Genetic, immune and environmental risk factors in Alzheimer's disease

Alzheimer's disease (AD) is a complex multi-factorial disease in which several pathogenetic, clinical, environmental and stochastic factors are involved. It is on record that persistent virus infections, the progressive decline of immune competence with ageing and chronic psychological stress exposures might play a pivotal role in AD. This study shows that in patients with clinical and neurological AD diagnosis, antiviral immune response is defective in the majority of AD brain samples. Moreover, gene variants of APOE and IRF7 strongly affect antiviral gene expression profiles in hippocampus. These findings suggest that brains from AD patients have defective antimicrobial immune defences and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, further decreases brain immune efficiency. Chronic stress at different stages of life, including intrauterine life, has a negative impact on AD pathology and prenatal stress (PNS) is an important programming factor in brain development and function. The second part of this thesis shows that experimental animal research has the advantage of enabling strict control of environmental factors, such as PNS exposure, that might have a role in AD-related behaviour and neuropathology. Long-term cognitive consequences of PNS in AD mice and the PNS-early neurobiological effects in wild type animals were investigated. As these, mouse represented a useful model to suggest that PNS affects the onset of AD cognitive deficit in a sex-dependent manner and that the impairment of fetal neurodevelopment might influence adult mental health and brain ageing. In conclusion, the presented study gives new perspectives for prevention and treatment of the ageing-associated cognitive decline and AD. Protecting women from chronic stress during pregnancy, on the one side, and maintenance of efficient immune responses during ageing, on the other one, might slowdown neurodegenerative mechanisms associated with senile dementia and positively influence both prevalence and incidence of AD

Main phases of wood formation in chestnut (Castanea sativa) in Central Italy: comparison of seasons 2008 and 2009

We present wood formation in chestnut (Castanea sativa) during the growing seasons 2008 and 2009, compare its dynamics in the two years and discuss possible effects on wood quality. To this purpose, microcores containing wood, cambium and phloem were collected at weekly intervals from 10 chestnut trees growing at the Cimini mountains near Viterbo, Central Italy. In 2008, the onset of wood formation started before the first sampling on 17 April 2008. Onset of lignifi cation of the fi rst formed vessels was observed around 23 April (day of the year DOY 113.8 ± 5.3) and the fi rst latewood vessels were observed around 5 June 2008 (DOY 156.5 ± 7.7). Latewood formation continued until 29 September 2008 (DOY 273.9 ± 10.5) when the terminal cells of the newly formed xylem ring were fully lignifi ed. In 2009, the main phases of wood formation generally occurred earlier than in 2008. The expansion of earlywood vessels was observed around 10 April (DOY 99.7 ± 6.1), the onset of lignifi cation around 22 April (DOY 111.9 ± 7.4) and the first latewood vessels around 28 May 2009 (DOY 147.9 ± 4.7). Lignifi cation of the last formed cells was completed by 26 September 2009 (DOY 273.9 ± 10.5). The average duration of tree-ring formation was 161 days in 2008 and 169 days in 2009, the average ring widths were 3296 ± 1514 μm in 2008 and 3166 ± 1073 μm in 2009, and latewood percentages comprised 76% and 74% of the 2008 and 2009 tree-rings, respectively. The small differences in timing of wood formation phases in the two study years are probably due to small variations in climatic conditions between the two years and they did not seem to have a major impact on ring widths and latewood percentages, which are two important parameters affecting wood quality in ring porous wood species

Glavne faze razvoja drva pitomog kestena (Castanea sativa) u središnjoj Italiji – usporedba sezone 2008 i 2009

We present wood formation in chestnut (Castanea sativa) during the growing seasons 2008 and 2009, compare its dynamics in the two years and discuss possible effects on wood quality. To this purpose, microcores containing wood, cambium and phloem were collected at weekly intervals from 10 chestnut trees growing at the Cimini mountains near Viterbo, Central Italy. In 2008, the onset of wood formation started before the first sampling on 17 April 2008. Onset of lignification of the first formed vessels was observed around 23 April (day of the year DOY 113.8 ± 5.3) and the first latewood vessels were observed around 5 June 2008 (DOY 156.5 ± 7.7). Latewood formation continued until 29 September 2008 (DOY 273.9 ± 10.5) when the terminal cells of the newly formed xylem ring were fully lignified. In 2009, the main phases of wood formation generally occurred earlier than in 2008. The expansion of earlywood vessels was observed around 10 April (DOY 99.7 ± 6.1), the onset of lignification around 22 April (DOY 111.9 ± 7.4) and the first latewood vessels around 28 May 2009 (DOY 147.9 ± 4.7). Lignification of the last formed cells was completed by 26 September 2009 (DOY 273.9 ± 10.5). The average duration of tree-ring formation was 161 days in 2008 and 169 days in 2009, the average ring widths were 3296 ± 1514 μm in 2008 and 3166 ± 1073 μm in 2009, and latewood percentages comprised 76% and 74% of the 2008 and 2009 tree-rings, respectively. The small differences in timing of wood formation phases in the two study years are probably due to small variations in climatic conditions between the two years and they did not seem to have a major impact on ring widths and latewood percentages, which are two important parameters affecting wood quality in ring porous wood species.Rad obrađuje stvaranje drva pitomog kestena (Castanea sativa) tijekom vegetacije u 2008. i 2009. godini. Uspoređuje se dinamika stvaranja drva u te dvije godine i raspravlja o mogućem utjecaju na njegovu kvalitetu. Za tu su svrhu s deset stabala pitomog kestena u planinama Cimini, pokraj mjesta Viterbo u središnjoj Italiji, u tjednim intervalima skupljeni mikroizvrtci koji su sadržavali drvo, kambij i floem. Početak stvaranja drva u 2008. godini dogodio se prije uzimanja prvih uzoraka 17. travnja 2008. Početak lignifikacije prvooblikovanih traheja primijećen je oko 23. travnja (dan u godini DOY 113,8 ± 5,3), a prve traheje kasnog drva primijećene su oko 5. lipnja (DOY 156,5 ± 7,7). Stvaranje kasnog drva nastavljeno je do 29. rujna 2008. (DOY 273,9 ± 10,5), kad su završne stanice novostvorenoga goda drva bile potpuno lignificirane. U 2009. godini glavne su se faze stvaranja drva uglavnom pojavile ranije nego u 2008. godini. Širenje traheja ranog drva primijećeno je oko 10. travnja (DOY 99,7 ± 6,1), početak lignifikacije oko 22. travnja (DOY 111,9 ± 7,4), a prve traheje kasnog drva oko 28. svibnja 2009. (DOY 147,9 ± 4,7). Lignifi kacija zadnjih proizvedenih stanica završena je do 26. rujna 2009. (DOY 273,9 ± 10,5). Prosječno trajanje stvaranja goda drva u 2008. godini iznosilo je 161 dan, a u 2009. godini 169 dana. Prosječne širine godova bile su 3296 ± 1514 μm u 2008. godini i 3166 ± 1073 μm u 2009. godini, a postotni udjel kasnog drva iznosio je 76 i 74% godova u 2008., odnosno u 2009. godini. Male razlike u vremenu početka pojedine faza stvaranja drva u dvjema promatranim godinama vjerojatno su posljedica malih varijacija klimatskih uvjeta između te dvije godine i čini se da nemaju velik utjecaj na širinu godova ni na postotak kasnog drva, a to su dva važna čimbenika koji utječu na kvalitetu drva prstenasto poroznih vrsta

The clinical efficacy of nitrofurantoin for treating uncomplicated urinary tract infection in adults: a systematic review of randomized control trials

OBJECTIVE: To provide an updated systematic review of randomized control trials (RCTs) to investigate the clinical and microbiological efficacy of nitrofurantoin compared to other antibiotics or placebo for treatment of uncomplicated urinary tract infections (uUTI). A secondary aim is to assess whether nitrofurantoin use is associated with increased side effects compared to other treatment regimens.SUMMARY: The review was performed according to PRISMA guidelines. We searched 4 databases for articles published from database inception to May 6, 2020: (1) PubMed electronic database of the National Library of Medicine, (2) Web of Science, (3) Embase, and (4) Cochrane Library. Nine RCTs were selected for the review. RCTs were a mixture of double-blind, single-blind, and open-label trials. The most common comparators were trimethoprim-sulfamethoxazole and fosfomycin tromethamine. Overall study quality was poor with a high risk of bias. The clinical cure rates in nitrofurantoin ranged from 51 to 94% depending on the length of follow-up, and bacteriological cure rates ranged from 61 to 92%. Overall the evidence suggests that nitrofurantoin is at least comparable with other uUTI treatments in terms of efficacy. Patients taking nitrofurantoin reported fewer side effects than other drugs and the most commonly reported were gastrointestinal and central nervous system symptoms. Key Messages: Evidence on the clinical and bacteriological efficacy of nitrofurantoin is sparse, with a lack of new data, and hampered by high risk of bias. Although no firm conclusions can be made on the current base of evidence, the studies generally suggest that nitrofurantoin is at least comparable to other common uUTI treatments in terms of clinical and bacteriological cure. More robust research with well-designed double-blinded RCTs is needed

Chromatic Pupillometry Findings in Alzheimer's Disease

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis

Adding systematic biopsy to magnetic resonance ultrasound fusion targeted biopsy of the prostate in men with previous negative biopsy or enrolled in active surveillance programs

Magnetic resonance imaging (MRI) targeted biopsy (TBx) of the prostate demonstrated to improve detection rate (DR) of clinically significant prostate cancer (csPCa) in biopsy-naive patients achieving strong level of evidence. Nevertheless, the csPCa yield for TBx alone versus TBx plus systematic biopsy (SBx) after accounting for overlapping of SBx cores with TBx cores, in prior-negative or active surveillance (AS) patients has not been well established.The objective of the study was to investigate benefits in terms of detection rate and pathological stratification of prostate cancer (PCa) using contextual SBx during MRI-TBx.Patients previously submitted to negative-SBx (cohort A) and those enrolled in an AS program (cohort B) who showed at least 1 suspicious area with a PIRADSv2 score ≥ 3 were prospectively and randomly assigned to only TBx strategy versus TBx plus SBx strategy. SBx locations could not encompass the TBx sites, so that the results of each type of biopsy were independent and did not overlap.A total of 312 patients were included in the 2 cohorts (cohort A: 213 cases; cohort B: 99 cases). No significant differences were found in terms of overall PCa-DR (77.6% vs 69.6% respectively; P = .36) and csPCa-DR (48.2% vs 60.9 respectively; P = .12). The MRI-TBx alone cohort showed higher csPCa/PCa ratio (87.5% vs 62.2%; P = .03). The MRI-TBx plus SBx group subanalysis showed significantly higher csPCa-DR obtained at the MRI-TBx cores when compared with the SBx cores (43.7% vs 24.1%, respectively; P = .01). Independently to age, prostatic-specific antigen and prostate imaging-reporting and data system score, either in rebiopsy (OR 0.43, 0.21-0.97) or AS (OR 0.46, 0.32-0.89) setting, SBx cores were negatively associated with the csPCa-DR when combined to TBx cores.MRI-TBx should be considered the elective method to perform prostate biopsy in patients with previous negative SBx and those considered for an AS program. Adding SBx samples to MRI-TBx did not improve detection rate of csPCa

AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability

PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show that, upon mitochondrial depolarization, the proautophagic protein AMBRA1 is recruited to the OMM and interacts with PINK1 and ATAD3A, a transmembrane protein that mediates mitochondrial import and degradation of PINK1. Downregulation of AMBRA1 expression results in reduced levels of PINK1 due to its enhanced degradation by the mitochondrial protease LONP1, which leads to a decrease in PINK1-mediated ubiquitin phosphorylation and mitochondrial PRKN/PARKIN recruitment. Notably, ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells upon mitochondrial damage. Overall, our findings underline an upstream contribution of AMBRA1 in the control of PINK1-PRKN mitophagy by interacting with ATAD3A and promoting PINK1 stability. This novel regulatory element may account for changes of PINK1 levels in neuropathological conditions.Abbreviations: ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATAD3A: ATPase family AAA domain containing 3A; BCL2L1/BCL-xL: BCL2 like 1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMA1: OMA1 zinc metallopeptidase; OMM: outer mitochondrial membrane; PARL: presenilin associated rhomboid like; PARP: poly(ADP-ribose) polymerase; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; SDHA: succinate dehydrogenase complex flavoprotein subunit A; TOMM70: translocase of outer mitochondrial membrane 70

Do all critically ill patients with COVID-19 disease benefit from adding tocilizumab to glucocorticoids? A retrospective cohort study.

Background: Treatment guidelines recommend the tocilizumab use in patients with a CRP of >7.5 mg/dL. We aimed to estimate the causal effect of glucocorticoids + tocilizumab on mortality overall and after stratification for PaO2/FiO2 ratio and CRP levels. Methods: This was an observational cohort study of patients with severe COVID-19 pneumonia. The primary endpoint was day 28 mortality. Survival analysis was conducted to estimate the conditional and average causal effect of glucocorticoids + tocilizumab vs. glucocorticoids alone using Kaplan–Meier curves and Cox regression models with a time-varying variable for the intervention. The hypothesis of the existence of effect measure modification by CRP and PaO2/FiO2 ratio was tested by including an interaction term in the model. Results: In total, 992 patients, median age 69 years, 72.9% males, 597 (60.2%) treated with monotherapy, and 395 (31.8%), adding tocilizumab upon respiratory deterioration, were included. At BL, the two groups differed for median values of CRP (6 vs. 7 mg/dL; p 7.5 mg/dL prior to treatment initiation and the largest effect for a CRP > 15 mg/dL. Large randomized studies are needed to establish an exact cut-off for clinical use

Case report: A novel patient presenting TRIM32-related limb-girdle muscular dystrophy

Limb-girdle muscular dystrophy autosomal recessive 8 (LGMDR8) is a rare clinical manifestation caused by the presence of biallelic variants in the TRIM32 gene. We present the clinical, molecular, histopathological, and muscle magnetic resonance findings of a novel 63-years-old LGMDR8 patient of Italian origins, who went undiagnosed for 24 years. Clinical exome sequencing identified two TRIM32 missense variants, c.1181G > A p.(Arg394His) and c.1781G > A p.(Ser594Asp), located in the NHL1 and NHL4 structural domains, respectively, of the TRIM32 protein. We conducted a literature review of the clinical and instrumental data associated to the so far known 26 TRIM32 variants, carried biallelically by 53 LGMDR8 patients reported to date in 20 papers. Our proband's variants were previously identified only in three independent LGMDR8 patients in homozygosis, therefore our case is the first in literature to be described as compound heterozygous for such variants. Our report also provides additional data in support of their pathogenicity, since p.(Arg394His) is currently classified as a variant of uncertain significance, while p.(Ser594Asp) as likely pathogenic. Taken together, these findings might be useful to improve both the genetic counseling and the diagnostic accuracy of this rare neuromuscular condition