How evolution makes us age: Introducing the evolvable soma theory of ageing.

At any moment in time, evolution is faced with a formidable challenge: refining the already highly optimised design of biological species, a feat accomplished through all preceding generations. In such a scenario, the impact of random changes (the method employed by evolution) is much more likely to be harmful than advantageous, potentially lowering the reproductive fitness of the affected individuals. Our hypothesis is that ageing is, at least in part, caused by the cumulative effect of all the experiments carried out by evolution to improve a species' design. These experiments are almost always unsuccessful, as expected given their pseudorandom nature, cause harm to the body and ultimately lead to death. This hypothesis is consistent with the concept of "terminal addition", by which nature is biased towards adding innovations at the end of development. From the perspective of evolution as an optimisation algorithm, ageing is advantageous as it allows to test innovations during a phase when their impact on fitness is present but less pronounced. Our inference suggests that ageing has a key biological role, as it contributes to the system's evolvability by exerting a regularisation effect on the fitness landscape of evolution.

Unravelling the nexus: Towards a unified model of development, ageing, and cancer.

This work presents a comprehensive model that aims to unify our understanding of embryogenesis, ageing, and cancer. While there have been previous attempts to construct models separately for two of these phenomena (such as embryogenesis and cancer, ageing and cancer), models encompassing all three are relatively scarce, if not entirely absent. The model's most notable feature is the presence of driver cells throughout the body, which may correspond to Spemann's organisers. These driver cells play a vital role in propelling development as they dynamically emerge from non-driver cells and inhabit specialised niches. Remarkably, this continuous process persists throughout an organism's entire lifespan, signifying that development unfolds from conception to the end of life. Driver cells orchestrate change events through the induction of distinctive epigenetic patterns of gene activation. Events occurring at young age drive development, are subject to high evolutionary pressure and hence carefully optimised. Events occurring after reproduction age are subject to decreasing evolutionary pressure: for this reason, such events are "pseudorandom" -deterministic but erratic. Some of these events lead to age-related benign conditions, such as gray hair. Some lead to serious age-related diseases, such as diabetes and Alzheimer's disease. Furthermore, some of these events might perturb epigenetically key pathways involved in driver activation and formation, leading to cancer. In our model, this driver cell-based mechanism represents the backbone of multicellular biology: understanding and correcting its functioning may give the chance to solve a wide range of conditions at once.

Oxygen-Ozone Therapy Associated with Alpha Lipoic Acid Plus Palmitoylethanolamide and Myrrh versus Ozone Therapy in the Combined Treatment of Sciatic Pain Due to Herniated Discs: Observational Study on 318 Patients.

BACKGROUND: The aim of our observational study is to compare the therapeutic efficacy of combined treatment of oxygen-ozone therapy and oral treatment with alpha-lipoic acid (ALA) + palmitoylethanolamide (PEA) and myrrh in patients with peripheral neuropathic pain (sciatica) on radicular disc conflict from disc herniation and the results obtained with oxygen-ozone treatment alone. METHODS: We enrolled 318 patients with the neuroradiological diagnosis of disc herniation performed with computed tomography (CT) or magnetic resonance imaging (MRI) and symptoms characterized by low back pain complicated by sciatica, which we divided into two groups. Group A was composed of 165 patients who were treated only with oxygen-ozone therapy with CT-guided intraforaminal technique, while the remaining 153 (Group B) have undergone combined oral treatment with ALA + PEA and myrrh. Follow-up visits for the evaluation of the clinical outcome of the treatment were conducted after 60 ± 8 days using a modified version of McNab's method. RESULTS: At the clinical check-up, 126/165 patients included in Group A had a complete remission of pain (76.4%), while in Group B, 119/153 (77.8%) had a complete remission of pain. CONCLUSION: The results highlight how the treatment associated with ozone therapy and oral administration of alpha-lipoic acid + palmitoylethanolamide and myrrh is preferred over the simple treatment with only ozone in such patients in the phase of greatest acuity of the disease, where the pain appears to be better controlled.

New Approach to Chronic Back Pain Treatment: A Case Control Study.

BACKGROUND AND OBJECTIVE: Our study compares the clinical outcome of chronic low back pain present for over six months treated with alpha-lipoic acid (ALA) + palmitoylethanolamide (PEA) and myrrh and periradicular infiltrations of oxygen-ozone under CT guide to periradicular steroidal infiltrations in a short (one week), medium (three months) and long-term period (six months). METHODS: We enrolled 246 patients (Group A) with low back pain treated with periradicular infiltrations of oxygen-ozone under CT guide combined with 800 mg/day of ALA + 600 mg/day of PEA + 200 mg/day of myrrh orally. Group B consisted of 176 patients with low back pain treated with periradicular infiltrations of steroids. Patients were clinically monitored one week after the end of treatment, at three months, and at six months using a modified version of McNab's method. RESULTS: In Group A, the one-week clinical follow-up registered a complete remission of painful symptoms in 206 patients (83.7%), and this manifestation remained optimal in 191 patients at the three-month follow-up (77.6%) and in 178 at six months (72.3%). While the results were satisfactory in 28 patients (10.9%) at one week, 32 (13%) in the medium term, and 41 (16.6%) in the long term, non-significant results were found in 12 patients in the control at one week (4.6%), in 23 at three months (9.3%) and in 27 at six months (10.9%). In Group B, at the short-term follow-up we obtained an excellent clinical result in 103 patients (80.5%), while at three months 85 patients reported the persistence of clinical benefit (66.4%) and at six months, 72 (56.2%) reported the same result. The result was rated satisfactory in 11 (8.5%) and poor in 4 (3%). At the three-month follow-up, 23 (18%) reported a satisfactory result, and 20 (15.6%) had a poor result. At six months, 24 (18.8%) reported the persistence of a satisfactory result while for 32 the result was poor (25%). CONCLUSION: The results highlight how the treatment associated with ozone therapy and oral administration of alpha-lipoic acid + palmitoylethanolamide and myrrh can be considered a valid alternative to common therapeutic approaches in the treatment of chronic low back pain.

Recurring flood distribution patterns related to short-term Holocene climatic variability.

Millennial- and multi-centennial scale climate variability during the Holocene has been well documented, but its impact on the distribution and timing of extreme river floods has yet to be established. Here we present a meta-analysis of more than 2000 radiometrically dated flood units to reconstruct centennial-scale Holocene flood episodes in Europe and North Africa. Our data analysis shows a general increase in flood frequency after 5000 cal. yr BP consistent with a weakening in zonal circulation over the second half of the Holocene, and with an increase in winter insolation. Multi-centennial length phases of flooding in UK and central Europe correspond with periods of minimum solar irradiance, with a clear trend of increasing flood frequency over the last 1000 years. Western Mediterranean regions show synchrony of flood episodes associated with negative phases of the North Atlantic Oscillation that are out-of-phase with those evident within the eastern Mediterranean. This long-term flood record reveals complex but geographically highly interconnected climate-flood relationships, and provides a new framework to understand likely future spatial changes of flood frequency.

Pseudorandomness of gene expression: a new evo-devo theory of ageing.

In contrast to the first part of life (development), ageing appears to be under less strict genetic control. The precise timing of events so characteristic of development seems to loosen its grasp, while stochastic and environmental factors seem to become the dominant force. Evolutionary theories put forward a decreasing evolutionary pressure over the course of life as the reason behind this pattern, yet dissenting views on ageing as a genetically programmed process linger. In this paper we address this dissent by presenting insights from an artificial evolutionary-developmental system, ET, and propose a new evo-devo theory of ageing-a theory that sees ageing as a continuation of development in the postreproductive period. In this theory both development and ageing are under genetic control. Nonetheless, while gene expression patterns that drive development are optimised by evolution, patterns that drive ageing are not optimised, because evolutionary pressure decreases with age. For these reasons, during ageing the changes orchestrated by genes are "pseudorandom"- deterministic but erratic-and their effects on an individual's health are more likely to be detrimental than beneficial. As such, they contribute to the continuous deterioration of bodily functions that characterise ageing.

Embryogenesis, morphogens and cancer stem cells: putting the puzzle together.

This paper describes a model which puts together three key elements of cancer theory: the analogies between embryogenesis and carcinogenesis, the role played in both processes by morphogens and related pathways, and the recently emerged paradigm of cancer stem cells. The model is called Epigenetic Tracking. Originally conceived as a model of embryonic development, it was later extended to interpret other aspects of biology, such as the presence of junk DNA, the phenomenon of ageing and the process of cancer formation. In this work we deepen our vision of carcinogenesis, and propose a novel hypothesis on the role of morphogen-processing pathways. According to the hypothesis, the interplay of these pathways leads in stem cells to the production of new transcription factors, which act as drivers of cellular differentiation. The disruption of these pathways, caused by mutations in specific genes, would represent the first and most distinctive event in the carcinogenic process. Our hypothesis allows us to make testable predictions on patterns of gene mutations involved in carcinogenesis. Our hypothesis also suggests that cancer stem cells can stay dormant until they are activated in a process that resembles activation of stem cells during tissue repair or at a specific time during development.

A model of evolution of development based on germline penetration of new "no-junk" DNA.

There is a mounting body of evidence that somatic transposition may be involved in normal development of multicellular organisms and in pathology, especially cancer. Epigenetic Tracking (ET) is an abstract model of multicellular development, able to generate complex 3-dimensional structures. Its aim is not to model the development of a particular organism nor to merely summarise mainstream knowledge on genetic regulation of development. Rather, the goal of ET is to provide a theoretical framework to test new postulated genetic mechanisms, not fully established yet in mainstream biology. The first proposal is that development is orchestrated through a subset of cells which we call driver cells. In these cells, the cellular state determines a specific pattern of gene activation which leads to the occurrence of developmental events. The second proposal is that evolution of development is affected by somatic transposition events. We postulate that when the genome of a driver cell does not specify what developmental event should be undertaken when the cell is in a particular cellular state, somatic transposition events can reshape the genome, build new regulatory regions, and lead to a new pattern of gene activation in the cell. Our third hypothesis, not supported yet by direct evidence, but consistent with some experimental observations, is that these new "no-junk" sequences-regulatory regions created by transposable elements at new positions in the genome-can exit the cell and enter the germline, to be incorporated in the genome of the progeny. We call this mechanism germline penetration. This process allows heritable incorporation of novel developmental events in the developmental trajectory. In this paper we will present the model and link these three postulated mechanisms to biological observations.

Oxygen-ozone therapy for degenerative spine disease in the elderly: a prospective study.

We describe our experience of oxygen-ozone therapy to treat degenerative spine disease in the elderly. From April 2004 to March 2008 we selected 129 patients with CT and/or MR evidence of spondyloarthrosis and disc degeneration of the lumbar spine. All patients enrolled in the study had contraindications to the administration of commonly used analgesic and anti-inflammatory drugs.Oxygen-ozone therapy was given by CT-guided intraforaminal injection as the first treatment followed by 4 weekly paralumbar infiltrations on an outpatient basis. The full treatment lasted a month. Clinical outcome was assessed 3 months and 1 year after treatment. The good results obtained indicate that oxygen-ozone therapy is an ideal treatment with no side-effects in elderly patients with degenerative spine disease.

A hypothesis on the role of transposons.

Genomic transposable elements, or transposons, are sequences of DNA that can move to different positions in the genome; in the process, they can cause chromosomal rearrengements and changes in gene expression. Despite their prevalence in the genomes of many species, their function is largely unknown: for this reason, they have been labelled "junk" DNA. "Epigenetic Tracking" is a model of development that, combined with a standard evolutionary algorithm, become an evo-devo method able to generate arbitrary shapes of any kind and complexity (in terms of number of cells, number of colours, etc.). The model of development has been also shown to be able to produce the artificial version of key biological phenomena such as the phenomenon of ageing, and the process of carcinogenesis. In this paper the evo-devo core of the method is explored and the result is a novel hypothesis on the biological role of transposons, according to which transposition in somatic cells during development drives cellular differentiation and transposition in germ cells is an indispensable tool to boost evolution. Thus, transposable elements, far from being "junk", have one of the most important roles in multicellular biology.

The map of Altinum, ancestor of Venice.

Processing and interpretation of July 2007 digital visible and near-infrared aerial photographs, coupled by a digital terrain model, has allowed for detailed reconstruction of the topography and the paleoenvironmental setting of the Roman city of Altinum, shedding new light on the far origins of Venice. Images were taken during severe dry conditions, which stressed the maize and soy crops. The city walls and doors, the street network, dwellings, theaters, amphitheater, forum, emporia, basilica, and a complex network of rivers and canals have been mapped.

Contrast-induced seizures after cardiac catheterization in a 6-year-old child.

Neurologic complications of cardiac catheterization are usually embolic events resulting in stroke or seizures of vascular origin. Contrast-induced seizures have been rarely described in children. This report presents clinical, neuroimaging, and follow-up data of a 6-year-old female subjected to cardiac catheterization for aortic coarctation who developed contrast-induced generalized seizures. Although rare, this condition adds to the neurologic complications of cardiac catheterization in children and should be considered in the differential diagnosis of seizures of vascular origin with obvious therapeutic and prognostic implications.

Intraforaminal O(2)-O(3) versus periradicular steroidal infiltrations in lower back pain: randomized controlled study.

BACKGROUND AND PURPOSE: Reports about steroids and oxygen-ozone therapy to treat lower back pain have been increasing. The purpose of our study was to compare the clinical outcomes in patients treated with infiltrations of O(2)-O(3) gas or steroids at short-, medium-, and long-term follow-up. METHODS: A total of 306 patients (166 with primarily disk disease, 140 with nondisk vertebral disease) with acute or chronic low back and sciatic nerve pain received a CT-guided intraforaminal infiltration of an O(2)-O(3) gas mixture or an periradicular infiltration of steroids. Neurologists unaware of the type of treatment assessed the patients. RESULTS: At 1-week follow-up, most patients had a complete remission of pain, regardless of the treatment. At 6-month follow-up, differences in favor of O(2)-O(3) treatment were significant in patients with disk disease (P = .0021) but not in those without disk disease (P = .0992). Clinical outcomes were poor in 13 (15.1%) of 86 patients receiving O(2)-O(3) infiltration and in 18 (22.5%) of 80 patients receiving steroid injection (P = .2226). Among patients without disk disease, six (8.6%) of 70 patients receiving O(2)-O(3) infiltration but 21.4% of the patients receiving steroid injections had poor outcomes (P = .0332). CONCLUSION: Oxygen-ozone treatment was highly effective in relieving acute and chronic lower back pain and sciatica. The gas mixture can be administered as a first treatment to replace epidural steroids.

[The early semiautomatic defibrillation: legislative Italian framing and medical-legal aspects]. / La defibrillazione semiautomatica precoce: inquadramento legislativo italiano e risvolti medico-legali.

Following Anglosaxon experience, automatic external defibrillators (AEDs), devices capable of automatically identifying a defibrillating rhythm and triggering a life-saving discharge, are now becoming widespread in Italy too. Their extremely simple functioning, and diagnostic sensitivity combined with diagnostic specificity all mean that AEDs can even be used by non-medical personnel (nurses) and, more extensively and after proper training, also by "first responders" who are not necessarily healthcare-related (red cross volunteers, members of the police force, firemen, etc.). In this sense Italian law no. 120/2001, enacted in the interests of the collectivity, and its later provisions approved at the conference of the Italian state and regional authorities in 2003, admits this type of application. AED safety assurance means that these devices can also be used by ordinary people who are not trained and have no specific obligations, but who suddenly find themselves in an emergency situation. However, medical personnel, paramedics and non-healthcare-related "first responders" trained in the use of AEDs, are required to apply them in suitable circumstances and, if they do not, may be accused of refusal to act in an official capacity, omission of first aid, and manslaughter.