[Toward a preventive management Alzheimer's disease]. / Pour une prise en charge préventive de la maladie d'Alzheimer.

Dementias, and Alzheimer's disease (AD) in particular, will increasingly become a public health issue. However, three major data may change the severity of these pathologies: in young adults, simple measures of healthy lifestyle (control of vascular risk factors, physical activity and cognitive stimulation), have an impact on a future cognitive decline; the same lifestyle interventions may delay the start of the disease for elderly people potentially at-risk; finally, and for the first time, a monoclonal antibody directed against amyloid lesions has just shown a significant effect on the progression of AD in patients at an early stage of the disease. According to these results, we will have to reconsider the strategy for managing minor or severe cognitive disorders and particularly AD. Nowadays, patients start the care process too late. The solution is to act earlier, even preventively. It is necessary to improve a care offer adapted to this new situation in order to impact on the disease as soon as possible, even before the onset of symptoms, based on: 1) predictive algorithms aimed at establishing whose cognitively unimpaired individuals may further develop the disease; these algorithms will be based on demographic, family, cognitive, genomic and biological data, such as in the "Santé Cerveau" project developed in partnership with the Health Regional Agency (ARS) and the general practitioners; 2)and on some expert centers which must become "dementia prevention clinics" to test prevention measures, initiate and validate multi-domain therapeutic education programs; to disclose about the risk in response to the request of worried patients; and to propose early pharmacological treatments if these individuals are on the way to declare AD in the coming months, taking into account competition between risks. This will allow to prepare to make use of new pharmacological treatments that might be discovered.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Alzheimer disease: from biomarkers to diagnosis.

The discovery of biomarkers, considered as surrogate markers of the underlying pathological changes, led an international work group (IWG) to propose a new conceptual framework for AD in 2007 Dubois et al. (2007). According to the IWG, AD is now defined as a dual clinico-biological entity that can be recognized in vivo, prior to the onset of the dementia syndrome, on the basis of: i) a specific core clinical phenotype comprised of an amnestic syndrome of the hippocampal type and ii) supportive evidence from biomarkers reflecting the location or the nature of Alzheimer-type changes. Therefore, AD is diagnosed with the same criteria throughout all symptomatic phases of the disease based on the biologically-based approach to diagnosis independent of clinical expression of disease severity. The definitions were further clarified in 2010 (Dubois et al., 2010). Although the new criteria are proposed for research purposes, we encourage expert centres with adequate resources to begin to use the proposed algorithm in order to move the field forward and facilitate translation into clinical practice.

Diagnostic Biomarkers of Amyloid and Tau Pathology in Alzheimer's Disease: An Overview of Tests for Clinical Practice in the United States and Europe.

Amyloid and tau biomarkers for Alzheimer's disease are widely recognized diagnostic tools for the identification of Alzheimer's disease pathology antemortem and are recommended by the most recent clinical and research guidelines. Approved biomarkers include positron emission tomography (PET)- and fluid-based markers derived from cerebrospinal fluid and, more recently, plasma. These biomarkers are still infrequently used in clinical practice, potentially due to challenges in access to and understanding of individual assay information and methodology. We provide an overview of the diagnostic biomarkers for amyloid and tau pathology that are currently available in the US and/or EU for clinical use. Available performance data from both labels/instructions for use and the scientific literature (with focus on autopsy or PET as standard of truth) are summarized to help healthcare providers navigate the biomarker landscape. All available PET amyloid and tau biomarkers demonstrate high accuracy in identifying amyloid and tau Alzheimer's disease pathology, respectively, at autopsy. Among cerebrospinal fluid biomarkers, all showed accurate prediction of Alzheimer's disease pathology, either based on autopsy or PET findings; greater accuracy was evident for concentration ratios (Aß42/40 or P-tau181/Aß42) versus individual biomarker concentrations. Among plasma biomarkers, Aß42/40 and P-tau181 demonstrated high agreement with PET findings. Overall, we conclude that commercially available PET, cerebrospinal fluid and plasma assays accurately identify Alzheimer's disease amyloid and tau pathology. The recent development of fully automated tests for fluid-based biomarkers improves test reliability. The continued development of plasma biomarkers holds promise for the future management of patients with Alzheimer's disease.

[African trypanosomiasis in children treated with eflornithine. A case]. / Trypanosomiase africaine de l'enfant traitée par éflornithine. Un cas.

We report the case of a 14-year old African girl presenting with late-stage African T. gambiense trypanosomiasis. She was treated with eflornithine, an ornithine decarboxylase inhibitor which is a key enzyme in the biosynthesis of polyamine. Polyamines are essential to the multiplication of trypanosomes. Two treatment courses were necessary to achieve an apparent cure after one year; however, a longer follow up will be required to confirm whether or not the cure is permanent. Determination of drug concentrations in plasma and cerebrospinal fluid was performed during the second treatment course. Side-effects were easily controlled.

Fiber Tracts Anomalies in APPxPS1 Transgenic Mice Modeling Alzheimer's Disease.

Amyloid beta (Aß) peptides are known to accumulate in the brain of patients with Alzheimer's disease (AD). However, the link between brain amyloidosis and clinical symptoms has not been elucidated and could be mediated by secondary neuropathological alterations such as fiber tracts anomalies. In the present study, we have investigated the impact of Aß overproduction in APPxPS1 transgenic mice on the integrity of forebrain axonal bundles (corpus callosum and anterior commissure). We found evidence of fiber tract volume reductions in APPxPS1 mice that were associated with an accelerated age-related loss of axonal neurofilaments and a myelin breakdown. The severity of these defects was neither correlated with the density of amyloid plaques nor associated with cell neurodegeneration. Our data suggest that commissural fiber tract alterations are present in Aß-overproducing transgenic mice and that intracellular Aß accumulation preceding extracellular deposits may act as a trigger of such morphological anomalies.

Verbal memory impairment in subcortical ischemic vascular disease: a descriptive analysis in CADASIL.

In the elderly, the high prevalence of Alzheimer's disease neuropathology presents a major challenge to the investigation of memory decline in common diseases such as small vessel disease. CADASIL represents a unique clinical model to determine the spectrum of memory impairment in subcortical ischemic vascular dementia (SIVD). One hundred and forty CADASIL patients underwent detailed clinical, neuropsychological and imaging analyses. The Free and Cued Selective Reminding Test was used as a measure of verbal memory. Forty-four out of 140 CADASIL patients (31.4%) presented with memory impairment according to this test. Eight out of 44 (18.2%) subjects with memory impairment matched the definition of the amnestic syndrome of hippocampal type. While alterations in spontaneous recall were related to the severity of subcortical ischemic lesions, the profile of memory impairment, particularly the sensitivity to cueing was found related to other factors such as hippocampal atrophy.

Two cases of papillary glioneuronal tumours.

We report two cases of papillary glioneuronal tumour. Both patients underwent gross total resection of their tumour. One of them was also treated by radiotherapy. Neither tumour had recurred, 19 and 2 years after treatment, thus confirming the good prognosis commonly associated with this tumour.

Metabolic effects of inhibitors of two enzymes of the branched-chain amino acid pathway in Salmonella typhimurium.

The metabolic effects of inhibitors of two enzymes in the pathway for biosynthesis of branched-chain amino acids were examined in Salmonella typhimurium mutant strain TV105, expressing a single isozyme of acetohydroxy acid synthase (AHAS), AHAS isozyme II. One inhibitor was the sulfonylurea herbicide sulfometuron methyl (SMM), which inhibits this isozyme and AHAS of other organisms, and the other was N-isopropyl oxalylhydroxamate (IpOHA), which inhibits ketol-acid reductoisomerase (KARI). The effects of the inhibitors on growth, levels of several enzymes of the pathway, and levels of intermediates of the pathway were measured. The intracellular concentration of the AHAS substrate 2-ketobutyrate increased on addition of SMM, but a lack of correlation between increased ketobutyrate and growth inhibition suggests that the former is not the immediate cause of the latter. The levels of the keto acid precursor of valine, but not of the precursor of isoleucine, were drastically decreased by SMM, and valine, but not isoleucine, partially overcame SMM inhibition. This apparent stronger effect of SMM on the flux into the valine arm, as opposed to the isoleucine arm, of the branched-chain amino acid pathway is explained by the kinetics of the AHAS reaction, as well as by the different roles of pyruvate, ketobutyrate, and the valine precursor in metabolism. The organization of the pathway thus potentiates the inhibitory effect of SMM. IpOHA has strong initial effects at lower concentrations than does SMM and leads to increases both in the acetohydroxy acid substrates of KARI and, surprisingly, in ketobutyrate. Valine completely protected strain TV105 from IpOHA at the MIC. A number of explanations for this effect can be ruled out, so that some unknown arrangement of the enzymes involved must be suggested. IpOHA led to initial cessation of growth, with partial recovery after a time whose duration increased with the inhibitor concentration. The recovery is apparently due to induction of new KARI synthesis, as well as disappearance of IpOHA from the medium.

Determination of products of acetohydroxy acid synthase by the colorimetric method, revisited.

The enzyme acetohydroxy acid synthase (AHAS, EC 4.1.3.18) catalyzes two competing reactions of physiological importance: condensation of two molecules of pyruvate to form acetolactate (AL) or condensation of pyruvate and 2-ketobutyrate to form acetohydroxybutyrate (AHB). The activity of AHAS is most frequently analyzed using the Westerfeld method, in which the acetoin formed upon decarboxylation of AL is determined by colorimetric reaction with creatine and alpha-naphthol. However, there has been confusion as to the interpretation of the results of this assay in the presence of both substrates, conditions which lead to formation of both AL and AHB. By applying this assay to enzymatically prepared samples of AL and AHB which have also been analyzed by two other independent methods, we show here that the color yield for AHB in the commonly used assay is 35-40% that for equivalent amounts of acetoin or AL. The relative color yield is not significantly affected by varying the time or temperature of various steps in the color-forming reaction. This information could in principle be used, together with an independent specific assay for AHB, to determine the composition of an AHAS product mixture; it would, however, be less accurate than a simultaneous chromatographic method.

Lysine-ketoglutarate reductase and saccharopine dehydrogenase from Arabidopsis thaliana: nucleotide sequence and characterization.

We isolated the gene encoding lysine-ketoglutarate reductase (LKR, EC 1.5.1.8) and saccharopine dehydrogenase (SDH, ED 1.5.1.9) from an Arabidopsis thaliana genomic DNA library based on the homology between the yeast biosynthetic genes encoding SDH (lysine-forming) or SDH (glutamate-forming) and Arabidopsis expressed sequence tags. A corresponding cDNA was isolated from total Arabidopsis RNA using RT-PCR and 5' and 3' Race. DNA sequencing revealed that the gene encodes a bifunctional protein with an amino domain homologous to SDH (lysine-forming), thus corresponding to LKR, and a carboxy domain homologous to SDH (glutamate-forming). Sequence comparison between the plant gene product and the yeast lysine-forming and glutamate-forming SDHs showed 25% and 37% sequence identity, respectively. No intracellular targeting sequence was found at the N-terminal or C-terminal of the protein. The gene is interrupted by 24 introns ranging in size from 68 to 352 bp and is present in Arabidopsis in a single copy. 5' sequence analysis revealed several conserved promoter sequence motifs, but did not reveal sequence homologies to either an Opaque 2 binding site or a Sph box. The 3'-flanking region does not contain a polyadenylation signal resembling the consensus sequence AATAAA. The plant SDH was expressed in Escherichia coli and exhibited similar biochemical characteristics to those reported for the purified enzyme from maize. This is the first report of the molecular cloning of a plant LKR-SDH genomic and cDNA sequence.

[Tumor epilepsy. Apropos of a case of temporal astrocytoma]. / Epilepsie tumorale. A propos d'un cas d'astrocytome temporal.

We report the case of a 15-year-old who sustained neonatal distress and subsequently presented temporal seizures. These were ascribed only several years later to a temporal astrocytoma. Tumor-related epilepsy is infrequent in children. Tumors may be responsible for a pattern of isolated partial epilepsy of several years duration. Advances in medical imaging techniques ensure earlier diagnosis, but some CT scan images may be difficult to read. CT scan is not indicated in functional epilepsy but should be performed in partial epilepsy with no known etiology.

[Value of the intestinal permeability test with lactulose-mannitol for screening and monitoring of celiac disease in children]. / Intérêt du test de perméabilité intestinale par lactulose-mannitol pour le dépistage et la surveillance de la maladie coeliaque chez l'enfant.

An intestinal permeability test (IPT) analysing the mannitol (M) and lactulose (L) clearances and the L/M ratios was performed in 15 children followed for celiac disease, before the onset of exclusion diet, during the gluten-free diet and after the reintroduction of gluten. The results showed a significant increase of the L/M ratios under normal diet, with respect to a control population. This increase was related to an increased L urinary excretion and to a decrease in M excretion. During gluten-free diet a normalization of the L/M ratios was observed. Reintroducing gluten altered the L/M ratios by increasing the L intestinal permeability and decreasing the M intestinal permeability. This study shows the value of the non invasive L/M IPT for the screening and monitoring of celiac disease in children.

[Respiratory arrest in an asthmatic girl treated with beta-2-mimetics and theophylline. Possible role of hypokalemia in sudden death in asthmatic patients]. / Arrêt respiratoire chez une enfant asthmatique traitée par bêta-2-mimétiques et théophylline. Rôle possible de l'hypokaliémie dans les décès subits des asthmatiques.

We report a case of respiratory arrest in a ten-year-old asthmatic girl under beta-2-agonists and theophylline. The possibility that hypokalemia plays a part in the sudden deaths seen in some asthmatic patients is discussed.

[Neisseria mucosa endocarditis complicated by intracerebral aneurysm]. / Endocardite à Neisseria mucosa compliquée d'anévrysmes intracérébraux.

BACKGROUND: Serious complications, such as emboli and mycotic aneurysms, are still frequent in documented cases of infective endocarditis. Infecting organisms other than Streptococcus viridans and Staphylococcus are becoming more common. CASE REPORT: A 8 year-old girl was admitted because of a sudden pain in the right calf followed by complete disability. She had low-grade fever and presented with a moderate heart murmur with no sign of congestive heart failure, a severe pain at palpation of her calf with no Homans sign; she had many dental caries. Laboratory data indicated leukocytosis with increased percentage of polymorphonuclear cells and increased sedimentation rate. Ultrasonography of the calf showed laceration of the muscle with blood suffusion. Echocardiography showed vegetations involving the mitral valve. Intravenous antibiotic therapy with penicillin G and netilmicin was instituted, but mitral insufficiency appeared 7 days later while the fever persisted. At that time, the brain CT scan showed ischemic lesions, while angiography showed several mycotic aneurysms. Neisseria mucosa was recovered from the 5 initial blood cultures 16 days after the onset, and penicillin G was replaced by ampicillin. A second vegetation involving the aortic valve was seen a few days later, and a recent arterial embolism to the right leg was suspected because fever and pain reappeared. The brain ischemic lesions gradually disappeared and a second angiography performed 3 months after the first showed that all but one large mycotic aneurysm had disappeared; this last aneurysm was excised. Four years later, the child is in good health without any neurological sequelae but having mitral insufficiency. CONCLUSION: This girl presented with classical complication of infective endocarditis due to Neisseria mucosa, a saprophytic organism of the oral cavity. This is the second report of such an infection in children.

[Dubowitz syndrome. A diagnosis not to be missed]. / Le syndrome de Dubowitz. Un diagnostic à ne pas méconnaître.

Dubowitz syndrome is a rare hereditary disorder whose main features are intra-uterine and post-natal growth retardation, characteristic facies, microcephaly, mental retardation and poor feeding. Because of the eczema which was present in half of the cases after 4 years of age, it cannot be mistaken for the more frequent fetal alcohol syndrome. We report 5 cases, among whom two sibs, confirming the recessive autosomal mode of inheritance and the necessity for genetic counseling.

[Diverticulum of the stomach in children. Apropos of a case of congenital diverticulum]. / Diverticule de l'estomac chez l'enfant. A propos d'un cas de diverticule congénital.

We describe a patient with a large diverticulum of the gastric fundus disclosed by an episode of epigastric pain. Hematemesis occurred, requiring surgical removal of the diverticulum. Gastric diverticula are uncommon embryologic anomalies that are usually asymptomatic. Surgical treatment is necessary if a complication develops.