Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

 Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

BMJ, Online First, Reducing door-to-needle times in stroke thrombolysis to 13 min through protocol...

BMJ, Online First,Reducing door-to-needle times in stroke thrombolysis to 13 min through protocol revision and simulation training: a quality improvement project in a Norwegian stroke centreBackgroundIn eligible patients with acute ischaemic stroke, rapid revascularisation is crucial for good outcome. At our treatment centre, we had achieved and sustained a median door-to-needle time of under 30 min. We hypothesised that further improvement could be achieved through implementing a revised treatment...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

12:00

 Latest headlines from BMJ, Doctors' pensions: no trust in this government Mahase reports that...

 Latest headlines from BMJ,Doctors' pensions: no trust in this governmentMahase reports that doctors will be able to halve pension contributions to ease tax burden.1 I won't hold my breath. A consultation will start at the end of June. Meanwhile, many doctors are worried...Latest headlines from BMJFri Jun 28, 2019 18:36NHS to change GP registration rules in response to growth of digital providersDigital first GP providers such as Babylon's GP at Hand should have to establish a physical location and...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

12:00

BMJ  Current issue, A focused mapping review and synthesis of a priori risk factors associated...

BMJ Current issue,A focused mapping review and synthesis of a priori risk factors associated with medical misconductBackgroundMedical misconduct is an international problem. It is judged according to whether a doctor has endangered the health of the public. Little is known about the risk factors associated with medical misconduct. To inform patient safety, we undertook a focused mapping review and synthesis (FMRS) of tribunal reports retrieved from the Medical Practitioners Tribunal Service (MPTS)....

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:59

 BMJ Open Current Issue, Research priorities in regional anaesthesia education and training: an...

 BMJ Open Current Issue,Research priorities in regional anaesthesia education and training: an international Delphi consensus surveyObjectivesEducation in regional anaesthesia covers several complex and diverse areas, from theoretical aspects to procedural skills, professional behaviours, simulation, curriculum design and assessment. The objectives of this study were to summarise these topics and to prioritise these topics in order of research importance. DesignElectronic structured Delphi questionnaire...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:59

 BMJ Case Reports Last 6 Issues, Ischaemic stroke as the initial manifestation of systemic amyloidosis...

 BMJ Case Reports Last 6 Issues,Ischaemic stroke as the initial manifestation of systemic amyloidosisA previously healthy 54-year-old woman was admitted to the stroke unit with an acute ischaemic stroke attributed to atrial fibrillation newly diagnosed at the emergency room. Nevertheless, preliminary investigation on stroke aetiology revealed incidental hypoalbuminaemia in the context of nephrotic syndrome, while clinically, the patient developed progressive signs of cardiac failure raising the suspicion...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:58

 BMC Research Notes, Gait screening of a population of young, healthy athletes by means of a...

 BMC Research Notes,Gait screening of a population of young, healthy athletes by means of a portable, low-cost device unveils hidden left–right asymmetries in both quadriceps and anterior cruciate ligament forcesThe present study reports the on-field screening of a population of young soccer players in the pursuit of alterations in gait using a portable and low-cost gait analysis system composed of a Wii Balance Board...BMC Research NotesFri Jun 28, 2019 03:00Low dietary diversity and its influencing...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:58

 International Journal of Radiation Oncology*Biology*Physics, Determining the "Organ-at-Risk"...

 International Journal of Radiation Oncology*Biology*Physics,Determining the "Organ-at-Risk" for Lymphedema Following Regional Nodal Irradiation in Breast CancerPublication date: Available online 28 June 2019Source: International Journal of Radiation Oncology*Biology*PhysicsAuthor(s): Jeffrey P. Gross, Connor M. Lynch, Anne Marie Flores, Sumanas W. Jordan, Irene B. Helenowski, Mahesh Gopalakrishnan, Dan Cutright, Eric D. Donnelly, Jonathan B. StraussAbstractPurposeLymphedema following regional nodal...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:57

 Medical Image Analysis, Hierarchical Spherical Deformation for Cortical Surface Registration...

 Medical Image Analysis,Hierarchical Spherical Deformation for Cortical Surface RegistrationPublication date: Available online 29 June 2019Source: Medical Image AnalysisAuthor(s): Ilwoo Lyu, Hakmook Kang, Neil D. Woodward, Martin A. Styner, Bennett A. LandmanAbstractWe present hierarchical spherical deformation for a group-wise shape correspondence to address template selection bias and to minimize registration distortion. In this work, we aim at a continuous and smooth deformation field to guide...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:57

 Medgadget, Protein-Loaded Antimicrobial Hydrogel to Treat, Prevent Bone Infections Bone infections...

 Medgadget,Protein-Loaded Antimicrobial Hydrogel to Treat, Prevent Bone InfectionsBone infections are quite common following orthopedic surgery or as a result of injury or disease. They can be incredibly difficult to treat, and heavy duty antibiotic regimens coupled with debridement surgery is the current approach. Even after all that, inflammation is a frequent side effect. Now, researchers at Georgia Tech have created a hydrogel material that can be used to treat bone infections and even prevent...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:57

 Clinical Chemistry and Laboratory Medicine (CCLM), Correlations between serum and CSF pNfH levels...

 Clinical Chemistry and Laboratory Medicine (CCLM),Correlations between serum and CSF pNfH levels in ALS, FTD and controls: a comparison of three analytical approachesJournal Name: Clinical Chemistry and Laboratory Medicine (CCLM)Issue: Ahead of printClinical Chemistry and Laboratory Medicine (CCLM)Fri Jun 28, 2019 15:56Mark above section as read Royal Society of Chemistry (Great Britain) Society for Analytical Chemistry Society of Public Analysts (Great Britain)Colorimetric detection of Ba2+, Cd2+...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:56

 Antioxidants, Antioxidants, Vol. 8, Pages 202: Dietary Flavonoids for Immunoregulation and Cancer:...

 Antioxidants,Antioxidants, Vol. 8, Pages 202: Dietary Flavonoids for Immunoregulation and Cancer: Food Design for Targeting DiseaseAntioxidants, Vol. 8, Pages 202: Dietary Flavonoids for Immunoregulation and Cancer: Food Design for Targeting Disease Antioxidants doi: 10.3390/antiox8070202 Authors: Ahn-Jarvis Parihar Doseff Flavonoids, one of the most abundant phytochemicals in a diet rich in fruits and vegetables, have been recognized as possessing anti-proliferative, antioxidant, anti-inflammatory,...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:55

 Allergology International, A case of anaphylaxis due to fish collagen in a gummy candy Publication...

 Allergology International,A case of anaphylaxis due to fish collagen in a gummy candyPublication date: Available online 28 June 2019Source: Allergology InternationalAuthor(s): Namiko Abe, Tomonobu Ito, Tomoko Kobayashi, Chizu Egusa, Tatsuo Maeda, Yukari Okubo, Ryoji TsuboiAllergology InternationalSat Jun 29, 2019 18:04γδ T cells enhance TSLP production and ILC2 accumulation in house dust mite-induced allergic airway inflammationPublication date: Available online 28 June 2019Source: Allergology InternationalAuthor(s):...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:55

 Annals of Diagnostic Pathology, BK virus histopathologic disease severity does not predict allograft...

 Annals of Diagnostic Pathology,BK virus histopathologic disease severity does not predict allograft outcome in renal transplant recipientsPublication date: Available online 27 June 2019Source: Annals of Diagnostic PathologyAuthor(s): M. Lee Sanders, Melissa Swee, Mony Fraer, Sarat Kuppachi, Patrick Ten Eyck, Prerna RastogiAbstractAimsBK polyomavirus nephropathy (BKPyVN) is an important cause of allograft failure after renal transplantation. Despite early screening for the virus, allograft loss from...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:54

 Anaesthesia Food, fads, allergies and anaphylaxis with propofol Anaesthesia Fri Jun 28,...

 AnaesthesiaFood, fads, allergies and anaphylaxis with propofolAnaesthesiaFri Jun 28, 2019 19:38Mark above section as read BMC Anesthesiology - Latest ArticlesContinuous Adductor Canal Block used for postoperative pain relief after medial Unicondylar Knee Arthroplasty: a randomized, double-blind, placebo-controlled trialPeripheral nerve block and local infiltration analgesia (LIA) provide good analgesia after knee replacement. This study evaluated the additional analgesic efficacy of continuous adductor...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:54

 Journal of Plastic, Reconstructive & Aesthetic Surgery Preserved Nipple Erectile Function...

 Journal of Plastic, Reconstructive & Aesthetic SurgeryPreserved Nipple Erectile Function after Free Nipple Areolar Complex TransplantationIt is generally believed that sensory innervation and preservation of nipple erectile function are lost after free nipple areolar complex (NAC) transplantation. We, however, would like to present a case that already reported 'restored' nipple erectile function two weeks after free NAC transplantation following bilateral mastectomy and breast free flap reconstruction...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:53

Synthese

The feeling of grip: novelty, error dynamics, and the predictive brainAbstractAccording to the free energy principle biological agents resist a tendency to disorder in their interactions with a dynamically changing environment by keeping themselves in sensory and physiological states that are expected given their embodiment and the niche they inhabit (Friston in Nat Rev Neurosci 11(2):127–138, 2010. doi:10.1038/nrn2787). Why would a biological agent that aims at minimising uncertainty in its encounters...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:42

Immunopathology

Inflammation and type 2 diabetes: from basic science to treatmentTreatment of type 2 diabetes by targeting interleukin-1: a meta-analysis of 2921 patientsAbstractWith obesity and type 2 diabetes prevalence steadily increasing and no effective means in sight to support the population in obtaining and maintaining stable weight loss, there is an imminent need for pharmacological therapy to treat and prevent type 2 diabetes. Current anti-diabetic treatment is symptomatic, and very few drugs have both...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:42

Diabetology

Clinical impact of sarcopenia and dynapenia on diabetesAbstractSarcopenia as a progressive and generalized skeletal muscle disorder that is associated with an increased likelihood of adverse outcomes, including falls, fractures, physical disability, and mortality. On the other hand, an age-related decline in muscle strength prior to the reduction of muscle mass, is proposed to be "dynapenia". Sarcopenia and dynapenia have recently been recognized as a diabetic complications in type 2 diabetes. We...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:41

Molecular Histology

Tamarixetin protects against cardiac hypertrophy via inhibiting NFAT and AKT pathwayAbstractCardiac hypertrophy is a compensatory response in reaction to mechanical load that reduces wall stress by increasing wall thickness. Chronic hypertrophic remodeling involves cardiac dysfunction that will lead to heart failure and ultimately death. Studies have been carried out on cardiac hypertrophy for years, whereas the mechanisms have not been well defined. Tamarixetin (TAM), a natural flavonoid derivative...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:40

Sophia

Problems with Compensation: Gleeson on Marilyn McCord Adams on EvilAbstractAccording to the most recent articulation of her view, Marilyn Adams's reply to the problem of horrendous evils states that God offers compensation to those who experience horrendous evils. This compensation includes the good of the incarnation of God and the good of identification with God in virtue of suffering horrendous evils. Andrew Gleeson has raised a series of objections to Adams's recent articulation. I argue that...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:40

DGNeurologie

Die Rubrik „Im Fokus"Tiefe Hirnstimulation des Kleinhirns reduziert die Ataxie bei der shaker -RatteVorsicht bei der Vernichtung von PatientenunterlagenIntrathekale Nusinersentherapie bei Erwachsenen mit spinaler MuskelatrophieAkinetisch-rigide Bewegungsstörungen unter AntikonvulsivaMagazinNeuromyelitis-optica-Spektrum-ErkrankungFacharzt für NeurologieErster epileptischer AnfallZusammenfassungZiel der Diagnostik nach einem ersten Anfallsereignis ist zunächst die ätiologische Einordnung, ob ein epileptischer...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:39

Designs, Codes and Cryptography

Correction to: Improved Singleton bound on frequency hopping sequences and optimal constructionsThe original version of this article unfortunately contained a mistake in an equation.Polynomial time bounded distance decoding near Minkowski's bound in discrete logarithm latticesAbstractWe propose a concrete family of dense lattices of arbitrary dimension n in which the lattice bounded distance decoding (BDD) problem can be solved in deterministic polynomial time. This construction is directly adapted...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:39

Stochastic Environmental Research and Risk Assessment

Spatial prediction of landslide susceptibility in Taleghan basin, IranAbstractIdentifying landslide-susceptible zones is warranted to prevent and mitigate associated hazards in mountainous regions, where a landslide is a destructive type of erosion. A landslide susceptibility map was developed for the Taleghan basin based on frequency ratio (FR), logistic regression (LR), maximum entropy (MaxEnt), and support vector machine (SVM) with radial base (RBF), sigmoid (SIG), linear (LN), and polynomial...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:38

Biogerontology

Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditionsAbstractNicotinamide adenine dinucleotide (NAD+) has been described as central coenzyme of redox reactions and is a key regulator of stress resistance and longevity. Aging is a multifactorial and irreversible process that is characterized by a gradual diminution in physiological functions in an organism over time, leading to development of age-associated pathologies and eventually increasing the probability...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:37

Gastroenterology

Serological screening for coeliac disease in patients with juvenile idiopathic arthritisPublication date: Available online 7 June 2019Source: Arab Journal of GastroenterologyAuthor(s): Yasin Sahin, Sezgin Sahin, Kenan Barut, Fugen Cullu Cokugras, Tulay Erkan, Amra Adrovic, Tufan Kutlu, Ozgur KasapcopurAbstractBackground and study aimsJuvenile idiopathic arthritis (JIA) is characterized by autoimmune aetiology. A gene locus 4q27 related to rheumatoid arthritis, psoriatic arthritis, and coeliac disease...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:36

Cancer Education

The Knowledge, Attitude, and Self-Reported Behaviors of Oncology Physicians Regarding Fertility Preservation in Adult Cancer PatientsAbstractThere is a growing concern about the fertility preservation for adult cancer patients of reproductive age. Very little literature exists about fertility preservation of cancer survivors in Chinese text. This study is first to describe the knowledge level, attitude, and practice behaviors among physicians concerning fertility preservation in adult cancer patients...

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

11:35

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Ιατρικά Άρθρα Medicine by Alexandros G. Sfakianakis,ENT PhD,Anapafseos 5 Agios Nikolaos 72100,Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com

Synthese

The feeling of grip: novelty, error dynamics, and the predictive brain Abstract According to the free energy principle biological agents resist a tendency to disorder in their interactions with a dynamically changing environment by keeping themselves in sensory and physiological states that are expected given their embodiment and the niche they inhabit (Friston in Nat Rev Neurosci 11(2):127–138, 2010. doi:10.1038/nrn2787). Why would a biological agent that aims at minimising uncertainty in its encounters with the world ever be motivated to seek out novelty? Novelty for such an agent would arrive in the form of sensory and physiological states that are unexpected. Such an agent ought therefore to avoid novel and surprising interactions with the world one might think. Yet humans and many other animals find play and other forms of novelty-seeking and exploration hugely rewarding. How can this be understood in frameworks for studying the mind that emphasise prediction error minimisation? This problem has been taken up in recent research concerned with epistemic action—actions an agent engages in to reduce uncertainty. However that work leaves two questions unanswered, which it is the aim of our paper to address. First, no account has been given yet of why it should feel good to the agent to engage the world playfully and with curiosity. Second an appeal is made to precision-estimation to explain epistemic action, yet it remains unclear how precision-weighting works in action more generally, or active inference. We argue that an answer to both questions may lie in the bodily states of an agent that track the rate at which free energy is being reduced. The recent literature on the predictive brain has connected the valence of emotional experiences to the rate of change in the reduction of prediction error (Joffily and Coricelli in PLoS Comput Biol 9(6):e1003094, 2013. doi:10.1371/journal.pcbi.1003094; Van de Cruys, in Metzinger and Wiese (eds) Philosophy and predictive processing, vol 24, MIND Group, Frankfurt am Main, 2017. doi:10.15502/9783958573253). In this literature valenced emotional experiences are hypothesised to be identical with changes in the rate at which prediction error is reduced. Experiences are negatively valenced when overall prediction error increases and are positively valenced when the sum of prediction errors decrease. We offer an ecological-enactive interpretation of the concept of valence and its connection to rate of change of prediction error. We show how rate of change should be understood in terms of embodied states of affordance-related action readiness. We then go on to apply this ecological-enactive account of error dynamics to provide an answer to the first question we have raised: It may explain why it should feel good to an agent to be curious and playful. Our ecological-enactive account also allows us to show how error dynamics may provide an answer to the second question we have raised regarding how precision-weighting works in active inference. An agent that is sensitive to rates of error reduction can tune precision on the fly. We show how this ability to tune precision on the go can allow agents to develop skills for adapting better and better to the unexpected, and search out opportunities for resolving uncertainty and progressing in its learning.

The challenge of many logics: a new approach to evaluating the role of ideology in Quinean commitment Abstract Can Quine's criterion for ontological commitment be comparatively applied across different logics? If so, how? Cross-logical evaluations of discourses are central to contemporary philosophy of mathematics and metaphysics. The focus here is on the influential and important arguments of George Boolos and David Lewis that second-order logic and plural quantification don't incur additional ontological commitments over and above those incurred by first-order quantifiers. These arguments are challenged by the exhibition of a technical tool—the truncation-model construction of notational equivalents—that compares the ontological role and increased expressive strength of non-first-order ideology to first-order ideology.

Possible predicates and actual properties Abstract In "Properties and the Interpretation of Second-Order Logic" (Hale, Philos Math 21:133–156, 2013) Bob Hale develops and defends a deflationary conception of properties where a property with particular satisfaction conditions actually (and in fact necessarily) exists if and only if it is possible that a predicate with those same satisfaction conditions exists. He argues further that, since our languages are finitary, there are at most countably infinitely many properties and, as a result, the account fails to underwrite the standard semantics for second-order logic. Here a more lenient version of the view is explored, which allows for the possibility of countably infinite predicates understood as the product of linguistic supertasks. This enriched deflationist account of properties—the Infinitary Deflationary Conception of Existence—supports the standard semantics for models with countable first-order domains, and allows one to prove the categoricity of the second-order Peano axioms.

A psychologistic theory of metaphysical explanation Abstract Many think that sentences about what metaphysically explains what are true iff there exist grounding relations. This suggests that sceptics about grounding should be error theorists about metaphysical explanation. We think there is a better option: a theory of metaphysical explanation which offers truth conditions for claims about what metaphysically explains what that are not couched in terms of grounding relations, but are instead couched in terms of, inter alia, psychological facts. We do not argue that our account is superior to grounding-based accounts. Rather, we offer it to those already ill-disposed towards grounding.

Bolzano and Kim on grounding and unification Abstract It is sometimes mentioned that Bernard Bolzano's work on grounding anticipates many insights of the current debate on metaphysical grounding. The present paper discusses a certain part of Bolzano's theory of grounding that has thus far not been discussed in the literature. This part does not so much anticipate what are nowadays common assumptions about grounding, but rather goes beyond them. Central to the discussion will be a thesis of Bolzano's by which he tries to establish a connection between grounding and (deductive) unification. The paper spells out this thesis in detail and discusses the assumptions on which it rests. Next to this mainly historical aim, the paper also presents reasons why philosophers who are not interested in the historical Bolzano should find the thesis interesting by relating it to a certain view on unification and explanation that has been put forward by Kim. A final part of the paper provides a critical evaluation of the thesis against the background of current accounts of grounding.

Aggregating incoherent agents who disagree Abstract In this paper, we explore how we should aggregate the degrees of belief of a group of agents to give a single coherent set of degrees of belief, when at least some of those agents might be probabilistically incoherent. There are a number of ways of aggregating degrees of belief, and there are a number of ways of fixing incoherent degrees of belief. When we have picked one of each, should we aggregate first and then fix, or fix first and then aggregate? Or should we try to do both at once? And when do these different procedures agree with one another? In this paper, we focus particularly on the final question.

Ambiguous signals, partial beliefs, and propositional content Abstract As the content of propositional attitudes, propositions are usually taken to help explain the behavior of rational agents. However, a closer look at signaling games suggests otherwise: rational agents often acquire partial beliefs, and many of their signals are ambiguous. Signaling games also suggest that it is rational for agents to mix their behavior in response to partial beliefs and ambiguous signals. But as I show in this paper, propositions cannot help explain the mixing behavior of rational agents: to explain mixing behavior, we need a probabilistic notion of content. I also show that a probabilistic notion of content renders propositions explanatorily idle in the case of unambiguous signals and full beliefs as well. My suggestion is thus that we should abandon propositions in explanations of rational behavior and adopt instead a probabilistic notion of content. The notion of probabilistic content ultimately provides a simpler framework for explanations of rational behavior than the notion of propositional content.

Evolutionary debunking: the Milvian Bridge destabilized Abstract Recent literature has paid attention to a demarcation problem for evolutionary debunking arguments. This is the problem of asking in virtue of what regulative metaepistemic norm evolutionary considerations either render a belief justified, or debunk it as unjustified. I examine the so-called 'Milvian Bridge principle' (cf. Griffiths and Wilkins (in: Maclaurin, Dawes (eds) A new science of religion, Routledge, New York, 2012; Sloan, McKenny, Eggelson (eds) Darwin in the 21st century: nature, humanity, and God, University Press, Notre Dame, 2015)), which offers exactly such a called for regulative metaepistemic norm. The Milvian Bridge principle suggests that the metaepistemic norm is: adaptive reliability for truth of cognitive processes that the existence of corresponding truth-making facts evolutionary theory justifies. I argue that the Milvian Bridge principle is problematic on a number of counts, something that is shown via spiraling 'companions in guilt arguments'. Finally, I consider 'the core reductionist objection' to the critique of the Milvian Bridge principle and offer a response. I conclude that the Milvian Bridge principle is destabilized.

The bifurcated conception of perceptual knowledge: a new solution to the basis problem for epistemological disjunctivism Abstract Epistemological disjunctivism says that one can know that p on the rational basis of one's seeing that p. The basis problem for disjunctivism says that that can't be since seeing that p entails knowing that p on account of simply being the way in which one knows that p. In defense of their view disjunctivists have rejected the idea that seeing that p is just a way of knowing that p (the \(\hbox {S}_{\mathrm{w}}\hbox {K}\) thesis). That manoeuvre is familiar. In this paper I explore the prospects for rejecting instead the thought that if the \(\hbox {S}_{\mathrm{w}}\hbox {K}\) thesis is true then seeing that p can't be one's rational basis for perceptual knowledge. I explore two strategies. The first situates disjunctivism within the context of a 'knowledge-first' approach that seeks to reverse the traditional understanding of the relationship between perceptual knowledge and justification (or rational support). But I argue that a more interesting strategy situates disjunctivism within a context that accepts a more nuanced understanding of perceptual beliefs. The proposal that I introduce reimagines disjunctivism in light of a bifurcated conception of perceptual knowledge that would see it cleaved along two dimensions. On the picture that results perceptual knowledge at the judgemental level is rationally supported by perceptual knowledge at the merely functional or 'animal' level. This supports a form of disjunctivism that I think is currently off the radar: one that's consistent both with the \(\hbox {S}_{\mathrm{w}}\hbox {K}\) thesis and a commitment to a traditional reductive account of perceptual knowledge.

Second-order logic: properties, semantics, and existential commitments Abstract Quine's most important charge against second-, and more generally, higher-order logic is that it carries massive existential commitments. The force of this charge does not depend upon Quine's questionable assimilation of second-order logic to set theory. Even if we take second-order variables to range over properties, rather than sets, the charge remains in force, as long as properties are individuated purely extensionally. I argue that if we interpret them as ranging over properties more reasonably construed, in accordance with an abundant or deflationary conception, Quine's charge can be resisted. This interpretation need not be seen as precluding the use of model-theoretic semantics for second-order languages; but it will preclude the use of the standard semantics, along with the more general Henkin semantics, of which it is a special case. To that extent, the approach I recommend has revisionary implications which some may find unpalatable; it is, however, compatible with the quite different special case in which the second-order variables are taken to range over definable subsets of the first-order domain, and with respect to such a semantics, some important metalogical results obtainable under the standard semantics may still be obtained. In my final section, I discuss the relations between second-order logic, interpreted as I recommend, and a strong version of schematic ancestral logic promoted in recent work by Richard Heck. I argue that while there is an interpretation on which Heck's logic can be contrasted with second-order logic as standardly interpreted, when it is so interpreted, its differences from the more modest form of second-order logic I advocate are much less substantial, and may be largely presentational.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Immunopathology

Inflammation and type 2 diabetes: from basic science to treatment

Treatment of type 2 diabetes by targeting interleukin-1: a meta-analysis of 2921 patients Abstract With obesity and type 2 diabetes prevalence steadily increasing and no effective means in sight to support the population in obtaining and maintaining stable weight loss, there is an imminent need for pharmacological therapy to treat and prevent type 2 diabetes. Current anti-diabetic treatment is symptomatic, and very few drugs have both a strong preclinical rationale and clinical proof-of-principle as therapies targeting pathogenic processes in type 2 diabetes. The emerging appreciation of low-grade inflammation as a significant cause of insulin resistance and beta cell failure warrants exploring anti-inflammatory compounds as drug candidates. Since recent studies have demonstrated considerable phenotypic heterogeneity in the type 2 diabetic syndrome, the concept of one drug fits all is naïve, and biomarkers for the selection of type 2 diabetes subtypes for differentiated treatment based on genetic and pathogenic stratification are urgently needed. Biologics antagonizing the master pro-inflammatory cytokine interleukin-1 is one of the few principles specifically targeting low-grade inflammation in type 2 diabetes. Although early phase II studies were encouraging, subsequent underpowered studies and phase III studies designed primarily with cardiovascular endpoints have discredited the potential of anti-interleukin-1 approaches to treat the subgroup of patients that may benefit from this treatment. In this meta-analysis of 2921 individuals from eight phase I–IV studies, we demonstrate a significant overall HbA1c-lowering effect of interleukin-1 antagonism. Meta-regression analyses demonstrated a significant correlation between baseline C-reactive protein and C-peptide, and HbA1c outcome. The identification of further biomarkers for future clinical trials to define the potential of anti-interleukin-1 therapies in type 2 diabetes is urgently needed.

The role of inflammation in diabetic eye disease Abstract Mounting evidence suggests that immunological mechanisms play a fundamental role in the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Upregulation of cytokines and other proinflammatory mediators leading to persistent low-grade inflammation is believed to actively contribute to the DR-associated damage to the retinal vasculature, inducing breakdown of the blood-retinal barrier, subsequent macular edema formation, and promotion of retinal neovascularization. This review summarizes the current knowledge of the biological processes providing an inflammatory basis for DR and DME. In addition, emerging therapeutic approaches targeting inflammation are discussed, including blockade of angiopoietin 2 and other molecular targets such as interleukin (IL)-6, IL-1β, plasma kallikrein, and integrins.

Chronic low-grade inflammation in polycystic ovary syndrome: is there a (patho)-physiological role for interleukin-1? Abstract The polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women of reproductive age. Its main characteristics are the ovarian overproduction of androgens and ovulatory dysfunction which lead to severe symptoms such as hirsutism, acne, insulin resistance, and infertility. Despite the frequency and disease burden of PCOS, its underlying causes remain unknown, and no causal therapeutic options are available. In recent years, several studies have shown that women with PCOS present with chronic low-grade inflammation indicating an overactivity of the pro-inflammatory cytokine interleukin-1 (IL-1). We show here how IL-1 might affect the ovarian physiology and pathophysiology in animals and humans by reviewing experimental studies on ovarian IL-1 system gene expression and on the effects of exogenous IL-1 on ovarian functions. Although IL-1 ligands and receptors are expressed within the ovarian cells, IL-1 seems to negatively affect the delicate balance between the sex hormones and dominant follicle development, as well as fertility. Whether blockade of the IL-1 signaling leads to an improvement of PCOS-related hormonal abnormalities and symptoms remains to be elucidated in future interventional studies.

The role of interleukin-6 in glucose homeostasis and lipid metabolism Abstract Low-grade inflammation is recognized as an important factor in the development and progression of a multitude of diseases including type 2 diabetes mellitus and cardiovascular disease. The potential of using antibody-based therapies that neutralize key players of low-grade inflammation has gained scientific momentum as a novel therapeutic strategy in metabolic diseases. As interleukin-6 (IL-6) is traditionally considered a key pro-inflammatory factor, the potential of expanding the use of anti-IL-6 therapies to metabolic diseases is intriguing. However, IL-6 is a molecule of a very pleiotropic nature that regulates many aspects of not only inflammation but also metabolism. In this review, we give a brief overview of the pro- and anti-inflammatory aspects of IL-6 and provide an update on its role in metabolic regulation, with a specific focus on glucose homeostasis and adipose tissue metabolism. Finally, we shall discuss the metabolic implications and clinical potential of blocking IL-6 signaling, focusing on glucose homeostasis and lipid metabolism.

Subclinical inflammation and depressive symptoms in patients with type 1 and type 2 diabetes Abstract Depression is a frequent comorbidity of type 1 diabetes (T1D) and type 2 diabetes (T2D). Depression and diabetes are linked by a bidirectional relationship, but the underlying mechanisms are still incompletely understood. Experimental, observational and intervention studies showed that inflammatory processes contribute to the development of depression in animal models and humans. Given the high risk of morbidity and mortality in patients with the double burden of diabetes and depression, this review provides an overview of epidemiological studies that addressed the relationship between biomarkers of inflammation and depressive symptoms or depression in diabetes patients. In patients with T1D, there is some evidence that higher levels of high-sensitivity C-reactive protein (hsCRP), IL-6, IL-1 receptor antagonist (IL-1RA) and sICAM-1 may be related to depressive symptoms or (for hsCRP) lower treatment response. For T2D, hsCRP, IL-1RA, CCL2 and adiponectin or its isoforms were associated with depressive symptoms in at least two studies, whereas positive associations of IL-1β, IL-6 and IL-18 with depressive symptoms or depression were reported from single cohorts. However, the number of studies is too low for any meaningful meta-analysis. Prospective life course studies including both patients with T1D and T2D, a comprehensive assessment of systemic inflammation and repeated assessment of depressive symptoms should represent a future research priority to clarify to what extent subclinical inflammation affects the risk of depression in patients with diabetes. A better understanding of the role of inflammatory processes may help to identify subtypes of depression with partly different pathogenesis, which could have consequences with respect to therapeutic options including immunomodulation.

Impact of bariatric surgery on type 2 diabetes: contribution of inflammation and gut microbiome? Abstract Obesity is a chronic low-grade inflammatory disease (both at the systemic and adipose tissue level) that continues to rise worldwide. It is associated with an abundance of comorbidities, including type 2 diabetes (T2D). Bariatric surgery, which induces modifications of the intestinal tract, is to date the most successful treatment for obesity. Its use has dramatically increased in number as it enables both weight reduction and metabolic improvements, with 60% of patients even achieving diabetes remission. Several mechanisms are actually demonstrated to be involved in those clinical improvements. Importantly, both obesity and T2D share many phenotypic characteristics, including increased systemic and adipose tissue inflammation, as well as gut microbiota dysbiosis. These characteristics are deeply modulated after bariatric surgery. This review will address the host metabolic changes observed after bariatric surgery, focusing on the induced gut architectural changes, as well as on the modifications of the inflammatory tone and the gut microbiota.

Islet inflammation in type 2 diabetes Abstract Metabolic diseases including type 2 diabetes are associated with meta-inflammation. β-Cell failure is a major component of the pathogenesis of type 2 diabetes. It is now well established that increased numbers of innate immune cells, cytokines, and chemokines have detrimental effects on islets in these chronic conditions. Recently, evidence emerged which points to initially adaptive and restorative functions of inflammatory factors and immune cells in metabolism. In the following review, we provide an overview on the features of islet inflammation in diabetes and models of prediabetes. We separately emphasize what is known on islet inflammation in humans and focus on in vivo animal models and how they are used to elucidate mechanistic aspects of islet inflammation. Further, we discuss the recently emerging physiologic signaling role of cytokines during adaptation and normal function of islet cells.

Transcriptional control of macrophage polarisation in type 2 diabetes Abstract Type-2 diabetes (T2D) is considered today as an inflammatory disease. Inflammatory processes in T2D are orchestrated by macrophage activation in different organs. Macrophages undergo classical M1 pro-inflammatory or alternative M2 anti-inflammatory activation in response to tissue microenvironmental signals. These subsets of macrophages are characterised by their expression of cell surface markers, secreted cytokines and chemokines. Transcriptional regulation is central to the polarisation of macrophages, and several major pathways have been described as essential to promote the expression of specific genes, which dictate the functional polarisation of macrophages. In this review, we summarise the current knowledge of transcriptional control of macrophage polarisation and the role this plays in development of insulin resistance.

Role of innate immune cells in metabolism: from physiology to type 2 diabetes Abstract Growing evidence suggests that components of the innate immune system play a crucial role in regulating metabolic homeostasis. Macrophages were the primary immune cells to be described in both the white adipose tissue and the pancreatic islets. Therein, their functions, beneficial or detrimental, are extending under steady state and in the context of obesity-induced type 2 diabetes. Other populations, including innate lymphoid cells, are emerging as key sentinels of metabolic tissues and privileged partners of macrophages. The present review will thus explore the phenotype and the role of innate immune cells in metabolic physiology and dysfunction. Discussion will tackle pending questions and future perspectives in the field of immunometabolism.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Diabetology

Clinical impact of sarcopenia and dynapenia on diabetes Abstract Sarcopenia as a progressive and generalized skeletal muscle disorder that is associated with an increased likelihood of adverse outcomes, including falls, fractures, physical disability, and mortality. On the other hand, an age-related decline in muscle strength prior to the reduction of muscle mass, is proposed to be "dynapenia". Sarcopenia and dynapenia have recently been recognized as a diabetic complications in type 2 diabetes. We firstly indicated that sarcopenia was frequently observed in 16.6% of patients with type 1 diabetes aged even over 40 years. Additionally, we recently reported that the prevalence rate of dynapenia was higher than sarcopenia in patients with type 2 diabetes. Chronic hyperglycemia accelerates accumulation of advanced glycation end products (AGEs), which causes diabetic vascular complications through oxidative stress and chronic inflammation. We also demonstrated that skin autofluorescence (AF) as a marker of AGEs, was the independent determinant for skeletal muscle mass and strength in patients with type 2 diabetes and muscle strength in type 1 diabetes. Therefore, the early diagnosis of muscle weakness is essential for patients with diabetes and sustained good glycemic control with exercise and dietary intervention might be beneficial to prevent the progression of muscle weakness in these patients.

Proposal of classification of "chronic kidney disease (CKD) with diabetes" in clinical setting Abstract The natural history of typical and classical "diabetic nephropathy" has been described as high levels of albuminuria and subsequent renal function decline. However, recent decades, the cases, who show the reduced glomerular filtration rate (GFR) without the progression of albuminuria, has been increased. "Diabetic kidney disease (DKD)" is a concept that widely recognizes the pathophysiological change induced by diabetes as the onset and progressive factor of renal injury and renal function decline, regardless of the level of albuminuria. However, we may confuse that "chronic kidney disease (CKD) with diabetes" is "DKD". Therefore, to choose the appropriate treatment that should be prioritized in the clinical setting, we propose that "CKD with diabetes" is classified as "DKD", "non-DKD (NDKD) with diabetes" or "combined disease of DKD and NDKD".

Clinical characteristics of Japanese diabetic patients with critical limb ischemia presenting Fontaine stage IV Abstract The aim of the current study was to reveal the clinical characteristics of Japanese diabetic patients with critical limb ischemia (CLI) presenting ischemic unhealed ulcer/gangrene (Fontaine stage IV) in the real-world settings. The current retrospective cross-sectional study included consecutive 282 Japanese diabetic patients who underwent endovascular therapy for CLI presenting Fontaine stage IV. The prevalence of diabetes-related complications was estimated adopting multiple imputation (50 times). The patients were aged 70 ± 10 years. Median duration of diabetes was 21 (interquartile range 12–31) years. The prevalence of proliferative diabetic retinopathy, end-stage renal disease on regular dialysis, stroke, coronary artery disease, and chronic heart failure was estimated at 48% (95% confidence interval 39–56%), 52% (46–58%), 34% (28–39%), 48% (42–54%), and 35% (29–41%), respectively. The prevalence of stroke, coronary artery disease, and chronic heart failure was not significantly associated with the duration of diabetes (all p > 0.05). On the other hand, the prevalence of proliferative diabetic retinopathy and end-stage renal disease on regular dialysis was significantly positively associated with the duration of diabetes (both p < 0.05). However, these prevalences reached as high as ~ 30% even in patients with duration of diabetes < 10 years. In conclusion, the advanced stage of diabetes-related complications was prevalent in patients with CLI presenting Fontaine stage IV.

Self-management behavior concerning physical activity of Japanese type 2 diabetes patients, characterized by sex, daily energy intake and body mass index Abstract Objectives We assess differences in physical activity self-management behavior in association with dietary intake and BMI between the sexes in patients with type 2 diabetes. Methods Patients with type 2 diabetes (n = 145) completed a self-administrated questionnaire. Patients were classified into four groups by BMI and dietary intake: non-obesity and non-overeating (NO/NOE); non-obesity and overeating (NO/OE); obesity and non-overeating (O/NOE); obesity and overeating (O/OE). Differences in physical activity self-management behavior between the four groups were determined by the analysis of variance using a Tukey–Kramer post hoc test. Results Male O/OE group showed higher HbA1c (p = 0.001) than the other groups. Male NO/OE group had higher steps/day than O/NOE (p = 0.036) and score of "Exercising to stimulate the enjoyment of eating" was higher than O/OE (p = 0.031). Female NO/OE group showed higher HbA1c (p = 0.001) than NO/NOE and O/NOE. Conclusions BMI and dietary intake were associated with frequencies of physical activity self-management strategies in men. Self-management behavior peculiar to male NO/OE group is "Exercising to stimulate the enjoyment of eating". Health professionals should assess sex, BMI, and dietary intake of patients and endeavor to improve individuals' ability to regulate their caloric balance based on physical activity level.

The association between glycemic control and lung function impairment in individuals with diabetes: the Saku study Abstract Aim Though diabetes is a risk factor for lung function impairment, whether the glycemic control level affects lung function in individuals with diabetes remains unclear. The present study aimed to assess the association between glycemic control level and restrictive or obstructive lung function impairment in individuals with diabetes. Methods This cross-sectional study included 1028 individuals with diabetes, aged 40–69 years, who underwent a medical checkup between April 2008 and March 2014. Hemoglobin A1c (HbA1c) was categorized as  < 6.9%, 7.0–7.9%, and  ≥ 8.0%. Restrictive and obstructive lung function impairment was defined by a forced vital capacity (FVC) < 80% predicted and a forced expiratory volume in 1 s to FVC ratio < 0.70. Results Of the participants, 8.7% and 6.3% were classified as having restrictive and obstructive lung function impairment, respectively. The multivariable-adjusted odds ratios and 95% confidence intervals for restrictive lung function impairment were 1.43 (0.84–2.42) in individuals with HbA1c 7.0–7.9%, and 2.42 (1.38–4.26) in individuals with HbA1c ≥ 8.0%, compared with those who had HbA1c < 6.9% (p for trend = 0.002). In contrast, glycemic control level was not associated with obstructive lung function impairment (p for trend = 0.749). Conclusions Poor glycemic control was associated with restrictive lung function impairment in individuals with diabetes. Good glycemic control would be important to minimize restrictive lung function impairment in individuals with diabetes.

Evaluation of the Diabetes Regional Coordination Path using the Diabetes Coordination Notebook in community-based diabetes care Abstract Aims A number of epidemiologic surveys have demonstrated that improving lifestyle habits, providing patient education, and regular screening of patients for early diabetic symptoms and complications through multidisciplinary collaboration are crucial for the management of diabetes. Methods To evaluate the Diabetes Coordination Notebook and the Diabetes Regional Coordination Path in management of diabetes, 217 community pharmacies conducted a survey by questionnaire in Gifu Prefecture, Japan. Results A reply to the questionnaire was obtained from 27,016 individuals, of whom 5,572 claimed to have diabetes or prediabetes. The rate of usage of the Diabetes Coordination Notebook and the Diabetes Regional Coordination Path was 40% and 7%, respectively. Interestingly, patients using the Diabetes Regional Coordination Path more frequently visited an ophthalmic clinic (p < 0.001) and a dental clinic (p < 0.05) than those not using it. Furthermore, multivariate logistic regression analysis revealed that use of the Diabetes Regional Coordination Path was the only factor associated with control of HbA1c < 7.0% (OR: 0.613, 95% CI: 0.395–0.951, p = 0.029). Conclusions The usage of the Diabetes Regional Coordination Path together with the Diabetes Coordination Notebook is associated not only with regular visits to both an ophthalmic clinic and a dental clinic but also with the maintenance of appropriate HbA1c.

Trends in the prevalence of type 2 diabetes and prediabetes in a Japanese community, 1988–2012: the Hisayama Study Abstract Objective We estimated secular trends in the prevalence of type 2 diabetes (T2DM) and prediabetes, and examined potential explanatory factors for these trends in a Japanese community. Methods 4 cross-sectional examinations were conducted among subjects aged 40–79 years in 1988 (n = 2,490), 2002 (n = 2,856), 2007 (n = 2,761), and 2012 (n = 2,644). Glucose tolerance status was defined by a 75g oral glucose tolerance test. Results The age-standardized prevalence of T2DM increased significantly in both sexes from 1988 to 2002, and thereafter it remained stable in men, and decreased nonsignificantly in women from 2002 to 2012. The age-standardized prevalence of prediabetes in men increased significantly between 1988 and 2002, but then decreased significantly. A similar trend was observed in women. The age-specific prevalence of T2DM increased greatly in men aged 60–79 years and women aged 70–79 years from 1988 to 2002, and then plateaued at a high level, while a significant decreasing trend was observed in women aged 40–49 years. The mean values of body mass index (BMI) increased steeply in these elderly subjects from 1988 to 2002, and remained at a high level, whereas those in middle-aged women decreased appreciably over the study period. Conclusions Our findings suggest that in Japanese, there was no further increase in the prevalence of T2DM or prediabetes in either men or women in the 2000s. Secular change in the BMI level was likely to contribute to trends in the prevalence of T2DM, and thus the management of obesity may be important to reduce the prevalence of T2DM.

Small-intestinal necrosis due to non-occlusive mesenteric ischemia with diabetic ketoacidosis after quetiapine treatment Abstract We report a 66-year-old male who developed diabetic ketoacidosis (DKA) and necrosis of the small intestine due to non-occlusive mesenteric ischemia (NOMI), 3 months after starting quetiapine treatment. He was transferred to our hospital and diagnosed as diabetic for the first time, associated with DKA. Despite improvement in DKA, abdominal pain worsened gradually 10 h after hospitalization. Computed tomography (CT) revealed bowel emphysema, and gas out of the gut wall, in the mesenteric veins and the intrahepatic portal vein, suggesting intestinal necrosis. He survived because of resection of necrotic small-intestinal tissue and he finally required no diabetes treatment. Mesenteric arteries were patent with good palpitation without occlusion or thrombosis, and pathological findings showed ischemic enteritis, which is consistent with NOMI. DKA is a rare but serious side effect of second-generation antipsychotic medications (SGAMs) such as quetiapine, which can result in NOMI: a life-threatening complication. We must keep in mind that the plasma glucose concentration may increase in patients taking SGAMs, or that NOMI may occur concurrently if DKA develops.

Diabetes care providers' manual for disaster diabetes care Abstract To ensure that experiences and lessons learned from the unprecedented 2011 Great East Japan Earthquake are used to improve future disaster planning, the Japan Diabetes Society (JDS) launched the "Research and Survey Committee for Establishing Disaster Diabetes Care Systems Based on Relevant Findings from the Great East Japan Earthquake" under the supervision of the Chairman of the JDS. The Committee conducted a questionnaire survey among patients with diabetes, physicians, disaster medical assistance teams (DMATs), nurses, pharmacists, and nutritionists in disaster areas about the events they saw happening, the situations they found difficult to handle, and the needs that they felt required to be met during the 2011 Great East Japan Earthquake. A total of 3,481 completed questionnaires were received. Based on these and other experiences and lessons reported following the 2011 Great East Japan Earthquake and the 2004 Niigata-Chuetsu Earthquakes, the current "Manual for Disaster Diabetes Care" has been developed by the members of the Committee and other invited authors from relevant specialties. To our knowledge, the current Manual is the world's first to focus on emergency diabetes care, with this digest English version translated from the Japanese original. It is sincerely hoped that patients with diabetes and healthcare providers around the world will find this manual helpful in promoting disaster preparedness and implementing disaster relief.

Low muscle mass and inflammation among patients with type 2 diabetes mellitus in Indonesia Abstract Introduction Chronic inflammation, as observed in type 2 diabetes mellitus (T2DM), is associated with complications. How chronic inflammation influences body composition in patients with T2DM remains to be investigated. Our study aimed to evaluate the difference of skeletal muscle mass between patients with and without inflammation indicated by plasma high sensitivity C-reactive protein (hs-CRP). Methods Patients with T2DM were recruited from primary health care in Sleman district, Indonesia. Measurements were performed to obtain information on body weight, body mass index, waist circumference, waist-to-height ratio, total body fat, subcutaneous fat, visceral fat, mid-upper arm circumference, and muscle mass. Spearman's rank correlation was performed to test the correlation between hs-CRP level and several components of body composition. To test the difference of percent skeletal muscle mass between subjects with and without inflammation (hs-CRP ≥ 3 or < 3 mg/dL), general linear model was utilized with adjustment for several variables. Analysis with p value of less than 0.05 is considered statistically significant. Result In all subjects, hs-CRP is correlated with skeletal muscle mass (r: − 0.343; p = 0.04), total body fat (r: 0.353; p = 0.04), and subcutaneous fat (r: 0.369; p = 0.02) but not visceral fat (p: − 0.065; p = ns). Significant difference of skeletal muscle mass between subjects with and without inflammation was found in all and female subjects after adjustment for covariates. Conclusion There was a negative correlation between skeletal muscle mass percentage and inflammation indicated by hs-CRP in type 2 diabetes patients.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Molecular Histology

Tamarixetin protects against cardiac hypertrophy via inhibiting NFAT and AKT pathway Abstract Cardiac hypertrophy is a compensatory response in reaction to mechanical load that reduces wall stress by increasing wall thickness. Chronic hypertrophic remodeling involves cardiac dysfunction that will lead to heart failure and ultimately death. Studies have been carried out on cardiac hypertrophy for years, whereas the mechanisms have not been well defined. Tamarixetin (TAM), a natural flavonoid derivative of quercetin, have been demonstrated possessing anti-oxidative and anti-inflammatory effects on multiple diseases. However, little is known about the function of TAM on the development of cardiac hypertrophy. Here, we found TAM could alleviate pressure-overload-induced cardiac hypertrophy in transverse aortic constriction (TAC) mouse model, assessed by ventricular weight/body weight, lung weight/body weight, echocardiographic parameters, as well as myocyte cross-sectional area and the expression of ANP, BNP and Myh7. In vitro, TAM showed a dose dependent inhibitory effect on phenylephrine-induced hypertrophy in H9c2 cardiomyocytes. Furthermore, TAM reversed cardiac remodeling of stress overloaded heart by suppressing apoptosis and the expression of fibrotic-related genes, reduced oxidative stress and ROS production both in vivo and in vitro. In addition, TAM could negatively modulate TAC-induced nuclear translocation of NFAT and the activation of PI3K/AKT signaling pathways. Therefore, these data indicate for the first time that TAM has a protective effect on experimental cardiac hypertrophy and might be a novel candidate for the treatment of cardiac hypertrophy in clinic.

In vitro assessment of PD-L1+ microvesicles in the cyst fluid of non-syndromic odontogenic keratocysts Abstract Odontogenic keratocysts (OKCs) are jaw cystic lesions which are characterized by local invasion and high recurrence rate. The majority of OKCs are exposed to microorganisms and occur along with focal inflammatory infiltrates. Cyst fluids are biological fluids that contain a large content of cytokines and immune globulins. Inhibitory receptor such as programmed death receptor 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1), which can induce a coinhibitory signal in activated T cells, plays a vital role in the differentiation, exhaustion and apoptosis of T cells. Cell derived microvesicles, carrying a cargo of functional proteins, nucleic acids and lipids, are important communication tools in the development of diseases. However, the expression of PD-L1 in OKCs tissues and whether PD-L1 could be carried by microvesicles are unexplored. Presently, we have isolated cyst fluid microvesicles and identified cell derived PD-L1+ cyst fluid microvesicles. PD-L1 was located in the membrane of the cyst fluid microvesicles. The main cellular origins of PD-L1+ cyst fluid microvesicles were dendritic cells followed by lymphocytes. Elevated PD-L1+ cyst fluid microvesicles were detected in the OKCs compared with dentigerous cysts. Isolated cyst fluid microvesicles could bind to the membrane of activated CD8 T cells and inhibit proliferation of stimulated peripheral blood CD8 T cells. In conclusion, the present study suggests that elevated PD-L1+ cyst fluid microvesicles might be related with the cyst development of OKCs.

Impaired autophagy mediates hyperhomocysteinemia-induced HA-VSMC phenotypic switching Abstract Hyperhomocysteinemia (HHcy) is a highly-related risk factor in vascular smooth muscle cell (VSMC) phenotypic modulation and atherosclerosis. Growing evidence indicated that autophagy is involved in pathological arterial changes. However, the risk mechanisms by which homocysteine and VSMC autophagy interact with cardiovascular disease are poorly understood. This study verified the homocysteine-responsive endoplasmic reticulum protein promotion of VSMC phenotypic switching, and the formation of atherosclerotic plaque in vitro. We found that impaired autophagy, as evidenced by decreased levels of MAP1LC3B II/MAP1LC3B I, has a vital role in HHcy-induced human aortic (HA)-VSMC phenotypic switching, with a decrease in contractile proteins (SM α-actin and calponin) and an increase in osteopontin. Knockdown of the essential autophagy gene Atg7 by small interfering RNA promoted HA-VSMC phenotypic switching, indicating that impaired autophagy induces phenotypic switching in these cells. HHcy co-treatment with rapamycin triggered autophagy, which alleviated HA-VSMC phenotypic switching. Finally, we found that Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor for maintaining genomic stability by resisting oxidative stress and restoring autophagy, is closely involved in this process. HHcy clearly decreased KLF4 expression. KLF4-specific siRNA aggravated defective autophagy and phenotypic switching. Mechanistically, KLF4 regulated the HHcy-induced decrease in HA-VSMC autophagy via the m-TOR signaling pathway. In conclusion, these results demonstrated that the KLF4-dependent rapamycin signaling pathway is a novel mechanism underlying HA-VSMC phenotypic switching and is crucial for HHcy-induced HA-VSMCs with defective autophagy to accelerate early atherosclerosis.

Faster regeneration associated to high expression of Fam65b and Hdac6 in dysferlin-deficient mouse Abstract Dysferlin is a sarcolemmal muscle protein associated with the processes of membrane repair, trafficking, and fusion of intracellular vesicles and muscle regeneration. Mutations in the DYSF gene cause clinically distinct forms of muscular dystrophies. The dysferlin-deficient SJL/J mouse model presents a reduction of 85% of the protein but shows mild weakness and discrete histopathological alterations. To study the effect of dysferlin deficiency in the muscle regenerative process, we used a model of electrical injury by electroporation to induce muscle degeneration/regeneration in the SJL/J mouse. The relative expression of the genes Pax7, MyoD, Myf5, and Myog was accompanied by the histopathological evaluation during muscle recovery at different time points after injury. We also investigated the effects of dysferlin deficiency in the expression of genes encoding FAM65B and HDAC6 proteins, recently described as forming a tricomplex with dysferlin at the beginning of myoblast differentiation. We observed an altered time course through the process of degeneration and regeneration in dysferlin-deficient mice, with remarkable regenerative capacity characterized by a faster and effective response in the first days after injury, as compared to the WT mice. Also, dysferlin deficiency seems to significantly alter the gene expression of Fam65b and Hdac6 during regeneration, since higher levels of expression of both genes were observed in dysferlin-deficient mice. These results need further attention to define their relevance in the disease mechanism.

MIF/CD74 axis participates in inflammatory activation of Schwann cells following sciatic nerve injury Abstract Based on deep RNA sequencing of distal segments of lesioned sciatic nerves, a huge number of differentially expression genes (DEGs) were thus obtained and functionally analyzed. The inflammatory response was denoted as one of most significant biological processes following sciatic nerve injury. In the present study, ingenuity pathway analysis (IPA) demonstrated that macrophage migration inhibitory factor (MIF) was identified as a core regulator of inflammatory response through interaction with CD74 membrane receptor. By establishment of rat sciatic nerve transection model, we displayed that MIF was upregulated following sciatic nerve axotomy, in colocalization with Schwann cells (SCs). MIF promoted migration, proliferation, together with inflammatory responses of SCs in vitro. Immunoprecipitation showed that MIF interacted with CD74 receptor, through which to activate intracellular ERK and JNK signaling pathways. Interference of CD74 receptor using specific siRNA showed that the transcription of proinflammatory cytokines including TNF-α, IL-1β, as well as cytokine receptor TLR4 in SCs was significantly attenuated, supporting an participation of MIF/CD74 signal axis in SCs inflammatory response. The data provide a novel role of MIF in eliciting inflammatory response of peripheral nerve injury, which might be beneficial for precise therapy of peripheral nerve inflammation.

MicroRNA-494 targets PTEN and suppresses PI3K/AKT pathway to alleviate hypertrophic scar formation Abstract Hypertrophic scar is a common complication after skin injury. MicroRNAs have been reported related to hypertrophic scar through posttranscriptional control of genes. Hypertrophic scar-derived fibroblast model and mice incision model were used to see the expression of microRNA-494 and whether the level changes of microRNA-494 could affect scar formation. It was found that in hypertrophic scar, the expression of microRNA-494 decreased. However, after over-express microRNA-494 in fibroblasts, the levels of scar related molecules such as Col I, Col III increased. And when suppress the level of microRNA-494 in fibroblasts, the levels of collagen decreased. Moreover, the up-regulation of microRNA-494 led to decreased apoptosis of fibroblasts while the down-regulation of it led to increased apoptosis. Further, it was found that PTEN was one of the downstream targets of microRNA-494. The up-regulation of PTEN led to inactivation of PI3K/AKT pathway and the decreased expression of collagens. In conclusion, we confirmed that microRNA-494 could be a key regulator to suppress hypertrophic scar formation. The suppression of microRNA-494 could eliminate its inhibition effect to PTEN and finally decrease the expression of collagen and inhibit hypertrophic scar formation.

Differential antigen expression between human eccrine sweat glands and hair follicles/pilosebaceous units Abstract Eccrine sweat glands and hair follicles are two primary skin appendages that serve different functions. Although the two appendages exhibit unique morphological patterns in adults, it is difficult to distinguish them morphologically in the early stages of development and regeneration. To research and compare the development, differentiation and regeneration between eccrine sweat glands and hair follicles/pilosebaceous units, specific antigen markers must be found first. Human skin samples were fixed, paraffin-embedded, and cut. The expression of K5, K7, K8, K14, K27, K31, K73, AE13, α-smooth muscle actin (α-SMA), epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), Na+/K+-ATPase α and Na+–K+–2Cl cotransporter 1 (NKCC1) in eccrine sweat glands, hair follicles and sebaceous glands was detected by immunofluorescence staining. The results showed that eccrine sweat glands expressed K5, K7, K8, K14, K31, α-SMA, CEA, EMA, Na+/K+-ATPase α and NKCC1, but did not express K27, K73 or K31. Hair follicles expressed K5, K8, K14, K27, K31, K73, α-SMA and AE13, but did not express K7, CEA, Na+/K+-ATPase α or NKCC1. Sebaceous glands expressed K5, K14, K73, and EMA, but did not express K7, K8, K31, α-SMA, CEA, EMA, Na+/K+-ATPase α or NKCC1. We concluded that K7, CEA, Na+/K+-ATPase and NKCC1 can be used as specific markers for eccrine sweat glands, K27 and AE13 can be used as specific markers for hair follicles, and K73 can be used as a specific marker for pilosebaceous unit. These specific markers may contribute to differentiate between eccrine sweat glands and hair follicle/pilosebaceous units.

Osteoclastogenesis from bone marrow cells during estrogen-induced medullary bone formation in Japanese quails Abstract Osteoclasts are differentiated from hematopoietic mononuclear cells by regulation of the receptor activator of nuclear factor kappa-B (RANK)/receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) system. Medullary bone (MB) that forms in the bone marrow of female birds is remodeled under the control of circulating estrogen (E2) during the laying period. Although the osteoclasts of MB are differentiated from mononuclear cells, the mechanism of osteoclastogenesis is not known. We investigated whether MB osteoclastogenesis is regulated by the RANK/RANKL/OPG system using MB from male quails induced with E2. Bone marrow cells (BMCs) differentiate into osteoclasts that have the ability of bone resorption via stimulation of RANKL/M-CSF, but this ability is suppressed by OPG and differentiation is inhibited by calcinurin inhibitors. We found that BMCs at 3 days after E2 administration had high bone osteoclastogenesis ability and colony forming unit-granulocyte/macrophage (CFU-GM)/colony forming unit-macrophage (CFU-M) formation abilities. We conclude that MB osteoclasts are differentiated from BMCs by the RANK/RANKL/OPG system, and that precursor cells of osteoclasts are increased during MB formation.

Rilpivirine as a potential candidate for the treatment of HIV-associated neurocognitive disorders (HAND) Abstract As the HIV epidemic continues to contribute to global morbidity and mortality, the prevalence of HIV-associated neurological disorders (HAND) also continues to be a major concern in infected individuals, despite the widespread use of combination antiretroviral therapy. Therefore, current antiretroviral drugs should be able to reach therapeutic levels in the brain for the treatment of HAND. The brain distribution of the next-generation non-nucleoside reverse transcriptase inhibitor, rilpivirine (RPV) was investigated in healthy female Sprague–Dawley (SD) rats. The presented study involves the use of liquid chromatography-tandem mass spectrometry (LC–MS/MS) to estimate the concentrations of RPV in plasma and brain homogenate samples. The use of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) provided regional spatial distribution of RPV in brain tissue sections. The localization of RPV was found to be relatively high in the hypothalamus, thalamus and corpus callosum, brain regions known to be associated with neurodegeneration during HAND (including the cerebral cortex). This study has shown that RPV has an excellent blood–brain barrier penetrability. Thus, in combination with other antiretroviral drugs, better central nervous system (CNS) protection against HAND can possibly be achieved.

Akt plays indispensable roles during the first cell lineage differentiation of mouse Abstract The first cell lineage differentiation occurs during the development of mouse 8-cell embryo to blastocyst. Akt is a potent kinase whose role during blastocyst formation has not been elucidated. In the present study, immunofluorescence results showed that the Akt protein was specifically localized to the outer cells of the morula. Akt-specific inhibitor MK2206 significantly inhibited mouse blastocyst formation and resulted in decreased expression of the trophectoderm marker Cdx2 and led to granular distribution of ERα in the cytoplasm. Furthermore, knockdown of ERα by siRNA microinjection can also lead to a decrease in the development rate of mouse blastocysts, accompanied by a decrease in the expression level of Yap protein. We conclude that Akt may be indispensable for the first cell lineage differentiation of mouse.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Sophia

Problems with Compensation: Gleeson on Marilyn McCord Adams on Evil Abstract According to the most recent articulation of her view, Marilyn Adams's reply to the problem of horrendous evils states that God offers compensation to those who experience horrendous evils. This compensation includes the good of the incarnation of God and the good of identification with God in virtue of suffering horrendous evils. Andrew Gleeson has raised a series of objections to Adams's recent articulation. I argue that all of Gleeson's arguments fail or fail to pose a distinct challenge. I then present a different challenge: that her view provides insufficient compensation for horrendous evils. I conclude by suggesting a development of her view.

A Zhuangzian Critique of John Hick's Theodicy Abstract Hick's soul-making theodicy defends the omnipotence, omniscience, and all-goodness of God in the face of evil. It holds that the end of the creation process is the development of human beings into children of God. In order to achieve the end, an evil-dependent soul-making process must be employed. It then concludes that, because the end is so valuable, the omnipotent and omniscient creator's not having prevented the existence of evil is morally justified and thus not in conflict with her being all-good. In particular, God's having created a world with evils and evil-dependent values, which may be called "an Irenaean world," is morally justified. In the Zhuangzi, Zhuangzi holds that the actual world is, in reality, a world without evils and evil-dependent values, but with evil-independent values, which may be called "a Zhuangzian world," while ordinary people mistakenly take the actual world to be an Irenaean world. In an insightful story in the Chapter "The Great and Venerable Teacher" of the Zhuangzi, he amounts to claiming that a Zhuangzian world is better than an Irenaean world. Without endorsing Zhuangzi's two positions, I argue against Hick's soul-making theodicy in this way: It is Hick's burden to prove either that a Zhuangzian world is metaphysically impossible, or that the actual world, as an Irenaean world, is better than any Zhuangzian world. However, there are not any resources in his soul-making theodicy that can provide any such proofs. Therefore, Hick has not justified, nor rationally established, his soul-making theodicy.

In Defense of Physicalist Christology Abstract Physicalist Christology (PC) is the view that God the Son (GS), in the Incarnation, became identical with the body of Jesus. The goal of this paper is to defend PC from two recent objections. One is that if GS is a physical object, then he cannot have properties had by God (e.g., necessary existence). Then, by Leibniz's law, the incarnate GS cannot be identical with the second Person of the Trinity. The other objection is that PC implies that the incarnate GS did not exist in the interim period between his death and resurrection. PC then leads to the theologically absurd consequence that one of the three Persons of the Trinity did not exist during this period. I argue that the first objection fails because the very same argumentative strategy applies to the Incarnation on any view. As for the second objection, I endorse an animalist theory of death and argue that the incarnate GS continues to exist as a dead person from his death to resurrection. This shows that there is still continuing Trinity of GS during this period.

The Holy Trinity and the Ontology of Relations Abstract I reconsider in this article the problem of the Holy Trinity from the standpoint of some recent theories of the ontology of relations. After having presented the problem and after having introduced some basic ontological concepts (i.e., substance, modes, person), I shall briefly dwell on the ontology of non-symmetrical relations and on the O-Roles theory suggested by Francesco Orilia. Afterwards, I shall develop my own solution to the problem of the Holy Trinity by exploring the status of Intratrinitarian relations and of divine Persons. Among other things, I shall defend the thesis that divine Persons are not substances, but peculiar modes of God. I shall also ground the distinction between the properties attributed to God himself and the ones attributed to specific divine Persons. Finally, I shall anticipate and face some objections against my account (e.g., the one of modalism) and argue that it is legitimate to maintain that there is no kind of persons in general—which is a consequence of my view.

Won't Get Fooled Again: Wittgensteinian Philosophy and the Rhetoric of Empiricism Abstract The debate surrounding eliminative materialism, and the role of empiricism more broadly, has been one of the more prominent philosophical debates of the last half-century. But too often what is at stake in this debate has been left implicit. This essay surveys the rhetoric of two participants in this debate, Paul Churchland and Thomas Nagel, on the question of whether or not scientific explanations will do away with the need for nonscientific descriptions. Both philosophers talk about this possibility in language reminiscent of revolutionary politics. These authors do not see eliminative materialism merely as an idea to be evaluated, but a revolution to be welcomed or quashed. After surveying their rhetoric, the paper turns to the work of four philosophers—G.E.M. Anscombe, Peter Winch, Paul Holmer, and G.H. von Wright—to suggest that there is within Wittgensteinian tradition a 'nonrevolutionary' approach to the question of eliminative materialism.

What Matters in Caring: Some Reflections on Derek Parfit's On What Matters Abstract This essay is prompted by the recent publication of a volume of critical essays on Derek Parfit's On What Matters, along with a third volume of On What Matters responding to those essays. Parfit and his interlocutors often end up either barely engaging with one another, or engaging on terms that are often questionable. As others have done, I question Parfit's radical bifurcation of a merely 'psychological' sense of caring, of what it is for a thing or creature to matter, and a 'purely normative reason-implying sense' of those things. But I question it in a distinctive way, by emphasising its moral as well as its philosophical implications. I argue that what Parfit gives us with his 'normative, reason-implying sense' of caring and mattering is not an account of genuine moral-normative responsiveness but a morally impoverishing rationalistic distortion of it. In the last part of the essay, I briefly undertake to put my specific criticisms on a wider canvas.

Review of Robert D. Stolorow and George E. Atwood, The Power of Phenomenology: Psychoanalytic and Philosophical Perspectives

Wang Yangming's Reductionist Account of Practical Necessity: General and Particular Abstract In this article, I argue that we can have a plausible account of the experience of practical necessity, namely, the experience that some action is necessitated for someone, by referring to the philosophy of Wang Yangming (1472–1529), a Neo-Confucian philosopher in Ming Dynasty China. The experience of practical necessity, according to Wang, can be of two kinds: general (to be a human) and particular (to be a particular person), both having their bases on human nature and related to the fulfillment of the self. I argue that this account fares better than the non-reductionist account and other reductionist accounts, including Christine Korsgaard's, which explains the experience in terms of the constitution of the self.

The Force of Existence. Looking for Spinoza in Heidegger Abstract In the perhaps most decisive reopening of philosophy in the twentieth century, Heidegger presented an existential analytic. This can be viewed as the highly complex analysis of one simple action: being-there (Dasein). In the paper at hand, a Spinozist interpretation of this action is proposed. This implies a shift in the Aristotelian conceptuality, which, to a large extent, informs Heidegger's analysis. The action of being-there is not a movement from potentiality (δύναμις) to actuality (ἐνέργεια). It is a force of existence (vis existendi). However, this force is located right at the threshold between potentiality and actuality. Accordingly, it is not a matter of dismissing Aristotle's concepts, but—with Heidegger—to observe carefully their deconstruction and pursue it to the point where these concepts become indistinct and where—beyond Heidegger—a Spinozian force of existence emerges.

Panentheism and the Conception of the Ultimate in John B. Cobb's Process Philosophy Abstract The concept of ultimate reality has an important role in the metaphysics of religious pluralism. John B. Cobb—a process philosopher in the Whiteheadian tradition—has suggested not only two ultimates, like other process philosophers, but three ultimates: God, creativity, and the cosmos. Based on this, I argue, firstly, that Cobb's tripartite conception of the ultimate offers greater conceptual resources for inter-religious dialog than, for example, John Hick's conception of ultimate reality or 'the Real'. In support of this first claim, I will apply Cobb's conception of the ultimate to Zen-Buddhism, thus exemplifying the resources of this conception. Secondly, given the conclusion that Cobb's conception of the ultimate does indeed offer greater conceptual resources, I further explicate how panentheism, understood as the thesis of a transcendent, immanent divine being who is bilaterally related to the world, can be read in terms of Cobb's conception of the ultimate. I thus argue that panentheism in general inherits and retains many of the conceptual resources of Cobb's understanding of the ultimate, and can be seen as a preferable position in relation to religious pluralism. Finally, I conclude from the example of Zen-Buddhism that, although Cobb's conception offers greater resources for engaging in a dialog from a metaphysical point of view, work has to be done to adequately address questions on the level of soteriology.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

DGNeurologie

Die Rubrik „Im Fokus"

Tiefe Hirnstimulation des Kleinhirns reduziert die Ataxie bei der shaker -Ratte

Vorsicht bei der Vernichtung von Patientenunterlagen

Intrathekale Nusinersentherapie bei Erwachsenen mit spinaler Muskelatrophie

Akinetisch-rigide Bewegungsstörungen unter Antikonvulsiva

Magazin

Neuromyelitis-optica-Spektrum-Erkrankung

Facharzt für Neurologie

Erster epileptischer Anfall Zusammenfassung Ziel der Diagnostik nach einem ersten Anfallsereignis ist zunächst die ätiologische Einordnung, ob ein epileptischer Anfall vorliegt. Bei Bestätigung ist das Risiko für weitere Anfälle einzuschätzen. Ein erster epileptischer Anfall ist nicht gleichbedeutend mit der Diagnose Epilepsie. Erste epileptische Anfälle können in engem zeitlichen Zusammenhang nach akuten strukturellen, toxischen, infektiösen oder metabolischen zerebralen Schädigungen als akute symptomatische Anfälle auftreten. Diese haben ein geringes Rezidivrisiko, weshalb keine dauerhafte antikonvulsive Therapie empfohlen wird. Bei Nachweis interiktaler epilepsietypischer EEG-Potenziale (EEG: Elektroenzephalographie) und/oder potenziell epileptogenem Bildbefund kann nach erstem Anfall bereits die Diagnose einer Epilepsie und damit die Indikation zur antikonvulsiven Therapie gestellt werden. Erste epileptische Anfälle, die keiner der beiden Kategorien zugeordnet werden können, sollen nicht antikonvulsiv behandelt werden.

Paranoide Schizophrenie mit subakuter Ataxie, Okulomotorikstörung und Parkinsonsyndrom

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com