The modes of inheritance of insulin-dependent diabetes mellitus or the genetics of IDDM, no longer a nightmare but still a headache.

The discovery of HLA antigen associations with juvenile-type insulin-dependent diabetes mellitus (IDDM) provided strong evidence separating this disorder, or group of disorders, from maturity-type noninsulin-dependent diabetes, as well as adding to the evidence for an immunologic pathogenesis. In addition, it was hoped that the use of these disease-marker associations in appropriate studies might clarify the genetics of IDDM. While these associations have provided a useful tool to further investigate the genetics and pathogenesis of IDDM, the mode or modes of inheritance of this group of disorders remain an area of great controversy. Susceptibility to IDDM is currently being proposed as being inherited as a single autosomal dominant, as a single autosomal recessive, as recessive and some dominant forms, in an intermediate gene dosage model, in a heterogeneous three-allele or two HLA loci model, and as a two-locus disorder. The arguments for each of these proposals is presented, as well as the problems of each. We surmise that the weight of evidence supports the heterogeneity hypothesis but that the modes of inheritance of IDDM will be fully resolved only when we can more reliably identify the diabetogenic genotype, rather than being limited in our investigations to the study of only full-blown clinical disease.     

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review

Neurodevelopmental disorders – including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders – manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence – from two or more studies from independent research groups, with results going into the same direction – of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.     

Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus.

Paramyotonia congenita (PC), an autosomal dominant muscle disease, shares some clinical and electrophysiological similarities with another myotonic muscle disorder, hyperkalemic periodic paralysis (HYPP). However, clinical and electrophysiologic differences allow differentiation of the two disorders. The HYPP locus was recently shown to be linked to a skeletal muscle sodium-channel gene probe. We now report that PC maps to the same locus (LOD score 4.4, theta = 0 at assumed penetrance of .95). These linkage results, coupled with physiological data demonstrating abnormal sodium-channel function in patients with PC, implicate a sodium-channel gene as an important candidate for the site of mutation responsible for PC. Furthermore, this is strong evidence for the hypothesis that PC and HYPP are allelic disorders.     

Anti-Narcoleptic Agent Modafinil and Its Sulfone: A Novel Facile Synthesis and Potential Anti-Epileptic Activity

We report a facile procedure to synthesize racemic modafinil (diphenylmethylsulfinylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modafinil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modafinil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modafinil is also nontoxic and almost as effective as an anticonvulsant as the parent.     

A Pilot Study of Neurofeedback for Chronic PTSD

EEG Biofeedback (also known as neurofeedback) has been in use as a clinical intervention for well over 30 years; however, it has made very little impact on clinical care. One reason for this has been the difficulty in designing research to measure clinical change in the real world. While substantial evidence exists for its efficacy in treating attention deficit/hyperactivity disorder, relatively little evidence exists for its utility in other disorders including posttraumatic stress disorder (PTSD). The current study represents a “proof-of-concept” pilot for the use of neurofeedback with multiply-traumatized individuals with treatment-resistant PTSD. Participants completed 40 sessions of neurofeedback training two times per week with sensors randomly assigned (by the study coordinator, who was not blind to condition) to sensor placements of either T4-P4 or T3-T4. We found that neurofeedback significantly reduced PTSD symptoms (Davidson Trauma Scale scores averaged 69.14 at baseline to 49.26 at termination), and preceded gains in affect regulation (Inventory of Altered Self-Capacities-Affect Dysregulation scores averaged 23.63 at baseline to 17.20 at termination). We discuss a roadmap for future research.     

New gene targets related to schizophrenia and other psychiatric disorders: enzymes, binding proteins and transport proteins involved in phospholipid and fatty acid metabolism.

Phospholipids make up about 60% of the brain's dry weight. In spite of this, phospholipid metabolism has received relatively little attention from those seeking genetic factors involved in psychiatric and neurological disorders. However, there is now increasing evidence from many quarters that abnormal phospholipid and related fatty acid metabolism may contribute to illnesses such as schizophrenia, bipolar disorder, depression and attention deficit hyperactivity disorder. To date the possible specific proteins and genes involved have been relatively ill-defined. This paper reviews the main pathways of phospholipid metabolism, emphasizing the roles of phospholipases of the A2 and C series in signal transduction processes. It identifies some likely protein candidates for involvement in psychiatric and neurological disorders. It also reviews the chromosomal locations of regions likely to be involved in these disorders, and relates these to the known locations of genes directly or indirectly involved in phospholipid and fatty acid metabolism.     

Old disease, new culprit: tumor stem cells in cancer

Eloquent studies from hematopoietic systems have provided proof that cancer arises from a tumor stem cell that possesses self-renewing properties. Until recently, it was believed that this tumor stem cell was unique to leukemic disorders; evidence now suggests that solid tumors also harbor cancer stem cells that are capable of initiating tumor growth in immunodeficient animals with as few as 10 cells. Consequently, the term "tumor-initiating cell" is now gaining favor within the field. Here, we conceptually discuss the current theories regarding tumor-initiating cells and their involvement in the development and progression of human malignancies. Special attention is given to laboratory techniques and strategies currently exploited to isolate tumor-initiating cells from larger populations, including their inherent strengths and weaknesses. The biological relevance of a tumor-initiating subpopulation is also pondered and arguments regarding their origin are presented. The therapeutic promise of targeting tumor-initiating cells is certainly eminent and we weigh the advantages of targeting this subpopulation. Lastly, the field of cancer stem cells appears to be well-placed to make significant strides over the next decade and we discuss potential obstacles that must be negotiated to achieve those objectives. The realization of these goals will undoubtedly further our understanding of this complex disease and should eventually lead to improved therapies in the not-so-distant future.     

An update on molecular genetic studies of human personality traits

Personality is a complex phenotype and people differ considerably when they are evaluated by self-report questionnaires. There is convincing evidence from twin studies that basic personality dimensions in men and women have a considerable genetic component. However, only recently have common genetic polymorphisms been associated with particular personality traits, especially the dopamine D4 receptor with novelty seeking and the serotonin transporter with anxiety-related traits or neuroticism. The current review examines progress in the past few years in molecular personality genetics and focuses on the reasons for difficulties in replicating first findings as well as the prospects for future studies in this area. The molecular genetic structure of human personality is worth studying both for its intrinsic interest in helping us to understand individual differences in human behaviour and the light it will shed on more complex behavioural disorders that are likely to partially share some common genetic variants.     

突触后致密物基因与孤独症

孤独症是一种病因不明的广泛性发育障碍疾病,它是孤独症谱系障碍的代表疾病,发病年龄早,大多在3岁以内起病,以社会交往障碍,言语交流障碍,动作行为的重复刻板和兴趣范围狭窄为三大临床核心症状。孤独症发病率呈逐年增高趋势,我国患者量已超过一百万。但是迄今为止仍没有特异的方法与手段对孤独症进行彻底有效地诊治,为社会和家庭带来了沉重的负担,因此,其发病机制是迫切需要研究的难题。目前国际上公认为遗传因素在孤独症的发病中起着重要作用,但对于致病基因的确定仍不明确。突触后致密物(PSD)在中枢神经系统神经递质和信息的传递过程中起重要作用,影响学习记忆及认知相关功能,而孤独症患者存在认知相关功能损伤的表现,二者可能存在一定的联系。本文对PSD基因功能以及与孤独症关系的研究加以综述,希望有助于孤独症的病因学研究,以期早日改善该病的诊疗及预防。     

The effectiveness of psychodynamic psychotherapies: An update

This paper provides a comprehensive review of outcome studies and meta‐analyses of effectiveness studies of psychodynamic therapy (PDT) for the major categories of mental disorders. Comparisons with inactive controls (waitlist, treatment as usual and placebo) generally but by no means invariably show PDT to be effective for depression, some anxiety disorders, eating disorders and somatic disorders. There is little evidence to support its implementation for post‐traumatic stress disorder, obsessive‐compulsive disorder, bulimia nervosa, cocaine dependence or psychosis. The strongest current evidence base supports relatively long‐term psychodynamic treatment of some personality disorders, particularly borderline personality disorder. Comparisons with active treatments rarely identify PDT as superior to control interventions and studies are generally not appropriately designed to provide tests of statistical equivalence. Studies that demonstrate inferiority of PDT to alternatives exist, but are small in number and often questionable in design. Reviews of the field appear to be subject to allegiance effects. The present review recommends abandoning the inherently conservative strategy of comparing heterogeneous “families” of therapies for heterogeneous diagnostic groups. Instead, it advocates using the opportunities provided by bioscience and computational psychiatry to creatively explore and assess the value of protocol‐directed combinations of specific treatment components to address the key problems of individual patients.     

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): I. Psychosis superspectrum

The Hierarchical Taxonomy of Psychopathology (HiTOP) is a scientific effort to address shortcomings of traditional mental disorder diagnoses, which suffer from arbitrary boundaries between psychopathology and normality, frequent disorder co‐occurrence, heterogeneity within disorders, and diagnostic instability. This paper synthesizes evidence on the validity and utility of the thought disorder and detachment spectra of HiTOP. These spectra are composed of symptoms and maladaptive traits currently subsumed within schizophrenia, other psychotic disorders, and schizotypal, paranoid and schizoid personality disorders. Thought disorder ranges from normal reality testing, to maladaptive trait psychoticism, to hallucinations and delusions. Detachment ranges from introversion, to maladaptive detachment, to blunted affect and avolition. Extensive evidence supports the validity of thought disorder and detachment spectra, as each spectrum reflects common genetics, environmental risk factors, childhood antecedents, cognitive abnormalities, neural alterations, biomarkers, and treatment response. Some of these characteristics are specific to one spectrum and others are shared, suggesting the existence of an overarching psychosis superspectrum. Further research is needed to extend this model, such as clarifying whether mania and dissociation belong to thought disorder, and explicating processes that drive development of the spectra and their subdimensions. Compared to traditional diagnoses, the thought disorder and detachment spectra demonstrated substantially improved utility: greater reliability, larger explanatory and predictive power, and higher acceptability to clinicians. Validated measures are available to implement the system in practice. The more informative, reliable and valid characterization of psychosis‐related psychopathology offered by HiTOP can make diagnosis more useful for research and clinical care.     

The Metabolic Syndrome - a global challenge for prevention.

In the last years we have learned a lot about the pathopysiology of a cluster of the diseases called Metabolic Syndrome but currently an exciting discussion debates the Metabolic Syndrome in a light of a mystery of medicine or a clinical paradigm with a controversary about diagnostic, treatment or preventive procedure. There is now convincing evidence that prevention is the most important and effective way to reduce the personal and socio-economic burden of the Metabolic Syndrome and its associated complications. Still, it is currently not clear how to implement preventive interventions into clinical practice but will require an integrated and transdisciplinary approach on an international level in order to efficiently reduce premature morbidity and mortality. Nevertheless, global strategies are still lacking but are needed to tackle inequalities in health between industrialized countries and the developing world. A global health strategy has to take into account political, epidemiological, environmental, infrastructural and genetic aspects. The Metabolic Syndrome is not a mystery - it is a clinical paradigm and global challenge.     

Vitiligo: Where Do We Stand?

Vitiligo is a puzzling disorder characterized by a disappearance of epidermal and/or follicular melanocytes by unknown mechanisms. This very common disorder involving 1–4% of the world population is thus of great importance for the practicing dermatologist. The cellular and molecular mechanisms leading to the destruction of melanocytes in this disorder have not yet been elucidated, making it of major interest for the cell biologist involved in melanocyte research. Recent advances in this field, due largely to the availability of techniques for culturing normal human melanocytes, opened new perspectives in the understanding of vitiligo. Although vitiligo has long been considered a disorder confined to the skin, there is now good evidence that it also involves the extracutaneous compartment of the “melanocyte organ.” It is also clear that vitiligo is not only a melanocyte disorder, but that it also involves cells, such as keratinocytes and Langerhans cells, found in the epidermis and follicular epithelium. The three prevailing theories of the pathogenesis of vitiligo are the immune hypothesis, the neural hypothesis, and the self-destruct hypothesis. New hypotheses suggest that vitiligo may be due to (1) a deficiency in an unidentified melanocyte growth factor, (2) an intrinsic defect of the structure and function of the rough endoplasmic reticulum in vitiligo melanocytes, (3) abnormalities in a putative melatonin receptor on melanocytes and (4) a breakdown in free radical defense in the epidermis. None of these hypotheses has been demonstrated, and according to the available data, it is likely that the loss of epidermal and follicular melanocytes in vitiligo may be the result of several different pathogenetic mechanisms.     

Broadening the diagnosis of bipolar disorder: benefits vs. risks

There is considerable debate over whether bipolar and related disorders that share common signs and symptoms, but are currently defined as distinct clinical entities in DSM-IV and ICD-10, may be better characterized as falling within a more broadly defined "bipolar spectrum". With a spectrum view in mind, the possibility of broadening the diagnosis of bipolar disorder has been proposed. This paper discusses some of the rationale for an expanded diagnostic scheme from both clinical and research perspectives in light of potential drawbacks. The ultimate goal of broadening the diagnosis of bipolar disorder is to help identify a common etiopathogenesis for these conditions to better guide treatment. To help achieve this goal, bipolar researchers have increasingly expanded their patient populations to identify objective biological or endophenotypic markers that transcend phenomenological observation. Although this approach has and will likely continue to produce beneficial results, the upcoming DSM-IV and ICD-10 revisions will place increasing scrutiny on psychiatry's diagnostic classification systems and pressure to re-evaluate our conceptions of bipolar disorder. However, until research findings can provide consistent and converging evidence as to the validity of a broader diagnostic conception, clinical expansion to a dimensional bipolar spectrum should be considered with caution.     

Getting under the skin: the immunogenetics of psoriasis

Psoriasis is a chronic inflammatory disorder of the skin that is mediated by T cells, dendritic cells and inflammatory cytokines. We now understand many of the cellular alterations that underlie this disease, and genomic approaches have recently been used to assess the alterations of gene expression in psoriatic skin lesions. Genetic susceptibility factors that contribute to predisposition to psoriasis are now also being identified. It is hoped that we will soon be able to correlate the cellular pathogenesis that occurs in psoriasis with these genetic factors. In this Review article, we describe what is known about genes that confer increased susceptibility to psoriasis, and we integrate this with what is known about the molecular and cellular mechanisms that occur in other inflammatory and autoimmune disorders.     

Are culture-bound syndromes as real as universally-occurring disorders?

This paper asks what it means to say that a disorder is a "real" disorder and then considers whether culture-bound syndromes are real disorders. Following J.L. Austin I note that when we ask whether some supposed culture-bound syndrome is a real disorder we should start by specifying what possible alternatives we have in mind. We might be asking whether the reported behaviours genuinely occur, that is, whether the culture-bound syndrome is a genuine phenomenon as opposed to a myth. We might be wondering whether the condition should rightly be considered a disorder, as opposed to some sort of non-disorder condition (for example, a non-disorder form of deviance, or a potentially valuable condition). We might want to know whether the culture-bound syndrome is really a distinct disorder, in the sense that scientific classification systems should include it as a separate category, or whether it is just a variant of a universally occurring disorder. I argue that some specific difficulties can arise with determining whether a culture-bound syndrome is a real disorder in each of these three senses. However, the frequent assumption that real disorders will necessarily occur universally, and that those that occur only in certain environments are suspicious is not generally justified.     

The neurobiology of apolipoproteins in psychiatric disorders

A genetic contribution to the transmission of psychiatric disorders has been established and it is now accepted that several genes confer susceptibility to schizophrenia, and similar disorders, giving rise to a complex polygenic mode of inheritance. With the high-throughput molecular profiling techniques available, apolipoproteins have emerged as being important factors in psychiatric disorders. This review will focus on three apolipoproteins that have recently been shown to be elevated in neuropsychiatric disorders: apoD, apoE, and apoL. Furthermore, the authors discuss the role of apoD in the pathology and pharmacotherapy of schizophrenia and bipolar disorder.     

Cattle MHC nomenclature: is it possible to assign sequences to discrete class I genes?

The cattle major histocompatibility complex (MHC) region contains a variable number of classical class I genes encoding polymorphic molecules involved in antigen presentation. Six classical class I genes have been described, but assigning sequences to these genes has proved problematic. We propose a refinement of the existing nomenclature, which currently names the 97 known classical class I sequences in a single series. Phylogenetic analysis of the 3' portion of the coding region allows segregation of these into six groups; thus, we have prefixed existing names with the appropriate number. Although it is clear that some of these groups correspond to discrete genes, it is currently not possible to state definitively that all do. However, the main groupings are consistent, and in conjunction with other evidence, we feel it is now appropriate to rename the sequences accordingly. Segregation of sequences into groups in this way will facilitate ongoing research and future use of the cattle MHC section of the Immuno Polymorphism Database.