Pathophysiology of dementias and implications for therapy

Dementia is characterized clinically by progressive cognitive decline, often with impairment of memory. The pathology of dementias is either focal as with infarcts in Vascular Dementia or diffuse as typified by Alzheimer's disease. In many cases of Alzheimer's disease there is a mixture of focal infarcts and diffuse changes. Diffuse pathology in dementias comprises mainly intracellular and extracellular protein deposits. Intracellular inclusions are of tau protein (Alzheimer's disease; and some frontotemporal dementias), alpha-synuclein (Dementia with Lewy bodies) and huntingtin (Huntington's disease). Soluble and insoluble peptides also accumulate in the extracellular spaces of brain parenchyma in dementias with diffuse pathology, mainly amyloid-beta (Abeta) in parenchymal plaques and in artery walls as cerebral amyloid angiopathy (Alzheimer's disease and Dementia with Lewy bodies). Insoluble prion protein (PrP) is deposited in brain parenchyma in Creutzfeldt-Jakob disease and other insoluble amyloid peptides accumulate in brain and vessel walls infamilial dementias. The pattern of extracellular deposits in brain and artery walls suggests that there is a failure of elimination of peptides, such as Abeta along perivascular interstitial fluid drainage pathways ("lymphatics") from the aged brain and in Alzheimer's disease. Such failure may be due to reduced pulsations as arteries stiffen with age and cerebrovascular disease. Immunization against Abeta removes insoluble deposits of Abeta from brain parenchyma and may allow improved clearance of soluble Abeta. Reducing cerebrovascular disease and facilitating elimination of Abeta along perivascular drainage routes may offer long-term preventative measuresfor both Vascular Dementia and for Alzheimer's disease.     

Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy

A dysfunction of amino acid neurotransmitter transporters occurs in a number of central nervous system disorders, including stroke, epilepsy, cerebral palsy and amyotrophic lateral sclerosis. This dysfunction can comprise a reversal of transport direction, leading to the release of neurotransmitter into the extracellular space, or an alteration in transporter expression level. This review analyses the role of glutamate and GABA transporters in the pathogenesis and therapy of a number of acute and chronic neurological disorders.     

9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene

Tuberous sclerosis is an autosomal dominant disease whose characteristicfeature is the development of multiple hamartomas in a varietyof organs and tissues. Two major loci have been identified sofar: TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3.Loss of heterozygosity at 16p13.3-associated markers has beenrecently observed in hamartomatous lesions of some tuberoussclerosis patients. Here we report the first evidence of lossof heterozygosity at the TSC1 critical region in a giant cellastrocytoma of a familial tuberous sclerosis case. Segregationanalysis showed that the 9q34 haplotype lost carried the putativenormal TSC1 gene. These data support the hypothesis of botha germline and somatic loss-of-function mutation for the developmentof tuberous sclerosis hamartomas and suggest a tumor-suppressor-likeactivity also for the TSC1 gene product. Finally, the possiblesignificance of a second small region of loss of heterozygosityat 9p21, found in the same astrocytoma, is discussed.     

The impact of working life on health behavior: the effect of job strain on the cognitive predictors of exercise

The theory of planned behavior (TPB) and R. A. Karasek's (1979) job strain model were used to investigate the predictors of exercise in a group of employees. A total of 241 employees completed an initial questionnaire; 1 week later 213 employees responded to a questionnaire measuring behavior. Employees in high-strain jobs did significantly less exercise than those in low-strain jobs, although they did not intend to do less, suggesting that work may impede the intention implementation. Intenders who failed to exercise had significantly higher work demands and lower exercise self-efficacy than intenders who succeeded in exercising. Work also affected exercise indirectly through self-efficacy. Thus, work may be a target for behavior change intervention because of its impact at 2 stages of the TPB.     

Loneliness,social support,social isolation and wellbeing among working age adults with and without disability: Cross-sectional study

BackgroundLoneliness is significantly related to health and wellbeing. However, there is little information on the prevalence of loneliness among people with disability or the association between disability, loneliness and wellbeing.Objective/hypothesisFor a nationally representative sample of adults (age 16–64) with/without disability, to examine exposure to three indicators of low social connectedness (loneliness, low perceived social support, social isolation), and to evaluate the association between low social connectedness and wellbeing. To test whether disability status moderated the relationship between low social connectedness and wellbeing.MethodsSecondary analysis of data from three annual rounds of the cross-sectional English Community Life Survey (CLS) 2016–19.ResultsPeople with disability experienced loneliness, low perceived social support and social isolation at significantly higher rates than people without disability. Effect sizes were significantly greater for loneliness. Disability was associated with lower wellbeing. With one exception, low social connectedness was associated with lower wellbeing. Again, effect sizes were significantly greater for loneliness. The prevalence of loneliness was highest among adults with disability who were younger, economically inactive, living in rented or other accommodation, living alone and with low levels of access to environmental assets. There was no evidence that disability status moderated the association between exposure to low social connectedness and low wellbeing.ConclusionsLoneliness was a particularly significant driver of poor wellbeing among people with disability. The relative independence between different indicators of social connectedness suggests that interventions to reduce loneliness will need to do more than simply increase rates of social contact or social support.     

Microbiome as Mediator of Diet on Colorectal Cancer Risk: The Role of Vitamin D,Markers of Inflammation and Adipokines

Obesity and diet are associated with colorectal cancer (CRC) risk, and microbiome could mediate this risk factor. To investigate this interaction, we performed a case–control study (34 CRC cases and 32 controls) and analyzed fecal microbiota composition using 16S rRNA metabarcoding and sub-sequential shotgun analyses of genomic bacterial DNA to evaluate the role of microbiome and diet in CRC etiology, taking into account vitamin D and other risk biomarkers. Dietary habits were evaluated using a short questionnaire. Multivariate methods for data integration and mediation analysis models were used to investigate causal relationships. CRC cases were significantly more often deficient in vitamin D than controls (p = 0.04); FokI and CYP24A1 polymorphism frequency were different between cases and controls (p = 0.03 and p = 0.02, respectively). A diet poor in fatty fish and rich in carbohydrates was found to be significantly associated with CRC risk (p = 0.011). The mediation analysis confirmed the significant role of the microbiome in mediating CRC risk—increasing levels of Bifidobacteria/Escherichia genera ratio, an indicator of “healthy” intestinal microbiome, can overcome the effect of diet on CRC risk (p = 0.03). This study suggests that microbiome mediates the diet effect on CRC risk, and that vitamin D, markers of inflammation, and adipokines are other factors to consider in order to achieve a better knowledge of the whole carcinogenic process.     

Vascular Effects of the Polyphenolic Nutraceutical Supplement Taurisolo®: Focus on the Protection of the Endothelial Function

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo^®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo^® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo^®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo^® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.     

A Three-Year Longitudinal Study Comparing Bone Mass,Density, and Geometry Measured by DXA,pQCT, and Bone Turnover Markers in Children with PKU Taking L-Amino Acid or Glycomacropeptide Protein Substitutes

In patients with phenylketonuria (PKU), treated by diet therapy only, evidence suggests that areal bone mineral density (BMDa) is within the normal clinical reference range but is below the population norm. Aims: To study longitudinal bone density, mass, and geometry over 36 months in children with PKU taking either amino acid (L-AA) or casein glycomacropeptide substitutes (CGMP-AA) as their main protein source. Methodology: A total of 48 subjects completed the study, 19 subjects in the L-AA group (median age 11.1, range 5–16 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5–16 years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5–16 years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5–15 years) (n = 16), children taking a combination of CGMP-AA and L-AA. Dual X-ray absorptiometry (DXA) was measured at enrolment and 36 months, peripheral quantitative computer tomography (pQCT) at 36 months only, and serum blood and urine bone turnover markers (BTM) and blood bone biochemistry at enrolment, 6, 12, and 36 months. Results: No statistically significant differences were found between the three groups for DXA outcome parameters, i.e., BMDa (L2–L4 BMDa g/cm²), bone mineral apparent density (L2–L4 BMAD g/cm³) and total body less head BMDa (TBLH g/cm²). All blood biochemistry markers were within the reference ranges, and BTM showed active bone turnover with a trend for BTM to decrease with increasing age. Conclusions: Bone density was clinically normal, although the median z scores were below the population mean. BTM showed active bone turnover and blood biochemistry was within the reference ranges. There appeared to be no advantage to bone density, mass, or geometry from taking a macropeptide-based protein substitute as compared with L-AAs.     

Cross-Sectional Serosurvey of Companion Animals Housed with SARS-CoV-2–Infected Owners,Italy

We conducted a serologic survey among dogs and cats in Italy to detect antibodies against severe acute respiratory syndrome virus 2 (SARS-CoV-2). We found that SARS-CoV-2 seroprevalence was higher among cats (16.2%) than dogs (2.3%). In addition, seroprevalence was higher among animals living in close contact with SARS-CoV-2–positive owners.