Figure Figure1 Research Articles

The first 100 years of the ILAE (1909-2009): Its landmarks, achievements, and challenges.

The article was commissioned for the 110 anniversary of the founding of the ILAE, to provide a short summary of ILAE history, listing not only its landmarks and achievements but also its challenges. The League is an extraordinary, complex, and multifaceted organization, and within the small space allowed only the briefest and selective account is possible (and taken largely from its centenary history book1) (Figure ​(Figure1).1). It is with these caveats, and with the reader’s forbearance, that this article should be read. Open in a separate window Figure 1 Cover of International League Against Epilepsy 1909‐2009: a centenary history. The Figure has been reproduced with permission from reference1

Metformin, Oxidative Stress, and Infertility: A Way Forward.

Metformin, Oxidative Stress, and Infertility: A Way Forward.

A Dual Route Model of Empathy: A Neurobiological Prospective.

Human beings are physically independent but are psychologically connected. We spend a lot of time dealing with others' intentions, experiences, and internal states. The term empathy describes these phenomena. Previous studies defined empathy as “the ability and tendency to share and understand others' internal state” (Zaki and Ochsner, 2012). Consistent with this definition, accumulated empirical evidence showed that empathy is a multifaceted construct composed of two components, including affective empathy and cognitive empathy (Hoffman, 1984; Decety and Jackson, 2004; Singer, 2006; Uddin et al., 2007; Shamay-Tsoory et al., 2009; Barrett et al., 2016). Recently, ever-growing studies have considered empathy under different viewpoints (e.g., developmental trajectories, naturalism, disordered population, and so on), and have summarized the independence and non-independence of affective empathy and cognitive empathy (Barrett et al., 2016). These studies provide significant contributions to the progress of empathy research. However, we are not yet to fully understand the neurocognitive mechanisms between the affective empathy and cognitive empathy. Three major limitations restrict our knowledge toward empathy. First, it is rare to characterize cognitive and affective empathy in terms of processing speed and involvement of consciousness. Second, previous research often studies cognitive and affective empathy separately. It is hard to identify and explain the interactive nature between these two components. Third, influential factors, including attention and prior knowledge, have not yet been considered in the framework of empathy, thus under-estimating their impacts on empathy processing. Attention and prior knowledge are closely linked with the two aforementioned limitations, specifically processing speed and consciousness involvement as well as the integration of affective empathy and cognitive empathy. Thus, these two factors are discussed in the present opinion. To address these limitations, the present opinion proposes a novel and general framework to summarize both behavioral and neural evidence in the literature. The proposed dual route model of empathy is mainly composed of an automatic, fast, and specific “lower route” with affective empathy as well as a complex, slow, and iterative “higher route” with cognitive empathy. This proposed empathy model aims to integrate these two routes and to include the influences of attention and prior knowledge. Previously, in the domain of emotion neuroscience, Joseph LeDuox, a pioneer to study emotions, proposed a framework with two parallel neural systems, namely a low road and a high road (LeDoux, 1998). Specifically, the low road, which is a fast, subcortical, short-latency pathway with minimal cortical involvement, directly conveys sensory information from the thalamus to the amygdala, allowing stimuli to be processed automatically without consciousness and awareness (Davis, 1992; LeDoux, 1995, 1997). These features of rapid and automatic processes construct the low road emotion processes. In contrast, the high road indicates the visual pathways from retina neuron to visual cortex, and then connects to inferior temporal lobe for processing higher level consciousness of emotion feeling, and finally directs to the amygdala (LeDoux, 1998). These features of slow processing and more involvement of consciousness establish the high road of emotion. The present opinion hypothesizes that empathy also has a similar dual route system, which includes an automatic, fast and lower-level route (i.e., lower route) and a complex, slow and higher-level route (i.e., higher route), inside our brain (Figure ​(Figure1).1). The rest of the paper is organized as a series of introductions for each component of empathy. Also, we consider these components in the proposed dual route model of empathy in order to obtain the whole picture of the empathy processing. Open in a separate window Figure 1 The conceptual visualization for the proposed dual route model of empathy.

Assessing Disease Severity in Common Variable Immunodeficiency Disorders (CVID) and CVID-Like Disorders.

Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic primary immune deficiency (PID) in adults. Current estimates suggest a prevalence of ~1:25,000, although a recent study has suggested an even greater frequency than previous estimates (1). The majority of CVID patients suffer recurrent infections because of late onset antibody failure (LOAF) leading to immune system failure (ISF). Current criteria do not allow CVID to be diagnosed before 4 years although some patients have symptoms dating back to infancy. Most patients experience recurrent or severe bacterial infections and less commonly autoimmunity as a result of CVID. Some patients present with a sarcoidosis-like disorder or enteritis (2, 3). A proportion of patients with CVID have a prominent T cell defect leading to severe viral or opportunistic infections. These patients have been deemed to have late onset combined immunodeficiency (LOCID) (4). LOCID is currently separated from CVID although I have argued LOCID should be included as a subset of CVID (5). In spite of major progress in the last decade, the genetic basis of CVID is unknown in most patients. A causative mutation has been identified in up to 30% (6). If a causative defect is identified, these patients are removed from the umbrella diagnosis of CVID and are reclassified as having a CVID-like disorder caused by a specific mutation. To fulfill a diagnosis, all current CVID criteria require exclusion of other immunodeficiencies including NFKB1, NFKB1, CTLA4 etc. It is however likely earlier series of patients with CVID included many with CVID-like disorders, whose mutations were undiscovered. We have recently discovered new genetic defects in two NZ families with CVID-like disorders. In the first family, we have confirmed the existence of quantitative epistasis in humans (7). Epistasis is the non-linear, synergistic interaction of two or more genetic loci either leading to a much more severe disorder or a novel phenotype (8, 9). The existence of epistasis was first predicted by William Bateson in 1909 but has remained highly controversial because of the lack of well characterized examples in humans (10). In this family, the synergistic interaction of TNFRSF13B/TACI and TCF3 mutations resulted in a severe immunodeficiency and systemic lupus erythematosus (SLE) in the proband (Figure ​(Figure1).1). Other members of the family who have various permutations of the two mutated genes had a milder phenotype, which was reflected in their in vitro B cell differentiation and antibody production studies (7). Open in a separate window Figure 1 Family with a digenic CVID-like disorder caused by epistatic interactions of TNFRSF13B/TACI and TCF3 genes. The proband (arrow) suffers from both a severe immunodeficiency as well as SLE. Other members are as described in our previous publications including a mild symptomatic brother (II.3) with severe hypogammaglobulinemia caused by homozygous C104R mutations of the TNFRSF13B/TACI gene. CDSS, CVID disease severity score; CS, clinical score. The CS was suggested as means of determining eligibility for SCIG/IVIG but we have used it as a surrogate marker of disease severity (5, 7, 11).

Commentary: Aiming for Study Comparability in Parkinson's Disease: Proposal for a Modular Set of Biomarker Assessments to be Used in Longitudinal Studies.

We read the conclusions of Lerche et al. (2016) with great interest. Various definitions exist in the literature for biological markers (often shortened to biomarkers). In medicine, a biomarker may refer to an indicator based upon which an inference about the person's health can be made. The National Health Institute's Biomarkers Definitions Working Group (Biomarkers Definitions Working Group, 2001) defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.” Despite the recent interest in finding biomarkers for Parkinson's disease (PD; as evident from the number of “Parkinson's disease biomarker” articles indexed by the MEDLINE® Database; see Figure ​Figure1),1), an acceptable biomarker for PD remains to be elusive. Given the complexity underpinning PD's pathological processes, a useful single biomarker is unlikely to encompass the plethora of disease facets. However, the diverse features of PD's aetiological process and manifestations lend it particularly suited to have a number of biomarkers (of different categories and types) that serve distinct purposes at various stages of the disease. Figure 1 Increasing numbers of PD biomarker-related articles, as indexed by MEDLINE® as of January 2016, are appearing in the literature. Challenges facing PD biomarker research As with other neurodegenerative disorders, several hurdles face biomarker discovery in PD. Such challenges include the general complexity of the human CNS, limited access and availability of tissue for histological diagnosis during the patient's lifetime and the restricted number of clinical end-points and the lack of validation models for present ones (Dunckley et al., 2005). Added to these general obstacles are the diagnostic uncertainties surrounding PD, including disease heterogeneity and the potential for atypical parkinsonian syndromes. The multiplicity of disease aspects of PD make it difficult for a single all-purpose biomarker to ever exist. This is evident from the current lack of such a “Holy Grail” biomarker to date. By the same token, “reductionist”-type biomarkers focusing on single aspects of PD molecular neuropathology are unlikely to be overly clinically useful in the general schema of disease (Mielke and Maetzler, 2014). It seems, therefore, that several biomarkers of different types may be utilized in conjunction to identify the person's disease stage. Taking PD diagnosis as an example, no one single biomarker to date has demonstrated perfect sensitivity and specificity; even post-mortem pathological examinations can be inconclusive at times (Lees et al., 2009; Berg et al., 2013). Instead, the suggested tier-based system of different types of biomarkers (e.g., clinical assessment by a specialist, biofluid analysis, genetic testing and/or imaging studies) used in concert is much more likely to yield much needed diagnostic accuracy (Streffer et al., 2012; Schlossmacher and Mollenhauer, 2014).

Patient Similarity: Emerging Concepts in Systems and Precision Medicine.

Patient Similarity: Emerging Concepts in Systems and Precision Medicine.

New name for the soft coral Alcyonium rubrum Stokvis & van Ofwegen, 2006 (Alcyonacea, Alcyoniidae): Alcyonium burmedju nom. n.

Alcyonium rubrum Stokvis & van Ofwegen, 2006, an encrusting soft coral (Figure ​(Figure1),1), was described from the Northeast Atlantic Ocean based on specimens collected during the Dutch CANCAP VII Expedition to the Cape Verde Archipelago (Stokvis and van Ofwegen 2006). This species was later reported from the Azores (Braga-Henriques et al. 2013).

Wide Distribution of Genes for Tetrahydromethanopterin/Methanofuran-Linked C1 Transfer Reactions Argues for Their Presence in the Common Ancestor of Bacteria and Archaea

In this opinion article, I wish to highlight the fact that reactions linked to tetrahydromethanopterin (H4MPT) and methanofuran (MF), the ones involved in methanogenesis as well as in methylotrophy, are much more widespread among both Bacteria and Archaea than originally thought. While, over the past two decades, databases of the respective genes have been steadily growing and expanding to include novel, divergent sequences, belonging to a variety of taxa, somehow a view still prevails of the limited distribution of these genes, along with an evolutionary scenario in which genes for the methanogenesis pathway were horizontally transferred from Euryarchaea into Proteobacteria (Graham et al., 2000; Gogarten et al., 2002; Boucher et al., 2003; Braakman and Smith, 2012; Arnold, 2015). The two main arguments originally used to support this scenario were (1) the limited distribution of the H4MPT/MF-dependent pathway in the bacterial domain of life, and (2) the low probability of the respective genes being lost in most bacterial lineages (Boucher et al., 2003). However, these arguments can be easily refuted in the light of the current knowledge. In Figure ​Figure1,1, I utilize the recently constructed universal tree of life (Hug et al., 2016), to map the taxa in which at least some of the genes for the H4MPT/MF-dependent C1 transfers are recognized. Among the Archaea, these include, in addition to the well-characterized methanonogens or methane oxidizers, members of Euryarchaeota not known for a methanogenic life style (Thermoplasmatales, Hadesarchaea; Baker et al., 2016), members of Crenarchaeota (Thermoproteales, Ignisphaera, Ingnispaeroid; Goker et al., 2010; Jay et al., 2016), Bathyarchaeota (Evans et al., 2015; Lazar et al., 2016), and Thorarchaeota (Seitz et al., 2016). Among the Bacteria, genes for the H4MPT/MF-dependent reactions have been identified, beside Alpha-, Beta-, and Gammaproteobacteria (Vorholt et al., 1999), in the genomes of Planctomycetes (Chistoserdova et al., 2004; Chistoserdova, 2013), Deltaproteobacteria, Firmicutes, Actinomycetes, Synergistetes, Chloroflexi (Brown et al., 2011 and unpublished genomes available through the NCBI), as well as in the Candidate phylum NC10 (Ettwig et al., 2010). This wide distribution across the tree of life (Figure ​(Figure1),1), along with great sequence divergence for the genes in question (Chistoserdova, 2013; Evans et al., 2015; Spang et al., 2015) support a scenario of a long evolution within both Archaea and Bacteria, and point to the emergence of these reactions in early life, before Bacteria and Archaea have branched apart.

Lutein and Neurodevelopment in Preterm Infants.

Lutein and Neurodevelopment in Preterm Infants.

Book review: The Logic of Madness: A New Theory of Mental Illness

Book review: The Logic of Madness: A New Theory of Mental Illness

Why Broca's Area Damage Does Not Result in Classical Broca's Aphasia

Why Broca's Area Damage Does Not Result in Classical Broca's Aphasia

VMMC Devices-Introducing a New Innovation to a Public Health Intervention.

Innovation, whether related to drugs, vaccines, or even program design, can allow services to be provided in a timely and efficient manner and to be appealing to beneficiaries. Examples such as point-of-care CD4 cell counts, rapid malaria diagnostic tests, tuberculosis diagnosis by cartridge-based nucleic acid amplification test, rapid HIV test kits (and more recently HIV self-testing), and fixed-dose combination antiretroviral therapy innovations in HIV treatment and prevention improve the efficiency and reach of services. Choice is also an important factor in acceptability and uptake of health services, as seen in contraceptive programs where an increased number of options are associated with increased contraceptive uptake.1 A recent example of an innovation with potential impact is medical devices developed for adolescent and adult voluntary medical male circumcision (VMMC) HIV prevention programs. VMMC progress in the 14 priority countries of southern and East Africa is an impressive public health HIV prevention effort. By the end of 2015, 10 million males had been provided with medical circumcision by HIV prevention programs, the vast majority also receiving HIV testing, many for the first time.2 Additionally, VMMC was one of 19 global health priorities referred to by the Copenhagen Consensus Centre as a ‘best-buy’ to reach the sustainable development goals.3 Beyond the prevention of HIV infection, added benefits of VMMC include prevention of other sexually transmitted infections such as herpes simplex virus and human papillomavirus infections.4,5 Not to be forgotten is the fact that an uninfected partner is the best protection against the sexual transmission of HIV, and therefore, the HIV prevention beneficiaries of male circumcision include women and also men. A model for Zambia predicts that reaching a goal of 80% circumcision among males of 15–49 years would reduce HIV incidence among females as much as 26% in the long term.6 Models predict that in some countries, almost half of HIV infections averted within a generation's time of VMMC scale-up will be among women.7 Achieving VMMC coverage of priority populations is not without challenges and complexities, including cultural barriers, establishment of new supply chains, need for high-quality services, creation of demand for services, funding, and need for efficiencies for service delivery.8 Given the goal of VMMC scale-up at a time of decreasing resources for primary prevention modalities, strategies and innovations are needed to improve accessibility, increase uptake of services, ensure sustainability, and improve cost efficiencies, all while maintaining public trust and safety of the program. In contrast to conventional surgical methods, medical devices for circumcision of adults and adolescent males are an innovation that may alleviate some scale-up challenges through the elimination of complexities inherent to surgery, including the need for sutures and injected anesthesia. Device-based techniques are typically shorter, easier to learn, simpler to perform, and have been safely conducted by nurses. Devices have thus been promoted as a means to extend the reach of programs, reduce costs, and potentially increase demand and program efficiency, while maintaining or even improving on safety.9 Advantages need to be weighed against the requirement that clients return 7 days after device placement for removal, whereas follow-up after surgical VMMC is voluntary. Two medical devices for adolescent and adult VMMC, PrePex and ShangRing, have been prequalified by World Health Organization (WHO) and can be used in VMMC programs supported by the President's Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund for AIDS, Tuberculosis and Malaria.10 Initial research on devices demonstrated safety and acceptability in the setting of clinical trials.11,12 Despite this, additional questions that cannot be answered in the clinical trial setting remain, including requirements and timelines for in-country regulatory processes, safety with use in routine service delivery settings (including at fixed, outreach, and mobile service delivery sites), strategies for integration of devices into ongoing programs, client demand, impact on program reach, and the cost of services. To further explore these issues, the Bill & Melinda Gates Foundation and PEPFAR developed a systematic research agenda, independent from device manufacturers, to understand the potential of devices to accelerate VMMC scale-up. As part of the evaluation agenda, it was also important that questions be addressed in contexts as close as possible to “real-life” scaled programs. This collection of 16 articles examines research on the introduction of the 2 devices prequalified by WHO, PrePex, and ShangRing. These studies provide a firm body of evidence to inform development of recommendations regarding device introduction into VMMC programs already operating at scale. We offer a brief description of the findings on introduction, including on safety, supply, demand, and cost of VMMC using devices, as summarized in Figure ​Figure11. FIGURE 1. Framework for systematically assessing the role of devices in accelerating the scale-up and improving the efficiency of the VMMC program. COGS, cost of goods sold; HR, human resources; OR, operational research.

Process vs. Processor Accounts of Stage Models: A Cautionary Tale. Commentary: Seeing changes: How familiarity alters our perception of change.

Process vs. Processor Accounts of Stage Models: A Cautionary Tale. Commentary: Seeing changes: How familiarity alters our perception of change.

Commentary: Oxygen regulation of breathing through an olfactory receptor activated by lactate.

Commentary: Oxygen regulation of breathing through an olfactory receptor activated by lactate.

Commentary: Agroforestry leads to shifts within the gammaproteobacterial microbiome of banana plants cultivated in Central America.

Commentary: Agroforestry leads to shifts within the gammaproteobacterial microbiome of banana plants cultivated in Central America.

Commentary: Evaluation of Models of Parkinson's Disease.

GENERAL COMMENTARY article Front. Neurosci., 19 April 2016Sec. Neurodegeneration https://doi.org/10.3389/fnins.2016.00161

Will Benchtop Sequencers Resolve the Sequencing Trade-off in Plant Genetics?

Will Benchtop Sequencers Resolve the Sequencing Trade-off in Plant Genetics?

Commentary: Coordinating Thalamocortical Connections and Interneuron Migration in the Mammalian Cortex: Role of the Intermediates.

Commentary: Coordinating Thalamocortical Connections and Interneuron Migration in the Mammalian Cortex: Role of the Intermediates.

Controversies of the Effect of Ketamine on Cognition.

Controversies of the Effect of Ketamine on Cognition.

Are all chemicals endocrine disruptors?

Are all chemicals endocrine disruptors?