Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease.

In adult mammals, neural progenitors located in the dentate gyrus retain their ability to generate neurons and glia throughout lifetime. In rodents, increased production of new granule neurons is associated with improved memory capacities, while decreased hippocampal neurogenesis results in impaired memory performance in several memory tasks. In mouse models of Alzheimer's disease, neurogenesis is impaired and the granule neurons that are generated fail to integrate existing networks. Thus, enhancing neurogenesis should improve functional plasticity in the hippocampus and restore cognitive deficits in these mice. Here, we performed a screen of transcription factors that could potentially enhance adult hippocampal neurogenesis. We identified Neurod1 as a robust neuronal determinant with the capability to direct hippocampal progenitors towards an exclusive granule neuron fate. Importantly, Neurod1 also accelerated neuronal maturation and functional integration of new neurons during the period of their maturation when they contribute to memory processes. When tested in an APPxPS1 mouse model of Alzheimer's disease, directed expression of Neurod1 in cycling hippocampal progenitors conspicuously reduced dendritic spine density deficits on new hippocampal neurons, to the same level as that observed in healthy age-matched control animals. Remarkably, this population of highly connected new neurons was sufficient to restore spatial memory in these diseased mice. Collectively our findings demonstrate that endogenous neural stem cells of the diseased brain can be manipulated to become new neurons that could allow cognitive improvement

Treatment for Severe Malaria: Post-Artesunate Delayed Haemolysis and Neutropenia.

Parenteral artesunate (AS) is the WHO first-line treatment recommended in adults and children for severe malaria. Post-artesunate delayed haemolysis (PADH) is an uncommon adverse reaction to AS with a mechanism that is not fully understood, occurring in adults and children. Neutropenia is another possible finding after AS treatment, albeit rare. We present the case of a child who experienced both effects after treatment with AS for imported severe Falciparum malaria with very high parasitaemia. In addition, thirty-five paediatric cases of PADH, five cases of delayed anaemia without known haemolysis, and fourteen cases of neutropenia after artesunate treatment were identified from the literature review. PADH seems to be a dose-independent reaction and is not strongly related to hyperparasitaemia, although it is more frequent in this case. To date, the benefits of AS outweigh its potential side effects. However, haematological follow-up is mandatory to avoid possible complications from anaemia and neutropenia, especially in children treated with other contemporary drugs

Crystal Structures of 3-halo-2-organochalcogenylbenzo[b]chalcogenophenes

The structure of the title compounds 3-bromo-2-(phenyl­sulfan­yl)benzo[b]thiophene (C(14)H(9)BrS(2); 1), 3-iodo-2-(phenyl­sulfan­yl)benzo[b]thio­phene (C(14)H(9)IS(2); 2), 3-bromo-2-(phenyl­selan­yl)benzo[b]seleno­phene (C(14)H(9)BrSe(2); 3), and 3-iodo-2-(phenyl­selan­yl)benzo[b]seleno­phene (C(14)H(9)ISe(2); 4) were determined by single-crystal X-ray diffraction; all structures presented monoclinic (P2(1)/c) symmetry. The phenyl group is distant from the halogen atom to minimize the steric hindrance repulsion for all structures. Moreover, the structures of 3 and 4 show an almost linear alignment of halogen–selenium–carbon atoms arising from the intra­molecular orbital inter­action between a lone pair of electrons on the halogen atom and the anti­bonding σ*(Se–C) orbital (n (halogen)→σ*(Se–C)). This inter­action leads to significant differences in the three-dimensional packing of the mol­ecules, which are assembled through π–π and C—H⋯π inter­actions. These data provide a better comprehension of the inter­molecular packing in benzo[b]chalcogenophenes, which is relevant for optoelectronic applications

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Seizure-Related Gene 6 (Sez-6) in Amacrine Cells of the Rodent Retina and the Consequence of Gene Deletion

Background: Seizure-related gene 6 (Sez-6) is expressed in neurons of the mouse brain, retina and spinal cord. In the cortex, Sez-6 plays a role in specifying dendritic branching patterns and excitatory synapse numbers during development. Methodology/Principal Findings: The distribution pattern of Sez-6 in the retina was studied using a polyclonal antibody that detects the multiple isoforms of Sez-6. Prominent immunostaining was detected in GABAergic, but not in All glycinergic, amacrine cell subpopulations of the rat and mouse retina. Amacrine cell somata displayed a distinct staining pattern with the Sez-6 antibody: a discrete, often roughly triangular-shaped bright spot positioned between the nucleus and the apical dendrite superimposed over weaker general cytoplasmic staining. Displaced amacrines in the ganglion cell layer were also positive for Sez-6 and weaker staining was occasionally observed in neurons with the morphology of alpha ganglion cells. Two distinct Sez-6 positive strata were present in the inner plexiform layer in addition to generalized punctate staining. Certain inner nuclear layer cells, including bipolar cells, stained more weakly and diffusely than amacrine cells, although some bipolar cells exhibited a perinuclear "bright spot" similar to amacrine cells. In order to assess the role of Sez-6 in the retina, we analyzed the morphology of the Sez-6 knockout mouse retina with immunohistochemical markers and compared ganglion cell dendritic arbor patterning in Sez-6 null retinae with controls. The functional importance of Sez-6 was assessed by dark-adapted paired-flash electroretinography (ERG). Conclusions: In summary, we have reported the detailed expression pattern of a novel retinal marker with broad cell specificity, useful for retinal characterization in rodent experimental models. Retinal morphology, ganglion cell dendritic branching and ERG waveforms appeared normal in the Sez-6 knockout mouse suggesting that, in spite of widespread expression of Sez-6, retinal function in the absence of Sez-6 is not affected

GlyT2+ Neurons in the Lateral Cerebellar Nucleus

The deep cerebellar nuclei (DCN) are a major hub in the cerebellar circuitry but the functional classification of their neurons is incomplete. We have previously characterized three cell groups in the lateral cerebellar nucleus: large non-GABAergic neurons and two groups of smaller neurons, one of which express green fluorescence protein (GFP) in a GAD67/GFP mouse line and is therefore GABAergic. However, as a substantial number of glycinergic and glycine/GABA co-expressing neurons have been described in the DCN, this classification needed to be refined by considering glycinergic neurons. To this end we took advantage of a glycine transporter isoform 2 (GlyT2)-eGFP mouse line that allows identification of GlyT2-expressing, presumably glycinergic neurons in living cerebellar slices and compared their electrophysiological properties with previously described DCN neuron populations. We found two electrophysiologically and morphologically distinct sets of GlyT2-expressing neurons in the lateral cerebellar nucleus. One of them showed electrophysiological similarity to the previously characterized GABAergic cell group. The second GlyT2+ cell population, however, differed from all other so far described neuron types in DCN in that the cells (1) are intrinsically silent in slices and only fire action potentials upon depolarizing current injection and (2) have a projecting axon that was often seen to leave the DCN and project in the direction of the cerebellar cortex. Presence of this so far undescribed DCN neuron population in the lateral nucleus suggests a direct inhibitory pathway from the DCN to the cerebellar cortex

Insufficient antiretroviral therapy in pregnancy: missed opportunities for prevention of mother-to-child transmission of HIV in Europe

Background: Although mother-to-child transmission (MTCT) rates are at an all-time low in Western Europe, potentially preventable transmissions continue to occur. Duration of antenatal combination antiretroviral therapy (ART) is strongly associated with MTCT risk.Methods: Data on pregnant HIV-infected women enrolled in the Western and Central European sites of the European Collaborative Study between January 2000 and July 2009 were analysed. The proportion of women receiving no antenatal ART or 1-13 days of treatment was investigated, and associated factors explored using logistic regression models.Results: Of 2,148 women, 142 (7%) received no antenatal ART, decreasing from 8% in 2000-2003 to 5% in 2004-2009 (chi(2)=8.73; P= 14 days antenatal ART and 7.4% (10/136) among those with insufficient ART.Conclusions: Over the last 10 years, around one in 11 women in this study received insufficient antenatal ART, accounting for 40% of MTCTs. One-half of these women were diagnosed before conception, suggesting disengagement from care

Combined antiretroviral therapy reduces hyperimmunoglobulinemia in HIV-1 infected children

Objective: To evaluate the effect of combined antiretroviral therapy on serum immunoglobulin (Ig) levels in HIV-1 perinatally infected children. Methods: Data from 1250 children recorded by the Italian Register for HIV Infection in Children from 1985 to 2002 were analysed. Since Ig levels physiologically vary with age, differences at different age periods were evaluated as differences in z-scores calculated using means and standard deviations of normal population for each age period. Combined antiretroviral therapy has become widespread in Italy since 1996, thus differences in Ig z-scores between the periods 1985-1995 and 1996-2002 were analysed. Data according to type of therapeutic regimen were also analysed. Results: Between the two periods 1985-1995 and 1996-2002, significant (P < 0.0001) decreases in IgG (6.29 ± 4.72 versus 4.44 ± 4.33), IgM (9.25 ± 13.32 versus 5.61 ± 7.93), and IgA (10.25 ± 15.68 versus 6.48 ± 11.56) z-scores, together with a parallel significant (P < 0.0001) increase in CD4 T-lymphocyte percentages, were found. These decreases were confirmed regardless of whether the children were receiving intravenous Ig or not. Ig z-scores were significantly higher in children receiving mono-therapy than in those receiving double-combined therapy (IgC, P < 0.0001; IgM, P = 0.003; IgA, P = 0.031) and in the latter children than in those receiving three or more drugs (P < 0.0001 for all z-scores). Ig z-scores correlated inversely with CD4 T-lymphocyte percentages and, directly, with viral loads. Conclusions: Our data show that in HIV-1 infected children combined antiretroviral therapy leads to reduction of hyperimmunoglobulinemia which parallels restoration of CD4 T-lymphocyte percentage and viral load decrease, which it turn probably reflects improved B-lymphocyte functions. © 2004 Lippincott Williams & Wilkins

Genetic Overexpression of NR2B Subunit Enhances Social Recognition Memory for Different Strains and Species

The ability to learn and remember conspecifics is essential for the establishment and maintenance of social groups. Many animals, including humans, primates and rodents, depend on stable social relationships for survival. Social learning and social recognition have become emerging areas of interest for neuroscientists but are still not well understood. It has been established that several hormones play a role in the modulation of social recognition including estrogen, oxytocin and arginine vasopression. Relatively few studies have investigated how social recognition might be improved or enhanced. In this study, we investigate the role of the NMDA receptor in social recognition memory, specifically the consequences of altering the ratio of the NR2B∶NR2A subunits in the forebrain regions in social behavior. We produced transgenic mice in which the NR2B subunit of the NMDA receptor was overexpressed postnatally in the excitatory neurons of the forebrain areas including the cortex, amygdala and hippocampus. We investigated the ability of both our transgenic animals and their wild-type littermate to learn and remember juvenile conspecifics using both 1-hr and 24-hr memory tests. Our experiments show that the wild-type animals and NR2B transgenic mice preformed similarly in the 1-hr test. However, transgenic mice showed better performances in 24-hr tests of recognizing animals of a different strain or animals of a different species. We conclude that NR2B overexpression in the forebrain enhances social recognition memory for different strains and animal species

Environmental Enrichment Induces Behavioral Recovery and Enhanced Hippocampal Cell Proliferation in an Antidepressant-Resistant Animal Model for PTSD

Background: Post traumatic stress disorder (PTSD) can be considered the result of a failure to recover after a traumatic experience. Here we studied possible protective and therapeutic aspects of environmental enrichment (with and without a running wheel) in Sprague Dawley rats exposed to an inescapable foot shock procedure (IFS). Methodology/Principal Findings: IFS induced long-lasting contextual and non-contextual anxiety, modeling some aspects of PTSD. Even 10 weeks after IFS the rats showed reduced locomotion in an open field. The antidepressants imipramine and escitalopram did not improve anxiogenic behavior following IFS. Also the histone deacetylase (HDAC) inhibitor sodium butyrate did not alleviate the IFS induced immobility. While environmental enrichment (EE) starting two weeks before IFS did not protect the animals from the behavioral effects of the shocks, exposure to EE either immediately after the shock or one week later induced complete recovery three weeks after IFS. In the next set of experiments a running wheel was added to the EE to enable voluntary exercise (EE/VE). This also led to reduced anxiety. Importantly, this behavioral recovery was not due to a loss of memory for the traumatic experience. The behavioral recovery correlated with an increase in cell proliferation in hippocampus, a decrease in the tissue levels of noradrenalin and increased turnover of 5-HT in prefrontal cortex and hippocampus. Conclusions/Significance: This animal study shows the importance of (physical) exercise in the treatment of psychiatri