutaneous exclusion of the left atrial appendage by the implantation of a prosthesis (PLAATO System, ev3 Inc., Plymouth, Minnesota) is a new approach to the prevention of these complications. The authors report the results observed in a series of 11 consecutive patients (7 men, mean age 72 +/- 9 years) in whom this procedure was proposed. All patients had atrial fibrillation for over 3 months, were at high risk and had contra-indications to oral anticoagulants. The implantation of the prosthesis was performed after treatment with aspirin and clopidogrel, under general anaesthesia radioscopy and transoesophageal echocardiographic guidance with success in 9 cases (1 implantation refused in the catheter laboratory and 1 failure). The only complication observed was transient ST elevation treated by emergency angioplasty. The echographic and angiographic criteria of success of left atrial appendage exclusion were fulfilled in all implanted patients. The hospital course was uncomplicated. One recurrence of stroke was observed at the second month: transoesophageal echocardiography confirmed the absence of thrombosis, of migration of the prosthesis and its impermeability in all the patients. After 7 +/- 5 months' follow-up, no other adverse event was observed. This new procedure is technically feasible. Despite encouraging results, its long-term efficacy in the prevention of thromboembolic complications of atrial fibrillation remains to be demonstrated.

In vivo middle cerebral artery plaque imaging by high-resolution MRI.

Middle cerebral artery (MCA) atherosclerosis is currently diagnosed by indirect angiographic methods. The authors used high-resolution MRI (HR-MRI) to study MCA stenosis in six patients. At the level of stenosis, an MCA plaque was clearly delineated and significantly measured vs nonatherosclerotic MCA segments, showing that HR-MRI is an accurate direct imaging method.

Post-infectious ophtalmoparesis associated with anti-GM1 but not with anti-GQ1b antibodies.

Acute paresis of extraocular muscles has been described following infection or immunization. It is usually associated with the presence of anti-GQ1b antibodies. We report a case of post-infectious ophtalmoparesis that was negative for anti-GQ1b antibodies and positive for anti-GM1 antibodies.

Global predictive real-time control of Quebec Urban Community's westerly sewer network.

Quebec Urban Community (QUC) has selected Global Predictive Real-Time Control (GP-RTC) as the most efficient approach to achieve environmental objectives defined by the Ministry of Environment. QUC wants to reduce combined sewer overflows (CSOs) frequency to the St Lawrence river to two events per summer period in order to reclaim the use of Jacques-Cartier Beach for recreational activities and sports of primary contact. QUC's control scheme is based on the Certainty Equivalent Control Open Loop Feedback (CEOLF) strategy which permits one to introduce, at each control period, updated measurements and meteorological predictions. A non-linear programming package is used to find the flow set points that minimise a multi-objective (cost) function, subjected to linear equality and inequality constraints representing the physical and operational constraints on the sewer network. Implementation of GP-RTC on QUC's westerly network was performed in the summer of 1999 and was operational by mid-August. Reductions in overflow volumes with GP-RTC compared to static control are attributed to the optimal use of two existing tunnels as retention facilities as well as the maximal use of the wastewater treatment plant (WWTP) capacity.

Parallel streams for the relay of vibrissal information through thalamic barreloids.

This study investigated the organization of a vibrissal pathway that arises from the interpolar division of the spinal trigeminal complex (SP5i), transits through the ventral posterior medial nucleus (VPM), and innervates the somatosensory cortical areas in the rat. Using Fluoro-Gold and biotinylated dextran amine, respectively, as retrograde and anterograde tracers, the following organization plan was disclosed. The SP5i projection arises from a population of small-sized neurons that selectively innervate the ventral lateral part of VPM. In cytochrome oxidase-stained material, this region does not display any barreloid arrangement, but Fluoro-Gold injections in single barrel columns labeled rods of cells that extend caudally into the ventral lateral division of VPM. Thus, on the basis of retrograde labeling, barreloids were divided into core and tail compartments, which correspond to the rod segments running across the dorsal and ventral lateral parts of VPM, respectively. Double-labeling experiments revealed that SP5i afferents innervate the tail of barreloids. The anterograde labeling of thalamocortical axons show that most "core cells" project to a single barrel column, whereas some "tail cells" give rise to branching axons that innervate the second somatosensory area and the dysgranular zone of the barrel field. Injections that straddled the transition zone between the core and tail regions disclosed cells projecting to a single barrel column and to the surrounding dysgranular zone. These results suggest that the projection of "barreloids cells" to the granular and/or dysgranular zones relates to the class of prethalamic input(s) they receive.

Subacute posttraumatic ascending myelopathy after spinal cord injury. Report of three cases.

Subacute posttraumatic ascending myelopathy is a rare disorder, unrelated to syrinx formation or mechanical instability, that may gradually emerge within the first 1 to 2 weeks after a spinal cord injury. The authors describe three patients with this syndrome and discuss its possible causes as well as its clinical presentation, imaging characteristics, treatment, and patient prognosis.

Corticothalamic projections from layer 5 of the vibrissal barrel cortex in the rat.

This study bears on the projections of layer 5 cells of the vibrissal sensory cortex to the somatosensory thalamus in rats. Small groups of cells were labeled with biotinylated dextran amine (BDA), and their axonal arborizations were individually reconstructed from horizontal sections counterstained for cytochrome oxidase. Results show that the vast majority ( approximately 95%) of layer 5 axons that innervate the somatosensory thalamus are collaterals of corticofugal fibers that project to the brainstem. The anterior pretectal nucleus, the deep layers of the superior colliculus, and the pontine nuclei are among the structures most often coinnervated. In the thalamus, layer 5 axons terminate exclusively in the dorsal part of the posterior group (Po), where they form clusters of large terminations. Because dorsal Po projects to multiple cortical areas, we sought to determine whether all recipient areas return a layer 5 projection to this part of the thalamus. Additional experiments using fluoro-gold and BDA injections provided evidence that the primary somatosensory area is the sole source of layer 5 projections to dorsal Po but that this thalamic region receives convergent layer 6 projections from the primary and second somatosensory areas and from the motor and insular cortices. These results show that layer 5 projections do not overlap in associative thalamic nuclei, thus defining area-related subdivisions. Furthermore, the coinnervation of brainstem nuclei by layer 5 CT axons suggests that this pathway conveys to the thalamus a copy of the cortical output aimed at brainstem structures.

Repressed expression of the human xanthine oxidoreductase gene. E-box and TATA-like elements restrict ground state transcriptional activity.

Studies were initiated to address the basis for the low xanthine oxidoreductase (XOR) activity in humans relative to nonprimate mammalian species. The expression of the XOR in humans is strikingly lower than in mice, and both transcription rates and core promoter activity of the gene are repressed. Analysis of human XOR promoter activity in hepatocytes and vascular endothelial cells showed that the region from -258 to -1 contains both repressor and activator binding regions regulating core promoter activity. The region between -138 and -1 is necessary and sufficient for initiating, and the region between -258 and -228 is critical for restricting core promoter activity. Within the latter region, site-directed mutations identified a consensus sequence "acacaggtgtgg" (-242 to -230) that contains an E-box that binds a repressor. In addition, the TATA-like element is also required to restrict promoter activity and TFIID binds to this site. The results demonstrate that both an E-box and TATA-like element are required to restrict gene activity. A model is proposed to account for human XOR regulation.

Single-axon tracing study of neurons of the external segment of the globus pallidus in primate.

Axonal projections arising from the external segment of the globus pallidus (GPe) in cynomolgus monkeys (Macaca fascicularis) were mapped after labeling small pools (5-15 cells) of neurons with biotinylated dextran amine. Seventy-six single axons were reconstructed from serial sagittal sections with a camera lucida. The majority of labeled GPe cells displayed long, aspiny, and poorly branched dendrites that arborized mostly along the sagittal plane, whereas others showed dendrites radiating in all directions. Numerous GPe axons emitted short, intranuclear collaterals that arborized close to their parent cell body. Based on their axonal targets, four distinct types of GPe projection neurons have been identified: 1) neurons that project to the internal segment of the globus pallidus (GPi), the subthalamic nucleus (STN), and the substantia nigra, pars reticulata (SNr; 13.2%); 2) neurons that target the GPi and the STN (18.4%); 3) neurons that project to the STN and the SNr (52.6%); and 4) neurons that target the striatum (15.8%). Labeled GPe axons displayed large varicosities that often were closely apposed to the somata and proximal dendrites of STN, GPi, and SNr neurons. At striatal levels, however, GPe axons displayed small axonal varicosities that did not form perineuronal nets. These results suggest that the GPe is an important integrative locus in primate basal ganglia. This nucleus harbors several subtypes of projection neurons that are endowed with a highly patterned set of collaterals. This organization allows single GPe neurons to exert a multifarious effect not only on the STN, which is the claimed GPe target, but also on the two major output structures of the basal ganglia, the SNr and the GPi.

Survey of USAF flight surgeons regarding clinical preventive services, using CHD as an indicator.

BACKGROUND: A recent Department of Defense study revealed that nonpharmacologic therapy is not well documented in medical records of individuals identified at risk for coronary heart disease (CHD). Exercise and weight control are often underemphasized relative to dietary and medication interventions, even in medical journal review articles on management of dyslipidemia. METHODS: A literature review of interventions consisting of exercise alone or with diet is presented. A brief survey was developed to assess the knowledge and beliefs of USAF flight surgeons regarding training received for, and delivery of, clinical preventive services. In addition, the respondents were given a scenario patient with high cholesterol to manage. RESULTS AND DISCUSSION: The literature review demonstrates the beneficial effect of exercise alone or with dietary interventions on reducing total cholesterol and increasing high-density lipoprotein (HDL). The survey reveals that USAF flight surgeons believe that more preventive medicine training is needed in the USAF flight surgeon course, graduate medical education, and medical school. Given a scenario patient with hypercholesterolemia, the flight surgeons believe that nonpharmacologic therapy with consults to the base Health and Wellness Center (HAWC), along with follow-up by the physician, is appropriate initial medical treatment rather than pharmacologic therapy. CONCLUSIONS: The primary treatment for prevention of CHD should be an organized exercise and diet program. This treatment is proven effective through clinical trials and is supported by the flight surgeon survey results. Additional benefits of an organized exercise and diet program include decreased obesity with its associated complications, decreased incidence of hypertension, decreased cancer risk, and decreased risk for diabetes mellitus.

Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy.

A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.

Novel small renin inhibitors containing 4,5- or 3,5-dihydroxy-2-substituted-6-phenylhexanamide replacements at the P2-P3 sites.

Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-phenylhexanamide fragment at the P2-P3 sites have been prepared and evaluated. The four possible diastereomeric diols of the two series of inhibitors were synthesized to determine the optimal configuration of the carbinol centers for these replacements. The most potent inhibitors of each series, la and 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility limited their further evaluation. The efficacy of these P2-P3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustment at the P2 side chain was required. These 4,5- and 3,5-dihydroxyhexanamide segments could be seen as novel N-terminal dipeptide replacements.

Peptidomimetic inhibitors of the human cytomegalovirus protease.

The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.

Crystallographic studies on the binding modes of P2-P3 butanediamide renin inhibitors.

The binding modes of three peptidomimetic P2-P3 butanediamide renin inhibitors have been determined by x-ray crystallography. The inhibitors are bound with their backbones in an extended conformation, and their side chains occupying the S5 to S1' pockets. A (2-amino-4-thiazolyl)methyl side chain at the P2 position shows stronger hydrogen-bonding and van der Waals interactions with renin than the His side chain, which is present in the natural substrate. The ACHPA-gamma-lactam transition state analog has similar interactions with renin as the dihydroxyethylene transition state analog.

[In vitro fertilization failures related to a sperm hyperactivation defect: indication for microinjection?]. / Echecs de FIV en relation avec un défaut d'hyperactivation des spermatozoïdes: indication de micro-injection?

Development of hyperactivated motility is considered as necessary for penetration through zona pellucida. In a study concerning 114 IVF attempts, we could not establish a significant correlation between fertilization rate and hyperactivation rate (HA). On the contrary, most fertilization failures (16/21) we found for HA values < 10%. 10 of such couples could benefit of ICSI for the next attempt: fertilization rates were strictly similar to the general rate observed for ICSI in our group (48%).