Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Cognitive impairment is very frequent during multiple sclerosis (MS), involving approximately 40–70% of the patients, with a profound impact on patient's life. It is now established that among the various central nervous system (CNS) structures involved during the course of MS, the hippocampus is particularly sensitive to the detrimental effects of neuroinflammation. Different studies demonstrated hippocampal involvement during MS, in association with depression and cognitive impairment, such as verbal and visuo-spatial memory deficits, even during the earlier phases of the disease. These cognitive alterations could represent the visible consequences of a hidden synaptic impairment. Indeed, neuronal and immune functions are intertwined and the immune system is able to modulate the efficacy of synaptic transmission and the induction of the main forms of synaptic plasticity, such as long term potentiation (LTP). Hippocampal synaptic plasticity has been studied during the last decades as the physiological basis of human learning and memory and its disruption can be associated with behavioral and cognitive abnormalities. The aim of the present work is to review the available evidence about the presence of hippocampal synaptic plasticity alterations in experimental models of MS, specifically during the course of experimental autoimmune encephalomyelitis (EAE) and to discuss their relevance with regard to human MS. Indeed, the failure of synapses to express plasticity during neuroinflammation could potentially lead to a progressive failure of the brain plastic reserve, possibly contributing to disability progression and cognitive impairment during MS

Effect of the αs1-casein genotype and its interaction with diet degradability on milk production, milk quality, metabolic and endocrinal response of Girgentana goats

We studied interaction between diet degradability and genotype at CSN1S1 locus in lactating goats.•We evaluated productive, metabolic and hormonal response of goats at different αs1-casein genotype.•Little effect of diet degradability and interaction with genotype on production and quality.•Higher milk yield, casein percentage and lower urea in goats with strong alleles at CSN1S1 locus.•Higher tyroid hormones in goats with strong alleles

Whole-exome analysis in osteosarcoma to identify a personalized therapy

Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy. We identified 18,275 somatic variations in 8,247 genes and we found three mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the highest number of variations; it is an important component of a histone H3 lysine 4 methyltransferase complex and it is one of the histone modifiers previously implicated in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15 genes that showed variations only in patients that did not respond to therapy and developed metastasis and some of these genes are involved in carcinogenesis and tumor progression in other tumors. These data could offer the opportunity to get a key molecular target to identify possible new strategies for early diagnosis and new therapeutic approaches for osteosarcoma and to provide a tailored treatment for each patient based on their genetic profile

Comparison of quality control for trauma management between Western and Eastern European trauma center

<p>Abstract</p> <p>Background</p> <p>Quality control of trauma care is essential to define the effectiveness of trauma center and trauma system. To identify the troublesome issues of the system is the first step for validation of the focused customized solutions. This is a comparative study of two level I trauma centers in Italy and Romania and it has been designed to give an overview of the entire trauma care program adopted in these two countries. This study was aimed to use the results as the basis for recommending and planning changes in the two trauma systems for a better trauma care.</p> <p>Methods</p> <p>We retrospectively reviewed a total of 182 major trauma patients treated in the two hospitals included in the study, between January and June 2002. Every case was analyzed according to the recommended minimal audit filters for trauma quality assurance by The American College of Surgeons Committee on Trauma (ACSCOT).</p> <p>Results</p> <p>Satisfactory yields have been reached in both centers for the management of head and abdominal trauma, airway management, Emergency Department length of stay and early diagnosis and treatment. The main significant differences between the two centers were in the patients' transfers, the leadership of trauma team and the patients' outcome. The main concerns have been in the surgical treatment of fractures, the outcome and the lacking of documentation.</p> <p>Conclusion</p> <p>The analyzed hospitals are classified as Level I trauma center and are within the group of the highest quality level centers in their own countries. Nevertheless, both of them experience major lacks and for few audit filters do not reach the mmum standard requirements of ACS Audit Filters. The differences between the western and the eastern European center were slight. The parameters not reaching the minimum requirements are probably occurring even more often in suburban settings.</p

Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

The development of midbrain dopaminergic (DA) neurons requires a fine temporal and spatial regulation of a very specific gene expression program. Here, we report that during mouse brain development, the microRNA (miR-) 204/211 is present at a high level in a subset of DA precursors expressing the transcription factor Lmx1a, an early determinant for DA-commitment, but not in more mature neurons expressing Th or Pitx3. By combining different in vitro model systems of DA differentiation, we show that the levels of Lmx1a influence the expression of miR-204/211. Using published transcriptomic data, we found a significant enrichment of miR-204/211 target genes in midbrain dopaminergic neurons where Lmx1a was selectively deleted at embryonic stages. We further demonstrated that miR-204/211 controls the timing of the DA differentiation by directly downregulating the expression of Nurr1, a late DA differentiation master gene. Thus, our data indicate the Lmx1a-miR-204/211-Nurr1 axis as a key component in the cascade of events that ultimately lead to mature midbrain dopaminergic neurons differentiation and point to miR-204/211 as the molecular switch regulating the timing of Nurr1 expression

Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

The development of midbrain dopaminergic (DA) neurons requires a fine temporal and spatial regulation of a very specific gene expression program. Here, we report that during mouse brain development, the microRNA (miR-) 204/211 is present at a high level in a subset of DA precursors expressing the transcription factor Lmx1a, an early determinant for DA-commitment, but not in more mature neurons expressing Th or Pitx3. By combining different in vitro model systems of DA differentiation, we show that the levels of Lmx1a influence the expression of miR-204/211. Using published transcriptomic data, we found a significant enrichment of miR-204/211 target genes in midbrain dopaminergic neurons where Lmx1a was selectively deleted at embryonic stages. We further demonstrated that miR-204/211 controls the timing of the DA differentiation by directly downregulating the expression of Nurr1, a late DA differentiation master gene. Thus, our data indicate the Lmx1a-miR-204/211-Nurr1 axis as a key component in the cascade of events that ultimately lead to mature midbrain dopaminergic neurons differentiation and point to miR-204/211 as the molecular switch regulating the timing of Nurr1 expression

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab

background: in the early stages of multiple sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. this study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. methods: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. results: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). after three years, the kaplan-meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR

miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation

The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons. Induced dopaminergic (iDA) cells synthesize dopamine and show spontaneous electrical activity, reversibly blocked by tetrodotoxin, consistent with the electrophysiological properties featured by brain dopaminergic neurons. Our findings point to a role for miR-34b/c in neuronal commitment and highlight the potential of exploiting its synergy with key transcription factors in enhancing in vitro generation of dopaminergic neurons.Peer reviewe

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT)

objective multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. this multicentre, case-control study involving 18 Italian MS centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. methods we identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were white Europeans and white northern americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) country and 241 (17.9%) in a low-middle-income (LMI) country. medical records and patients interviews were used to collect demographic and disease data. results we included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. at onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had &gt; 3 STIR spine lesions. at recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). at disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). discussion our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective

miR-218 promotes dopaminergic differentiation and controls neuron excitability and neurotransmitter release through the regulation of a synaptic-related genes network

In the brain microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher-level by acting as an additional mechanism of translational regulation, alongside the mRNAs/polysome system. Despite extensive research, our understanding of the specific contribution of individual miRNA to the function of dopaminergic neurons (DAn) remains limited. By performing a dopaminergic-specific miRNA screening, we have identified miR-218 as a critical regulator of DAn activity in male and female mice. We have found that miR-218 is specifically expressed in mesencephalic DAn and is able to promote dopaminergic differentiation of embryonic stem cells and functional maturation of transdifferentiated induced DA neurons. Midbrain-specific deletion of both genes encoding for miR-218 (referred to as miR-218-1 and mir218-2) affects the expression of a cluster of synaptic-related mRNAs and alters the intrinsic excitability of DAn, as it increases instantaneous frequencies of evoked action potentials, reduces rheobase current, affects the ionic current underlying the action potential after hyperpolarization phase and reduces dopamine efflux in response to a single electrical stimulus. Our findings provide a comprehensive understanding of the involvement of miR-218 in the dopaminergic system and highlight its role as a modulator of dopaminergic transmission