The role of POLG mutations in human disease

PhD ThesisMitochondrial diseases due to mutations in the nuclear Polymerase gamma (POLG) gene, have emerged as a common group of disorders, collectively referred to as POLG-related disorders. POLG is responsible for mitochondrial DNA (mtDNA) replication and repair. Defects in POLG result in secondary mtDNA defects including mtDNA depletion and deletions, which result in respiratory chain deficiency in affected tissues. POLG-related disorders are characterised by phenotypic diversity with common neurological deficits such as epilepsy, which constitutes its predominant manifestation. Alpers’ syndrome is a severe form of POLG-related disorders and it is a rare, early-onset, progressive encephalohepatopathy characterised by: intractable seizures, developmental delay, ataxia, visual loss and liver dysfunction. It is particularly devastating as effective treatments do not currently exist, and little is known about its molecular pathophysiology downstream from POLG mutations. The aim of this work was to gain further insight into the pathogenesis of Alpers, through the characterisation of mitochondrial dysfunction in POLG-mutant fibroblasts, and neuropathological investigation of post-mortem brain tissue from affected patients. Fibroblast characterisation using quantitative methodologies, revealed no evidence of mitochondrial dysfunction in primary POLG-mutant fibroblasts derived from patients with Alpers. Neuropathological assessment of three cortical regions revealed extensive respiratory chain deficiencies in interneurons and to a lesser extent pyramidal neurons in patients with Alpers, which was associated with severe pyramidal neuron loss. A variable degree of astrogliosis, was also observed. Additionally, mtDNA depletion was found in tissue from adult patients with POLG-mutations as well as occasional mtDNA deletions. This study provides evidence that POLG mutations exert a tissue-specific effect in Alpers. Mitochondrial respiratory chain deficiencies in interneurons and pyramidal neurons, combined with extensive pyramidal neuron loss may result in altered neuronal dynamics and contribute to the underlying neuropathology and clinical manifestations of Alpers.The Ryan Stanford Appea

Role of brain perfusion SPECT with 99mTc HMPAO in the assessment of response to drug therapy in patients with autoimmune vasculitis: a prospective study

Abstract BACKGROUND: The diagnosis of vasculitis in the brain remains a quite difficult achievement. To the best of our knowledge, there is no imaging method reported in literature which is capable of reaching to a diagnosis of vasculitis with very high sensitivity. AIM: The aim of this study was to determine whether perfusion brain single photon emission computed tomography (SPECT) can be usefully employed in monitoring the treatment of vasculitis, allowing treating only potentially responder patients and avoiding the side effects on patients who do not respond. MATERIALS AND METHODS: Twenty patients (two males and 18 females) suffering from systemic lupus erythematosus (SLE; n = 5), Behcet's disease (BD; n = 5), undifferentiated vasculitis (UV; n = 5), and Sjogren's syndrome (SS; n = 5) were included in the study. All patients underwent a wide neurological anamnestic investigation, a complete objective neurological examination and SPECT of the brain with 99mTc-hexamethyl-propylene-aminoxime (HMPAO). The brain SPECT was then repeated after appropriate medical treatment. The neurological and neuropsychiatric follow-up was performed at 6 months after the start of the treatment. RESULTS: Overall, the differences between the scintigraphic results obtained after and before the medical treatment indicated a statistically significant increase of the cerebral perfusion (CP). In 19 out of 200 regions of interest (ROI) studied, the difference between pre- and post treatment percentages had negative sign, indicating a worsening of CP. This latter event has occurred six times (five in the same patients) in the UV, 10 times (eight in the same patients) in the SLE, never in BD, and three times (two in the same patient) in the SS. CONCLUSION: The reported results seem to indicate the possibility of identifying, by the means of a brain SPECT, responder and nonresponder (unchanged or worsened CP) patients, affected by autoimmune vasculitis, to the therapy

Current Options for Second-Line Systemic Therapy in Metastatic Renal Cell Carcinoma

Standard systemic therapy of advanced renal cell carcinoma (RCC) involves targeting angiogenesis, mainly through tyrosine kinase inhibitors (TKI) against the vascular endothelial growth factor receptor (VEGFR) pathway and targeting the immune checkpoints, namely, programmed death-1 (PD-1) or its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). With current strategies of combining these two approaches in the front-line setting, less is known about optimal selection of therapy upon development of resistance in the second and later lines of treatment for progressive disease. This review discusses currently available therapeutic options in patients who have progressive RCC after prior treatment with double immune check-point inhibitors (ICIs) or ICI-TKI combinations

Testing optically stimulated luminescence dating on sand-sized quartz of deltaic deposits from the Sperchios delta plain, central Greece

This study reports on the first investigation into the potential of luminescence dating to establish a chronological framework for the depositional sequences of the Sperchios delta plain, central Greece. A series of three borehole cores (20 m deep) and two shallow cores (4 m deep), from across the delta plain, were extracted, and samples were collected for luminescence dating. The luminescence ages of sand-sized quartz grains were obtained from small aliquots of quartz, using the Single-Aliquot Regenerative-dose (SAR) protocol. The equivalent dose determination included a series of tests and the selection of the Minimum Age Model (MAM) as the most appropriate statistical model. This made it possible to confirm the applicability of quartz Optically Stimulated Luminescence (OSL) dating to establish absolute chronology for deltaic sediments from the Sperchios delta plain.Testing age results of the five cores showed that the deltaic sediments were deposited during the Holocene. A relatively rapid deposition is implied for the top ∼14 m possibly as a result of the deceleration in the rate of the sea-level rise and the transition to terrestrial conditions, while on the deeper parts, the reduced sedimentation rate may indicate a lagoonal or coastal environment

Open data, Science and Society: launching Oasis, the flagship initiative of the Istituto Italiano di Antropologia

The Open Data philosophy has gained considerable momentum in recent years, both in society and the scientific community. The accessibility via web of open data from the public sector has remarkably increased in the last decade, although there are substantial differences among nations (http://datacatalogs.org/). The expectation of many citizens, organizations and pressure groups (the so called “open government” movement) is that the free release of data from public administrations may help increase government transparency and accountability

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

Intercalibration of the barrel electromagnetic calorimeter of the CMS experiment at start-up

Calibration of the relative response of the individual channels of the barrel electromagnetic calorimeter of the CMS detector was accomplished, before installation, with cosmic ray muons and test beams. One fourth of the calorimeter was exposed to a beam of high energy electrons and the relative calibration of the channels, the intercalibration, was found to be reproducible to a precision of about 0.3%. Additionally, data were collected with cosmic rays for the entire ECAL barrel during the commissioning phase. By comparing the intercalibration constants obtained with the electron beam data with those from the cosmic ray data, it is demonstrated that the latter provide an intercalibration precision of 1.5% over most of the barrel ECAL. The best intercalibration precision is expected to come from the analysis of events collected in situ during the LHC operation. Using data collected with both electrons and pion beams, several aspects of the intercalibration procedures based on electrons or neutral pions were investigated