A simple novel approach for detecting blood-brain barrier permeability using GPCR internalization.

AIMS: Impairment of blood-brain barrier (BBB) is involved in numerous neurological diseases from developmental to aging stages. Reliable imaging of increased BBB permeability is therefore crucial for basic research and preclinical studies. Today, the analysis of extravasation of exogenous dyes is the principal method to study BBB leakage. However, these procedures are challenging to apply in pups and embryos and may appear difficult to interpret. Here we introduce a novel approach based on agonist-induced internalization of a neuronal G protein-coupled receptor widely distributed in the mammalian brain, the somatostatin receptor type 2 (SST2). METHODS: The clinically approved SST2 agonist octreotide (1 kDa), when injected intraperitoneally does not cross an intact BBB. At sites of BBB permeability, however, OCT extravasates and induces SST2 internalization from the neuronal membrane into perinuclear compartments. This allows an unambiguous localization of increased BBB permeability by classical immunohistochemical procedures using specific antibodies against the receptor. RESULTS: We first validated our approach in sensory circumventricular organs which display permissive vascular permeability. Through SST2 internalization, we next monitored BBB opening induced by magnetic resonance imaging-guided focused ultrasound in murine cerebral cortex. Finally, we proved that after intraperitoneal agonist injection in pregnant mice, SST2 receptor internalization permits analysis of BBB integrity in embryos during brain development. CONCLUSIONS: This approach provides an alternative and simple manner to assess BBB dysfunction and development in different physiological and pathological conditions.

Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

Early Recruitment of Cerebral Microcirculation by Neuronal Nitric Oxide Synthase Inhibition in a Juvenile Ischemic Rat Model.

BACKGROUND: The development of collateral circulation is proposed as an inherent compensatory mechanism to restore impaired blood perfusion after ischemia, at least in the penumbra. We have studied the dynamic macro- and microcirculation after ischemia-reperfusion in the juvenile rat brain and evaluated the impact of neuronal nitric oxide synthase (nNOS) inhibition on the collateral flow. METHODS: Fourteen-day-old (P14) rats were subjected to ischemia-reperfusion and treated with either PBS or 7-nitroindazole (7-NI, an nNOS inhibitor, 25 mg/kg). Arterial blood flow (BF) was measured using 2D-color-coded pulsed ultrasound imaging. Laser speckle contrast (LSC) imaging and sidestream dark-field videomicroscopy were used to measure cortical and microvascular BF, respectively. RESULTS: In basal conditions, 7-NI reduced BF in the internal carotids (by ∼ 25%) and cortical (by ∼ 30%) BF, as compared to PBS. During ischemia, the increased mean BF velocity in the basilar trunk after both PBS and 7-NI demonstrated the establishment of collateral support and patency. Upon re-flow, BF immediately recovered to basal values in the internal carotid arteries under both conditions. The 7-NI group showed increased collateral flow in the penumbral tissue during early re-flow compared to PBS, as shown with both LSC imaging and side-stream dark-field videomicroscopy. The proportion of perfused capillaries was significantly increased under 7-NI as compared to PBS when given before ischemia (67.0 ± 3.9 vs. 46.8 ± 8.8, p < 0.01). Perfused capillaries (63.1 ± 17.7 vs. 81.1 ± 20.7, p < 0.001) and the BF index (2.4 ± 0.6 vs. 1.3 ± 0.1, p < 0.001) significantly increased under 7-NI given at the re-flow onset. CONCLUSIONS: Collateral support in the penumbra is initiated during ischemia, and may be increased during early re-flow by neuronal NOS inhibition (given in pre- and post-treatment), which may preserve brain tissue in juvenile rats.

Dicer-2- and Piwi-mediated RNA interference in Rift Valley fever virus-infected mosquito cells.

Rift Valley fever virus (RVFV) is a Phlebovirus (Bunyaviridae family) transmitted by mosquitoes. It infects humans and ruminants, causing dramatic epidemics and epizootics in Africa, Yemen, and Saudi Arabia. While recent studies demonstrated the importance of the nonstructural protein NSs as a major component of virulence in vertebrates, little is known about infection of mosquito vectors. Here we studied RVFV infection in three different mosquito cell lines, Aag2 cells from Aedes aegypti and U4.4 and C6/36 cells from Aedes albopictus. In contrast with mammalian cells, where NSs forms nuclear filaments, U4.4 and Aag2 cells downregulated NSs expression such that NSs filaments were never formed in nuclei of U4.4 cells and disappeared at an early time postinfection in the case of Aag2 cells. On the contrary, in C6/36 cells, NSs nuclear filaments were visible during the entire time course of infection. Analysis of virus-derived small interfering RNAs (viRNAs) by deep sequencing indicated that production of viRNAs was very low in C6/36 cells, which are known to be Dicer-2 deficient but expressed some viRNAs presenting a Piwi signature. In contrast, Aag2 and U4.4 cells produced large amounts of viRNAs predominantly matching the S segment and displaying Dicer-2 and Piwi signatures. Whereas 21-nucleotide (nt) Dicer-2 viRNAs were prominent during early infection, the population of 24- to 27-nt Piwi RNAs (piRNAs) increased progressively and became predominant later during the acute infection and during persistence. In Aag2 and U4.4 cells, the combined actions of the Dicer-2 and Piwi pathways triggered an efficient antiviral response permitting, among other actions, suppression of NSs filament formation and allowing establishment of persistence. In C6/36 cells, Piwi-mediated RNA interference (RNAi) appeared to be sufficient to mount an antiviral response against a secondary infection with a superinfecting virus. This study provides new insights into the role of Dicer and Piwi in mosquito antiviral defense and the development of the antiviral response in mosquitoes.

Proposal for a systematic analysis of polygraphy or polysomnography for identifying and scoring abnormal events occurring during non-invasive ventilation.

Non-invasive ventilation (NIV) is recognised as an effective treatment for chronic hypercapnic respiratory failure. Monitoring NIV during sleep may be preferable to daytime assessment. This paper reports the findings of an international consensus group which systematically analysed nocturnal polygraphic or polysomnographic tracings recorded with either volume-cycled or pressure-cycled ventilators. A systematic description of nocturnal respiratory events which occur during NIV is proposed: leaks, obstruction at different levels of the upper airway (glottis and/or pharynx), with or without decrease of respiratory drive and asynchrony.

Nonstructural NSs protein of rift valley fever virus interacts with pericentromeric DNA sequences of the host cell, inducing chromosome cohesion and segregation defects.

Rift Valley fever virus (RVFV) is an emerging, highly pathogenic virus; RVFV infection can lead to encephalitis, retinitis, or fatal hepatitis associated with hemorrhagic fever in humans, as well as death, abortions, and fetal deformities in animals. RVFV nonstructural NSs protein, a major factor of the virulence, forms filamentous structures in the nuclei of infected cells. In order to further understand RVFV pathology, we investigated, by chromatin immunoprecipitation, immunofluorescence, fluorescence in situ hybridization, and confocal microscopy, the capacity of NSs to interact with the host genome. Our results demonstrate that even though cellular DNA is predominantly excluded from NSs filaments, NSs interacts with some specific DNA regions of the host genome such as clusters of pericentromeric gamma-satellite sequence. Targeting of these sequences by NSs was correlated with the induction of chromosome cohesion and segregation defects in RVFV-infected murine, as well as sheep cells. Using recombinant nonpathogenic virus rZHDeltaNSs210-230, expressing a NSs protein deleted of its region of interaction with cellular factor SAP30, we showed that the NSs-SAP30 interaction was essential for NSs to target pericentromeric sequences, as well as for induction of chromosome segregation defects. The effect of RVFV upon the inheritance of genetic information is discussed with respect to the pathology associated with fetal deformities and abortions, highlighting the main role played by cellular cofactor SAP30 on the establishment of NSs interactions with host DNA sequences and RVFV pathogenesis.

High-fidelity vibrokinetic stimulation induces sustained changes in intercortical coherence during a cinematic experience.

OBJECTIVE: High-fidelity vibrokinetic (HFVK) technology is widely used to enhance the immersiveness of audiovisual (AV) entertainment experiences. However, despite evidence that HFVK technology does subjectively enhance AV immersion, the underlying mechanism has not been clarified. Neurophysiological studies could provide important evidence to illuminate this mechanism, thereby benefiting HFVK stimulus design, and facilitating expansion of HFVK technology. APPROACH: We conducted a between-subjects (VK, N = 11; Control, N = 9) exploratory study to measure the effect of HFVK stimulation through an HFVK seat on electroencephalographic cortical activity during an AV cinematic experience. Subjective appreciation of the experience was assessed and incorporated into statistical models exploring the effects of HFVK stimulation across cortical brain areas. We separately analyzed alpha-band (8-12 Hz) and theta-band (5-7 Hz) activities as indices of engagement and sensory processing, respectively. We also performed theta-band (5-7 Hz) coherence analyses using cortical seed areas identified from the theta activity analysis. MAIN RESULTS: The right fusiform gyrus, inferiotemporal gyrus, and supramarginal gyrus, known for emotion, AV-spatial, and vestibular processing, were identified as seeds from theta analyses. Coherence from these areas was uniformly enhanced in HFVK subjects in right motor areas, albeit predominantly in those who were appreciative. Meanwhile, compared to control subjects, HFVK subjects exhibited uniform interhemispheric decoherence with the left insula, which is important for self-processing. SIGNIFICANCE: The results collectively point to sustained decoherence between sensory and self-processing as a possible mechanism for how HFVK increases immersion, and that coordination of emotional, spatial, and vestibular processing hubs with the motor system may be required for appreciation of the HFVK-enhanced experience. Overall, this study offers the first ever demonstration that HFVK stimulation has a real and sustained effect on brain activity during a cinematic experience.

Invasive pulmonary aspergillosis in an ICU patient with Legionnaires' disease: A diagnostic challenge.

Aspergillus fumigatus can cause a wide range of diseases, from hypersensitivity to invasive infection. Invasive disease usually occurs in severely immunocompromised patients with deep and prolonged neutropenia. It is a less well-recognized complication in critically ill patients without traditional risk factors. We describe a case of early invasive pulmonary aspergillosis (IPA) secondary to Legionella pneumophila serogroup 1 pneumonia in a patient on an intensive care unit (ICU). In addition to commonly accepted risk factors for IPA in ICU patients, we hypothesis that L. pneumophilia pneumonia could enhance this type of infection. We also reviewed all published cases of coinfection with L. pneumophila and A. fumigatus to assess whether Legionnaires' disease could be a risk factor for IPA.

Prevalence of peripheral arterial disease in high-risk patients using ankle-brachial index in general practice: a cross-sectional study.

AIMS: The deleterious nature of peripheral arterial disease (PAD) is compounded by a status of underdiagnosed and undertreated disease. We evaluated the prevalence and predictive factors of PAD in high-risk patients using the ankle-brachial index (ABI). METHODS: The ABI was measured by general practitioners in France (May 2005-February 2006) in 5679 adults aged 55 years or older and considered at high risk. The primary outcome was prevalence of PAD (ABI strictly below 0.90). RESULTS: In all, 21.3% patients had signs or symptoms suggestive of PAD, 42.1% had previous history of atherothrombotic disease and 36.6% had two or more cardiovascular risk factors. Prevalence of PAD was 27.8% overall, ranging from 10.4% in patients with cardiovascular risk factors only to approximately 38% in each other subgroup. Prevalence differed depending on the localization of atherothrombotic events: it was 57.1-75.0% in patients with past history of symptomatic PAD; 24.6-31.1% in those who had experienced cerebrovascular and/or coronary events. Regarding the classical cardiovascular risk factors, PAD was more frequent when smoking and hypercholesterolemia history were reported. PAD prevalence was also higher in patients with history of abdominal aortic aneurysm, renal hypertension or atherothrombotic event. Intermittent claudication, lack of one pulse in the lower limbs, smoking, diabetes and renovascular hypertension were the main factors predictive of low ABI. CONCLUSIONS: Given the elevated prevalence of PAD in high-risk patients and easiness of diagnosis using ABI in primary care, undoubtedly better awareness would help preserve individual cardiovascular health and achieve public health goals.

Neonatal and pediatric ECMO organization in France: A national survey.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in France has increased since the H1N1 pandemic in 2009. By contrast, neonatal and pediatric ECMO support in France was known to be limited to a few centers offering congenital cardiac surgery. The purpose of this survey conducted in 2017 was to identify the neonatal and pediatric ECMO centers in France as well as networks existing between ECMO and non-ECMO centers. RESULTS: Seventy-two neonatal or pediatric intensive care unit medical directors answered the survey (84% of the centers surveyed). Twenty were identified as ECMO centers, defined as a unit able to start ECMO with its own resources. ECMO centers ranged from 470,000 to 1,180,000 inhabitants (neonates or children under 18). Thirteen of them (65%) reported that they were affiliated with a congenital cardiac surgery department. A total of 187 patients were supported with ECMO in these centers in 2016. Only six of these centers estimated an activity greater than 15 cases per year over the last 5 years. Nearly 30% of ECMO runs were indicated before or after congenital heart surgery. Four of the ECMO centers offered off-site facilities (mobile team). Non-ECMO centers are likely to be neonatal intensive care units. Nine of them (18.7%) declared knowing an ECMO center that provided mobile care with predefined organization, 11 (22.9%) reported knowing an ECMO center providing a mobile activity without predefined organization, nine (18.%), and 18 (37.5%) ICUs declared they knew of the existence of an ECMO program but did not report any possibility of mobile care or any procedure for transfer. CONCLUSIONS: Of the centers reporting the highest case volumes, four offered mobile ECMO abilities. Well-organized networks for the most severe neonates and children were not identified in France.

[Feasibility and benefits of training to screen for chronic obstructive pulmonary disease]. / Faisabilité et bénéfices de la formation au dépistage du trouble ventilatoire obstructif.

INTRODUCTION: Though still under-diagnosed, chronic obstructive pulmonary disease (COPD) currently affects nearly 3.5 million people in France. The present study presents the results of continuing medical education sessions on COPD screening by electronic mini-spirometry. METHODS: From April 2013 to December 2015, the sessions involved 73 health professionals. The study analysed three questionnaires administered before, after, and long after sessions led by experts within a professional associative network. RESULTS: The sessions proved efficient in increasing the participants' theoretical knowledge. It increased the percentage of correct answers regarding the nature of COPD (90 % vs. 81%), the functions, features, and outputs of mini-spirometers, and the treatment recommendations. The sessions led to non-negligible changes in everyday medical practice regarding the acquisition of a mini-spirometer (+13 devices), the presentation of COPD to the patients (+33 practitioners), the dialogue on tobacco use (+32 practitioners), vaccination (+33 practitioners), and compliance with the treatment recommendations (+43 practitioners). CONCLUSION: These results encourage both holding and following up such sessions. The specialized professional environment ensures knowledge updates and offers subsequent assistance. Further improving these sessions will increase their benefits in terms of diagnosis, treatment, and health economy.

Tei index to assess perioperative left ventricular systolic function in patients undergoing mitral valve repair.

BACKGROUND: Using echocardiography, perioperative assessment of systolic function by fractional area change (FAC) is questionable in patients suffering from mitral regurgitation (MR). Tei index, an index expressing global cardiac function, has been reported to be unchanged after mitral valve surgery. We tested the hypothesis where the Tei index could be useful in assessing the perioperative cardiac function in patients undergoing mitral valve repair (MVR). METHODS: Twenty-five patients were enrolled. Transoesophageal echocardiography was performed perioperatively before and after the correction of MR. We compared the impact of the MVR on the left ventricular FAC and the Tei index. FAC was calculated from the transgastric short-axis view and Tei index was determined from the four chambers and deep transgastric views. RESULTS: Two patients were excluded because of poor acoustic windows. FAC significantly decreased after MVR from 53 (9)% to 42 (10)% (P<0.001), while Tei index was unaffected [0.46 (0.16) vs 0.47 (0.17), NS]. A significant relationship was found between the preoperative Tei index and the postoperative FAC (R=-0.64, P<0.001). Moreover, a significant and clinically relevant relationship was determined between the predicted (using preoperative Tei index) and the measured postoperative FAC (R=0.64, P<0.001). CONCLUSIONS: FAC but not the Tei index is influenced by MVR. The preoperative determination of the Tei index allows predicting postoperative FAC and offers the opportunity to identify patients in whom a severe unsuspected systolic dysfunction could render difficult the weaning from cardiopulmonary bypass.

[Epileptogenic brain malformations: radiological and clinical presentation and indications for genetic testing]. / Malformations cérébrales et épilepsie: présentations radiocliniques et implications pour le diagnostic génétique.

Malformations of cortical development (MCD) represent a major cause of developmental disabilities and severe epilepsy. Advances in imaging and genetics have improved the diagnosis and classification of these conditions. Up to now, eight genes have been involved in different types of MCD. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Additional forms are X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia associated with mutations of the ARX gene. Lissencephaly with cerebellar hypoplasia (LCH) encompass heterogeneous disorders named LCH type a to d. LCHa are related with mutation in LIS1 or DCX, LCHb with mutation of RELN gene, and LCHd could be related with TUBA1A gene. Polymicrogyria encompass a wide range of clinical, aetiological and histological findings. Among several syndromes, recessive bilateral fronto-parietal polymicrogyria has been associated with mutations of the GPR56 gene. Bilateral perisylvian polymicrogyria showed a linkage to chromosome Xq28 in some pedigrees, and mutations in SRPX2 gene in others conditions. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of BPNH with focal epilepsy in females and prenatal lethality in males. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. It is possible to infer the most likely causative gene by brain imaging studies and other clinical findings. Based on this experience, a detailed phenotype analysis is needed to develop the most efficient research on MCD in the future.

[Lower extremity arteriopathy disease in the elderly: A systematic review]. / Artériopathie distale du sujet âgé : revue de la littérature.

Lower Extremity Arteriopathy Disease in the elderly is frequent with an ongoing increase of it prevalence and incidence mainly due to diabetes, hypertension and aging of the population. Despite improvement of revascularization therapy, outcome in this population is poor affected by frailty of elderly patient. Aging is associated with a higher prevalence of below the knee disease and wound, often with diagnostic delay leading to a major rate of amputation, mortality and alteration of quality of life. Moreover, it leads to an important health cost for society. This review aims to describe main features of LEAD in the elderly, providing keys for early recognition and managing of such disease in this population.

[The best of vascular medicine in 2006]. / L'essentiel de 2006 en médecine vasculaire.

Peripheral arterial disease (PAD) remains an under-diagnosed affection, and the ankle-brachial index (ABI), a simple diagnostic method, is poorly known and seldom used, and the vascular patient's prescription list is frequently insufficient regarding results obtained in large trials with good methodology. The French ATTEST study underlines the fact that ABI is measured in less than 1 out of 3 patients with PAD. In ATTEST study, less than 10% have the triple therapy validated in PAD : antiplatelet drugs, statins and ACE-inhibitors. The international REACH registry included more than 60 000 patients suffering from atherosclerosis, including 8 000 cases with PAD. This survey evidences that in PAD patients, the annual cardiovascular complication rate is significantly higher than in patients with coronary artery disease (18 vs 13%); again PAD appears systematically under-treated when compared to CAD. These epidemiological surveys highlight the importance of screening of atherosclerotic lesions with the aim of setting an active prevention of CV complications. The new guidelines insist on the screening of PAD in patients at risk, as well as on the importance of the global management after initiating the triple therapy, independent of the CV risk factors. In a 5-year longitudinal study from an initial cohort of 2265 subjects, Aboyans et al. studied the progression of PAD by repeated measurements of ABI at the level of ankles and toes. Factors of progression for large-vessels PAD were active smoking, the total/HDL-cholesterol ratio, Lp(a) and CRP. Importantly, diabetes was not associated to the PAD progression in large vessels, but in contrast, it was the sole factor associated to the progression of PAD in small vessels. In an Austrian study published this year in the NEJM, Schillinger et al. compared balloon angioplasty versus the use of Nitinol stent for the treatment of long stenoses of the superficial femoral artery. In case of claudication, these lesions are usually treated medically, whereas surgery is required for more severe cases. The fact that stenting these long lesions of the superficial femoral artery provides benefits in terms of restenosis opens a approach for the endovascular therapy, to be confirmed by larger trials.

[Extracorporeal membrane oxygenation in critically ill neonates and children]. / Place de l'assistance respiratoire et circulatoire extracorporelle de courte durée (ECMO), post-cardiotomie exclue, dans la prise en charge des défaillances graves du nouveau-né et de l'enfant.

Extracorporeal membrane oxygenation is used as a last resort during neonatal and pediatric resuscitation in case of refractory circulatory or respiratory failure under maximum conventional therapies. Different types of ECMO can be used depending on the initial failure. The main indications for ECMO are refractory respiratory failure (acute respiratory distress syndrome, status asthmaticus, severe pneumonia, meconium aspiration syndrome, pulmonary hypertension) and refractory circulatory failure (cardiogenic shock, septic shock, refractory cardiac arrest). The main contraindications are a gestational age under 34 weeks or birth weight under 2kg, severe underlying pulmonary disease, severe immune deficiency, a neurodegenerative disease and hereditary disease of hemostasis. Neurological impairment can occur during ECMO (cranial hemorrhage, seizure or stroke). Nosocomial infections and acute kidney injury are also frequent complications of ECMO. The overall survival rate of ECMO is about 60 %. This survival rate can change depending on the initial disease: from 80 % for meconium aspiration syndrome to less than 10 % for out-of-hospital refractory cardiac arrest. Recently, mobile ECMO units have been created. These units are able to perform ECMO out of a referral center for untransportable critically ill patients.

[What's new in mechanical circulatory assistance: from clinical indications to material]. / Quoi de neuf en assistance circulatoire mécanique? Des indications au matériel.

Over the years, mechanical circulatoryassistance has progressively improved with the evolution of the clinical indications and the introduction of new devices. The management of situations of extreme emergency, cardiac arrest, acute myocardial infarction with cardiogenic shock, drug overdose, acute myocarditis, postoperative cardiac failure and post-transplantation right ventricular failure, may be undertaken with relatively simple systems such as the ECMO, in the catheter laboratory or at the bedside in the intensive care unit. These systems enable stabilisation of the circulatory problems in order to pass a difficult situation and then withdraw the assistance when myocardial function has been restored. When this is not possible and there is no contra-indication to cardiac transplantation, patients may benefit from more complex assistance devices as a bridge to transplantation. Many continuous flow pumps have been introduced recently. These small mono, left ventricular, assist devices provide improved patient comfort and suggest wider indications of long duration assist devices.

[Neonatal epilepsy and inborn errors of metabolism]. / Epilepsies néonatales et erreurs innées du métabolisme.

Metabolic disorders constitute an important cause of neurologic disease, including neonatal epilepsy. Epilepsy rarely dominates the clinical presentation, which is more frequently associated with other neurologic symptoms, such as hypotonia and/or vigilance disturbances. In most cases, epilepsy secondary to inherited metabolic disorders presents with polymorphic clinical and electrographic features that are difficult to classify into precise epileptic syndromes. However, specific types of seizures, such as myoclonic seizures or distinctive electroencephalographic patterns, such as suppression burst patterns, epileptic syndrome or early myoclonic encephalopathy, may suggest a specific metabolic disease. The aim of this article is to help clinicians in reviewing potential metabolic diagnoses and approaching metabolic evaluations.

Chronotropic competence in endurance trained heart transplant recipients: heart rate is not a limiting factor for exercise capacity.

OBJECTIVES: The purpose of this study was to show that the chronotropic potential of the well trained heart transplant recipient (HTR) does not limit exercise capacity. BACKGROUND: Chronotropic incompetence is considered to be the main limiting factor of the functional capacity of heart transplant recipients. However, no systematic study had been published on patients who had spontaneously undergone heavy endurance training for several years. METHODS: Heart rate (HR) and respiratory gas exchanges (VO2, VCO2, VE) were measured in 14 trained HTRs (T-HTRs) during exercise tests on a bicycle, on a treadmill and by Holter electrocardiography during a race. RESULTS: Peak values observed in T-HTRs during the treadmill test were higher than those reached during the bicycle test (VO2peak: 39.8+/-6.9 vs. 32.5+/-7.8 ml x kg(-1) x min(-1), p < 0.001; HRpeak: 169+/-14 vs. 159+/-16 bpm, p < 0.01). During treadmill exercise VO2peak and HRpeak values observed were very close to the mean predicted VO2pmax and HRpmax. The maximum heart rate during the race (HRrace) was greater than HRpeak values during the treadmill test (179+/-14 vs 169+/-14 bpm, p < 0.01) and slightly above the mean predicted values (HRrace/HRpmax X 100 = 101+/-10%). The treadmill exercise test yields more reliable data than does the bicycle test. CONCLUSIONS: Extensive endurance training enables heart transplant recipients to reach physical fitness levels similar to those of normal sedentary subjects; heart rate does not limit their exercise capacity.

Doppler echocardiography for the diagnosis of acute cardiac allograft rejection.

To evaluate the changes in left ventricular filling associated with acute cardiac rejection, serial Doppler echocardiographic examinations were prospectively performed on the same day as endomyocardial biopsy in 55 consecutive patients who successfully underwent orthotopic transplantation and were free of a previous episode of rejection. On average, 8.6 Doppler studies per patient were performed within a 6 month period after transplantation. Recordings of mitral flow were made with pulsed Doppler and two-dimensional echocardiography from an apical four chamber view; isovolumic relaxation time, peak early mitral flow velocity and pressure half-time were measured. The patients were classified into two groups on the basis of the histopathologic findings: group I (25 patients with at least one episode of mild or moderate rejection) and group II (30 patients without rejection). In group I, rejection was associated with a significant decrease of isovolumic relaxation time (p less than 0.005) and especially pressure half-time (p less than 0.0005) with no change in heart rate and peak early mitral flow velocity. In group II, Doppler indexes remained unchanged. These changes were not associated with alterations in left ventricular systolic function assessed by echocardiography. Isovolumic relaxation time and pressure half-time both returned to values similar to baseline values after immunosuppressive therapy (p less than 0.05 and p less than 0.0005, respectively). With 20% decrease in pressure half-time as a criterion for acute rejection, sensitivity was 88%, specificity 87% and positive predictive value 85%. Thus, Doppler echocardiographic evaluation of left ventricular diastolic function provides an excellent tool for early detection of acute rejection and noninvasive monitoring of the cardiac transplant recipient.