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Many studies have found that memory for affective material is better than memory for neutral information and memory for positive material compared to negative material is better in older adults. Behavioral, neurophysiological as well as single polymorphism differences have been advanced to account for these effects. Here, we aimed to examine whether the combination of two polymorphisms (ADRA2B and CB1) in older adults influences active maintenance and manipulation of emotional information in aging working memory. We examined genotype data from 207 older adults (56 double deletion carriers, 116 single deletion carriers and 35 no deletion carriers) who performed a verbal operation span-like task with positive, negative and neutral words. We found that subjects carrying both ADRA2B and CB1 variants generally remembered a higher number of words. In addition, double carriers showed positivity effects while single carriers showed more general emotional enhancement effects, especially as strings lengthened. These findings are amongst the first to suggest a haplotype account of positivity effects in older adults' memory.

Zinc (Zn 2+ ) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn 2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn 2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn 2+ levels, we employed the Zn 2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn 2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn 2+ levels. Our findings confirm the importance of targeting Zn 2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn 2+ availability upon the early stages of development.

Multiple Sclerosis (MS) is an autoimmune disease, having not fully understood aetiology, and both genetic and environmental factors contribute to the pathogenesis of the disease. The cholinergic system has been indicated as a mediator of neuro-immune interactions, as well as an internal regulator of immune responses. The aim of the present research was to assess the associations between BChE and AChE genetic variations and serum cholinergic and inflammatory profiles in 102 Relapsing Remitting-MS patients and 117 healthy controls. An increased frequency of the BChE K-allele in MS patients as compared to controls was found. In addition, data showed that patients had higher BChE enzymatic activity, which is increased by the presence of the polymorphic allele and reduced amounts of circulating ACh. AChE polymorphism was significantly associated to reduced activity in both patients and controls. We propose that serum BChE and AChE activity may be used as a secondary markers to assess the role of non-neuronal cholinergic system in regulating peripheral inflammation via ACh regulation. This pilot study shed light on the role of the non-neuronal cholinergic system in immune cells to better understand MS pathogenesis. The cross-talk between the periphery and the CNS could have a new undescribed crucial role for MS, regarded as a systemic disease.

The main genetic cause of male infertility is represented by the Klinefelter Syndrome (KS), a condition accounting for 3% of all cases of infertility and up to15% of cases of azoospermia. KS is generally characterized by azoospermia; approximately 10% of cases have severe oligozoospermia. Among these, the 30-40% of patients show hypospermatogenesis. The mechanisms leading to adult testis dysfunctions are not completely understood. A microarray transcriptome analysis was performed on testis biopsies obtained from three KS patients with hypospermatogenesis and three control subjects. KS testis showed a differential up- and down-regulation of 303 and 747 transcripts, respectively, as compared to controls. The majority of down-regulated transcripts were involved in spermiogenesis failure and testis morphological defects, whereas up-regulated genes were responsible for testis apoptotic processes. Functional analysis of the transcriptionally altered genes indicated a deregulation in cell death, germ cell function and morphology as well as blood-testis-barrier maintenance and Leydig cells activity. These data support a complex scenario in which spermatogenic impairment is the result of functional and morphological alterations in both germinal and somatic components of KS testis. These findings could represent the basis for evaluating new markers of KS spermatogenesis and potential targets of therapeutic intervention to preserve residual spermatogenesis.

Replication-competent oncolytic herpes simplex viruses (HSVs) are considered a promising therapeutic approach for treatment of high-grade gliomas (HGGs), which are usually resistant to all the available treatments. We previously demonstrated that R-LM113, a recombinant HSV-1 fully retargeted to the human epidermal growth factor receptor 2 (HER2), is safe and prolongs survival of immunodeficient NOD/SCID mice in an intracranial model of HGG. However, because the treatment is designed to be employed on immunocompetent patients, it is necessary to test whether the host immune system impairs the viral efficacy or triggers a potentially fatal reaction. Here we confirmed the safety of R-LM113 in the immunocompetent mouse strain BALB/c, where it does not trigger encephalitis when intracranially inoculated. Then, we set up a syngeneic HGG model expressing HER2 in adult BALB/c mice and evaluated R-LM113 therapeutic efficacy. We found that R-LM113 leads to a significant improvement in animal survival when administered at the time of tumor inoculation, as well as when injected into an already established tumor. This study suggests that the host immune defenses do not curtail the oncolytic antitumor activity of replication-competent HSV R-LM113, which results effective in counteracting tumor growth.

Genetic testing of the cystic fibrosis transmembrane conductance (CFTR) gene is currently performed in couples undergoing assisted reproduction techniques (ART), because of the high prevalence of healthy carriers in the population and the pathogenic relationship with congenital bilateral absence of vas deferens (CBAVD). However, discordant data have been reported concerning the usefulness of this genetic test in couples with no family history of cystic fibrosis (CF). In this study, we report the results of CFTR molecular screening in 1195 couples entering ART. Genetic testing was initially carried out in a single partner of each couple. CFTR mutations were detected in 55 subjects (4.6%), a percentage that overlaps with the one reported in the general population. However, significantly higher frequencies of were found in CBAVD individuals (37.5%) and in males with nonobstructive azoospermia (6.6%). The 5T allele was found in 78 patients (6.5%). This figure was again significantly different in males with nonobstructive-azoospermia (9.9%) and in those with CBAVD (100%). All together, 139 subjects (11.6%) had either a CFTR mutation or the 5T allele. Subsequent molecular analysis of their partners disclosed a CFTR mutation or 5T allele in nine cases (6.5%). However, none of these couples had CFTR alterations in both members, a CFTR mutation being invariably present in one partner and the 5T allele in the other. In order to improve genetic counselling of these couples, the TG-M470V-5T association was analyzed, and a statistically significant relationship between 12TG-V470 and CBAVD was detected.

The C677T polymorphism of the MTHFR gene has been associated to maternal risk of Down syndrome, due to the detection of an higher prevalence of the T allele among mothers of children with trisomy 21, compared to control mothers. In order to confirm this association, we studied the presence of the C677T in 64 mothers of Down syndrome children and 112 controls from central Italy. An higher incidence of the mutant T allele in controls (48.2%) than in Down syndrome children mothers (44%) was detected. These results do not support the presence of an increased risk of Down syndrome in mothers carriers of the T allele in the Italian population.

A patient with a Ph-positive chronic myeloid leukaemia (CML) was submitted to allogeneic peripheral blood stem cell transplantation from an HLA-haploidentical related donor 7 years after the diagnosis. Six months later, he showed a disease relapse while cytogenetic analysis displayed a complex karyotype. To characterise the chromosomal rearrangements spectral karyotype (SKY) analysis was used. This redefined all chromosome rearrangements and revealed a t(20;21)(q11;q22). FISH analysis with a specific probe for the AML1 gene disclosed disruption of this gene which was partially translocated on to the long arm of chromosome 20. It is likely that this rearrangement, unusual for CML, was implicated in the disease evolution towards blastic crisis (BC).

Y-chromosomal DNA haplotypes were determined in 74 infertile and 216 control Italian males using eight biallelic markers. A significant difference in haplotype frequency was found, but could be explained by the geographical origins of the samples. The Y chromosome is thus a sensitive marker for population substructuring and may be useful for determining whether two population samples come from a single population, for example in association studies.