Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental ...and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.
T- and B-lymphocytes play an important role in the pathogenesis of type 1 diabetes (T1D), a chronic disease caused by the autoimmune destruction of the insulin-producing cells in the pancreatic ...islets. Flow cytometry allows their characterization in peripheral blood, letting to investigate changes in cellular subpopulations that can provide insights in T1D pathophysiology. With this purpose, CD4
and CD8
T cells (including naïve, central memory, effector memory and terminally differentiated effector (TEMRA), Th17 and Tregs) and B cells subsets (naïve, unswitched memory, switched memory and transitional B cells) were analysed in peripheral blood of adult T1D patients at disease onset and after ≥2 years using multiparametric flow cytometry. Here we report changes in the percentage of early and late effector memory CD4
and CD8
T cells as well as of naïve subsets, regulatory T cells and transitional B cells in peripheral blood of adult patients at onset of T1D when compared with HD. After 2 years follow-up these changes were maintained. Also, we found a decrease in percentage of Th17 and numbers of T cells with baseline. In order to identify potential biomarkers of disease, ROC curves were performed being late EM CD4 T cell subset the most promising candidate. In conclusion, the observed changes in the percentage and/or absolute number of lymphocyte subpopulations of adult T1D patients support the hypothesis that effector cells migrate to the pancreas and this autoimmune process perseveres along the disease. Moreover, multiparametric flow allows to identify those subsets with potential to be considered biomarkers of disease.
Early life stress, in the form of MD (24h at pnd 9), interferes with brain developmental trajectories modifying both behavioral and neurobiochemical parameters. MD has been reported to enhance ...neuroendocrine responses to stress, to affect emotional behavior and to impair cognitive function. More recently, changes in body weight gain, metabolic parameters and immunological responding have also been described. Present data give support to the fact that neuronal degeneration and/or astrocyte proliferation are present in specific brain regions, mainly hippocampus, prefrontal cortex and hypothalamus, which are particularly vulnerable to the effects of neonatal stress. The MD animal model arises as a valuable tool for the investigation of the brain processes occurring at the narrow time window comprised between pnd 9 and 10 that are critical for the establishment of brain circuitries critical for the regulation of behavior, metabolism and energy homeostasis. In the present review we will discuss three possible mechanisms that might be crucial for the effects of MD, namely, the rapid increase in glucocorticoids, the lack of the neonatal leptin surge, and the enhanced endocannabinoid signaling during the specific critical period of MD. A better understanding of the mechanisms underlying the detrimental consequences of MD is a concern for public health and may provide new insights into mental health prevention strategies and into novel therapeutic approaches in neuropsychiatry.
Data from both human and animal studies suggest that exposure to stressful life events at neonatal stages may increase the risk of psychopathology at adulthood. In particular, early maternal ...deprivation, 24 h at postnatal day (pnd) 9, has been associated with persistent neurobehavioural changes similar to those present in developmental psychopathologies such as depression and schizophrenic-related disorders. Most neuropsychiatric disorders first appear during adolescence, however, the effects of MD on adolescent animals' brain and behaviour have been scarcely explored. In the present study, we aimed to investigate the emotional and cognitive consequences of MD in adolescent male and female rats, as well as possible underlying neurobiological mechanisms within frontal cortex and hippocampus. Animals were exposed to a battery of behavioural tasks, from pnd 35 to 42, to evaluate cognitive spontaneous alternation task (SAT) and novel object test (NOT) and anxiety-related responses elevated plus maze (EPM) during adolescence. Changes in neuronal and glial cells, alterations in synaptic plasticity as well as modifications in cannabinoid receptor expression were investigated in a parallel group of control and adolescent (pnd 40) male and female animals. Notably, MD induced a significant impairment in recognition memory exclusively among females. A generalized decrease in NeuN expression was found in MD animals, together with an increase in hippocampal glial fibrillar acidic protein (GFAP) expression exclusively among MD adolescent males. In addition, MD induced in the frontal cortex and hippocampus of male and female adolescent rats a significant reduction in brain derived neurotrophic factor (BDNF) and postsynaptic density (PSD95) levels, together with a decrease in synaptophysin in frontal cortex and neural cell adhesion molecule (NCAM) in hippocampus. MD induced, in animals of both sexes, a significant reduction in CB1R expression, but an increase in CB2R that was statistically significant only for the frontal cortex. Taken together, these results indicate that adolescent females are more vulnerable than males to the cognitive deficits derived from MD despite the changes in neural cells, cannabinoid receptors, as well as the reduction in neural plasticity seem to be similar in both sexes. Further investigation is needed to understand the neurobiological mechanisms underlying the sexual dimorphisms associated to the MD effects, and thus, for a better understanding of the specific sex-dependent vulnerabilities to early life stress.
This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.
► MD induced a significant impairment in recognition memory exclusively among adolescent females. ► Increases in GFAP expression were found only in MD adolescent males. ► MD induced changes in BDNF, PSD95, synaptophysin and NCAM in both males and females. ► MD induced a significant reduction in CB1R expression in both males and females. ► Sexual dimorphisms seem to exist in response to early life stress.
Exposure to psychostimulants, including both abused and therapeutic drugs, can occur first during human adolescence. Animal modeling is useful not only to reproduce adolescent peculiarities but also ...to study neurobehavioral adaptations to psychostimulant consumption. Human adolescence (generally considered as the period between 9/12 and 18 years old) has been compared with the age window between postnatal days (pnd) 28/35 and 50 in rats and mice. These adolescent rodents display basal hyperlocomotion and higher rates of exploration together with a marked propensity for sensation-seeking and risk-taking behaviors. Moreover, peculiar responses to psychostimulants, including enhanced locomotor sensitization, no drug-induced stereotypy and reduced place conditioning have been described in adolescent rodents. During this age window, forebrain dopamine systems undergo profuse remodeling, thus providing a neuro-biological substrate to explain behavioral peculiarities observed during adolescence, as well as the reported vulnerabilities to several drugs. Further, methylphenidate (MPH, better known as Ritalin®), a psychostimulant extensively prescribed to children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD), raises concerns for its long-term safety. Using magnetic resonance techniques, MPH-induced acute effects appear to be different in adolescent rats compared to adult animals. Moreover, adolescent exposure to MPH seems to provoke persistent neurobehavioral consequences: long-term modulation of self-control abilities, decreased sensitivity to natural and drug reward, enhanced stress-induced emotionality, together with an enhanced cortical control over sub-cortical dopamine systems and an enduring up-regulation of Htr7 gene expression within the nucleus accumbens (NAcc). In summary, additional studies in animal models are necessary to better understand the long-term consequences of adolescent MPH, and to further investigate the safety of the prescription and administration of such pharmacological treatment at early life stages.
A disruption in normal brain development has been hypothesized to contribute to the aetiology of major psychiatric disorders. According to the ‘double-hit’ hypothesis, mutant genes-based deviations, ...associated with specific environmental insults during brain development, may result in neurobehavioural disturbances. The existence of age windows of vulnerability to environmental conditions during brain maturation will be discussed, using as examples a series of studies we have performed during the last years. Major deviations from normative neurobehavioural trajectories have been reported in animal models following exposure to severe stress (either episodes of maternal separation, deprivation or corticosterone supplementation) early in infancy. Rodent models of difficult and/or stressful pregnancies, including obstetric complications (e.g. prenatal restrain stress or neonatal hypoxia) and gestational exposure to infection (e.g prenatal immune challenge), have been associated with profound long-lasting deficits in the offspring’s emotional and social behaviour, and with immune and endocrine changes. More recently, adolescence, characterized by elevated rates of brain plasticity, has emerged as an additional period during which sensitivity to environmental influence (either adverse or stimulatory) is maximal. We have reported that both pharmacological (methylphenidate) and environmental (physical or social enrichment) interventions can be used to counteract the detrimental effects of earlier-origin developmental insults. Present findings indicate that these age periods (i.e. prenatal stage, early infancy and adolescence) do represent critical windows open to plastic changes and might be susceptible to both adverse and supportive shaping environmental forces. Taken together, age-related neuroplasticity might be considered not only as a risk factor for psychopathology but also as a potent mechanism for compensation. A better understanding of these critical periods of brain development is a concern for public health and may provide new insights into prevention strategies and into novel therapeutic approaches in neuropsychiatry.
JCO
The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor-positive (ER/PgR+) early breast cancer randomly assigned to 5 years of ...exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio HR, 0.79; 95% CI, 0.70 to 0.90;
< .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98;
= .03), but not overall survival (90.1%
89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS.Media: see text.
Alterations in emotion regulation processes may form the basis of psychopathologies. The endocannabinoid (eCB) system, composed of endogenous ligands, the enzymatic machinery in charge of their ...metabolism and the specific metabotropic receptors, has emerged as a major neuromodulatory system critically involved in the control of emotional homeostasis and stress responsiveness. Data from animal models indicate that the eCB system plays a key role in brain development, and is probably involved in the control of emotional states from early developmental stages. The present review summarizes the latest information on the role of the eCB system in emotionality and anxiety-related disorders throughout the lifespan. Putative therapeutic strategies based on the pharmacological modulation of this system will be discussed. Given the fact that the pharmacological modulation of the eCB system has recently arisen as a promising strategy in the management of anxiety and mood disorders, the potential efficacy of this pharmacological approach (i.e. blockers of the catabolic pathway) will be discussed, as well as pharmacological alternatives such as modulators of cannabinoid receptors other than the classical CB1 receptor, or administration of other plant-derived compounds (e.g. cannabidiol).
Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies ...associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.
Background: Graves' disease (GD) is characterized by the production of autoantibodies against the TSHR (TRAbs). With long-term treatment, serum concentrations of TRAbs decline but in some patients, ...despite being clinically stable, TRAbs persist for many years.
Objective: To investigate whether GD patients with persistence of TRAbs constitute a subset of patients that could be identified by phenotypic analysis of circulating lymphocytes, suggesting disease heterogeneity.
Materials and methods: Peripheral blood lymphocytes (including naïve, memory and effector T and B cells, Th17, regulatory T cells (Treg), recent thymic emigrants (RTEs) and double positive CD4
+
CD8
+
(DP) cells) were analysed by flow cytometry in a cross-sectional study in 25 clinically stable GD patients, five patients at onset of GD disease and 40 healthy donors (HDs).
Results: GD patients with persistence of TRAbs showed a lower percentage of Treg and lower absolute numbers of central and effector memory CD8
+
T cells than HD. No differences in RTEs were found in peripheral blood from GD patients compared to HD. Stable GD patients had higher percentage of DP cells of effector phenotype than HD.
Conclusions: Using extensive phenotypic analysis of lymphocyte subpopulations, it is possible to detect changes that help to identify patients with persistent TSHR antibodies and may contribute to understand why the autoimmune response is maintained.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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