Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms.

Perturbation of iron distribution is observed in many neurodegenerative disorders, including Alzheimer's and Parkinson's disease, but the comprehension of the metal role in the development and progression of such disorders is still very limited. The combination of more powerful brain imaging techniques and faster genomic DNA sequencing procedures has allowed the description of a set of genetic disorders characterized by a constant and often early accumulation of iron in specific brain regions and the identification of the associated genes; these disorders are now collectively included in the category of neurodegeneration with brain iron accumulation (NBIA). So far 10 different genetic forms have been described but this number is likely to increase in short time. Two forms are linked to mutations in genes directly involved in iron metabolism: neuroferritinopathy, associated to mutations in the FTL gene and aceruloplasminemia, where the ceruloplasmin gene product is defective. In the other forms the connection with iron metabolism is not evident at all and the genetic data let infer the involvement of other pathways: Pank2, Pla2G6, C19orf12, COASY, and FA2H genes seem to be related to lipid metabolism and to mitochondria functioning, WDR45 and ATP13A2 genes are implicated in lysosomal and autophagosome activity, while the C2orf37 gene encodes a nucleolar protein of unknown function. There is much hope in the scientific community that the study of the NBIA forms may provide important insight as to the link between brain iron metabolism and neurodegenerative mechanisms and eventually pave the way for new therapeutic avenues also for the more common neurodegenerative disorders. In this work, we will review the most recent findings in the molecular mechanisms underlining the most common forms of NBIA and analyze their possible link with brain iron metabolism

The prognostic importance of chronic end-stage diseases in geriatric patients admitted to 163 Italian ICUs

BACKGROUND: The number of elderly patients undergoing major surgical interventions and then needing admission to intensive care unit (ICU) grows steadily. We investigated this issue in a cohort of 232,278 patients admitted in five years (2011-2015) to 163 Italian general ICUs. METHODS: Surgical patients older than 75 registered in the GiViTI MargheritaPROSAFE project were analyzed. The impact on hospital mortality of important chronic conditions (severe COPD, NYHA class IV, dementia, end-stage renal disease, cirrhosis with portal hypertension) was investigated with two prognostic models developed yearly on patients staying in the ICU less or more than 24 hours. RESULTS: 44,551 elderly patients (19.2%) underwent emergency (47.3%) or elective surgery (52.7%). At least one severe comorbidity was present in 14.6% of them, yielding a higher hospital mortality (32.4%, vs. 21.1% without severe comorbidity). In the models for patients staying in the ICU 24 hours or more, cirrhosis, NYHA class IV, and severe COPD were constant independent predictors of death (adjusted odds ratios [ORs] range 1.67-1.97, 1.54-1.91, and 1.34-1.50, respectively), while dementia was statistically significant in four out of five models (adjusted ORs 1.23-1.28). End-stage renal disease, instead, never resulted to be an independent prognostic factor. For patients staying in the ICU less than 24 hours, chronic comorbidities were only occasionally independent predictors of death. CONCLUSIONS: Our study confirms that elderly surgical patients represent a relevant part of all ICUs admissions. About one of seven bear at least one severe chronic comorbidity, that, excluding end-stage renal disease, are all strong independent predictors of hospital death

Bi-Allelic Mutations in Zebrafish pank2 Gene Lead to Testicular Atrophy and Perturbed Behavior without Signs of Neurodegeneration

Coenzyme A (CoA) is an essential cofactor in all living organisms, being involved in a large number of chemical reactions. Sequence variations in pantothenate kinase 2 (PANK2), the first enzyme of CoA biosynthesis, are found in patients affected by Pantothenate Kinase Associated Neurodegeneration (PKAN), one of the most common forms of neurodegeneration, with brain iron accumulation. Knowledge about the biochemical and molecular features of this disorder has increased a lot in recent years. Nonetheless, the main culprit of the pathology is not well defined, and no treatment option is available yet. In order to contribute to the understanding of this disease and facilitate the search for therapies, we explored the potential of the zebrafish animal model and generated lines carrying biallelic mutations in the pank2 gene. The phenotypic characterization of pank2-mutant embryos revealed anomalies in the development of venous vascular structures and germ cells. Adult fish showed testicular atrophy and altered behavioral response in an anxiety test but no evident signs of neurodegeneration. The study suggests that selected cell and tissue types show a higher vulnerability to pank2 deficiency in zebrafish. Deciphering the biological basis of this phenomenon could provide relevant clues for better understanding and treating PKAN

Bulk Cr tips for scanning tunneling microscopy and spin-polarized scanning tunneling microscopy

A simple, reliable method for preparation of bulk Cr tips for Scanning Tunneling Microscopy (STM) is proposed and its potentialities in performing high-quality and high-resolution STM and Spin Polarized-STM (SP-STM) are investigated. Cr tips show atomic resolution on ordered surfaces. Contrary to what happens with conventional W tips, rest atoms of the Si(111)-7x7 reconstruction can be routinely observed, probably due to a different electronic structure of the tip apex. SP-STM measurements of the Cr(001) surface showing magnetic contrast are reported. Our results reveal that the peculiar properties of these tips can be suited in a number of STM experimental situations

Boosting Biomass Quantity and Quality by Improved Mixotrophic Culture of the Diatom Phaeodactylum tricornutum

Diatoms are photoautotrophic unicellular algae and are among the most abundant, adaptable, and diverse marine phytoplankton. They are extremely interesting not only for their ecological role but also as potential feedstocks for sustainable biofuels and high-value commodities such as omega fatty acids, because of their capacity to accumulate lipids. However, the cultivation of microalgae on an industrial scale requires higher cell densities and lipid accumulation than those found in nature to make the process economically viable. One of the known ways to induce lipid accumulation in Phaeodactylum tricornutum is nitrogen deprivation, which comes at the expense of growth inhibition and lower cell density. Thus, alternative ways need to be explored to enhance the lipid production as well as biomass density to make them sustainable at industrial scale. In this study, we have used experimental and metabolic modeling approaches to optimize the media composition, in terms of elemental composition, organic and inorganic carbon sources, and light intensity, that boost both biomass quality and quantity of P. tricornutum. Eventually, the optimized conditions were scaled-up to 2 L photobioreactors, where a better system control (temperature, pH, light, aeration/mixing) allowed a further improvement of the biomass capacity of P. tricornutum to 12 g/L

Resonant Hawking radiation in Bose-Einstein condensates

We study double-barrier interfaces separating regions of asymptotically subsonic and supersonic flow of Bose condensed atoms. These setups contain at least one black hole sonic horizon from which the analog of Hawking radiation should be generated and emitted against the flow in the subsonic region. Multiple coherent scattering by the double-barrier structure strongly modulates the transmission probability of phonons, rendering it very sensitive to their frequency. As a result, resonant tunneling occurs with high probability within a few narrow frequency intervals. This gives rise to highly non-thermal spectra with sharp peaks. We find that these peaks are mostly associated to decaying resonances and only occasionally to dynamical instabilities. Even at achievable nonzero temperatures, the radiation peaks can be dominated by the spontaneous emission, i.e. enhanced zero-point fluctuations, and not, as often in analog models, by stimulated emission.Comment: 20 pages, 9 figures, revised versio

Probing the in-plane electron spin polarization in Ge/Si0.15 Ge0.85 multiple quantum wells

We investigate spin transport in a set of Ge/Si0.15Ge0.85 multiple quantum wells (MQWs) as a function of the well thickness. We exploit optical orientation to photogenerate spin-polarized electrons in the discrete energy levels of the well conduction band at the Γ point of the Brillouin zone. After diffusion, we detect the optically oriented spins by means of the inverse spin-Hall effect (ISHE) taking place in a thin Pt layer grown on top of the heterostructure. The employed spin injection/detection scheme is sensitive to in-plane spin-polarized electrons, therefore, by detecting the ISHE signal as a function of the photon energy, we evaluate the spin polarization generated by optical transitions driven by the component of the light wave vector in the plane of the wells. In this way, we also gain insight into the electron spin-diffusion length in the MQWs. The sensitivity of the technique to in-plane spin-related properties is a powerful tool for the investigation of the in-plane component of the spin polarization in MQWs, which is otherwise commonly inaccessible

Can circumcision be avoided in adult male with phimosis? Results of the PhimoStopTM prospective trial

Background: Circumcision as surgical treatment of adult phimosis is not devoid of complications. Efficacy of alternative non-surgical options is unclear. PhimoStop (TM) is a therapeutic protocol which involves the use of appropriately shaped silicone tuboids of increasing size to obtain a non-forced dilation of the prepuce. The aim of the study was to evaluate the efficacy and durability of results of PhimoStop (TM) device for the treatment of adult male phimosis.Methods: A prospective trial was conducted between 2018 and 2020 on 85 consecutive adult male patients affected by phimosis and with an indication for circumcision. Patients were treated with PhimoStop (TM) protocol and they were evaluated at baseline and after treatment through a subjective (patient self-reported information on various domains of his sexual function) and an objective assessment (evaluation of phimosis severity grade according to the Kikiros scale pre- and post-treatment, re-assessment of indication for circumcision post-treatment and validated questionnaires scores). Primary endpoint was to avoid the scheduled circumcision in 33% of the patients enrolled.Results: Seventy-one patients (84%) completed the device usage phase as per study protocol. Median duration of tuboid application was 60 days. Thirty-seven patients (52.1%) had no indication for circumcision after treatment. Even considering patients lost to follow-up as failures, primary endpoint was reached in 43.5% of cases. There was a significant reduction of the grade of phimosis after treatment (P<0.001). Moreover IIEF-5 showed a statistically significant improvement after treatment (P< 0.001). Thirty/37 patients who met the primary endpoint (81%) still have a successful resolution of their phimosis avoiding circumcision at a median follow-up of 24 months.Conclusions: PhimoStop (TM) device is effective for the treatment of adult male phimosis of Kikiros grade < 2. The results seem to be durable in most patients at a median follow-up of 24 months. Randomized clinical trials are necessary in order to confirm our results and assess cost-efficacy

Dynamics of four-photon photoluminescence in gold nanoantennas

Two-pulse correlation is employed to investigate the temporal dynamics of both two-photon photoluminescence (2PPL) and four-photon photoluminescence (4PPL) in resonant and nonresonant nanoantennas excited at a wavelength of 800 nm. Our data are consistent with the same two-step model being the cause of both 4PPL and 2PPL, implying that the first excitation step in 4PPL is a three-photon sp->sp direct interband transition. Considering energy and parity conservation, we also explain why 4PPL behavior is favored over three-and five-photon photoluminescence in the power range below the damage threshold of our antennas. Since sizeable 4PPL requires larger peak intensities of the local field, we are able to select either 2PPL or 4PPL in the same gold nanoantennas by choosing a suitable laser pulse duration. We thus provide a first consistent model for the understanding of multiphoton photoluminescence generation in gold nanoantennas, opening new perspectives for applications ranging from the characterization of plasmonic resonances to biomedical imaging