A Novel Study and Meta-Analysis of the Genetic Variation of the Serotonin Transporter Promoter in the Italian Population Do Not Support a Large Effect on Alzheimer's Disease Risk

Alzheimer's disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped the SLC6A4 promoter functional variant rs25531 (A → G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between 5-HTTLPR and AD (odds ratio for the L-allele versus the S-allele: 0.74, associated P value = .03), while no difference was found for the rs25531. A meta-analysis of studies in Italy assessing 5-HTTLPR and AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associated P value = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk

Genistein reduces angiogenesis and apoptosis in women with endometrial hyperplasia

Roberta Granese,1,* Alessandra Bitto,2,* Francesca Polito,2 Onofrio Triolo,1 Domenico Giordano,1 Angelo Santamaria,1 Francesco Squadrito,2 Rosario D'Anna1 1Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, 2Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Messina, Messina, Italy*These authors contributed equally to this workAbstract: Endometrial hyperplasia without cytological atypia is commonly treated with progestins, but other treatments may be available with equivalent efficacy and reduced side effects. Here, we evaluate the effect of genistein aglycone on angiogenesis and apoptosis-related markers women with endometrial hyperplasia. Premenopausals (n=38) with nonatypical endometrial hyperplasia were administered either genistein aglycone (54 mg/day, n=19) or norethisterone acetate (10 mg/day, n=19) on days 16–25 of the menstrual cycle and evaluated for 6 months. Biopsies were taken during hysteroscopy at baseline and 6 months, and symptoms including excessive uterine bleeding were assessed at baseline and 3 and 6 months following recruitment. The expression of angiogenesis (Vegf), epithelial (Egf and Tgfb), and apoptosis-related (Bax, Bcl-2, and Casp-9) molecules, were assessed in uterine biopsies at baseline and after 6 months of therapy. Follicle-stimulating hormone, luteinizing hormone, estradiol, SHBG, and progesterone levels were also measured. After 6 months, 42% of genistein aglycone-administered patients had a significant improvement of symptoms compared to 47% of norethisterone acetate subjects. No significant differences were noted in hormone levels for any treatment. Gene expression revealed a significant reduction in Vegf, Egf, and Tgfb (P<0.05 versus baseline), and an increase in proapoptotic molecules (Bax and Casp-9), with a concomitant decrease in Bcl-2 values (P<0.05) in both groups. These results suggest that genistein aglycone might be useful for the management of endometrial hyperplasia without atypia in women who cannot or do not wish to be treated with progestin.Keywords: genistein, endometrial hyperplasia, Vegf, Bcl-2, Bax, Casp-

MiRNA expression profiling regulates necroptotic cell death in hepatocellular carcinoma

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Influence of socio-demographic features and apolipoprotein E epsilon 4 expression on the prevalence of dementia and cognitive impairment in a population of 70-74-year olds: The InveCe.Ab study

Abstract The age-specific prevalence rates of dementia vary widely. Studies focusing on specific age groups are needed to provide reliable estimates for healthcare providers and policy makers. We estimated the prevalence of dementia, dementia subtypes and cognitive impairment in "InveCe.Ab" (ClinicalTrials.gov, NCT01345110 ), a single-step multidimensional population-based study of 70–74-year olds living in Abbiategrasso (Milan, Italy). We also looked for associations with socio-demographic factors and the presence of the apolipoprotein E-ɛ4 allele. The overall dementia prevalence was 3% (95%CI: 2.1–4.1%) [Alzheimer's disease (AD): 1.2% (95%CI 0.6–1.9%); vascular dementia (VD): 1.4% (95%CI: 0.8–2.2%)]. Being single was found to be a risk factor for vascular dementia; subjects born in southern Italy were shown to be at greater risk both of overall dementia and of vascular dementia. The prevalence of cognitive impairment, with or without subjective cognitive complaints (cognitive impairment, no dementia, CIND) was 7.8% (95%CI: 6.4–9.4%). As regards the CIND subgroups, the prevalence of subjects with subjective cognitive complaints (mild cognitive impairment, MCI) was 5.0% (95%CI 3.9–6.3%), while the prevalence of those without MCI (CIND-other) was 2.8% (95%CI: 1.9–3.8). The males had a higher risk of MCI and CIND-other; the older subjects were more likely to have MCI, and those born in north-eastern Italy to have CIND-other. The prevalence of AD was higher among the apolipoprotein E-ɛ4 carriers. Our data highlight the importance of dementia and cognitive impairment in the transitional period from adulthood to old age, and reveal the presence of different associations with socio-demographic and genetic factors

Neurovascular coupling in patients with type 2 diabetes mellitus

Functional and metabolic neural changes in Type 2 diabetes mellitus (T2DM) can be associated with poor cognitive performances. Here we analyzed the functional-metabolic neurovascular coupling (NVC) in the brain of T2DM patients. Thirty-three patients (70 +/- 6 years, 15 males) with recent T2DM diagnosis and 18 healthy control (HC) subjects (65 +/- 9 years, 9 males) were enrolled in a brain MRI study to identify the potential effects of T2DM on NVC. T2DM patients were either drug-naive (n = 19) or under treatment with metformin (n = 14) since less than 6 months. Arterial spin labeling and blood oxygen level dependent resting-state functional MRI (RS-fMRI) images were combined to derive NVC measures in brain regions and large-scale networks in a standard brain parcelation. Altered NVC values in T2DM patients were correlated with cognitive performances spanning several neurological domains using Spearman correlation coefficients. Compared to HC, T2DM patients had reduced NVC in the default mode network (DMN) and increased NVC in three regions of the dorsal (DAN) and salience-ventral (SVAN) attention networks. NVC abnormalities in DAN and SVAN were associated with reduced visuo-spatial cognitive performances. A spatial pattern of NVC reduction in the DMN, accompanied by isolated regional NVC increases in DAN and SVAN, could reflect the emergence of (defective) compensatory processes in T2DM patients in response to altered neurovascular conditions. Overall, this pattern is reminiscent of neural abnormalities previously observed in Alzheimer's disease, suggesting that similar neurobiological mechanisms, secondary to insulin resistance and manifesting as NVC alterations, might be developing in T2DM pathology

Epistasis between IL1A, IL1B, TNF, HTR2A, 5-HTTLPR and TPH2 Variations Does Not Impact Alcohol Dependence Disorder Features

We assessed a set of biological (HDL, LDL, SGOT, SGPT, GGT, HTc, Hb and T levels) and psychometric variables (investigated through HAM-D, HAM-A, GAS, Liebowitz Social Anxiety Scale, Mark & Mathews Scale, Leyton scale, and Pilowski scale) in a sample of 64 alcohol dependent patients, at baseline and after a detoxification treatment. Moreover, we recruited 47 non-consanguineous relatives who did not suffer alcohol related disorders and underwent the same tests. In both groups we genotyped 11 genetic variations (rs1800587; rs3087258; rs1799724; 5-HTTLPR; rs1386493; rs1386494; rs1487275; rs1843809; rs4570625; rs2129575; rs6313) located in genes whose impact on alcohol related behaviors and disorders has been hypothesized (IL1A, IL1B, TNF, 5-HTTLPR, TPH2 and HTR2A). We analyzed the epistasis of these genetic variations upon the biological and psychological dimensions in the cases and their relatives. Further on, we analyzed the effects of the combined genetic variations on the short – term detoxification treatment efficacy. Finally, being the only not yet investigated variation within this sample, we analyzed the impact of the rs6313 alone on baseline assessment and treatment efficacy. We detected the following results: the couple rs6313 + rs2129575 affected the Leyton -Trait at admission (p = 0.01) (obsessive-compulsive trait), whilst rs1800587 + 5-HTTLPR impacted the Pilowski test at admission (p = 0.01) (hypochondriac symptoms). These results did not survive Bonferroni correction (p ≤ 0.004). This lack of association may depend on the incomplete gene coverage or on the small sample size which limited the power of the study. On the other hand, it may reflect a substantial absence of relevance of the genotype variants toward the alcohol related investigated dimensions. Nonetheless, the marginal significance we detected could witness an informative correlation worth investigating in larger samples

Comparing the effects of augmented virtual reality treadmill training versus conventional treadmill training in patients with stage II-III Parkinson’s disease: the VIRTREAD-PD randomized controlled trial protocol

BackgroundIntensive treadmill training (TT) has been documented to improve gait parameters and functional independence in Parkinson’s Disease (PD), but the optimal intervention protocol and the criteria for tailoring the intervention to patients’ performances are lacking. TT may be integrated with augmented virtual reality (AVR), however, evidence of the effectiveness of this combined treatment is still limited. Moreover, prognostic biomarkers of rehabilitation, potentially useful to customize the treatment, are currently missing. The primary aim of this study is to compare the effects on gait performances of TT + AVR versus TT alone in II-III stage PD patients with gait disturbance. Secondary aims are to assess the effects on balance, gait parameters and other motor and non-motor symptoms, and patient’s satisfaction and adherence to the treatment. As an exploratory aim, the study attempts to identify biomarkers of neuroplasticity detecting changes in Neurofilament Light Chain concentration T0-T1 and to identify prognostic biomarkers associated to blood-derived Extracellular Vesicles.MethodsSingle-center, randomized controlled single-blind trial comparing TT + AVR vs. TT in II-III stage PD patients with gait disturbances. Assessment will be performed at baseline (T0), end of training (T1), 3 (T2) and 6 months (T3, phone interview) from T1. The primary outcome is difference in gait performance assessed with the Tinetti Performance-Oriented Mobility Assessment gait scale at T1. Secondary outcomes are differences in gait performance at T2, in balance and spatial–temporal gait parameters at T1 and T2, patients’ satisfaction and adherence. Changes in falls, functional mobility, functional autonomy, cognition, mood, and quality of life will be also assessed at different timepoints. The G*Power software was used to estimate a sample size of 20 subjects per group (power 0.95, α &lt; 0.05), raised to 24 per group to compensate for potential drop-outs. Both interventions will be customized and progressive, based on the participant’s performance, according to a predefined protocol.ConclusionThis study will provide data on the possible superiority of AVR-associated TT over conventional TT in improving gait and other motor and non-motor symptoms in persons with PD and gait disturbances. Results of the exploratory analysis could add information in the field of biomarker research in PD rehabilitation