Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

An RNA interference screen identifies new avenues for nephroprotection.

This corrects the article DOI: 10.1038/cdd.2015.128.

An RNA interference screen identifies new avenues for nephroprotection.

Acute kidney injury is a major public health problem, which is commonly caused by renal ischemia and is associated with a high risk of mortality and long-term disability. Efforts to develop a treatment for this condition have met with very limited success. We used an RNA interference screen to identify genes (BCL2L14, BLOC1S2, C2ORF42, CPT1A, FBP1, GCNT3, RHOB, SCIN, TACR1, and TNFAIP6) whose suppression improves survival of kidney epithelial cells in in vitro models of oxygen and glucose deprivation. Some of the genes also modulate the toxicity of cisplatin, an anticancer agent whose use is currently limited by nephrotoxicity. Furthermore, pharmacological inhibition of TACR1 product NK1R was protective in a model of mouse renal ischemia, attesting to the in vivo relevance of our findings. These data shed new light on the mechanisms of stress response in mammalian cells, and open new avenues to reduce the morbidity and mortality associated with renal injury.

Identification of p53 genetic suppressor elements which confer resistance to cisplatin.

Loss of p53 function is associated with the acquisition of cisplatin resistance in the human ovarian adenocarcinoma A2780 cell line. Selection for cisplatin resistance of A2780 cells was used to isolate genetic suppressor elements (GSEs) from a retroviral library expressing random fragments of human or murine TP53 cDNA. Six GSEs were identified, encoding either dominant negative mutant peptides or antisense RNA molecules which corresponded to various regions within the TP53 gene. Both types of GSE induced cisplatin resistance when introduced individually into A2780 cells. Expression of antisense GSEs led to decreased intracellular levels of p53 protein. One sense GSE induced loss of p53-mediated activities such as DNA damage induced cell cycle arrest and apoptosis. A synthetic peptide, representing the predicted amino acid sequence of this GSE, conferred resistance to cisplatin when introduced into A2780 cells and inhibited the sequence specific DNA binding activity of p53 protein in vitro. Overall, these results directly indicate that inactivation of p53 function confers cisplatin resistance in these human ovarian tumour cells. We have identified short structural domains of p53 which are capable of independent functional interactions and highlighted the efficacy of this approach to discriminate biologically active GSEs from a random fragment library.

Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs.

Exposure of human tumor cell lines to moderate doses of anticancer agents induces terminal proliferation arrest accompanied by morphologic and enzymatic changes that resemble senescence of normal cells. We have investigated the role of p53 and p21waf1/cip1 in the induction of this response in drug-treated tumor cells. Doxorubicin treatment induced the senescence-like phenotype (SLP) and its associated terminal growth arrest in wild-type HCT116 colon carcinoma cells; this response was strongly decreased but not abolished in HCT116 lines with homozygous knockout of p53 or p21. Transduction of HT1080 fibrosarcoma cells with a genetic inhibitor of p53 also decreased the induction of SLP and increased drug-induced mitotic cell death. To determine if drug-stimulated p21 expression was responsible for senescence-like growth arrest, we have expressed different levels of p21 from an inducible promoter. While high-level overexpression of p21 was sufficient to induce SLP in HT1080 cells, the levels of p21 expressed in doxorubicin-treated cells could account for only a fraction of doxorubicin-induced SLP. Our results indicate that p53 and p21 act as positive regulators of senescence-like terminal proliferation arrest, but their function is neither sufficient nor absolutely required for this treatment response in tumor cells.

The BDNF-Val66Met polymorphism: implications for susceptibility to multiple sclerosis and severity of disease.

Neurodegeneration following inflammatory injury is considered to be a pathological correlate of irreversible disability in patients with multiple sclerosis. The availability of neurotrophins could influence the probability or rate of disease progression and the time of onset. The BDNF-Val66Met-polymorphism leads to altered intracellular transport and secretion of BDNF, and is thus a logical candidate for a gene that influences susceptibility and, more specifically, the clinical course of multiple sclerosis. In order to test this hypothesis we genotyped the polymorphism in 951 UK multiple sclerosis trio families, but found no evidence for association before (p=0.63) or after stratification for clinical course (p=0.73).

5-HTTLPR/rs25531 polymorphism and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus.

The s/s-genotype of the 5-HTTLPR polymorphism and the personality trait of neuroticism have both been associated with experiences of negative affect, anxiety and mood disorders, as well as an emotional processing bias towards negative facial emotions. On a neural level, this bias can be characterized by altered amygdala and fusiform gyrus (FFG) activity during perception of negative facial expressions. Using resting-state functional magnetic resonance imaging in a multi-center-sample of 178 healthy subjects of European descent, this study investigated the association of 5-HTTLPR (short s- and long l-allele) including the genotype of the single nucleotide polymorphism (SNP) rs25531 (A/G) within this region polymorphism, and trait neuroticism on resting-state functional connectivity (rs-FC) between amygdala and the FFG. Moreover, we aimed to identify additional brain regions with associations of 5-HTTLPR/rs25531 (combined according to its expression; low: s/s; high: l(A)/l(A); intermediate: s/l(A), s/l(G), l(G)/l(G), l(A)/l(G)) and trait neuroticism to amygdala rs-FC. Separate analyses for 5-HTTLPR/rs25531 and neuroticism (controlling for age, gender, handedness, and research site) revealed that s/s-homozygotes and individuals high in neuroticism obtained altered amygdala rs-FC in the right occipital face area, which is considered to be a "core component" of the face processing system. Importantly, effects of neuroticism were replicated across three independent research sites. Additionally, associations of 5-HTTLPR/rs25531 genotype and amygdala rs-FC were observed in the anterior and posterior cingulate cortex, whereas neuroticism was not related to rs-FC in these areas. The presented data implies that 5-HTTLPR/rs25531 variants and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus and suggests that variants of 5-HTTLPR/rs25531 genotype and different levels of neuroticism may partly account for altered processing of negative facial emotions.

Comparative activity of anthracycline 13-dihydrometabolites against rat glioblastoma cells in culture.

We have studied the growth inhibition, DNA synthesis inhibition and cell incorporation of five 13-dihydrometabolites of anthracyclines in a model of doxorubicin-sensitive and -resistant rat C6 glioblastoma cells. These compounds were major metabolites for doxorubicin, epirubicin, daunorubicin, idarubicin and the new anthracycline 4'-deoxy-4'-iododoxorubicin and are known to be present in appreciable amounts in the plasma of patients treated with these drugs. We have shown that in vitro growth inhibition in sensitive cells was either much lower than that of the parent drug (doxorubicinol, epirubicinol, daunorubicinol), or similar to it (idarubicinol, 4'-iodoxorubicinol). In resistant cells, growth inhibition was about 100 times lower than in wild cells, and was always lower than that of the parent anthracycline. DNA synthesis inhibition occurred in sensitive cells for doses about 100 times higher than those required for growth inhibition, but in resistant cells, similar doses provided growth inhibition and DNA synthesis inhibition. Metabolite incorporation was always lower than that of the corresponding parent anthracycline; it was greatly reduced in resistant cells as compared to sensitive ones. The calculated intracellular concentrations obtained for the same growth inhibition are higher in resistant cells than in sensitive cells; in contrast, the calculated intracellular concentrations obtained for the same DNA synthesis inhibition are similar in resistant and sensitive cells, and similar for all the metabolites studied. These results suggest that the amount of drug incorporated is primarily responsible for DNA synthesis inhibition, which is directly correlated to growth inhibition in resistant cells, but not in sensitive cells.

Comparative cytotoxicity, DNA synthesis inhibition and drug incorporation of eight anthracyclines in a model of doxorubicin-sensitive and -resistant rat glioblastoma cells.

We have compared the growth inhibition, DNA synthesis inhibition and cell incorporation of eight anthracyclines in a model of doxorubicin-sensitive and -resistant rat C6 glioblastoma cells. The anthracyclines studied were both the reference molecules (daunorubicin, doxorubicin) and the new drugs recently introduced in clinical use or in trials (epirubicin, idarubicin, pirarubicin, esorubicin, rubidazone, 4'-deoxy-4'-iododoxorubicin). We have shown that the in vitro growth inhibition was correlated with the LD50. The new anthracyclines were more potent than the reference drugs in the sensitive cells and the resistance patterns revealed a reduced cross resistance of idarubicin, pirarubicin and 4'-deoxy-4'-iododoxorubicin towards the doxorubicin-resistant line. DNA synthesis inhibition occurred for much higher doses than growth inhibition in sensitive cells, but for similar doses in resistant cells. This suggests that different mechanisms could be involved in the mechanism of growth inhibition in sensitive and resistant cells. For similar exposures, reduction of drug incorporation was a general feature in the resistant line when compared to the sensitive one. However, no correlation was shown, for the various drugs, between the reduction of incorporation and the resistance factor. Moreover, the intracellular concentration required for growth inhibition is much higher in resistant cells than in sensitive cells, suggesting that increased drug efflux might not be the only mechanism to explain drug resistance.

Pharmacological and molecular characterization of intrinsic and acquired doxorubicin resistance in murine tumor cell lines.

We have studied the pharmacological parameters of doxorubicin resistance in three lines of murine cells selected by long-term culture in the presence of this drug or vincristine. A line originating from rat hepatoma spontaneously presented an intrinsic doxorubicin resistance as compared to the other lines, originating from a rat glioblastoma and from simian-virus-40-transformed mouse hepatocytes. This intrinsic resistance, as well as the doxorubicin resistance exhibited by the vincristine-selected glioblastoma variant, could be entirely attribute to decreased drug accumulation due to drug efflux. In contrast, the doxorubicin-selected variants of the three lines exhibited an intracellular tolerance to this drug. Despite a reduction in drug accumulation when exposed to the same amount of doxorubicin, they accumulated 6-12 times more doxorubicin than wild lines when submitted to equitoxic exposures. Verapamil could restore in these lines the doxorubicin accumulation observed in sensitive lines but could not restore doxorubicin cytotoxicity. Quantitative evaluation of P-glycoprotein expression by Western blotting with the C219 antibody indicated that the wild hepatoma line overexpressed P-glycoprotein by a factor of 5 in comparison with the other wild lines, and that the vincristine-selected glioblastoma variant overexpressed this protein almost as much as the doxorubicin-selected variants. These observations favor the existence of P-glycoprotein-independent mechanisms of doxorubicin resistance, which are added to the classical multidrug-resistant phenotype in doxorubicin-selected highly resistant variant cell lines.

[Amnesic syndrome of posterior cerebral ischemia]. / Le syndrome amnésique des ischémies cérébrales postérieures.

30 patients with acute onset of memory disturbances and visual impairment (cortical blindness or hemianopsia) are reported. For all of them, there was evidence of posterior cerebral artery ischemia. This clinical syndrome is compared with Dide and Botcazo's case report. The amnesia never recovered in 17 patients and was transient in 13 patients: in 4 of them it occurred during vertebral angiography and in 4 during general anaesthesia with anoxia. The main clinical features of the syndrome and the related bibliography are reviewed.

Dimyelia, diplomyelia, and diastematomyelia.

Four types of rare human spinal cord duplications are reported. (1) Dimyelia, a complete duplication of the spinal cord, was observed in a female stillborn dicephalus dibrachius. Histologically the two spinal cords showed symmetric medial hemihypoplasia that included the roots. (2) Diplomyelia, an isolated accessory spinal cord without roots at the ventral lumbosacral level, was observed in a newborn female with a cardiovascular malformation. (3) Complex diastematomyelia: a 9-day-old boy had Arnold-Chiari malformation and an additional diastematomyelia with thoracic meningomyelocele; the left branch of the cord showed further complex multifurcations. (4) Typical diastematomyelia was observed in a stillborn female, born to an adolescent mother at 34 weeks of gestation. The term dimyelia is used to express the condition of total duplication of the spinal cord, by analogy to the term dicephalus in the case of duplicitas. Diastematomyelia means a lateral bifurcation of the spinal cord, independent of whether or not the branches show completely differentiated cord structures with four columns and segmental roots. The term diplomyelia, on the other hand, should be limited to cases of an isolated accessory spinal cord, ventral or dorsal to the normal cord.

Mechanocardiographic evaluation of left ventricular diastolic function in hypertrophic cardiomyopathy and hypertensive cardiomyopathy.

Usefulness of computerized mechanocardiography and echocardiography in the diagnosis of impaired left ventricular diastolic function is shown in a study comparing 17 hypertrophic obstructive cardiomyopathy and 17 hypertensive cardiomyopathy patients to 20 normal subjects. Mechanocardiography allows the evaluation of three different parameters of diastolic function: isovolumic relaxation evaluated by S2a-O or better by t-dr/dt and dr/dt/A2 ratio, left ventricular compliance by the A/H ratio and time of rapid filling. All the parameters are impaired in both pathological populations. Isovolumic relaxation being more depressed in hypertensive cardiomyopathy and duration of rapid filling being prolonged especially in the hypertrophic obstructive cardiomyopathy patients. Although the differences are small indicating only trends computerized mechanocardiography gives some evidence for difference in the alteration of diastolic function in hypertrophic obstructive cardiomyopathy and hypertensive cardiomyopathy.

[Left ventricular diastolic function in hypertensive heart diseases. Comparison of results obtained by echocardiography and mechanocardiography]. / Fonction diastolique ventriculaire gauche dans la cardiopathie hypertensive. Comparaison des résultats obtenus par l'échocardiographie et les mécanocardiogrammes.

Usefulness of computerized mechanocardiography and echocardiography in the bedside diagnosis of impaired left ventricular diastolic function is established in a study comparing 17 hypertensive cardiomyopathy patients and 17 hypertrophic obstructive patients to 20 control. The echocardiographic study involves the ratio A/E obtained from the diastolic motion of the mitral valve and max DD/dtN, the peak rate of maximal diastolic dimension change. Both measurements allow statistical differentiation between pathological conditions and the control. The mechanocardiographic evaluation of left ventricular diastolic function provides easily three different parameters of diastolic function: isovolumic relaxation by the interval B2 alpha-0 or by t-dr/dt and the ratio dr/dt/A2, left ventricular stiffness by the A/H ratio and TRR the time of rapid filling. The mechanocardiographic indices allow clear distinction between the control group and the hypertrophic conditions for all the measured parameters giving evidence for an increased isovolumic relaxation period with a reduced velocity of relaxation, an increase in left ventricular stiffness and in the case of the hypertrophic obstructive cardiomyopathy, a prolonged time of rapid filling.

[History of Guillain-Barré syndrome]. / Histoire du syndrome de Guillain et Barré.

1916: birth in Paris of a modest syndrome presented to a weekly meeting of the Société Médicale by Georges Guillain, Jean-Alexandre Barré and André Strohl. 1981: glorification of the syndrome as a world event in Santa Inez Valley at the International Conference held under the auspices of the Kroc Foundation. This is indeed a long way from a few clinicians and internists to the representatives of all branches of the Neurological Sciences for "la radiculo-névrite avec dissociation albumino-cytologique à évolution spontanément régressive "studied in two soldiers of the Vth French Army. Every neurologist from clinician to researcher currently knows this model of inflammatory and demyelinating diseases of the peripheral nervous system and the pros and cons of cellular vs humeral immunity which are presumed to be its pathophysiological process. What is less known is "la petite histoire" i.e. that of men and events which surrounded its birth and growth to being an entity. Why did André Strohl disappear? Who were L. Duménil and O. Landry? Should we say Guillain-Barré?, Landry-Guillain-Barré?, Duménil-Landry-Guillain-Barré? Unexpected or poorly known facts are not lacking in this story the last of which being that most references to that most French syndrome are to be found in English and American books.

[Thalamic pain: critical study of 43 cases]. / Les douleurs thalamiques: étude critique de 43 cas.

Apart from hyperpathia, which is an entity in itself, thalamic pain presents a clinical spectrum of variable quality and intensity that justifies the description of "thalamic pains". Their mechanisms can be related to two basic mechanisms. The first involves the dependence of the thalamus to the afferent spinothalamic system. A lesion of the lemniscal system resulting from lesions of the thalamic sensory nuclei--capable of provoking a syndrome of paresthesia-hyperpathia (P-HI)--provokes a loss of gate control normally ensured by this discriminatory system and thus releases the pathologic nociceptive reactivity. Some authors think that the thalamic lesion alters the activity of control of the VPL nucleus on the lumbosacral spinothalamic tract. This concept considers thalamic pain as identical with brain stem spinothalamic pain provoked by exclusion of the control system arising in the giant-cell reticular nucleus and projecting onto onto the posterior horns. However, most cases of thalamic pain appear to be dependent on another mechanism involving the thalamocortical loop. In this case the thalamic sensory nucleus lesion is involved insofar as it implicates the reciprocal thalamocortical connections and the reticular nucleus. Involvement of the Th-C-Th loop as the ultimate representative of the lemniscal gate control is supported by "pseudo-thalamic" pains related to cortico-subcortical lesions with abolished SEP. But the numerous cases of painful thalamic syndromes with lemniscal sparing and normal SEP lead to incriminate a lesion of a specific thalamocortical control system for pain.(ABSTRACT TRUNCATED AT 250 WORDS)

[Familial paroxysmal ataxia sensitive to acetazolamide. 3 cases in a new European family]. / Ataxie paroxystique familiale sensible à l'acétazolamide. Trois cas dans une nouvelle famille européenne.

UNLABELLED: This family is the tenth reported world-wide and the second reported in Europe. Two of 3 brothers, their mother and probably their maternal grandmother were affected. CLINICAL FEATURES: paroxysmal bouts of ataxia and dysarthria, nystagmus of permanent gaze, the dominant autosomal transmission, the benign nature of the affection and the remarkable efficacy of acetazolamide were typical of familial paroxysmal ataxia. Specific points emphasized are the presence of a mild pyramidal syndrome as a permanent finding in 2 of these patients, and the anomalies of visual (longer lag period) and somesthetic (slowed conduction rate in the lemniscus medialis) evoked potentials probably the result of extension into other pathways than the cerebellar system. The finding of some degree of glucose intolerance, noted previously (Aimard, Vighetto et al., 1983) raises the question of the place of this disease in the group of paroxysmal ataxias due to pyruvic metabolism disorders.

[Anatomical and clinical correlations in a case of alexia without agraphia (author's transl)]. / Alexie sans agraphie chez un malade ayant un hémisphère gauche déafférenté (hémianopsie, hémianesthésie, hémianacousie).

The authors report the anatomical and clinical findings observed in a case of alexia iwthout agraphia due to left posterior cerebral artery infarction, in which there were lesions of the occipital and thalamic regions, the splenium of the corpus callosum, and the hippocampus. They discuss, more particularly, the memory difficulties, and the objects naming trouble.

[Acute necrotizing herpetic encephalitis with a spontaneously improving clinical course]. / Encéphalite herpétique aiguë nécrosante d'évolution clinique spontanément régressive.

A 70 year-old-man with recurrent herpetic keratitis had a meningo-encephalitis with transient left hemiplegia and disorders of consciousness. EEG disclosed periodic slow waves on the right temporal region. Isotope and CT scans showed focal abnormalities in the same region. Antibodies to herpes simplex virus were demonstrated by complement fixation in serum and specific antiherpes IgG and IgM by immunofluorescence assay in serum and CSF. A year later the patient had a status epilepticus. CT scan showed a large right temporal hypodense area. CSF was abnormal with pleiocytosis, increased protein and IgG levels. High titers of antiherpes IgG persisted in serum and CSF. Neuropsychological tests did not demonstrate any memory impairment. The occurrence of persistent inflammation after herpes simplex encephalitis is discussed. The unusual benign course without antiviral therapy, may be related to the reactivation of a latent infection with an efficient immunological response. The unilateral temporal necrosis may explain the absence of amnestic sequelae.

[Motor negligence in a case of right thalamic hematoma (author's transl)]. / Négligence motrice par hématome thalamique droit.

In a patient with left motor negligence CT scan showed a right thalamic hematoma of small size, involving the posterior thalamic region. The clinical picture was pure, including neither marked distal or proximal motor deficiency, nor auditory or visual or somesthetic disorders except sensory extinction. Cortical somesthetic evoked potentials were normal. Motor negligence presented 3 basic elements: 1) lack of spontaneous movements of the left side of the body, particularly of the upper limb; 2) absence of nociceptive reactivity; 3) immediate total reversibility of the disorder following verbal commands. Emphasis is placed on this latter sign which indicates the thalamic origin of the disturbance. Of the various explanations proposed for the disorder the most likely one would appear to be a disorder of a relatively specific activation system of motor activities, a system arising from the posterior thalamic nuclei: 1) pulvinar and laterodorsal nuclei projecting over area 23 (posterior cingulum); 2) intralaminar formations, particularly the lateral superior central nucleus, projecting over area 24 (anterior cingulum). The disturbance in this system, at its thalamic origin, might explain the differences between this motor negligence behaviour and lack of spontaneous motility syndromes resulting from frontal cortical lesions. It might also be that the right lateralisation of the lesion plays a relatively minor role.