Schizophrenia and smoking: evidence for a common neurobiological basis?

Several previous investigations have suggested that the gene for the alpha 7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the alpha 7-nicotinic receptor, 2) to test the diagnostic specificity of alpha 7-receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the alpha 7-nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co-occurrence of psychopathology with no clear-cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of alpha 7-receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:173-177, 2000.     

Schizophrenia and smoking: Evidence for a common neurobiological basis?

Several previous investigations have suggested that the gene for the α7‐nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the α7‐nicotinic receptor, 2) to test the diagnostic specificity of α7‐receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the α7‐nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co‐occurrence of psychopathology with no clear‐cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of α7‐receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:173–177, 2000. © 2000 Wiley‐Liss, Inc.     

Is there a common genetic basis for autoimmune diseases?

Autoimmune diseases (ADs) represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the "common genetic origin" theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sj?gren's (pSS) syndrome or type 1 diabetes mellitus (T1D). A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22) influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy) and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies.     

Major affective disorders and schizophrenia: a common molecular signature?

Psychiatric disorders, including affective disorders (AD) and schizophrenia (SZ) are among the most common disabling brain diseases in Western populations and result in high costs in terms of morbidity as well as mortality. Although their etiology and pathophysiology is largely unknown, family-, twin-, and adoption studies argue for a strong genetic determination of these disorders. These studies indicate that there is between 40 and 85% heritability for these disorders but point also to the importance of environmental factors. Therefore, any research strategy aiming at the identification of genes involved in the development of AD and SZ should account for the complex nature (multifactorial) of these disorders. During the last decade, molecular genetic studies have contributed a great deal to the identification of genetic factors involved in complex disorders. Here we provide a comprehensive review of the most promising genes for AD and SZ, and the methods and approaches that were used for their identification. Also, we discuss the current knowledge and hypotheses that have been formulated regarding the effect of variations on protein functioning as well as recent observations that point to common molecular mechanisms.     

A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms?

Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N?=?54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level?Cdependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward-related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group.     

Fibroadenoma and intraduct papilloma—a common pathogenesis?

This report describes two cases, each showing fibroepithelial proliferation, admixed with intraduct papillomas. Case 1 was from a 13-year-old female who presented with a breast mass, while case 2 was from a 60-year-old female who also had a breast lump. Case 1 showed proliferative breast disease with multiple small papillomas, some with leaf-like contours. Broad-based parenchymal proliferations protruding into ducts were also seen, and there were overlap features between the two ends of this spectrum. Case 2, similarly, demonstrated a mixed intraductal proliferation, with papillomas on narrow stalks together with low-grade phyllode areas extending into ducts from a wider base. That fibroadenoma and intraduct papilloma may have a common pathogenesis is discussed.     

Of skin and bone: did Langerhans cells and osteoclasts evolve from a common ancestor?

Skin Langerhans cells are antigen‐presenting cells of the interfollicular epidermis and the upper part of the hair follicle, whereas osteoclasts are specialized bone‐resorbing macrophages. Although at first view these two cell types appear to have little in common, a closer analysis reveals shared features, and when taking into account their surrounding environment, a hypothesis can be developed that Langerhans cells and osteoclasts have evolved from a common ancestral cell type. In this mini‐review, we have compared the ontogenetic features of Langerhans cells and osteoclasts from a genetic and a functional point of view, an issue that so far has been overlooked. The gene programs that control cell differentiation, and the body parts where they reside, present surprising similarities. Whereas the function of osteoclasts in bone degradation has been established since the first vertebrates, Langerhans cells may have undergone a stepwise adaptation from aquatic to terrestrial life. Their cell function co‐evolved with the imperatives of the skin to protect against physical impact, heat, water loss and pathogens, which implied the capacity of Langerhans cells to associate with skin appendages and to develop immunostimulatory functions. For the highly versatile and efficient immune system of modern vertebrates, Langerhans cells may be a memory of the past.     

Tel2: a common partner of PIK-related kinases and a link between DNA checkpoint and nutritional response?

A recent paper (Hayashi et al. 2007) in this issue of Genes to Cells shows that the fission yeast Schizosaccharomyces pombe Tel2, a homologue of mammalian/worm CLK2/Clk-2/Rad-5, physically interacts with all the phosphoinositide 3-kinase-related kinases (PIKKs) that include Rad3/Tel1 (ATR/ATM homologues), Tor1/Tor2 (TOR kinases) and Tra1/Tra2 (TRRAP homologues), raising the possibility that Tel2 family proteins link various PIKK-related cellular processes by interacting with PIKK family proteins. In this minireview, implications and impact of the findings, and a possibility that PIKKs are functionally related through Tel2, are discussed.     

Clinical medicine,public health and ecological health: a new basis for education and prevention?

In contrast to public health and the resolution to further increase the health care of the whole community in regions worldwide, current clinical medicine has its limits. Further improvement in public health – rather than individual diseases – can only be achieved by integrating new views into treatment. Some years ago, the concept of biopsychosocial medicine was integrated into patient treatment and is now generally accepted. Therefore the author describes here a new dimension to treatment and presents substantial evidence to include ecological health in this already existing concept. The problem of community education is discussed.     

Glycogenosis type I and diabetes mellitus: a common mechanism for renal dysfunction?

Diabetes mellitus and glycogen storage disease type I (GSDI) may initially appear disparate in metabolic profile: one characterized by uncontrolled hyperglycaemia due to disturbed insulin function and the other by fasting hypoglycaemia caused by impaired gluconeogenesis and glycogenolysis. However, they share a remarkably similar pattern and progression of renal dysfunction. This may be, we suggest, due to a convergence of their metabolic sequelae in upregulation of flux through the pentose phosphate pathway. This pathway yields triose phosphate molecules, which are precursors of the lipid, diacylglycerol (DAG). DAG plays an important role in the intrarenal renin-angiotensin system via the protein kinase C pathway. GSDI may be an interesting model which helps to unravel further the contributions of the many, varied nephropathic influences in diabetes. Conversely patients with this rare disorders would have much to gain from the innovative and vastly greater body of research carried out in diabetes.     

Stroke recovery and sensory plasticity: common mechanisms?

Presentations in this symposium are considered in the context of mechanisms of sensory plasticity, particularly in the auditory system. The auditory nervous system has two discrete end organs that are separately vulnerable to clinical and experimental injury, and brainstem processing mechanisms that are highly specialized for temporal, spectral, and spatial coding. These include giant axo-somatic synapses and neurons with spatially segregated bipolar dendrites, each innervated exclusively from one ear. This architecture allows exquisite control of afferent-target interactions, including known excitatory and inhibitory couplings, and consequently enhanced interpretation of data from other brain systems. For example, deafening can silence the auditory nerve, but has surprisingly little impact on normal brain function, as evidenced by the success of cochlear implants. The observed amplification from one brain region to another of degeneration following stroke or discrete brain lesions may thus be due to secondary rather than primary afferent consequences of the lesion.     

Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy?

Sepsis is a frequent complication of multiple organ dysfunction syndrome and remains a major problem of intensive care medicine. It is also a common factor in the final cause of death in hospital populations. Clinical observations, assisted by invasive monitoring techniques as well as pathological-anatomical studies, clearly indicate that microcirculatory dysfunction lies at the centre of sepsis pathogenesis. Numerous animal models, from rodents to primates, many of which employ bacteria or their toxins, especially endotoxins, have helped to shed light on the pathomechanisms leading to this dysregulation in the peripheral circulation. Among these are activation of humoral and cellular inflammatory mediator systems, with special emphasis on neutrophil-endothelial interactions, affecting endothelial barrier function and vasoregulation and ultimately leading to severely perturbed oxygen transport and utilization. In vitro studies have provided more insight into the molecular mechanisms involved in this microcirculatory dysfunction, although much more attention must be directed towards microvascular endothelial cells and the role of heterogeneity of response in various vascular beds. These experimental data must in turn be validated by comparing with the human in situ situation, both clinical and morphological. This review aims at a critical appraisal of the clinical and experimental evidence for sepsis-induced dysregulation of the microcirculation and how knowledge of the underlying cellular and molecular pathology could be used to make therapy more rational and effective. To date, therapeutic approaches, such as anti-cytokine and anti-oxidant regimens, which have been highly successful in experimental models, have failed to demonstrate clinical efficacy. Newer approaches, such as targeting the coagulation system, nitric oxide synthesis or intracellular signal transduction, are also discussed. The necessity to focus on the role of anti-inflammatory mediators, as well as the pathogenetic significance of important molecular groups, such as the heat shock proteins, which until now have been given scant attention, will be stressed.     

Evolution of neural crest and placodes: amphioxus as a model for the ancestral vertebrate?

Recent studies of protochordates (ascidian tunicates and amphioxus) have given insights into possible ancestors of 2 of the characteristic features of the vertebrate head: neural crest and placodes. The neural crest probably evolved from cells on either side of the neural plate-epidermis boundary in a protochordate ancestral to the vertebrates. In amphioxus, homologues of several vertebrate neural crest marker genes (BMP2/4, Pax3/7, Msx, Dll and Snail) are expressed at the edges of the neural plate and/or adjacent nonneural ectoderm. Some of these markers are also similarly expressed in tunicates. In protochordates, however, these cells, unlike vertebrate neural crest, neither migrate as individuals through embryonic tissues nor differentiate into a wide spectrum of cell types. Therefore, while the protochordate ancestor of the vertebrates probably had the beginnings of a genetic programme for neural crest formation, this programme was augmented in the earliest vertebrates to attain definitive neural crest. Clear homologues of vertebrate placodes are lacking in protochordates. However, both amphioxus and tunicates have ectodermal sensory cells. In tunicates these are all primary neurons, sending axons to the central nervous system, while in amphioxus, the ectodermal sensory cells include both primary neurons and secondary neurons lacking axons. Comparisons of developmental gene expression suggest that the anterior ectoderm in amphioxus may be homologous to the vertebrate olfactory placode, the only vertebrate placode with primary, not secondary, neurons. Similarly, biochemical, morphological and gene expression data suggest that amphioxus and tunicates also have homologues of the adenohypophysis, one of the few vertebrate structures derived from nonneurogenic placodes. In contrast, the origin of the other vertebrate placodes is very uncertain.     

Evolution of neural crest and placodes: amphioxus as a model for the ancestral vertebrate?

Recent studies of protochordates (ascidian tunicates and amphioxus) have given insights into possible ancestors of 2 of the characteristic features of the vertebrate head: neural crest and placodes. The neural crest probably evolved from cells on either side of the neural plate–epidermis boundary in a protochordate ancestral to the vertebrates. In amphioxus, homologues of several vertebrate neural crest marker genes ( BMP2/4 , Pax3/7 , Msx , Dll and Snail ) are expressed at the edges of the neural plate and/or adjacent nonneural ectoderm. Some of these markers are also similarly expressed in tunicates. In protochordates, however, these cells, unlike vertebrate neural crest, neither migrate as individuals through embryonic tissues nor differentiate into a wide spectrum of cell types. Therefore, while the protochordate ancestor of the vertebrates probably had the beginnings of a genetic programme for neural crest formation, this programme was augmented in the earliest vertebrates to attain definitive neural crest. Clear homologues of vertebrate placodes are lacking in protochordates. However, both amphioxus and tunicates have ectodermal sensory cells. In tunicates these are all primary neurons, sending axons to the central nervous system, while in amphioxus, the ectodermal sensory cells include both primary neurons and secondary neurons lacking axons. Comparisons of developmental gene expression suggest that the anterior ectoderm in amphioxus may be homologous to the vertebrate olfactory placode, the only vertebrate placode with primary, not secondary, neurons. Similarly, biochemical, morphological and gene expression data suggest that amphioxus and tunicates also have homologues of the adenohypophysis, one of the few vertebrate structures derived from nonneurogenic placodes. In contrast, the origin of the other vertebrate placodes is very uncertain.     

The perceptual control of goal-directed locomotion: a common control architecture for interception and navigation?

Intercepting a moving object while locomoting is a highly complex and demanding ability. Notwithstanding the identification of several informational candidates, the role of perceptual variables in the control process underlying such skills remains an open question. In this study we used a virtual reality set-up for studying locomotor interception of a moving ball. The subject had to walk along a straight path and could freely modify forward velocity, if necessary, in order to intercept—with the head—a ball moving along a straight path that led it to cross the agents displacement axis. In a series of experiments we manipulated a local (ball size) and a global (focus of expansion) component of the visual flow but also the egocentric orientation of the ball. The experimental observations are well captured by a dynamic model linking the locomotor acceleration to properties of both global flow and egocentric direction. More precisely the changes in locomotor velocity depend on a linear combination of the change in bearing angle and the change in egocentric orientation, allowing the emergence of adaptive behavior under a variety of circumstances. We conclude that the mechanisms underlying the control of different goal-directed locomotion tasks (i.e. steering and interceptive tasks) could share a common architecture.