Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures

Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models

Prognostic differences between VAP caused by Acinetobacter baumannii and VAP caused by other microorganisms

Nosocomial infection, in particular pneumonia, is an important risk factor for hospital mortality and morbidity. Acinetobacter baumannii is a common multi-resistant microorganism responsible of Ventilator Associated Pneumonia (VAP). Currently Colistin is a rescue therapy for this pathogen. The purpose of this study is to compare the outcome of VAP caused by Acinetobacter baumannii and VAP by other microorganisms in critical patients. Comorbidity, prognostic scores, mortality and eradication frequency did not turn out significantly different between the two study groups. Colistin safety was tested

Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice

Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4(+) and CD8(+) T cells depletion in peripheral blood. In Tat-positive thymus, we observed the increased p65/NF-κB activity and deregulated expression of cytokines/chemokines and microRNA-181a-1, which are involved in T-lymphopoiesis. Upon LPS intraperitoneal injection, Tat-Tg mice developed an abnormal acute inflammatory response, which was characterized by enhanced lethality and production of inflammatory cytokines. Based on these findings, Tat-Tg mouse could represent an animal model for testing adjunctive therapies of HIV-1-associated inflammation and immune deregulation

An ecological study on the relationship between supply of beds in long-term care institutions in Italy and potential care needs for the elderly

<p>Abstract</p> <p>Background</p> <p>The ageing population in Europe is putting an ever increasing demand on the long-term care (LTC) services provided by these countries. This study analyses the relationship between the LTC institutional supply of beds and potential care needs, taking into account the social and health context, the supply of complementary and alternative services, along with informal care.</p> <p>Methods</p> <p>An observational, cross-sectional, ecological study was carried out. Statistical data were obtained from the Italian National Institute of Statistics and Ministry of Health. Indicators, regarding 5 areas (Supply of beds in long term care institutions, Potential care needs, Social and health context, Complementary and alternative services for the elderly, Informal care), were calculated at Local Health Unit (LHU) level and referred to 2004.</p> <p>Two indicators were specifically used to measure supply of beds in long term care institutions and potential care needs for the elderly. Their values were grouped in tertiles. LHU were classified according to the combination of tertiles in three groups: A. High level of supply of beds in long term care institutions associated with low level of potential care needs; B. Low level of supply of beds in long term care institutions associated with high level of potential care needs; C. Balanced level of supply of beds in long term care institutions with potential care needs. For each group the indicators of 5 areas were analysed.</p> <p>The Index Number (IN) was calculated for each of these indicators.</p> <p>Results</p> <p>Specific factors that need to be carefully considered were highlighted in each of the three defined groups. The highest level of alternative services such as long-stay hospital discharges in residence region (IN = 125), home care recipients (HCR) (IN = 123.8) were reported for Group A. This group included North regions. The highest level of inappropriate hospital discharges in (IN = 124.1) and out (IN = 155.8) the residence region, the highest value of families who received help (IN = 106.4) and the lowest level of HCR (IN = 68.7) were found in Group B. South regions belong to this group. The highest level of families paying a caregiver (IN = 115.8) was shown in Group C. Central regions are included in third group.</p> <p>Conclusion</p> <p>Supply of beds in long term care institutions substantially differs across Italian regions, showing in every scenario some imbalances between potential care needs and other studied factors. Our study suggests the need of a comprehensive rethinking of care delivery "system".</p

Direct Cell Conversion of Somatic Cells into Dopamine Neurons: Achievements and Perspectives

In the last decade, direct reprogramming has emerged as a novel strategy to obtain mature and functional dopamine neurons from somatic cells. This approach could overcome issues linked to the use of human pluripotent stem cells such as ethical concerns and safety problems that can arise from the overgrowth of undifferentiated cells after transplantation. Several conversion methodologies have been developed to obtain induced DA neurons (iDANs) or induced DA neuron progenitors (iDPs). iDANs have also proved to successfully integrate in mice striatum, alleviating Parkinson's disease (PD) motor symptoms. In the next decade, human iDANs and/or iDPs could be translated to clinic to achieve a patient-tailored therapy, but current critical issues hinder this goal, such as the low conversion rate of adult human fibroblasts and the risks associated with lentiviral delivery of conversion factors. In this study, we summarize the strategies and recent improvements developed for the generation of mouse and human iDANs/iDPs. Furthermore, we discuss the more recent application of in vivo direct conversion, which may enable clinical therapies for PD by means of brain in situ delivery of dopaminergic reprogramming transcription factors

Direct Cell Conversion of Somatic Cells into Dopamine Neurons: Achievements and Perspectives

In the last decade, direct reprogramming has emerged as a novel strategy to obtain mature and functional dopamine neurons from somatic cells. This approach could overcome issues linked to the use of human pluripotent stem cells such as ethical concerns and safety problems that can arise from the overgrowth of undifferentiated cells after transplantation. Several conversion methodologies have been developed to obtain induced DA neurons (iDANs) or induced DA neuron progenitors (iDPs). iDANs have also proved to successfully integrate in mice striatum, alleviating Parkinson's disease (PD) motor symptoms. In the next decade, human iDANs and/or iDPs could be translated to clinic to achieve a patient-tailored therapy, but current critical issues hinder this goal, such as the low conversion rate of adult human fibroblasts and the risks associated with lentiviral delivery of conversion factors. In this study, we summarize the strategies and recent improvements developed for the generation of mouse and human iDANs/iDPs. Furthermore, we discuss the more recent application of in vivo direct conversion, which may enable clinical therapies for PD by means of brain in situ delivery of dopaminergic reprogramming transcription factors

Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures

Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models

Advantages of QBI in TBSS analyses

Diffusion-weighted magnetic resonance imaging (DWMRI) is used to study white matter (WM) in normal and clinical populations. In DWMRI studies, diffusion tensor imaging (DTI) models the WM anisotropy with one dominant direction, detecting possible pathway abnormalities only in large and highly coherent fiber tracts. However, more general anisotropy models like Q-ball imaging (QBI) may provide more sensitive WM descriptors in single patients. The present study aimed to compare DTI and QBI models in a group-level population analysis, using Amyotrophic Lateral Sclerosis (ALS) as a pathological case model of WM tract degeneration. DWMRI was performed in 19 ALS patients and 19 age and sex-matched healthy controls. DTI and QBI estimates were compared in whole-brain tract-based spatial statistics (TBSS) and volume of interest (VOI) analyses, and correlated with ALS clinical scores of disability. A significant decrease of the QBI-derived generalized fractional anisotropy (GFA) was observed in both motor and extramotor fibers of ALS patients compared to controls. Homologue DTI-derived FA maps were only partially overlapping with GFA maps. Particularly, the left corticospinal tracts resulted more markedly depicted by the QBI than by the DTI model, with GFA predicting ALS disability better than FA. The present findings demonstrate that QBI model is suitable for studying WM tract degeneration in population-level clinical studies. Particularly, group-level studies of fiber integrity may benefit from QBI when DTI is biased towards low values, such as in cases of fiber degeneration, and in regions with more than one dominant fiber direction

Current concepts in the management of inguinal hernia and hydrocele in pediatric patients in laparoscopic era

The surgical repair of inguinal hernia and hydrocele is one of the most common operations performed in pediatric surgery practice. This article reviews current concepts in the management of inguinal hernia and hydrocele based on the recent literature and the authors׳ experience. We describe the principles of clinical assessment and anesthetic management of children undergoing repair of inguinal hernia, underlining the differences between an inguinal approach and minimally invasive surgery (MIS). Other points discussed include the current management of particular aspects of these pathologies such as bilateral hernias; contralateral patency of the peritoneal processus vaginalis; hernias in premature infants; direct, femoral, and other rare hernias; and the management of incarcerated or recurrent hernias. In addition, the authors discuss the role of laparoscopy in the surgical treatment of an inguinal hernia and hydrocele, emphasizing that the current use of MIS in pediatric patients has completely changed the management of pediatric inguinal hernias