Choline Metabolites Reverse Differentially the Habituation Deficit and Elevated Memory of Tau Null Drosophila.

Impaired neuronal plasticity and cognitive decline are cardinal features of Alzheimer's disease and related Tauopathies. Aberrantly modified Tau protein and neurotransmitter imbalance, predominantly involving acetylcholine, have been linked to these symptoms. In Drosophila, we have shown that dTau loss specifically enhances associative long-term olfactory memory, impairs foot shock habituation, and deregulates proteins involved in the regulation of neurotransmitter levels, particularly acetylcholine. Interestingly, upon choline treatment, the habituation and memory performance of mutants are restored to that of control flies. Based on these surprising results, we decided to use our well-established genetic model to understand how habituation deficits and memory performance correlate with different aspects of choline physiology as an essential component of the neurotransmitter acetylcholine, the lipid phosphatidylcholine, and the osmoregulator betaine. The results revealed that the two observed phenotypes are reversed by different choline metabolites, implying that they are governed by different underlying mechanisms. This work can contribute to a broader knowledge about the physiologic function of Tau, which may be translated into understanding the mechanisms of Tauopathies.

Differential Effects of Human Tau Isoforms to Neuronal Dysfunction and Toxicity in the Drosophila CNS.

Accumulation of highly post-translationally modified tau proteins is a hallmark of neurodegenerative disorders known as tauopathies, the most common of which is Alzheimer's disease. Although six tau isoforms are found in the human brain, the majority of animal and cellular tauopathy models utilize a representative single isoform. However, the six human tau isoforms present overlapping but distinct distributions in the brain and are differentially involved in particular tauopathies. These observations support the notion that tau isoforms possess distinct functional properties important for both physiology and pathology. To address this hypothesis, the six human brain tau isoforms were expressed singly in the Drosophila brain and their effects in an established battery of assays measuring neuronal dysfunction, vulnerability to oxidative stress and life span were systematically assessed comparatively. The results reveal isoform-specific effects clearly not attributed to differences in expression levels but correlated with the number of microtubule-binding repeats and the accumulation of a particular isoform in support of the functional differentiation of these tau isoforms. Delineation of isoform-specific effects is essential to understand the apparent differential involvement of each tau isoform in tauopathies and their contribution to neuronal dysfunction and toxicity.

A Girl with 10 Mb Distal Xp Deletion Arising from Maternal Pericentric Inversion: Clinical Data and Molecular Characterization.

BACKGROUND: Short arm deletions of the X-chromosome are challenging issues for genetic counseling due to their low penetrance in population. Female carriers of these deletions have milder phenotype than male ones, considering the intellectual ability and social skills, probably because of the X-chromosome inactivation phenomenon. CASE REPORT: A female patient with a 10Mb distal Xp deletion and an Xq duplication, showing mild intellectual disability, is described in this report. While the deletion arose from a maternal pericentric inversion, the duplication was directly transmitted from the mother who is phenotypically normal. CONCLUSION: This report underlines the usefulness of molecular cytogenetic technics in postnatal diagnosis.

7q Deletion/12q Duplication Is the Possible Cause of an Alobar Holoprosencephaly Case.

Holoprosencephaly (HPE) spectrum disorder is the most common congenital malformation of the human brain with absence of or incomplete midline cleavage. Its cause is heterogenic, making genetic counseling a challenge. In this case report, a pregnancy affected by alobar HPE is described. Using aCGH, an 8.9-Mb deletion at 7q36.1q36.3 together with a 4.9-Mb duplication at 12q24.32q24.33 is assumed to be the possible reason for this alobar HPE case. It is discussed that disruption of key elements of the developing brain, taking environmental factors into account, contributes to the HPE spectrum. The use of aCGH for invasive prenatal testing is starting to become the standard technique, providing accurate information about the cause of congenital diseases for couples receiving genetic counseling.

Prenatal diagnosis of 1p34.3 interstitial microdeletion by aCGH in a fetus with jaw bone abnormalities.

BACKGROUND: Interstitial microdeletions in 1p are extremely rare, as very few cases have been reported postnatally and only one prenatally, yet. There is a variability of phenotypic findings such as hypotonia, facial dysmorphisms, mild microcephaly, with being most common developmental delay. CASE PRESENTATION: The present case involved a female fetus with an interstitial deletion on 1p, presenting with micrognathia in the 2nd trimester routine ultrasound examination. Array-based comparative genomic hybridization (a-CGH) revealed a 2,7 Mb deletion located on 1p34.3 which could not be detected by standard karyotyping. CONCLUSIONS: This is the first prenatal case of an interstitial deletion in 1p34.3 with facial dysmorphism detected by a-CGH. Due to the use of a-CGH techniques submicroscopic imbalances could be detected, and a refined genotype-phenotype correlation could be achieved.

Complex Rearrangement Involving Three Chromosomes, Four Breakpoints and a 2.7-Mb Deletion in the 18q Segment Observed in a Girl with Mild Learning Difficulties.

Complex chromosomal rearrangements (CCRs) are balanced or unbalanced structural rearrangements involving 3 or more cytogenetic break events on 2 or more different chromosomes. Here, we report a 7-year-old girl referred to our unit because of mild dysmorphic facial features, mild learning difficulties together with very mild mental retardation. Standard cytogenetic banding analysis revealed a de novo CCR involving chromosomes 1, 2 and 18. Further molecular investigation with aCGH revealed a cryptic interstitial deletion of 2.7 Mb in 18q22.1, which does not elicit a significant clinical phenotype. FISH was performed to confirm both molecular and cytogenetic results.

Interstitial deletion at 11q14.2-11q22.1 may cause severe learning difficulties, mental retardation and mild heart defects in 13-year old male.

Interstitial deletions of the long arm of chromosome 11 are rare, and they could be assumed as non-recurrent chromosomal rearrangements due to high variability of the size and the breakpoints of the deleted region. The exact region of the deletion was difficult to be determined before the use of molecular cytogenetic techniques such as array comparative genomic hybridization (aCGH). Here, a 13-year old boy with severe learning difficulties, mental retardation and mild heart defects is described. Conventional G-band karyotyping was performed and it is found that the patient is a carrier of a de novo interstitial deletion on the long arm of chromosome 11, involving 11q14 and 11q22 breakpoints. Further investigation, using aCGH, specified the deleted region to 11q14.2-11q22.1. There was a difficulty in correlating the genotype with the phenotype of the patient due to lack of similar cases in literature. More studies should be done in order to understand the genetic background that underlies the phenotypic differences observed in similar cases.

Deletion of 4.4 Mb at 2q33.2q33.3 May Cause Growth Deficiency in a Patient with Mental Retardation, Facial Dysmorphic Features and Speech Delay.

A patient with a rare interstitial deletion of chromosomal band 2q33.2q33.3 is described. The clinical features resembled the 2q33.1 microdeletion syndrome (Glass syndrome), including mental retardation, facial dysmorphism, high-arched narrow palate, growth deficiency, and speech delay. The chromosomal aberration was characterized by whole genome BAC aCGH. A comparison of the current patient and Glass syndrome features revealed that this case displayed a relatively mild phenotype. Overall, it is suggested that the deleted region of 2q33 causative for Glass syndrome may be larger than initially suggested.

A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis.

INTRODUCTION: Regenerative medicine and particular adult stem cells represent an alternative option with several fruitful therapeutic applications in patients suffering from chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Nevertheless, lack of knowledge regarding the origin and the potential of mesenchymal stem cells (MSCs) to differentiate into fibroblasts has limited their use for the treatment of this dismal disease. PATIENTS AND METHODS: To this end, we conducted a phase Ib, non-randomized, clinical trial to study the safety of three endobronchial infusions of autologous adipose derived stromal cells (ADSCs)-stromal vascular fraction (SVF) (0.5 million cells per kgr of body weight per infusion) in patients with IPF (n=14) of mild to moderate disease severity (forced vital capacity -FVC>50% predicted value and diffusion lung capacity for carbon monoxide-DLCO>35% of predicted value). Our primary end-point was incidence of treatment emergent adverse events within 12 months. Alterations of functional, exercise capacity and quality of life parameters at serial time points (baseline, 6 and 12 months after first infusion) were exploratory secondary end-points. RESULTS: No cases of serious or clinically meaningful adverse events including short-term infusional toxicities as well as long-term ectopic tissue formation were recorded in all patients. Detailed safety monitoring through several time-points indicated that cell-treated patients did not deteriorate in both functional parameters and indicators of quality of life. CONCLUSIONS: The clinical trial met its primary objective demonstrating an acceptable safety profile of endobronchially administered autologous ADSCs-SVF. Our findings accelerate the rapidly expanded scientific knowledge and indicate a way towards future efficacy trials.

Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal.

BACKGROUND: Idiopathic pulmonary fibrosis represents a lethal form of progressive fibrotic lung disorder with gradually increasing incidence worldwide. Despite intense research efforts its pathogenesis is still elusive and controversial reflecting in the current disappointing status regarding its treatment. PATIENTS AND METHODS: We report the first protocol proposal of a prospective, unicentric, non-randomized, phase Ib clinical trial to study the safety and tolerability of the adipose-derived stem cells (ADSCs) stromal vascular fraction (SVF) as a therapeutic agent in IPF. After careful patient selection based on functional criteria (forced vital capacity-FVC > 50%, diffuse lung capacity for carbon monoxide-DLCO > 35% of the predicted values) all eligible subjects will be subjected to lipoaspiration resulting in the isolation of approximately 100- 500 gr of adipose tissue. After preparation, isolation and labelling ADSCs-SVF will be endobronchially infused to both lower lobes of the fibrotic lungs. Procedure will be repeated thrice at monthly intervals. Primary end-point represent safety and tolerability data, while exploratory secondary end-points include assessment of clinical functional and radiological status. RESULTS: Preliminary results recently presented in the form of an abstract seem promising and tantalizing since there were no cases of clinically significant allergic reactions, infections, disease acute exacerbations or ectopic tissue formation. In addition 6 months follow-up data revealed a marginal improvement at 6-minute walking distance and forced vital capacity. CONCLUSIONS: Adipose tissue represents an abundant, safe, ethically uncontested and potentially beneficial source of stem cells for patients with IPF. Larger multicenter phase II and III placebo-controlled clinical trials are sorely needed in order to prove efficacy. However, pilot safety studies are of major importance and represent the first hamper that should be overcome to establish a rigid basis for larger clinical trials.