Perturbations in iron homeostasis and iron accumulation feature in several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis ...(ALS). Proteins such as α-synuclein, tau and amyloid precursor protein that are pathologically associated with neurodegeneration are involved in molecular crosstalk with iron homeostatic proteins. Quantitative susceptibility mapping, an MRI based non-invasive technique, offers proximal evaluations of iron load in regions of the brain and powerfully predicts cognitive decline. Further, small molecules that target elevated iron have shown promise against PD and AD in preclinical studies and clinical trials. Despite these strong links between altered iron homeostasis and neurodegeneration the molecular biology to describe the association between enhanced iron levels and neuron death, synaptic impairment and cognitive decline is ill defined. In this review we discuss the current understanding of brain iron homeostasis and how it may be perturbed under pathological conditions. Further, we explore the ramifications of a novel cell death pathway called ferroptosis that has provided a fresh impetus to the “metal hypothesis” of neurodegeneration. While lipid peroxidation plays a central role in the execution of this cell death modality the removal of iron through chelation or genetic modifications appears to extinguish the ferroptotic pathway. Conversely, tissues that harbour elevated iron may be predisposed to ferroptotic damage. These emerging findings are of relevance to neurodegeneration where ferroptotic signalling may offer new targets to mitigate cell death and dysfunction.
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•Iron accumulation is a feature of several neurodegenerative disorders.•Ferroptosis is a novel regulated cell death modality dependent on iron and lipid peroxidation.•Growing evidence implicates ferroptosis in neurodegenerative disease.•Iron chelation or small molecule anti-ferroptotic agents may be neurotherapeutics.
Early adolescence (ages 10-14) is a period of increased expectations for boys and girls to adhere to socially constructed and often stereotypical norms that perpetuate gender inequalities. The ...endorsement of such gender norms is closely linked to poor adolescent sexual and reproductive and other health-related outcomes yet little is known about the factors that influence young adolescents' personal gender attitudes.
To explore factors that shape gender attitudes in early adolescence across different cultural settings globally.
A mixed-methods systematic review was conducted of the peer-reviewed literature in 12 databases from 1984-2014. Four reviewers screened the titles and abstracts of articles and reviewed full text articles in duplicate. Data extraction and quality assessments were conducted using standardized templates by study design. Thematic analysis was used to synthesize quantitative and qualitative data organized by the social-ecological framework (individual, interpersonal and community/societal-level factors influencing gender attitudes).
Eighty-two studies (46 quantitative, 31 qualitative, 5 mixed-methods) spanning 29 countries were included. Ninety percent of studies were from North America or Western Europe. The review findings indicate that young adolescents, across cultural settings, commonly express stereotypical or inequitable gender attitudes, and such attitudes appear to vary by individual sociodemographic characteristics (sex, race/ethnicity and immigration, social class, and age). Findings highlight that interpersonal influences (family and peers) are central influences on young adolescents' construction of gender attitudes, and these gender socialization processes differ for boys and girls. The role of community factors (e.g. media) is less clear though there is some evidence that schools may reinforce stereotypical gender attitudes among young adolescents.
The findings from this review suggest that young adolescents in different cultural settings commonly endorse norms that perpetuate gender inequalities, and that parents and peers are especially central in shaping such attitudes. Programs to promote equitable gender attitudes thus need to move beyond a focus on individuals to target their interpersonal relationships and wider social environments. Such programs need to start early and be tailored to the unique needs of sub-populations of boys and girls. Longitudinal studies, particularly from low-and middle-income countries, are needed to better understand how gender attitudes unfold in adolescence and to identify the key points for intervention.
Abstract Parkinson's disease (PD) is a complex illness characterized by progressive dopaminergic neuronal loss. Several mechanisms associated with the iron-induced death of dopaminergic cells have ...been described. Ferroptosis is an iron-dependent, regulated cell death process that was recently described in cancer. Our present work show that ferroptosis is an important cell death pathway for dopaminergic neurons. Ferroptosis was characterized in Lund human mesencephalic cells and then confirmed ex vivo (in organotypic slice cultures) and in vivo (in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model). Some of the observed characteristics of ferroptosis differed from those reported previously. For example, ferroptosis may be initiated by PKCα activation, which then activates MEK in a RAS-independent manner. The present study is the first to emphasize the importance of ferroptosis dysregulation in PD. In neurodegenerative diseases like PD, iron chelators, Fer-1 derivatives and PKC inhibitors may be strong drug candidates to pharmacologically modulate the ferroptotic signaling cascade.
To evaluate whether the uterine environment is associated with the risk of ectopic implantation by comparing outcomes of fresh and frozen-thawed embryo transfers.
Retrospective historical cohort.
Not ...applicable.
We used the Society for Assisted Reproductive Technologies (SART) database to identify pregnancies that resulted from fresh and frozen blastocyst transfers from 2008 to 2011.
None.
We determined the proportion of ectopic (EP) versus intrauterine-only pregnancies resulting from fresh or frozen embryo transfers in autologous and donor-oocyte cycles. Generalized estimation equation regression models were used to adjust for maternal and treatment characteristics.
Among 103,070 cycles that resulted in a clinical pregnancy, 1.38% were ectopic. The odds of EP were 65% lower in women who had a frozen compared with a fresh transfer in autologous cycles. Donor-oocyte transfers had lower odds of EP compared with autologous cycles, with no difference between fresh and frozen donor transfers. Women who had both a fresh and a frozen transfer with autologous oocytes had a higher risk of EP in their fresh cycles compared with their frozen cycles.
Embryo transfers in cycles without ovarian hyperstimulation, such as frozen or donor cycles, were associated with lower rates of EP compared with fresh autologous cycles, suggesting that a difference in the tubal-uterine environment contributes to abnormal implantation after IVF.
Although acetaminophen (APAP) is usually considered as a safe drug, this painkiller can lead to acute liver failure after overdoses. Moreover, there is evidence that the maximum recommended dosage ...can induce hepatic cytolysis in some individuals. Several predisposing factors appear to enhance the risk and severity of APAP‐induced liver injury including chronic alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions linked to obesity. In contrast, obesity by itself does not seem to be associated with a higher risk of APAP‐induced liver injury. Since 1987, seven studies dealt with APAP‐induced hepatotoxicity in rodent models of NAFLD and five of them found that this liver disease was associated with higher APAP toxicity. Unfortunately, these studies did not unequivocally established the mechanism(s) whereby NAFLD could favour APAP hepatotoxicity, although some investigations suggested that pre‐existent induction of hepatic cytochrome P450 2E1 (CYP2E1) could play a significant role by increasing the generation of N‐acetyl‐p‐benzoquinone imine (NAPQI), the toxic metabolite of APAP. Moreover, pre‐existent mitochondrial dysfunction associated with NAFLD could also be involved. In contrast, some investigations suggested that factors that could reduce the risk and severity of APAP hepatotoxicity in obesity and NAFLD include higher hepatic APAP glucuronidation, reduced CYP3A4 activity and increased volume of body distribution. Thus, the occurrence and the outcome of APAP‐induced liver injury in an obese individual with NAFLD might depend on a delicate balance between metabolic factors that can be protective and others that favour large hepatic levels of NAPQI.
In Parkinson's disease (PD), respiratory insufficiency (including functional and muscle disorders) can impact dysarthria and swallowing. Most studies of this topic have been performed retrospectively ...in populations of patients with advanced PD. The objective of the present study was to characterize lung function (under off-drug conditions) in early-stage PD patients at baseline and then again two years later.
Forty-one early-stage PD patients (mean ± SD age: 61.7 ± 7.7; mean ± SD disease duration: 1.9 ± 1.7 years) were prospectively enrolled and compared with 36 age-matched healthy controls. Neurological evaluations and pulmonary function testing were performed in the off-drug condition at the inclusion visit and then two years later.
Pulmonary function testing did not reveal any restrictive or obstructive disorders; at baseline, inspiratory muscle weakness was the only abnormality observed in the PD group (in 53.7% of the patients, vs. 25% in controls; p = 0.0105). The PD patients had a lower mean maximal inspiratory mouth pressure than controls and a lower sniff nasal inspiratory pressure. Two years after the initiation of chronic treatment with antiparkinsonian medications, the maximal inspiratory mouth pressure and the sniff nasal inspiratory pressure tended to be higher. Lastly, overall motor outcomes were not significantly worse in patients with inspiratory muscle weakness than in patients without inspiratory muscle weakness.
Inspiratory muscle weakness seems to be common in patients with early-stage PD, and was seen to be stable over a two-year period. Additional long-term follow-up studies are required to specify the impact of this new feature of PD.
An urgent need for efficacious disease modifying therapies is required to slow downParkinson’s disease (PD) progression. Iron is required as a cofactor in metabolic processesthroughout the body and ...specifically in tissues of high oxygen consumption, such as thecentral nervous system. The redox chemistry of iron is critical for neurotransmitter regulationas well as mitochondrial oxidative phosphorylation, nitric oxide metabolism and oxygentransport.1 Iron homeostasis involves the orchestration of systemic and cellular networks forthe acquisition, internal distribution and utilization of iron.2 Disruption of links can lead toabnormal redistribution of iron, causing deleterious consequences (siderosis) either bylocalized accumulation and/or deficits in specific cellular compartments or tissues. Excessivelabile iron in the substantia nigra pars compacta (SNc) has become a pathognomonic hallmarkof PD and leads to increased production of noxious reactive oxygen species (ROS), which isalso prevalent in PD. Conversely, a deficiency in iron impairs energy production2 and can alsocause dopaminergic neurodegeneration in mice.3 In mammalian models, chelators thatscavenge intracellular iron protect against oxidative neuronal damage. However, these strongiron chelation regimens are designed to treat systemic siderosis and are not suitable for PDpatients, as iatrogenic iron depletion and anaemia may ensue. Moderate iron chelationmodality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection.
Interpersonal violence has physical, emotional, educational, social, and economic implications. Although there is interest in empowering young people to challenge harmful norms, there is scant ...research on how individual agency, and, specifically, the "power to" resist or bring about an outcome relates to peer violence perpetration and victimization in early adolescence. This manuscript explores the relationship between individual agency and peer violence perpetration and victimization among very young adolescents (VYAs) living in two urban poor settings in sub-Saharan Africa (Kinshasa, Democratic Republic of Congo (DRC) and Blantyre, Malawi).
The study draws on two cross-sectional surveys including 2,540 adolescents 10 to 14 years from Kinshasa in 2017 (girls = 49.8% and boys = 50.2%) and 1,213 from Blantyre in 2020 (girls = 50.7% and boys = 49.3%). The sample was school based in Malawi but included in-school and out-of-school participants in Kinshasa due to higher levels of early school dropout. Peer violence in the last 6 months (dependent variable) was defined as a four categorical variable: (1) no victimization or perpetration; (2) victimization only; (3) perpetration only; and (4) both victimization and perpetration. Agency was operationalized using 3 scales: freedom of movement, voice, and decision-making, which were further divided into tertiles. Univariate analysis and multivariable multinomial logistic regressions were conducted to evaluate the relationships between each agency indicator and peer violence. The multivariable regression adjusted for individual, family, peer, and community level covariates. All analyses were stratified by gender and site. In both sites, adolescents had greater voice and decision-making power than freedom of movement, and boys had greater freedom of movement than girls. Boys in both settings were more likely to report peer violence in the last six months than girls (40% to 50% versus 32% to 40%, p < 0.001), mostly due to higher rates of a perpetration-victimization overlap (18% to 23% versus 10% to 15%, p < 0.001). Adolescents reporting the greatest freedom of movement (Tertile 3) (with the exception of girls in Kinshasa) had a greater relative risk ratio (RRR) of reporting a perpetrator-victim overlap (boys Kinshasa: RRR = 1.9 (1.2 to 2.8, p = 0.003); boys Blantyre: RRR = 3.8 (1.7 to 8.3, p = 0.001); and girls Blantyre: RRR = 2.4 (1.1 to 5.1, p = 0.03)). Adolescents with the highest decision-making power in Kinshasa also had greater RRR of reporting a perpetrator-victim overlap (boys: RRR = 3.0 (1.8 to 4.8, p < 0.001). Additionally, girls and boys in Kinshasa with intermediate decision-making power (tertile 2 versus 1) had a lower RRR of being victimized (Girls: RRR = 1.7 (1.02 to 2.7, p = 0.04); Boys: RRR = 0.6 (0.4 to 0.9, p = 0.01)). Higher voice among boys in Kinshasa (Tertile 2: RRR = 1.9 (1.2 to 2.9, p = 0.003) and Tertile 3: 1.8 (1.2 to 2.8, p = 0.009)) and girls in Blantyre (Tertile 2: 2.0 (1.01 to 3.9, p = 0.048)) was associated with a perpetrator-victim overlap, and girls with more voice in Blantyre had a greater RRR of being victimized (Tertile 2: RRR = 1.9 (1.1 to 3.1, p = 0.02)). Generally, associations were stronger for boys than girls, and associations often differed when victimization and perpetration occurred in isolation of each other. A main limitation of this study is that the cross-sectional nature of the data does not allow a causal interpretation of the findings, which need further longitudinal exploration to establish temporality.
In this study, we observed that peer violence is a gendered experience that is related to young people's agency. This stresses the importance of addressing interpersonal violence in empowerment programs and of including boys who experience the greatest perpetration-victimization overlap.
The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting ...circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments.
For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial.
A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD.
The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.
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