National energy policies and global environmental issues : a theoretical framework for reconciling domestic and international law

The concern relating to the greenhouse effect, which is presumed to be the result of carbon dioxide emissions created when fossil fuels such as petroleum and coal are burned, is affecting even more the energy matter which stands at the top of the domestic and foreign policy agendas of several countries. National strategies to confront these challenges are variably assorted according to the diverse geopolitical and geological backgrounds. A multiplication of regional institutions may render the experiment of integrating climate change and energy security policies more open to other solutions than experimented by world economy since the end of Cold war. Furthermore, the new global players have the possibilities in the regional institutions to gradually prepare their own legal systems and policy priorities to be compatible with the global environmental challenges.Paper presented by Paolo Farah at the Conference \u201cItalian Researchers in China", Embassy of Italy, Scientific and Technological Office, Beijing, China. Panel discussants of the submitted paper composed by Prof. Nerina Boschiero \u2013 Full Professor of International Law, Director, Department of Public, Civil Procedure, International and European Law, Faculty of Law, University of Milan and Huang Zhenzhong - Vice-Dean, Faculty of Law, Beijing Normal University. Beijing, 24th September 200

Autonomic function in amnestic and non-amnestic mild cognitive impairment : spectral heart rate variability analysis provides evidence for a brain–heart axis

Mild cognitive impairment (MCI) is a heterogeneous syndrome with two main clinical subtypes, amnestic (aMCI) and non-amnestic (naMCI). The analysis of heart rate variability (HRV) is a tool to assess autonomic function. Cognitive and autonomic processes are linked via the central autonomic network. Autonomic dysfunction entails several adverse outcomes. However, very few studies have investigated autonomic function in MCI and none have considered MCI subtypes or the relationship of HRV indices with different cognitive domains and structural brain damage. We assessed autonomic function during an active orthostatic challenge in 253 oupatients aged\u2009 65\u200965, [n\u2009=\u200982 aMCI, n\u2009=\u200993 naMCI, n\u2009=\u200978 cognitively normal (CN), neuropsychologically tested] with power spectral analysis of HRV. We used visual rating scales to grade cerebrovascular burden and hippocampal/insular atrophy (HA/IA) on neuroimaging. Only aMCI showed a blunted response to orthostasis. Postural changes in normalised low frequency (LF) power and in the LF to high frequency ratio correlated with a memory test (positively) and HA/IA (negatively) in aMCI, and with attention/executive function tests (negatively) and cerebrovascular burden (positively) in naMCI. These results substantiate the view that the ANS is differentially impaired in aMCI and naMCI, consistently with the neuroanatomic substrate of Alzheimer's and small-vessel subcortical ischaemic disease

A Brief History, Status, and Perspective of Modified Oligonucleotides for Chemotherapeutic Applications

The advent of rapid and efficient methods of oligonucleotide synthesis has allowed the design of modified oligonucleotides that are complementary to specific nucleotide sequences in mRNA targets. Such modified oligonucleotides can be used to disrupt the flow of genetic information from transcribed mRNAs to proteins. This antisense strategy has been used to develop therapeutic oligonucleotides against cancer and various infectious diseases in humans. This overview reports recent advances in the application of oligonucleotides as drug candidates, describes the relationship between oligonucleotide modifications and their therapeutic profiles, and provides general guidelines for enhancing oligonucleotide drug properties.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143788/1/cpnc0401.pd

Counter-propagating entangled photons from a waveguide with periodic nonlinearity

The conditions required for spontaneous parametric down-conversion in a waveguide with periodic nonlinearity in the presence of an unguided pump field are established. Control of the periodic nonlinearity and the physical properties of the waveguide permits the quasi-phase matching equations that describe counter-propagating guided signal and idler beams to be satisfied. We compare the tuning curves and spectral properties of such counter-propagating beams to those for co-propagating beams under typical experimental conditions. We find that the counter-propagating beams exhibit narrow bandwidth permitting the generation of quantum states that possess discrete-frequency entanglement. Such states may be useful for experiments in quantum optics and technologies that benefit from frequency entanglement.Comment: submitted to Phys. Rev.

N-of-1 Randomized Trials of Ultra-Micronized Palmitoylethanolamide in Older Patients with Chronic Pain

Background: Ultra-micronized palmitoylethanolamide (um-PEA) represents an attractive option for chronic pain control in complex older patients at higher risk of adverse effects with traditional analgesics. Objective: The aim of this study was to determine the effectiveness of um-PEA versus placebo on chronic pain intensity and function in individual geriatric patients. Design: We performed randomized, blinded N-of-1 trials with two 3-week um-PEA versus placebo comparisons, separated by 2-week washout periods. Participants: The study included outpatients aged\ua0 65\ua065\ua0years with chronic, non-cancer, non-ischemic pain in the back, joints, or limbs. Intervention: Patients were randomized to Um-PEA 600\ua0mg or placebo twice daily. Measurements: Pain intensity was measured using an 11-point visual numeric scale. Functional impairment was measured using a Back Pain Functional Scale. Impact of each N-of-1 trial was measured on the clinician\u2019s intention to treat and confidence. Results: Ten of 11 eligible patients consented over 7\ua0months [all female, mean age 83.2\ua0years (SD 4.6)]. Three patients interrupted the trial: one had diarrhea (under placebo), one for low adherence, and one for intercurrent pneumonia. A small statistically significant effect in favor of um-PEA was seen at the mixed method analyses in two patients (effect size equal to 8% of the baseline pain). A statistically significant impact on function was found in one patient. After the trial, um-PEA was prescribed to four patients; in two patients the clinician changed their pre-trial intention to treat; the clinician confidence in the treatment plan either increased (5) or remained the same (2). Conclusions: Our experience confirmed that N-of-1 trials may help make personalized evidence-based decisions in complex older patients, with special feasibility considerations. ClinicalTrials.gov: NCT02699281

Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain : study protocol for a series of N-of-1 randomized trials

Background: Chronic pain in older people is highly prevalent, often underestimated, and associated with adverse outcomes. Most available analgesic drugs are often either ineffective or not tolerated, with many side effects. Palmitoylethanolamide (PEA) is an endogenous widely distributed N-acylethanolamina involved in neuroinflammation and pain-generating processes. Formulations containing ultra-micronized palmitoylethanolamide (um-PEA) are available but their effectiveness on chronic pain in highly heterogeneous geriatric patients is not clear and probably not generalizable. We planned to adopt the N-of-1 trial approach to test the effectiveness of um-PEA objectively at the individual level in our older outpatients. Methods/Design: Persons 65 years or older referring to the Geriatric Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan complaining of noncancer chronic pain of any origin will be eligible. Each trial will be a placebo-controlled randomized crossover trial including two um-PEA (600 mg twice a day) and placebo treatment pairs. The um-PEA or placebo 3-week periods will be separated by 2-week washout intervals to overcome possible carryover effects. Pain intensity, need of on-demand analgesic medications, and impact on daily activities will be evaluated. Cognitively impaired patients will be eligible as long as an expression of pain can be recognized and its frequency assessed by a caregiver. Trial results will be discussed with the patient or caregiver and the treating physician to decide whether to continue the treatment. The impact of the N-of-1 approach on the physician's management plan and confidence will be assessed. We will secondarily meta-analyze the performed N-of-1 trials to obtain an estimate of the average effect of um-PEA compared with placebo using a frequentist and Bayesian approach. Discussion: While pursuing an ultimate clinical objective, i.e. to empirically and objectively decide the best treatment choice for an individual older patient with chronic pain, these series of geriatric N-of-1 trials on PEA will bring the principles of evidence-based medicine into the care of patients not usually represented in conventional randomized controlled trials, and realize a patient-centered outcome approach necessary to improve appropriate prescribing in elderly patients with multimorbidity and polypharmacy. Trial registration: ClinicalTrials.gov NCT02699281. Registered on 3 March 2016

Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer's Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus : A New/Old Potential Target

As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies

Different Aaenosine A2A receptor expression in peripheral cells from elderly patients with vascular dementia and Alzheimer's disease

The line between vascular dementia (VaD) and Alzheimer's disease (AD) is often blurred. In this study we investigated whether adenosine A2A receptor (A2AR) expression can be used to differentiate between VaD and AD. We evaluated the expression of this receptor in the peripheral blood mononuclear cells of patients with VaD, mild cognitive impairment, AD, and controls. We found statistically significant lower levels of A2AR mRNA in VaD compared to AD subjects. These data suggest that A2AR expression may help in the differential diagnosis between VaD and AD

25th-order high-temperature expansion results for three-dimensional Ising-like systems on the simple cubic lattice

25th-order high-temperature series are computed for a general nearest-neighbor three-dimensional Ising model with arbitrary potential on the simple cubic lattice. In particular, we consider three improved potentials characterized by suppressed leading scaling corrections. Critical exponents are extracted from high-temperature series specialized to improved potentials, obtaining $\gamma=1.2373(2)$, $\nu=0.63012(16)$, $\alpha=0.1096(5)$, $\eta=0.03639(15)$, $\beta=0.32653(10)$, $\delta=4.7893(8)$. Moreover, biased analyses of the 25th-order series of the standard Ising model provide the estimate $\Delta=0.52(3)$ for the exponent associated with the leading scaling corrections. By the same technique, we study the small-magnetization expansion of the Helmholtz free energy. The results are then applied to the construction of parametric representations of the critical equation of state, using a systematic approach based on a global stationarity condition. Accurate estimates of several universal amplitude ratios are also presented.Comment: 40 pages, 15 figure

Knowledge-based energy functions for computational studies of proteins

This chapter discusses theoretical framework and methods for developing knowledge-based potential functions essential for protein structure prediction, protein-protein interaction, and protein sequence design. We discuss in some details about the Miyazawa-Jernigan contact statistical potential, distance-dependent statistical potentials, as well as geometric statistical potentials. We also describe a geometric model for developing both linear and non-linear potential functions by optimization. Applications of knowledge-based potential functions in protein-decoy discrimination, in protein-protein interactions, and in protein design are then described. Several issues of knowledge-based potential functions are finally discussed.Comment: 57 pages, 6 figures. To be published in a book by Springe