Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 mu g/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 mu g/l, P = 0.0004; itself higher than the normal level (3.4 mu g/l, range from 0.5 to 17.2 mu g/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level >= 7 mu g/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels >= 7 mu g/l is 46%. Therefore, selection of patients with an AFP level above 7 mu g/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy

Tetherin Restricts Productive HIV-1 Cell-to-Cell Transmission

The IFN-inducible antiviral protein tetherin (or BST-2/CD317/HM1.24) impairs release of mature HIV-1 particles from infected cells. HIV-1 Vpu antagonizes the effect of tetherin. The fate of virions trapped at the cell surface remains poorly understood. Here, we asked whether tetherin impairs HIV cell-to-cell transmission, a major means of viral spread. Tetherin-positive or -negative cells, infected with wild-type or ΔVpu HIV, were used as donor cells and cocultivated with target lymphocytes. We show that tetherin inhibits productive cell-to-cell transmission of ΔVpu to targets and impairs that of WT HIV. Tetherin accumulates with Gag at the contact zone between infected and target cells, but does not prevent the formation of virological synapses. In the presence of tetherin, viruses are then mostly transferred to targets as abnormally large patches. These viral aggregates do not efficiently promote infection after transfer, because they accumulate at the surface of target cells and are impaired in their fusion capacities. Tetherin, by imprinting virions in donor cells, is the first example of a surface restriction factor limiting viral cell-to-cell spread

The Brain-Specific Beta4 Subunit Downregulates BK Channel Cell Surface Expression

The large-conductance K+ channel (BK channel) can control neural excitability, and enhanced channel currents facilitate high firing rates in cortical neurons. The brain-specific auxiliary subunit β4 alters channel Ca++- and voltage-sensitivity, and β4 knock-out animals exhibit spontaneous seizures. Here we investigate β4's effect on BK channel trafficking to the plasma membrane. Using a novel genetic tag to track the cellular location of the pore-forming BKα subunit in living cells, we find that β4 expression profoundly reduces surface localization of BK channels via a C-terminal ER retention sequence. In hippocampal CA3 neurons from C57BL/6 mice with endogenously high β4 expression, whole-cell BK channel currents display none of the characteristic properties of BKα+β4 channels observed in heterologous cells. Finally, β4 knock-out animals exhibit a 2.5-fold increase in whole-cell BK channel current, indicating that β4 also regulates current magnitude in vivo. Thus, we propose that a major function of the brain-specific β4 subunit in CA3 neurons is control of surface trafficking

Does “soft conditionality” increase the impact of cash transfers on desired outcomes? Evidence from a randomized control trial in Lesotho

Cash transfers programs have been shown to have positive effects on a variety of outcomes. While much of the literature focuses on the role of conditionality in achieving desired impact, this paper focuses on the role of ‘soft conditionality’ implemented through both ‘labeling’ and ‘messaging’ in evaluating the impact of the Child Grants Program in Lesotho, an unconditional cash transfer targeting poor households with orphans and vulnerable children. Beneficiary households received a clear message that the transfer should be spent on the interest and needs of children. Our findings are based on a randomized experiment and suggest that ‘soft conditionality’ does play a strong role in increasing expenditure for children, especially on education, clothing and footwear. Results indicate in fact that transfer income is spent differently from general income as it exerts both an income and a substitution effect. This behavioral change is confirmed by comparing the ex-ante expected behaviors with the ex-post actual response to the program. We find that for expenditure categories linked to the wellbeing of children the ex-post response was much higher than the ex-ante expected behavior

Large-conductance calcium-dependent potassium channels prevent dendritic excitability in neocortical pyramidal neurons

Large-conductance calcium-dependent potassium channels (BK channels) are homogeneously distributed along the somatodendritic axis of layer 5 pyramidal neurons of the rat somatosensory cortex. The relevance of this conductance for dendritic calcium electrogenesis was studied in acute brain slices using somatodendritic patch clamp recordings and calcium imaging. BK channel activation reduces the occurrence of dendritic calcium spikes. This is reflected in an increased critical frequency of somatic spikes necessary to activate the distal initiation zone. Whilst BK channels repolarise the somatic spike, they dampen it only in the distal dendrite. Their activation reduces dendritic calcium influx via glutamate receptors. Furthermore, they prevent dendritic calcium electrogenesis and subsequent somatic burst discharges. However, the time window for coincident somatic action potential and dendritic input to elicit dendritic calcium events is not influenced by BK channels. Thus, BK channel activation in layer 5 pyramidal neurons affects cellular excitability primarily by establishing a high threshold at the distal action potential initiation zon

Prevalencia de la resistencia a betalactámicos en cepas clínicas de Escherichia coli procedentes de un hospital en Argelia

La prevalencia de la resistencia a los betalactámicos entre las enterobacterias es alta en todo el mundo, pero en Argelia no se dispone de suficientes datos. Se determinó la sensibilidad a los betalactámicos de 203 cepas clínicas de Escherichia coli mediante difusión en agar y se analizó la producción de betalactamasas de espectro extendido (BLEE) mediante la técnica de la sinergia del doble disco. Este análisis mostró cinco fenotipos bien definidos: 1) 62 cepas (30,5%) fueron sensibles a todos los betalactámicos; 2) 135 cepas (66,5%) presentaron un fenotipo caracterizado por betalactamasas de amplio espectro (BLEA); 3) 3 cepas (1,5%) se definieron como productoras de BLEE; 4) 2 cepas (1%) fueron productoras de cefalosporinasa tipo AmpC; y 5) una (0,5%) presentó un fenotipo de disminución de la permeabilidad celular a los betalactámicos. La determinación del punto isoeléctrico mostró betalactamasas con puntos isoeléctricos de 5,4 o 7,6 para las cepas con fenotipo BLEA; ¡"9,0 para 2 cepas productoras de BLEE; 5,4, 7,6 y ¡"9,0 para la tercera cepa productora de BLEE; y 5,4 y ¡"9,0 para las cepas productoras de cefalosporinasa AmpC. La hidrólisis de cefotaxima se corresponde con las bandas básicas con un punto isoeléctrico de ¡"9,0. El ensayo de conjugación mostró una transferencia de los fenotipos de resistencia de penicilinasas y cefalosporinasa AmpC y sus correspondientes betalactamasas a E. coli BM21 en asociación con plásmidos de 71,4 kb para las cepas productoras de cefalosporinasa AmpC y de 40-56 kb para las productoras de penicilinasas. Este resultado mostró que el fenotipo productor de cefalosporinasa AmpC está mediado por plásmidos. Las cepas productoras de BLEE no transfirieron su resistencia mediante el ensayo de conjugación. La reacción en cadena de la polimerasa utilizando primers específicos para los genes blaTEM, blaAmpC y blaCTX-M mostró una amplificación específica con el primer para blaCTX-M en dos cepas productoras de BLEE; los primers para blaTEM y blaCTX-M para la tercera cepa productora de BLEE; y los primers para blaTEM y blaAmpC para las cepas productoras de cefalosporinasa AmpC y sus cepas transconjugantes correspondientes. El estudio mostró una alta tasa de cepas productoras de penicilinasas y una baja frecuencia de fenotipos productores de AmpC y BLEE. Las betalactamasas productoras de cefalosporinasa AmpC estaban mediadas por plásmidos y las BLEE pertenecieron al tipo CTM-M

Poliovirus, pathogenesis of poliomyelitis, and apoptosis.

Poliovirus (PV) is the causal agent of paralytic poliomyelitis, an acute disease of the central nervous system (CNS) resulting in flaccid paralysis. The development of new animal and cell models has allowed the key steps of the pathogenesis of poliomyelitis to be investigated at the molecular level. In particular, it has been shown that PV-induced apoptosis is an important component of the tissue injury in the CNS of infected mice, which leads to paralysis. In this review the molecular biology of PV and the pathogenesis of poliomyelitis are briefly described, and then several models of PV-induced apoptosis are considered; the role of the cellular receptor of PV, CD155, in the modulation of apoptosis is also addressed

Poliovirus and apoptosis.

International audienc