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Uterus transplantation (UTx) is fast evolving from an experimental to a clinical procedure, combining solid organ transplantation with assisted reproductive technology. The commencement of the first human uterus transplant trial in the United Kingdom leads us to examine and reflect upon the legal and regulatory aspects closely intertwined with UTx from the process of donation to potential implications for fertility treatment and the birth of the resultant child. As the world's first ephemeral transplant, the possibility of organ restitution requires consideration and is discussed herein. Uterine transplantation warrants a closer look at the legal frameworks on fertility treatment and transplantation in England. Uterine transplantation warrants a closer look at the legal frameworks on fertility treatment and transplantation in England. [ABSTRACT FROM AUTHOR]

Keywords: Hysterectomy; recipient-graft time; second pregnancy; transplantation guidelines; uterus transplantation EN Hysterectomy recipient-graft time second pregnancy transplantation guidelines uterus transplantation 1610 1614 5 08/18/21 20210901 NES 210901 Introduction Since the first live birth to a woman after uterus transplantation (UTx) was reported in 2014,1 the number of UTx procedures has increased and births have occurred in multiple centers worldwide.2 Despite the growth of UTx, it is a novel procedure, with most cases having been done under experimental protocols, and there remains much debate about the ethics of UTx. Three elected to have graft hysterectomy at the time of the caesarean section and four elected to have graft hysterectomy after the postpartum period (Table 1). If a graft hysterectomy is planned, the decision regarding timing of the graft hysterectomy should begin with a discussion of the UTx recipient's preference and then consider whether there are medical indications that would favour a particular option. Preference for timing of graft hysterectomy The graft hysterectomy can occur at the time of caesarean section, during the postpartum period (<8 weeks) or after the postpartum period. [Extracted from the article]

Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women's reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation. [ABSTRACT FROM AUTHOR]

Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication. [ABSTRACT FROM AUTHOR]

The first successful live birth after uterus transplantation occurred in 2014.[1] Since then, successful live births have been replicated, offering hope to women with uterine factor infertility who want to carry a pregnancy.[2] However, in kidney transplantation, the goal is to preserve long-term function of the graft, whereas in uterus transplantation, one consideration is a decrease in recipient graft time, defined as time from uterus transplantation to graft hysterectomy (Figure), to reduce the risks and long-term side effects of immunosuppression. Our team shortened the time from uterus transplant to ET to 6 months in the first live birth after uterus transplantation in the USA[2] (Table), and that timeframe has been applied by several other uterus transplant teams worldwide. Our experience, the experience of other uterus transplant programmes, and results of successful pregnancies in other solid organ transplant recipients suggest ET could be considered as soon as 3 months after uterus transplantation if the above criteria are met (Table). [Extracted from the article]

Mediterranean forage systems suffer from limited availability of fresh forage because of water deficits and extreme temperatures. Consequently, fresh forage is unavailable for at least 6-7 months a year, and farmers must buy feed to support livestock production. With the aim of overcoming these limitations, a 2-year trial was conducted on three distinct sites in Sicily (at 10, 600 and 1200 m elevation) with thirty-four varieties of forage species belonging to nine biennial/perennial and thirteen annual species. Results showed that by integrating grasses and legumes, species from environments with different climatic conditions enable the season of forage production to be extended from mid- April to mid- November. Quality traits of forage in different areas varied in relation to species and varieties. In general, the sown-forage quality was better than in pastures and fallows in the same areas commonly used to feed animals. This also leads to a reduction in the use of supplementary feeds. Among the tested species, Lolium multiflorum and Medicago sativa emerged as the most promising for filling the forage-deficit periods, and Trifolium spp. and Vicia sativa were found to be superior for increasing forage quality. The results are discussed in the context of adapting Mediterranean forage supplies for ensuring greater sustainability of livestock production in mountain, hill and plain areas. The proposed forage chain arrangement represents part of local potential adaptation to climate limitations and climate change. [ABSTRACT FROM AUTHOR]

Background The elderly are characterized by a high prevalence of chronic heart failure (CHF) and frailty, which is a complex interaction of physical, psychological and social impairment. This study aimed to examine the predictive role of frailty on long-term mortality in elderly subjects with CHF. Materials and methods The study assessed long-term mortality after 12-year follow up in 120 subjects with CHF and 1139 subjects without CHF, selected in 1992, from a random sample of the elderly population in the Campania region of Italy. Frailty was assessed according to a ‘Frailty Staging System’. Results Subjects with CHF were prevalently female (60%) and older than 75 years (mean 75·9 ± 6·7); subjects without CHF were prevalently female (56·4%) and younger than 75 years (mean 74·0 ± 6·3). In subjects with and without CHF stratified into classes of frailty there was a statistically significant increase in age, comorbidity, disability and low social support, and a decrease in MMSE score. Moreover, death progressively increased more with frailty in subjects (70·0% to 94·4%, P < 0·03) than in those without (43·8.% to 88·3%, P < 0·0001) CHF. The Kaplan–Meier analysis shows that at 9 years the probability of survival progressively decreased as frailty increased (45·5% to 0%) in subjects with CHF and from 62·8% to 25·9% in subjects without CHF. The Cox regression analysis indicated that frailty is predictive of mortality in the multivariate model adjusted for several variables including sex and age in subjects with and without CHF. Moreover, the analysis showed that frailty is more predictive of mortality in elderly subjects with CHF when it was analyzed either as continuous (1·48 vs. 1·36) or as a dummy (3 vs. 1 = 1·62 vs. 1·24) variable. Conclusions Thus mortality among elderly subjects with or without CHF increases with frailty. Moreover, frailty is more predictive of long-term mortality in elderly subjects with than in those without CHF. Hence, frailty represents a new independent variable for predicting long-term mortality in elderly subjects with CHF. [ABSTRACT FROM AUTHOR]

The recent in vitro derivation of gamete-like cells from mouse embryonic stem (mES) cells is a major breakthrough and lays down several challenges, both for the further scientific investigation and for the bioethical and biolegal discourse. We refer here to these cells as gamete-like (sperm-like or oocyte-like, respectively), because at present there is still no evidence that these cells behave fully like bona fide sperm or oocytes, lacking the fundamental proof, i.e. combination with a normally derived gamete of the opposite sex to yield a normal individual. However, the results published so far do show that these cells share some defining features of gametes. We discuss these results in the light of the bioethical and legal questions that are likely to arise would the same process become possible with human embryonic stem (hES) cells. [ABSTRACT FROM AUTHOR]

Testa G, Malagó M, Broelsch CE. From living related to in-situ split liver transplantation: How to reduce waiting-list mortality. Pediatr Transplantation 2001: 5: 16-20. © Munksgaard, 2001 Abstract: The insufficient number of suitable cadaveric organs for pediatric recipients is the cause of high pretransplant mortality rates and long waiting times. With the introduction of split and living related liver transplantation, the waiting list mortality rate has dropped from greater than 15% to less than 5% and children are transplanted more rapidly. A 5-year patient and graft survival rate of greater than 80% has been obtained in those centers where split and living related liver transplantations are routinely performed. The data analyzed in this paper show that the only current solution to cadaveric organ shortage is a 'multimodal' approach, where whole liver cadaveric transplantation is associated with split and living related liver transplantation. [ABSTRACT FROM AUTHOR]

Fetal goiter is an extremely rare complication of pregnancy. The goiter was not clinically apparent and the newborn with an euthyroid status was discharged home on the second day of life with levothyroxine treatment. In-utero treatment with 400 mcg levothyroxine injected weekly into the amniotic sac, and later increased to 600 mcg resulted in a progressive reduction of the goiter (area 1.60 cm SP 2 sp near term). [Extracted from the article]

HLA-C*07:555 differs from C*07:01:01:01 by a C to G substitution in exon 2. [ABSTRACT FROM AUTHOR]

HLA-B*35:240 shows one nucleotide change from B*35:01:01 at nt 160 from G to T. [ABSTRACT FROM AUTHOR]

The novel allele HLA-DQB1*04:09 differs from DQB1 *04:02:01 by three nonsynonymous nucleotide substitutions in exon 2. [ABSTRACT FROM AUTHOR]

New allele B*0769 showed one nucleotide difference with B*0732 at codon 272 (TTC→TGC). [ABSTRACT FROM AUTHOR]

Presents the case of a 44-year-old man with end-stage liver disease due to hepatitis C who underwent a liver graft from a 55-year-old man who died from a cerebral hemorrhage. Normal liver function tests of the donor; Presence of small whitish lesions on the surface of the cadaveric liver; Documentation of the first case of a donor liver affected by multiple biliary hamartomas.

This article, accompanied by technical notes and video, presents a case of an 85-year-old patient with a cT2N0 laryngeal squamous cell carcinoma treated using CO 2 transoral laser exoscopic surgery (TOLES). The procedure achieved en bloc tumor removal with negative margins, preserving laryngeal and swallowing functions, demonstrating TOLES as a viable alternative to traditional microsurgery with enhanced visualization and ergonomics. Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Uterine transplantation (UT) is an emerging medical treatment for women affected by absolute uterine factor infertility (AUFI). To date there have been over 90 documented cases of UT performed worldwide, with over 50 live births. UT allows women affected by AUFI the opportunity to carry and deliver a childd. The Royal Prince Alfred Hospital (RPAH) introduced a UT study in 2019; however, due to the impacts of the COVID pandemic the study was placed on hold for two years. In February 2023, RPAH performed the centre's first UT from a living unrelated donor to a 25-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome. The donor and recipient surgeries were uncomplicated and both are recovering well in the early post-operative period., (© 2023 Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Despite advances in technologies and clinical experience, conduction disorders, after transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR), represent the weak point of these procedures, requiring permanent pacemaker implantation (PPI) till 37.7% of patients in TAVR recipients. The role of PPI in TAVR and SAVR remains controversial in mid- and long-term outcomes. Indeed, many studies have been published with contradictory results, leaving doubts rather than certainties., (© 2022 Wiley Periodicals LLC.)

Introduction: In this prospective multicenter analysis, we aimed to investigate the predictive role of neutrophil/lymphocyte ratio (NLR) in permanent pacemaker implantation (PPI) in patients undergoing transcatheter aortic valve replacement (TAVR)., Materials and Methods: One hundred and seventy-nine consecutive patients without previous PPI underwent TAVR from February 2017 to September 2021. Patients were further divided based on presence (n = 48) and absence of conduction abnormalities (CAs) at hospital admission (n = 131)., Results: In patients with previous CAs, NLR values did not differ significantly between patients requiring PPI (n = 16, 33%) and those not requiring it. In contrast, in patients with no CAs at hospital admission, NLR values measured at admission and on TAVR day were significantly higher in patients requiring PPI (n = 17, 13%) (4.07 ± 3.22 vs. 3.01 ± 1.47, p = .025, and 10.81 ± 7.81 vs. 5.84 ± 3.78, p = .000, respectively). Multivariable analysis showed that NLR at TAVR day was an independent predictor of PPI in patients without CAs (OR 1.294; 95% CI 1.028-1.630; p = .028), but not in those with previous CAs. ROC curve analysis showed that the cut point was a NLR value of >7.25. Time to PPI was delayed till 21 days in patients without CAs., Conclusions: In this prospective study, higher NLR values on the day of TAVR day were associated with an increased PPI rate in patients undergoing TAVR with no previous CAs. It is advisable, being inflammation part of the process, to prolong the time of observation for all patients without CAs till at least 21 days not to miss any new CA necessitating PPI., (© 2022 Wiley Periodicals LLC.)

Objective: To describe outcomes in the first 2 years of life for the children born in the Dallas UtErus Transplant Study., Design: Cohort study comprising all live births from uterus transplantation at a single centre., Setting: Baylor University Medical Center, Dallas, Texas., Population: A total of 14 children from 12 uterus transplantation recipients., Methods: Retrospective review of data through 2 years of life., Main Outcome Measures: Information on children's development was collected based on the Bright Futures Guideline and the Bright Futures Previsit Questionnaire. Primary outcomes were anthropometric measures (children's body length, weight, head circumference), neurological status, cognitive status and physical development at 6, 12, 18 and 24 months of age., Results: The median gestational age at delivery was 36 +6  weeks, with a median birthweight of 2940 g. Follow-up data were available for 13 offspring. Physical and neurological developmental milestones were met and were age appropriate in all children within the first 24 months. General health was good, and no abnormalities in immune development were found. Cognitive deviations were only mild and temporary and improved with interventions., Conclusions: The children's growth and physical, neurological and cognitive development were age appropriate within the first 2 years of life. To confirm these outcomes, further data should be collected in collaboration with other centres., (© 2022 John Wiley & Sons Ltd.)

Objective: To assess how absolute uterine factor infertility affects women who undergo uterus transplantation, how uterus transplantation impacts women with absolute uterine factor infertility and how uterus transplant recipients view uterus transplantation in terms of their reproductive autonomy., Design: Qualitative semi-structured interview study., Setting: Uterus transplant programme in a large academic medical centre in the USA., Population/sample: Twenty one uterus transplant recipients., Methods: A medical chart review was conducted to collect patient demographic information and clinical outcomes. Semi-structured interviews collected information regarding participants' experience., Main Outcome Measure(s): The outcomes of interest were participants' experience of infertility, experience with uterus transplantation and general perceptions of uterus transplantation., Results: Six participants were pregnant (one with a second child), six had experienced early graft failure and removal, five had delivered a healthy baby, and four had a viable graft and were awaiting embryo transfer. The primary themes identified were: the negative impact of absolute uterine factor infertility diagnosis on psychological wellbeing, relationships and female identity; the positive impact of uterus transplantation on healing the emotional scars of absolute uterine factor infertility, female identity and value of research trial participation and the perception of uterus transplantation as an expansion of reproductive autonomy. All participants reported that uterus transplantation was worthwhile, regardless of individual outcome., Conclusion: Absolute uterine factor infertility has a negative impact on women from a young age, affects multiple relationships and challenges female identity. Uterus transplantation helps to reverse this impact, transforming women's life narrative of infertility and enhancing female identity., Tweetable Abstract: Absolute uterine factor infertility (AUFI) adversely affects women. Uterus transplantation helps mitigate the negative impact of AUFI, by transforming women's life narratives of infertility and enhancing female identity., (© 2021 John Wiley & Sons Ltd.)

Uterus transplantation (UTx) is fast evolving from an experimental to a clinical procedure, combining solid organ transplantation with assisted reproductive technology. The commencement of the first human uterus transplant trial in the United Kingdom leads us to examine and reflect upon the legal and regulatory aspects closely intertwined with UTx from the process of donation to potential implications for fertility treatment and the birth of the resultant child. As the world's first ephemeral transplant, the possibility of organ restitution requires consideration and is discussed herein. TWEETABLE ABSTRACT: Uterine transplantation warrants a closer look at the legal frameworks on fertility treatment and transplantation in England., (© 2021 John Wiley & Sons Ltd.)

Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Absolute uterine factor infertility (AUFI) is defined as the absence of a uterus or the presence of a non-functional uterus. Before the first live birth from a uterus transplant in 2014, the only fertility options for women with AUFI were surrogacy and adoption. In November 2019, our team was granted approval for the first uterus transplant trial in Australia using known living donors. Our program is based on that of our overseas collaborators in Dallas, Texas; this team will also be proctoring us for our first two cases., (© 2021 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

It now seems technically feasible to culture human embryos beyond the "fourteen-day limit," which has the potential to increase scientific understanding of human development and perhaps improve infertility treatments. The fourteen-day limit was adopted as a compromise but subsequently has been considered an ethical line. Does it remain relevant in light of technological advances permitting embryo maturation beyond it? Should it be changed and, if so, how and why? What justifications would be necessary to expand the limit, particularly given that doing so would violate some people's moral commitments regarding human embryos? Robust stakeholder engagement preceded adoption of the fourteen-day limit and should arguably be part of efforts to reassess it. Such engagement could also consider the need for enhanced oversight of human embryo research. In the meantime, developing and implementing reliable oversight systems should help foster high-quality research and public confidence in it., (© 2021 The Hastings Center.)

Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women's reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication., (© 2019 Royal College of Obstetricians and Gynaecologists.)

A relevant number of patients undergoing total cavopulmonary connection (TCPC) experience heart failure (HF). Heart transplant is then the final option when all other treatments fail. The axial flow blood pumps are now the state of the art; however, there is little experience in low-pressure circuits, such as support of the right ventricle or even a TCPC circulation. A new T-shaped model of mechanically assisted TCPC using the "Jarvik Child 2000" axial pump, (flow rates between 1 and 3 L/m in a range of 5000-9000 rpm) was designed, simulated numerically, and then tested in animals. Eight sheep (42-45 kg) were studied: two pilot studies, four pump-supported (PS) TCPC for 3 h, and two not pump-supported (NPS) TCPC. In the PS, the axial pump was set to maintain the baseline cardiac output (CO). Pressures, CO, systemic and pulmonary vascular resistance, lactate levels, and blood gases were recorded for 3 h. Computational fluid dynamics (CFD) study allows us to set the feasible operating condition and the safety margins to minimize the venous collapse risk. In the NPS animals, a circulatory deterioration, with increasing lactate level, occurred rapidly. In the PS animals, there was a stable cardiac index of 2.7 ± 1.4 L/min/m(2), central venous pressure of 12.3 ± 1 mm Hg, and a mean pulmonary artery pressure (PAP) of 18.1 ± 6 after 3 h of support up to 9000 rpm. systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), blood gasses, and arterial lactate levels remained stable to baseline values. No caval collapse occurred. A new pediatric axial flow pump provides normal CO and physiologic stability in a new T-shaped model of TCPC in sheep, in vivo. CFD and in vivo data showed that this experimental arrangement will allow us to evaluate the potential for mechanical support in patients with Fontan failure avoiding major adverse events., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

It is now thought that atherosclerosis, although due to increased plasma lipids, is mainly the consequence of a complicated inflammatory process, with immune responses at the different stages of plaque development. Increasing evidence points to a significant role of Toll-like receptor 4 (TLR4), a key player in innate immunity, in the pathogenesis of atherosclerosis. This study aimed to determine the effects on TLR4 activation of two reactive oxidized lipids carried by oxidized low-density lipoproteins, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE), both of which accumulate in atherosclerotic plaques and play a key role in the pathogenesis of atherosclerosis. Secondarily, it examined their potential involvement in mediating inflammation and extracellular matrix degradation, the hallmarks of high-risk atherosclerotic unstable plaques. In human promonocytic U937 cells, both 27-OH and HNE were found to enhance cell release of IL-8, IL-1β, and TNF-α and to upregulate matrix metalloproteinase-9 (MMP-9) via TLR4/NF-κB-dependent pathway; these actions may sustain the inflammatory response and matrix degradation that lead to atherosclerotic plaque instability and to their rupture. Using specific antibodies, it was also demonstrated that these inflammatory cytokines increase MMP-9 upregulation, thus enhancing the release of this matrix-degrading enzyme by macrophage cells and contributing to plaque instability. These innovative results suggest that, by accumulating in atherosclerotic plaques, the two oxidized lipids may contribute to plaque instability and rupture. They appear to do so by sustaining the release of inflammatory molecules and MMP-9 by inflammatory and immune cells, for example, macrophages, through activation of TLR4 and its NF-κB downstream signaling., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

The brains of teleost fish show extensive adult neurogenesis and neuronal regeneration. The patterns of gene regulation during fish brain aging are unknown. The short-lived teleost fish Nothobranchius furzeri shows markers of brain aging including reduced learning performances, gliosis, and reduced adult neurogenesis. We used RNA-seq to quantify genome-wide transcript regulation and sampled five different time points to characterize whole-genome transcript regulation during brain aging of N. furzeri. Comparison with human datasets revealed conserved up-regulation of ribosome, lysosome, and complement activation and conserved down-regulation of synapse, mitochondrion, proteasome, and spliceosome. Down-regulated genes differ in their temporal profiles: neurogenesis and extracellular matrix genes showed rapid decay, synaptic and axonal genes a progressive decay. A substantial proportion of differentially expressed genes (~40%) showed inversion of their temporal profiles in the last time point: spliceosome and proteasome showed initial down-regulation and stress-response genes initial up-regulation. Extensive regulation was detected for chromatin remodelers of the DNMT and CBX families as well as members of the polycomb complex and was mirrored by an up-regulation of the H3K27me3 epigenetic mark. Network analysis showed extensive coregulation of cell cycle/DNA synthesis genes with the uncharacterized zinc-finger protein ZNF367 as central hub. In situ hybridization showed that ZNF367 is expressed in neuronal stem cell niches of both embryonic zebrafish and adult N. furzeri. Other genes down-regulated with age, not previously associated with adult neurogenesis and with similar patterns of expression are AGR2, DNMT3A, KRCP, MEX3A, SCML4, and CBX1. CBX7, on the other hand, was up-regulated with age., (© 2014 The Authors. Aging cell published by the Anatomical Society and John Wiley & Sons Ltd.)

An abnormal accumulation of cholesterol oxidation products in the brain of patients with Alzheimer's disease (AD) would further link an impaired cholesterol metabolism in the pathogenesis of the disease. The first evidence stemming from the content of oxysterols in autopsy samples from AD and normal brains points to an increase in both 27-hydroxycholesterol (27-OH) and 24-hydroxycholesterol (24-OH) in the frontal cortex of AD brains, with a trend that appears related to the disease severity. The challenge of differentiated SK-N-BE human neuroblastoma cells with patho-physiologically relevant amounts of 27-OH and 24-OH showed that both oxysterols induce a net synthesis of Aβ1-42 by up-regulating expression levels of amyloid precursor protein and β-secretase, as well as the β-secretase activity. Interestingly, cell pretreatment with N-acetyl-cysteine (NAC) fully prevented the enhancement of β-amyloidogenesis induced by the two oxysterols. The reported findings link an impaired cholesterol oxidative metabolism to an excessive β-amyloidogenesis and point to NAC as an efficient inhibitor of oxysterols-induced Aβ toxic peptide accumulation in the brain., (© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

All three cholesterol oxidation products implicated thus far in the pathogenesis of Alzheimer's disease, 7β-hydroxycholesterol, 24-hydroxycholesterol, and 27-hydroxycholesterol, markedly enhance the binding of amyloid-beta (Aβ) to human differentiated neuronal cell lines (SK-N-BE and NT-2) by up-regulating net expression and synthesis of CD36 and β1-integrin receptors. However, only 24-hydroxycholesterol markedly potentiates the pro-apoptotic and pro-necrogenic effects of Aβ(1-42) peptide on these cells: 7β-hydroxycholesterol and 27-hydroxycholesterol, like unoxidized cholesterol, show no potentiating effect. This peculiar behavior of 24-hydroxycholesterol at physiologic concentrations (1 μm) depends on its strong enhancement of the intracellular generation of NADPH oxidase-dependent reactive oxygen species (ROS), mainly H(2) O(2) , and the consequent impairment of neuronal cell redox equilibrium, measured in terms of the GSSG/GSH ratio. Cell incubation with antioxidants quercetin or genistein prevents 24-hydroxycholesterol's pro-oxidant effect and potentiation of Aβ-induced necrosis and apoptosis. Thus, the presence of 24-hydroxycholesterol in the close vicinity of amyloid plaques appears to enhance the adhesion of large amounts of Aβ to the plasma membrane of neurons and then to amplify the neurotoxic action of Aβ by locally increasing ROS steady-state levels. This report further supports a primary involvement of altered brain cholesterol metabolism in the complex pathogenesis of Alzheimer's disease., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)