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As a reaction to Putnam’s multiple-realization argument, several philosophers have attempted to develop non-reductive physicalist theories in which the mental supervenes on its physical basis. Putnam himself presents a functionalist interpretation of the mind analogous to the functions of the software in a computer. The problem with functionalism in this version is that it presupposes that it is possible to simulate the mind regardless of whether it is a biological or non-biological matter upon which the functional “software” [or algorithm] is implemented. Another non-reductive theory regards the mental to emerge from the mechanisms operating in the brain. Seeing the mental as “emergent” from the physical not only implies different levels of reality, just like functionalism, but also allows the possibility of “downwards” causation in which events on the mental level may actively cause what happens on the physical level. Alternatively, to deny such a possibility makes the mental become a causally impotent epiphenomenon. The chapter concludes by rejecting the vertical perspective on the relation between the mental and the physical, which this debate presupposes.

The nature of consciousness remains one of the main unsolved questions in neurobiology. Although recent advances suggest that sooner or later we will be able to understand the neural mechanisms underlying awareness, it seems very difficult to understand how neural activity becomes a subjective experience, the so-called hard-problem of consciousness. The apparent intractable nature of this problem causes some scientists to avoid it altogether and deal only with the neural correlates of consciousness. However, for others, consciousness is an epiphenomenon, that is, something without a direct function, like the redness of blood – a characteristic which was not selected for, but was a consequence of the mechanism selected to deliver oxygen. In that view, qualia, the phenomenological experiences, correspond to internal discriminations that are reliable correlates of underlying neural mechanisms. Consciousness itself is not causal. It is the neural structures underlying conscious experience that are causal. In contrast, a hypothesis is proposed here for which the functional integration of cortical circuits could generate the conscious experience as a feedback mechanism that allows the brain to continuously alter its ongoing operation in order to get a very precise adjustment of the organism to its internal and external environment. This means that without consciousness the brain function would lose versatility and effectiveness.

The concept of ‘markedness’ has been influential in phonology for almost a century. Theoretical phonology has found it useful to describe some segments as more ‘marked’ than others, referring to a cluster of language-internal and -external properties (Jakobson 1968, Haspelmath 2006). We argue, using a simple mathematical model based on Evolutionary Phonology (Blevins 2004), that markedness is an epiphenomenon of phonetically grounded sound change.

It is a joyous relief when an event we dread fails to materialize. In fear extinction, the appetitive nature of an omitted aversive event is not a mere epiphenomenon but drives the reduction of fear responses and the formation of long-term extinction memories. Dopamine emerges as key neurobiological mediator of these related processes.

Purpose of review Excessive trabeculation attracting a diagnosis of left ventricular noncompaction cardiomyopathy (LVNC) has been reported in ostensibly healthy athletes. This review aims to explain why this occurs and whether this represents a spectrum of athletic physiological remodelling or unmasking of occult cardiomyopathy. Recent findings Genetic studies have yet to identify a dominant mutation associated with the LVNC phenotype and reported gene mutations overlap with many distinct cardiomyopathies and ion channel disorders, implying that the phenotype is shared across different genetic conditions. Large contemporary cohort studies indicate that current LVNC imaging criteria are oversensitive and not predictive of adverse clinical outcomes. Summary The majority of excessive LV trabeculation, as assessed by current quantification methods, is not due to cardiomyopathy but forms part of the normal continuum in health with potential contributions from cardiac remodelling processes. The study of rare, severe LVNC phenotypes may yield insights into an underlying molecular pathogenesis but in the absence of a universally accepted definition, contamination with aetiologically distinct conditions expressing a similar phenotype will remain an issue. Automated, objective quantification of trabeculation will help to define the normal distribution using big data without the constraint of wide interobserver variation.

The migratory movements of architects, town planners and landscape designers might appear to be an epiphenomenon when compared to the major upheavals experienced in the world in the twentieth century. Yet, the number and diversity of these different life paths can undoubtedly provide us with precious information on the circulation of ideas, techniques and know-how in the contemporary period. Whether these migrations were caused by economic reasons, or were a form of political exile or escape,...

Ever since the discovery of mirror neurons in the ventral premotor cortex (area F5) of the macaque brain, in the late 1980s, by Rizzolatti and his University of Parma colleagues, the question was put forward whether the same type of neurons could be found in the human brain. Could it be possible that these same neurons that activate not only when the monkey reaches for or takes a bite out of some sort of food -like a nut or a raisin- but also when someone picks it up to hand it to the monkey, be found in our brains? This essay does not have the scope to consider all concepts of empathy nor to include all relevant studies on mirror neurons concerning its relation to empathy. That being so, I shall take the following path: 1) introduce mirror neurons, what they are, where they are and their implications; 2) consider some aspects of empathy from different areas of research and present Edith Stein and Theodor Lipps's ideas; 3) relate the philosophers' ideas with the discussion put forward by Iacoboni, Gallese, Rizzolatti and Ramachandran concerning mirror neurons and empathy.

Migraine is one of the most prevalent and disabling neurovascular disorders worldwide. However, despite the increase in awareness and research, the understanding of migraine pathophysiology and treatment options remain limited. For centuries, migraine was considered to be a vascular disorder. In fact, the throbbing, pulsating quality of the headache is thought to be caused by mechanical changes in vessels. Moreover, the most successful migraine treatments act on the vasculature and induction of migraine can be accomplished with vasoactive agents. However, over the past 20 years, the emphasis has shifted to the neural imbalances associated with migraine, and vascular changes have generally been viewed as an epiphenomenon that is neither sufficient nor necessary to induce migraine. With the clinical success of peripherally-acting antibodies that target calcitonin gene-related peptide (CGRP) and its receptor for preventing migraine, this neurocentric view warrants a critical re-evaluation. This review will highlight the likely importance of the vasculature in migraine.

Recent studies suggest a role of the autoimmune system dysregulation in Frontotemporal dementia (FTD). In the present study, we performed a broad immunological screening in a large sample of sporadic FTD patients. We reported a significant increase of antinuclear autoantibodies (ANA) positivity in 100 FTD patients as compared to 100 healthy controls (HC) (60% vs. 13%, p .001). In FTD, ANA-positive and ANA-negative patients did not differ for any clinical feature. These data extend and further confirm autoimmune dysregulation in FTD. However, it still remains to be clarified whether these antibodies have a potential pathogenic role or represent simply an epiphenomenon.

There is an ongoing debate why a trait like human menopause should have evolved. Adaptive explanations explain menopause with fitness benefits of ceasing reproduction, whereas non-adaptive explanations view it as an epiphenomenon. Here we present data in support of non-adaptive explanations of menopause suggesting a maximum shelf-life of oocytes. By analyzing the association between lifespan and age at reproductive senescence across 49 mammal species, we find that the positive association levels off in long lived species, indicating that the age at reproductive senescence has an upper limit. Only in baleen whales there seems to be no evidence for reproductive senescence. We suggest that apart from the baleen whales, the confinement of reproductive senescence in long-lived species may be the result of physiological constraints imposed by the long period of time oocytes remain inactive in an arrested phase of meiosis from their production in utero until ovulation. We therefore conclude that menopause may be an implication of the long duration of meiotic arrest caused by semelgametogenesis together with long lifespan.

In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption.

The widespread use of MRI has led to a wealth of structural and functional anatomical findings in patients with diverse psychiatric disorders that may represent insights into pathobiology. However, recent technical reports indicate that data from popular MRI research-particularly structural MRI, resting--state functional MRI, and diffusion tensor imaging--are highly sensitive to common artifacts (e.g., head motion and breathing effects) that may dominate the results. Because these and other important confounders of MRI data (e.g., smoking, body weight, metabolic variations, medical comorbidities, psychoactive drugs, alcohol use, mental state) tend to vary systematically between patient and control groups, the evidence that findings are neurobiologically meaningful is inconclusive and may represent artifacts or epiphenomena of uncertain value. The authors caution that uncritically accepting from study to study findings that may represent fallacies of all sorts carries the risk of misinforming practitioners and patients about biological abnormalities underlying psychiatric illness.

Recently, conciliating findings from molecular genetics, evolutionary biology, along with empirical clinical evidence regarding the major mental disorders (MMDs) namely bipolar affective disorder (BPAD), schizophrenia, obsessive compulsive disorder (OCD), the anxieties with depression, autism and attention deficit/hyperactivity disorder (ADHD) all point to a common neural-developmental origin. Genetic loci associated with schizophrenia do not directly lead to the disorder; instead, they code for the expression of lopsided, temperamental, variants in individuals that originate mainly from one part of our human nature which applies also, to the rest of the MMDs. These individuals contribute to the flexibility, robustness, and creative input of our species, concomitantly, they incur vulnerability to the development of a MMD as an evolutionary trade off. MMDs initially, are expressed as periodic epiphenomena on the underlying temperamental extreme variants of brain function. Their expressions tend to become permanent. Underlying, aberrant traits remain unaltered. Their clinical expressions are characterized by “either-or”, antithetical substitutes, in addition to co-occurring psychosis. The latter is a common occurrence to other assaults on brain function. Characteristic, “ether-or” symptoms are the result of a disturbed, overall, coordinating property of brain function, normally responsive to the smooth, synchronizing expression of all higher mental faculties. Clinical findings point to the need of modifying the current schema in order to better reflect their collective significance in order to help guide research to a new, more promising direction in elucidating their triggers, development, and mechanisms whereby opening a new horizon for therapy and treatment.

Synchronous motor unit firing instances have been attributed to anatomical inputs shared by motoneurons. Yet, there is a lack of empirical evidence confirming the notion that common inputs elicit synchronization under voluntary conditions. We tested this notion by measuring synchronization between motor unit action potential trains (MUAPTs) as their firing rates progressed within a contraction from a relatively low force level to a higher one. On average, the degree of synchronization decreased as the force increased. The common input notion provides no empirically supported explanation for the observed synchronization behavior. Therefore, we investigated a more probable explanation for synchronization. Our data set of 17,546 paired MUAPTs revealed that the degree of synchronization varies as a function of two characteristics of the motor unit firing rate: the similarity and the slope as a function of force. Both are measures of the excitation of the motoneurons. As the force generated by the muscle increases, the firing rate slope decreases, and the synchronization correspondingly decreases. Different muscles have motor units with different firing rate characteristics and display different amounts of synchronization. Although this association is not proof of causality, it consistently explains our observations and strongly suggests further investigation. So viewed, synchronization is likely an epiphenomenon, subject to countless unknown neural interactions. As such, synchronous firing instances may not be the product of a specific design and may not serve a specific physiological purpose. Our explanation for synchronization has the advantage of being supported by empirical evidence, whereas the common input does not.

Bu çalışma, dil yetisinin ortaya çıkışında mutasyon sürecine uyum gösteren bakteri, virüs gibi mikro-organizmaların evriminin rolüne odaklanmaktadır. Dil yetisinin evriminde bu ilişkinin salt bir benzerlikten öteye geçtiğini, sensörial-motor sistemin gelişiminde mikrobiyomun (yani bedenimizi kalıcı veya geçici olarak kolonize eden tüm mikroorganizmaların) zorunlu bir rolünün olması gerektiğini ileri sürmektedir. Bu çerçevede çalışmada, bu ?krin (yani insan bedeninin tek bir organizma olmadığı, aksine çok sayıda organizmadan oluşan bir ekosistem olduğu ?krinin) arkaplanını oluşturan moleküler biyoloji ve mikrobiyolojideki yakın gelişmeler özetlenmekte ve bu gelişmelerden yola çıkarak dilin evrimi probleminin sınırları içinde şu ?kirler öne çıkarılmaktadır: 1.(Gould ve Chomsky'nin izinde) dil yetisi, uyarlanmanın aksine, bir epifenomen (side-effect) olarak ortaya çıkmış olabilir.2.Dilin epifenomen olarak ortaya çıktığı asıl adaptasyonel gelişme nedir öyleyse? Erken atamızın bipedal duruma evrilerek ellerinin serbest kalması olabilir.3.Türümüzü bipedal yapan evrimsel süreçte mikro-organizmik ekosistemin eşevriminin rolü göz ardı edilemez. O halde, mikrobiyomun evrimi beynin evrimi üzerinde doğrudan, dil yetisinin evriminde ise epifenomenal olarak etkilidir. This study focuses on the role of microorganismic (such as bacteria and viruses) evolution and microorganisms' accordance with mutation process in the context of language emergence. It also asserts that the relationship is not merely resemblance, rather the microbiome (the complete microbiota which either permanently or temporary colonize our body) plays a requisite role in the process of developing sensory-motor system. In this framework, this study brie?y describes contemporary developments in molecular biology and microbiology backs up the background of the idea that human body is not a single organism, on the contrary it is an ecosystem consists of many organisms. Within the limits of problem of evolution of language based on these developments, following ideas are put forward:1.(Following Gould and Chomsky) Language faculty might be emerged as an epiphenomenon (side-effect), not as an adaptation.2.Then, what is the real adaptational development that arised language as epiphenomenon? It might be our early ancestors who were evolved to bipedal position while getting an opportunity to set their hands free.3.In the evolution process which provided a transformation of our species to bipedal animals, the role of coevolution of microorganismic ecosystem could not be ignored. Then, the evolution of microbiome has an impact on language faculty sideeffectively, while being directly on brain evolution.

Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT): the first (somatic mutation) occurs only after the second (onset of cancer) and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature. A minority of all cancers is indeed caused by mutations but the SMT has been applied to all cancers, and even to chemical carcinogenesis, in the absence of hard evidence of causality. Herein, we review the 100 year story of SMT and aspects that show why genes are not just blueprints, how radiation and mutation are associated in a more nuanced view, the proposed risk of cancer and bad luck, and the in vitro and in vivo evidence for a new cancer paradigm. This paradigm is scientifically applicable for the majority of non-heritable cancers and consists of a six-step sequence for the origin of cancer. This new cancer paradigm proclaims that somatic mutations are epiphenomena or later events occurring after carcinogenesis is already underway. This serves not just as a plausible alternative to SMT and explains the origin of the majority of cancers, but also provides opportunities for early interventions and prevention of the onset of cancer as a disease.

Vitamin D is not only a key component in the maintenance of calcium homeostasis and bone health, but has also been implicated in a myriad of other non-skeletal biologic systems. The frailty syndrome is an emerging and increasingly important concept in the field of aging, with the "physical" clinical phenotype being initially presented as the operational definition. The relationship between vitamin D and frailty is postulated to be largely mediated via the development of sarcopenia, a condition characterised by a combination of the reduction of muscle mass, plus either muscle strength or performance. Several molecular pathways may account for the development of muscle wasting in sarcopenia, and there is mounting epidemiological and laboratory evidence that supports a role of vitamin D on muscle cell proliferation and function. Although observational studies on vitamin D and frailty have not definitively established an independent relationship, interventional studies of the effect of supplemental vitamin D have yielded a positive influence on the frailty status, mainly via improvements in the physical performance. Further studies that are adequately powered and well-designed are warranted in an attempt to establish a causal relationship between vitamin D and frailty. In the absence of a consensus on the definition of the frailty syndrome, an appropriate and well-validated measure instrument for this health outcome would be recommended in the realm of frailty research.

Many individuals with autism have epileptiform discharges on their EEG without having definite clinical seizures. The clinical significance of epileptiform activity in patients with autism is controversial. Some consider it an epiphenomenon of the underlying condition that should be ignored, and others believe that frequent spikes may contribute to the cognitive impairment and advocate treatment. Several studies have reported variable rates of epileptiform activity and variable response to treatment. There is an urgent need to conduct controlled clinical trials to assess the true incidence of epileptiform activity in children with autism, develop a risk assessment model, and study the effectiveness of treatment. This article is part of a Special Issue entitled "Autism and Epilepsy".

Coloration can play critical roles in a species' biology. The allometry of color patterns may be useful for elucidating the evolutionary mechanisms responsible for shaping the traits. We measured characteristics relating to eight aspects of color patterns from Graptemys oculifera and G. flavimaculata to investigate the allometric differences among male, female, and unsexed juvenile specimens. Additionally, we investigated ontogenetic shifts by incorporating the unsexed juveniles into the male and female datasets. In general, male color traits were isometric (i.e., color scaled with body size), while females and juvenile color traits were hypoallometric, growing in size more slowly than the increase in body size. When we included unsexed juveniles in our male and female datasets, our linear regression analyses found all relationships to be hypoallometric and our model selection analysis found support for nonlinear models describing the relationship between body size and color patterns, suggestive of an ontogenetic shift in coloration traits for both sexes at maturity. Although color is critical for many species' biology and therefore under strong selective pressure in many other species, our results are likely explained by an epiphenomenon related to the different selection pressures on body size and growth rates between juveniles and adults and less attributable to the evolution of color patterns themselves.

First clinical report of Harlequin color change (HCC) phenomenon came in 1952 from Neligan and Strang. Since then, HCC has been described in a fairly broad number of clinical reports involving neonates, infants, children, and adult patients. We here present a small case series of HCC occurring in neonates, pointing out three of the different possible presentations (hemifacial, patchy scattered across the whole body, and hemiscrotal) of this phenomenon. A brief discussion and literature review encompassing epidemiology, clinical features, physiopathology, associated conditions, and differential diagnoses of HCC is then presented. In most cases, HCC represents a benign, idiopathic, and rapidly autoresolutive phenomenon, with no need for treatment. Some drugs (especially anesthetics and prostaglandin E) are thought to enhance HCC expression through their influence on the capillary tone in the peripheral vascular bed; this effect is anyway promptly reversible with drug withdrawal. Only in rare circumstances, HCC may act as a clue for serious central nervous system disorders (e.g., meningitis; hypothalamic, brain stem, or sympathetic nervous system lesions); anyway, in these rare occurrences HCC always represents an epiphenomenon of the disease, never acting as the sole sign of the underlying disorder.

It is established that increased autophagy is readily detectable after various types of acute brain injury, including trauma, focal and global cerebral ischemia. What remains controversial, however, is whether this heightened detection of autophagy in brain represents a homeostatic or pathologic process, or an epiphenomenon. The ultimate role of autophagy after acute brain injury likely depends upon: (1) the degree of brain injury and the overall autophagic burden; (2) the capacity of individual cell types to ramp up autophagic flux; (3) the local redox state and signaling of parallel cell death pathways; (4) the capacity to eliminate damage associated molecular patterns and toxic proteins and metabolites both intra- and extracellularly; and (5) the timing of the pro- or anti-autophagic intervention. In this review, we attempt to reconcile conflicting studies that support both a beneficial and detrimental role for autophagy in models of acute brain injury.

Objectives To estimate associations between long‐term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care. Design Longitudinal analyses of electronic medical records. Setting England Participants Individuals aged 60 and older in primary care receiving PPIs for 1 year or longer (N=75,050) and age‐ and sex‐matched controls (N=75,050). Measurements Net hazard ratios for pneumonia incidence in Year 2 of treatment were estimated using the prior event rate ratio (PERR), which adjusts for pneumonia incidence differences before initiation of treatment. Inverse probability weighted models adjusted for 78 demographic, disease, medication, and healthcare usage measures. Results During the second year after initiating treatment, PPIs were associated with greater hazard of incident pneumonia (PERR‐adjusted hazard ratio=1.82, 95% confidence interval=1.27–2.54), accounting for pretreatment pneumonia rates. Estimates were similar across age and comorbidity subgroups. Similar results were also obtained from propensity score– and inverse probability–weighted models. Conclusion In a large cohort of older adults in primary care, PPI prescription was associated with greater risk of pneumonia in the second year of treatment. Results were robust across alternative analysis approaches. Controversies about the validity of reported short‐term harms of PPIs should not divert attention from potential long‐term effects of PPI prescriptions on older adults.

The role of antipituitary antibodies in the pathophysiology of pituitary hormone deficiency has been increasingly elucidated over the last decade. Prader-Willi syndrome is a genetic disorder which includes hypothalamic/pituitary dysfunction as one of its main features. We looked for autoimmune pituitary involvement in 55 adults with Prader-Willi syndrome, discovering that about 30% of them have a positive titer of antipituitary antibodies. Although the presence of these autoantibodies could only be an "epiphenomenon", our results suggest that autoimmune mechanisms might contribute, at least in part, to the pituitary impairment of Prader-Willi syndrome, and in addition to genetically determined dysfunction of the central nervous system. This paper provides a new perspective on pituitary impairment in these patients, suggesting that the search for hypophisitis could be a reasonable and interesting field for further research.

SummaryBiological circuits can be controlled by two general schemes: environmental sensing or autonomous programs. For viruses such as HIV, the prevailing hypothesis is that latent infection is controlled by cellular state (i.e., environment), with latency simply an epiphenomenon of infected cells transitioning from an activated to resting state. However, we find that HIV expression persists despite the activated-to-resting cellular transition. Mathematical modeling indicates that HIV’s Tat positive-feedback circuitry enables this persistence and strongly controls latency. To overcome the inherent crosstalk between viral circuitry and cellular activation and to directly test this hypothesis, we synthetically decouple viral dependence on cellular environment from viral transcription. These circuits enable control of viral transcription without cellular activation and show that Tat feedback is sufficient to regulate latency independent of cellular activation. Overall, synthetic reconstruction demonstrates that a largely autonomous, viral-encoded program underlies HIV latency—potentially explaining why cell-targeted latency-reversing agents exhibit incomplete penetrance.

Complexity and related phenomena exist as at least as “objective” and primary aspects/elements of the world as matter, space, and time. On the other hand, space, time, and matter become more and more subjective in modern physics. Complexity causes “something new” to emerge at the level of the whole complex system, which is not present at the level of the elements of this system and cannot be fully reduced to the interactions between these elements. This fact concerns both simple systems, such as atoms composed of a nucleus and electrons or (macro)molecules composed of atoms, as well as very complex systems such as living individuals built of (macro)molecules, organelles, cells, and organs, and conscious brains composed of networks of neurons. In other words, the dynamic complexity consisting of a special concrete spatiotemporal organisation of matter/ energy is as real as space, time, and matter themselves. Therefore, one can speak about the “objective” existence of such a “subjective” phenomenon as (self-)consciousness. The last phenomenon constitutes an aspect, epiphenomenon, or “by-product” of the functional complexity of the (part of the) neural network in the human brain. (Self-)consciousness is equivalent to a certain kind of such complexity and must emerge as a necessary aspect of an appropriately organised dynamic neural network. Therefore, for instance, zombies cannot exist or are even nonsensical. Each dynamic state of the neural network underling self-consciousness is univocally related to one psychic state, and inversely. It is postulated that the mind-body problem can be explained/resolved by a special kind of complexity, which consists of recurrent self-reference, directing on itself the “cognitive centre” in the neural network in the human brain.

Religion in contemporary society acts as a strategic resource, in the global, regional, and national and state developments. Religiosity becomes an epiphenomenon, not only in the context of its beingness as a significant characteristic of the mentality, but also as an institutional system. Manifesting itself as one of the fundamental characteristics of mentality religiosity points to the involvement of individuals, groups and society as a religion as the institutional framework governing the life of the communities with the help of symbolic belief systems corresponding ritual practices and traditions. The study of the states, the dynamics and the trends of religiosity helps to understand the trends of societal changes, which is extremely important in the development of mechanisms and strategies of social development.

It is fairly well accepted in the scientific community that atherosclerosis carries features of a local and low-grade systemic inflammation. However, it was unclear thus far whether this is simply an epiphenomenon or if it plays a causal role in atherosclerosis and its clinical complications. After several failed attempts, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence of interleukin-1 beta as a target whose neutralisation by a selective antibody reduces major cardiovascular events without affecting LDL-cholesterol. This provides strong evidence in support of the inflammation hypothesis and will certainly stimulate research in this area and open the way for novel therapy in high-risk patients following MI.

In this paper, the authors propose classifying the epiphenomenon of spinal deformity in two different categories: structural deformity, when the main driver of the observed deformity is a fixed and stiff alteration of the spinal segments, and compensatory deformity, which includes cases where the observed deformity is due to focal abnormalities. This last category comprises, but is not limited to, spinal stenosis, spondylolisthesis, disc herniation, infection or tumor, hip disease or neurological disease (such as Parkinson’s disease). Narrative review article. We analyzed the focal diseases of the spine that may cause a compensatory deformity inducing adaptation in the unaffected part of the spine. The compensatory mechanisms involved in adaptive deformity represent an attempt to maintain a global alignment, to escape from pain or to control body posture. These slides can be retrieved under Electronic Supplementary material.

Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Chronic hepatitis C virus infection (HCV) is the most common cause of HCC in many European countries, Japan and Pakistan. Introduction of the new direct acting antivirals (DAAs) has revolutionized the management of HCV worldwide, with high rates of sustained virologic response in patients who could not have tolerated the previous interferon based treatments. However, recently there have been reports raising caution about the long term effects of DAAs, particularly a possible increased risk of HCC. Therefore this review explores the current molecular studies as well as clinical data that investigate the impact of DAAs on occurrence and recurrence of HCC.

Cerebral amyloid angiopathy (CAA), first described in 1927 as a congophilic angiopathy associated with amyloid plaque in brains of patients with Alzheimer dementia,1 has an association with large and small intracranial hemorrhages (ICH). The differential diagnosis of ICH therefore includes CAA, especially in older patients or those without hypertension. The widely used Boston Criteria for diagnosis of CAA in vivo rely on the hemorrhagic characteristics of the disease.2 The pathophysiology of ICH in CAA remains uncertain. Thus, its prognosis, risk stratification, and clinical management present a challenge. Additional imaging features of CAA have contributed potential new perspectives on pathophysiology. The report of ischemic lesions in CAA may represent a novel concept for most clinicians accustomed to thinking about CAA as a hemorrhagic disease. The observation that Alzheimer dementia brains with severe amyloid angiopathy had more prevalent infarcts3–5 prompted subsequent investigations suggesting that amyloid deposition in small and medium-sized cortical vessels may play an active role in ischemia through pathologic thickening of the vessel wall, producing reduction or obliteration of the vessel lumen.6,7 Cortical superficial siderosis (cSS), easy to detect with modern MRI, is a striking and common feature of CAA. How these additional imaging features fit into a larger model of CAA remains unclear. Are they an epiphenomenon or can they teach us about the disease? In the current issue of Neurology® , a pair of articles suggest that CAA might be a multifaceted vascular entity in its own right, and elucidation of these newer features may increase our understanding of its pathophysiology, leading to better prognosis and management.

Why are neighbouring genes co‐expressed at the RNA level? While it is tempting to think that this is to enable coordination of functionally related proteins, analysis of human proteomics data by Rappsilber and colleagues (Kustatscher et al , 2017) suggests this is the exception not the rule. Rather it might either be just something that happens or, in some instances, an epiphenomenon of coordination of expression to enable reduced gene expression noise.

The fluorescence of many marine organisms is a visually compelling phenomenon. Descriptions of the phenomenon have at times been accompanied by suggestions of a visual function, but with minimal supporting evidence. It is possible to make quantitative estimates of the contribution of fluorescence emission to a visual signal under arbitrary illumination conditions. This analysis can help in deciding whether further research into a visual function is warranted, or whether the fluorescence is an interesting epiphenomenon associated with biomaterials that are present for other purposes. This paper describes the concepts associated with visual signals consisting of both reflected and fluoresced light, and methods for determining the underlying optical properties and using that information to model visual signal under environmentally relevant illumination conditions.

No abstract available Keywords: Coma; Cortical spreading depolarizations; Electroencephalography; Encephalopathy; Ischemia; Seizures.

Background Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges. Methods In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines. Results Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance. Conclusions Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3383-5) contains supplementary material, which is available to authorized users.

There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients., Shun-Fa Yang, Grant #CHS-2016-E-002-Y2.