Biological Dysfunction Research Articles

Increased Lead Biomarker Levels Are Associated with Changes in Hormonal Response to Stress in Occupationally Exposed Male Participants

Background: Lead (Pb) exposure has been associated with a host of pathological conditions in humans. In rodents Pb exposure has been shown to alter the hypothalamic–pituitary–adrenal (HPA) axis function.Objective: We investigated the effects of lead on responses of the HPA axis to a psychosocial laboratory stressor administered to Pb-exposed workers.Methods: Seventy male participants completed the Trier Social Stress Test (TSST). Serum cortisol (CORT) and plasma adrenocorticotropic hormone (ACTH) were assessed in response to and during recovery from the stressor. We measured Pb in blood, a biomarker of recent exposure, and in tibia bone by X-ray fluorescence (XRF), a biomarker of chronic exposure.Results: The TSST induced statistically significant increases in ACTH and CORT in the participants. At baseline, ACTH was not significantly higher (p = 0.052) in participants with higher blood Pb concentration, but CORT was significantly lower in these participants (p = 0.016). Adjusted linear regression models indicated a positive association between blood and bone Pb and the increase in ACTH in response to stress. However, Pb was not strongly associated with changes in CORT in response to stress. Pb was also associated with the ACTH:CORT ratio at baseline and throughout the course of the protocol, suggesting an adrenal hyporesponsiveness in participants with higher Pb concentrations.Conclusion: The altered HPA-axis stress response observed in participants exposed to higher levels of Pb further supports the idea that lead may contribute to a host of biological dysfunctions beyond the classical neurotoxic effects.

Increased Mitochondrial DNA Copy Number in Occupations Associated with Low-Dose Benzene Exposure

Background: Benzene is an established leukemogen at high exposure levels. Although low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses.Objectives: Our goals were to determine in a large multicenter cross-sectional study whether low-level benzene is associated with increased blood mitochondrial DNA copy number (mtDNAcn, a biological oxidative response to mitochondrial DNA damage and dysfunction) and to explore potential links between mtDNAcn and leukemia-related epigenetic markers.Methods: We measured blood relative mtDNAcn by real-time polymerase chain reaction in 341 individuals selected from various occupational groups with low-level benzene exposures (> 100 times lower than the Occupational Safety and Health Administration/European Union standards) and 178 referents from three Italian cities (Genoa, Milan, Cagliari).Results: In each city, benzene-exposed participants showed higher mtDNAcn than referents: mtDNAcn was 0.90 relative units in Genoa bus drivers and 0.75 in referents (p = 0.019); 0.90 in Milan gas station attendants, 1.10 in police officers, and 0.75 in referents (p-trend = 0.008); 1.63 in Cagliari petrochemical plant workers, 1.25 in referents close to the plant, and 0.90 in referents farther from the plant (p-trend = 0.046). Using covariate-adjusted regression models, we estimated that an interquartile range increase in personal airborne benzene was associated with percent increases in mtDNAcn equal to 10.5% in Genoa (p = 0.014), 8.2% (p = 0.008) in Milan, 7.5% in Cagliari (p = 0.22), and 10.3% in all cities combined (p < 0.001). Using methylation data available for the Milan participants, we found that mtDNAcn was associated with LINE-1 hypomethylation (–2.41%; p = 0.007) and p15 hypermethylation (+15.95%, p = 0.008).Conclusions: Blood MtDNAcn was increased in persons exposed to low benzene levels, potentially reflecting mitochondrial DNA damage and dysfunction.

Medico-ethical versus biological evaluationism, and the concept of disease

According to the 'fact-plus-value' model of pathology propounded by K. W. M. Fulford, 'disease' is a value term that ought to reflect a 'balance of values' stemming from patients and doctors and other 'stakeholders' in medical nosology. In the present article I take issue with his linguistic-analytical arguments for why pathological status must be relative to such a kind of medico-ethical normativity. Fulford is right to point out that Boorse and other naturalists are compelled to utilize evaluative terminology when they characterize the nature of diseases and biological dysfunctions. But the relevant 'biofunctional judgements' are no less factual and empirical for that. While it is indeed evaluative to say that biological dysfunctions involve failures to execute naturally selected functions, such judgments are not bound to entail anything about what is good or bad for us, and what should be treated or not. In the last part of the paper I ruminate briefly on the relationship between 'biological evaluationism', on my construal, and descriptions of 'causal biology'. As I note in my conclusion, a strict bioevaluative concept of disease can be valid for every species on earth, and thus be of particular usefulness in general biological contexts.

“Yo soy Yahvé, el que te sana” (Ex 15,26): enfermedad y salud en la Torá

That which is implied in the Torah as “health” and “illness” is not completely related to current Western culture perception of the issue. In ancient Israel, Yahweh is the main agent of its health and wellbeing; and the fulfillment of the Torah is prophylaxis against all kinds of health problems. It is this religious framework the one which allows the understanding of the biological dysfunction and the health problems mentioned in the Torah (infertility, physical disorders, skin diseases…) based on what the modern anthropology of health understands as the three dimensions of health problems: the biological one (disease), the subjective one (illness), and the social one (sickness).

A conceptual framework for the revision of the ICD‐10 classification of mental and behavioural disorders

A conceptual framework for the revision of the ICD‐10 classification of mental and behavioural disorders

Diagnostic evaluation of left-sided prosthetic heart valve dysfunction

Prosthetic heart valve (PHV) dysfunction is a rare, but potentially life-threatening, complication. In clinical practice, PHV dysfunction poses a diagnostic dilemma. Echocardiography and fluoroscopy are the imaging techniques of choice and are routinely used in daily practice. However, these techniques sometimes fail to determine the specific cause of PHV dysfunction, which is crucial to the selection of the appropriate treatment strategy. Multidetector-row CT (MDCT) can be of additional value in diagnosing the specific cause of PHV dysfunction and provides valuable complimentary information for surgical planning in case of reoperation. Cardiac magnetic resonance imaging (CMR) has limited value in the evaluation of biological PHV dysfunction. In this Review, we discuss the use of established imaging modalities for the detection of left-sided mechanical and biological PHV dysfunction and discuss the complementary role of MDCT in this context.

Is it possible to explain complex mental disorders at the biological level?

The Forum which appears in this issue of World Psychiatry and the one we published in the previous issue 1,2,3,4,5,6,7 aim to help practising clinicians to orient themselves in the huge mass of data which have accumulated in the past decades concerning the pathophysiology of two major mental disorders, schizophrenia and depression. It is a fact that the gap between the restricted circle of researchers working in this area and the large population of clinicians dealing with patients worldwide has been constantly increasing over the years. The average psychiatrist does not follow the progress of biological research with the same attention and confidence as the average clinician in the other branches of medicine. He either does not believe at all in that research, or does not expect that research to produce in the near future anything which may be of practical utility for his daily practice. Furthermore, he does not perceive the gradual accumulation of “evidence” as an indication of a continuing increase of “knowledge”, but rather as a sign of uncertainty and confusion. Is there anything, in the mass of biological data on schizophrenia and depression, which promises to become in the foreseeable future of any usefulness for everyday clinical practice? This is the question that the two Forums were expected to address, and the reader will see that the views expressed by the participants are quite different. They can be schematically reconducted to two main positions. The first position is that we are on the wrong track. This may be because the current characterization of the phenotypes (schizophrenia and depression) is inadequate, or because these conditions are very heterogeneous and largely overlap with each other, or because the biological level at which our current research efforts are being displayed (e.g., neuronal circuits, neurotransmitters) is very far from the one at which a convincing explanation of the disorders is likely to be found; or because brain dysfunctions can only account for a vulnerability to something which emerges at the interface between the brain and the world of interpersonal relationships, so that many different brain dysfunctions can be found in patients with schizophrenia or with depression, but the essence of these disorders cannot be delineated at the biological level. The second position is that we are on the right track, but we are dealing with conditions that are very complex, much more than those which are the subject of investigation of the other branches of medicine. The functions which are perturbed in schizophrenia and in depression are the most complex of human beings. Most of them involve an interaction between such a composite organ as the brain and the even more composite world of interpersonal relationships in which all of us are immersed. It is not surprising that research is progressing so slowly and that many alternative avenues are being pursued. Our current technology and modeling may not be adequate to address that complexity, and the future may bring out very important advances in this respect. Furthermore, we cannot expect a single model to explain all the constituents of the complex picture of schizophrenia or depression: “decomposing” these disorders in their various elements may be very helpful. On the other hand, the many models which are currently proposed should not be regarded as mutually exclusive: they may address different levels of the complexity and may turn out to be consistent with each other. Time will tell whether it is possible to explain complex mental disorders at the biological level, or whether biological dysfunctions can only account for various pathways of vulnerability to those disorders, whose identity emerges at a higher level. Meanwhile, we hope these Forums will offer to our readers a clear and accessible picture of the ongoing research and of the hypotheses which are currently put forward.

Are We Heading Into a Workforce Crisis?

Thirty-three years ago, George Engel (1) contended that all of medicine was in crisis. The crisis, he suggested, had its origin in medicine’s adherence to a model of disease defined solely in terms of “somatic parameters”—a model that was no longer adequate for the “scientific tasks and social responsibilities” of the profession. Speaking of psychiatry, he stated that our specialty had been falsely polarized into those who held that psychiatry should concern itself with “problems of living” and, in contrast, those who held that the scope of psychiatry should be the identification, treatment, and cure of “biological brain dysfunctions, either biochemical or neurophysiological in nature.” Engel summarized that modern medicine was “faced with the necessity and the challenge to broaden the approach to disease to include the psychosocial without sacrificing the enormous advantages of the biomedical model,” which had become a “cultural imperative” in today’s society (1). Whether taken individually or together, the articles that make up this issue of Academic Psychiatry suggest that the biopsychosocial model has indeed emerged as a predominant paradigm in our field. It is clear that psychiatry concerns itself with problems of living as well as biologically driven conditions. It is clear that psychiatric educators concern themselves with preparing professional learners to provide pharmacotherapies as well as psychotherapies and to become astute scientists, teachers, clinicians, learners, advocates, and good citizens of the profession. Psychiatric educators work to help early career colleagues to serve in community-based programs and highly specialized academic centers and to be generalistspecialists as well as subspecialty experts. It is clear that psychiatrists-in-training have the courage to face tragedy, whether in caring for individual patients or seeking to help in truly catastrophic situations in our world, and they embrace their colleagues from many nations in their work.

Biological artificial valve dysfunction – single-centre, observational echocardiographic study in patients operated on before age 65 years

IntroductionPatients with implanted bioprostheses are at risk of structural dysfunction which results from the limited durability of biological valves. The aim of this study was to analyse the mechanism of bioprosthesis degeneration and to evaluate the usability of transthoracic and transoesophageal echocardiography in determining the indications for reoperation in 117 patients with a bioprosthesis implanted before 65 years old.Material and methodsThe study comprised 117 consecutive patients (M – 27, F – 90, age 48-74 years, 57.5 ±9.5 years) with a bioprosthesis implanted under the age of 65, who were examined in accordance with the accepted protocol and whose complete clinical and echocardiographic documentation was collected. The scheduled echocardiographic examination was performed annually from the 5 year after implantation of the bioprosthesis in patients with a valve implanted over the age of 35 years and from the 1 year after bioprosthesis implantation in patients with a prosthesis implanted at a younger age. Unscheduled echocardiographic examinations were performed only on clinical indications.ResultsDuring the period under observation, due to degeneration of the bioprosthesis 76 patients were reoperated, including 62 patients with mitral bioprostheses. In 88.7% of patients with degeneration of mitral valve bioprostheses, regurgitation was observed. In 69% of patients with aortic bioprostheses, valve dysfunction was the dominant mechanism of stenosis.ConclusionsThe most common mechanism of structural dysfunction of a mitral bioprosthesis is regurgitation caused by prolapse or perforation of one of the leaflets. Degeneration of an aortic bioprosthesis usually results in aortic stenosis. In cases of bioprosthesis degeneration connected with stenosis, transthoracic echocardiography was sufficient for the evaluation of valve dysfunction. In the case of bioprosthesis dysfunction accompanied by regurgitation, transoesophageal echocardiography was more informative to decide when the operation should be performed.

HomoFRET Fluorescence Anisotropy Imaging as a Tool to Study Molecular Self‐Assembly in Live Cells

Molecular self-assembly is a defining feature of numerous biological functions and dysfunctions, ranging from basic cell signalling to diseases mediated by protein aggregation. There is current demand for novel experimental methods to study molecular self-assembly in live cells, and thereby in its physiological context. Förster resonance energy transfer (FRET) between fluorophores of a single type, known as homoFRET, permits noninvasive detection and quantification of molecular clusters in live cells. It can thus provide powerful insights into the molecular physiology of living systems and disease. HomoFRET is detected by measuring the loss of fluorescence anisotropy upon excitation with polarised light. This article reviews recent key developments in homoFRET fluorescence anisotropy imaging for the detection and quantification of molecular self-assembly reactions in biological systems. A summary is given of the current state-of-the-art and case studies are presented of successful implementations, highlighting technical aspects which have to be mastered to bridge the gap between proof-of-concept experiments and biological discoveries.

Schizophrenia and the Dysfunctional Brain

Scientists, philosophers, and even the lay public commonly accept that schizophrenia stems from a biological or internal ``dysfunction.`` However, this assessment is typically accompanied neither by well-defined criteria for determining that something is dysfunctional nor empirical evidence that schizophrenia satisfies those criteria. In the following, a concept of biological function is developed and applied to a neurobiological model of schizophrenia. It concludes that current evidence does not warrant the claim that schizophrenia stems from a biological dysfunction, and, in fact, that unusual neural structures associated with schizophrenia may have functional or adaptive significance. The fact that current evidence is ambivalent between these two possibilities (dysfunction versus adaptive function) implies that schizophrenia researchers should be much more cautious in using the ``dysfunction`` label than they currently are. This has implications for both psychiatric treatment as well as public perception of mental disorders.

Comorbidity between ADHD and Obesity: Exploring Shared Mechanisms and Clinical Implications

Recent studies suggest an association between attention-deficit/hyperactivity disorder (ADHD) and obesity. In this article, we systematically review and critically discuss evidence on the prevalence of ADHD in obese patients as well as the weight status of individuals with ADHD. Relevant articles were searched in PubMed, PsychInfo, and ISI Web of Science (January 1980 to June 2010). We found that current evidence indicates a high prevalence of ADHD in clinical samples of patients seeking treatment for their obesity. Moreover, available studies show that individuals with ADHD have higher-than-average body mass index z scores and/or a significantly higher prevalence of obesity compared with subjects without ADHD. Three mechanisms underlying the association between ADHD and obesity have been proposed: 1) it is possible that obesity and/or factors associated with it (such as sleep-disordered breathing) manifest as ADHD-like symptoms; 2) ADHD and obesity share common biological dysfunctions; and 3) ADHD contributes to obesity. With regards to the possible clinical implications, our findings suggest that it is noteworthy to screen for ADHD in patients with obesity and to look for abnormal eating behaviors as possible contributing factors of obesity in patients with ADHD. Based on preliminary findings, appropriate treatment of ADHD may improve the weight status of individuals with both obesity and ADHD.

The cycling hair follicle as an ideal systems biology research model.

In the postgenomic era, systems biology has rapidly emerged as an exciting field predicted to enhance the molecular understanding of complex biological systems by the use of quantitative experimental and mathematical approaches. Systems biology studies how the components of a biological system (e.g. genes, transcripts, proteins, metabolites) interact to bring about defined biological function or dysfunction. Living systems may be divided into five dimensions of complexity: (i) molecular; (ii) structural; (iii) temporal; (iv) abstraction and emergence; and (v) algorithmic. Understanding the details of these dimensions in living systems is the challenge that systems biology aims to address. Here, we argue that the hair follicle (HF), one of the signature features of mammals, is a perfect and clinically relevant model for systems biology research. The HF represents a stem cell-rich, essentially autonomous mini-organ, whose cyclic transformations follow a hypothetical intrafollicular "hair cycle clock" (HCC). This prototypic neuroectodermal-mesodermal interaction system, at the cross-roads of systems and chronobiology, encompasses various levels of complexity as it is subject to both intrafollicular and extrafollicular inputs (e.g. intracutaneous timing mechanisms with neural and systemic stimuli). Exploring how the cycling HF addresses the five dimensions of living systems, we argue that a systems biology approach to the study of hair growth and cycling, in man and mice, has great translational medicine potential. Namely, the easily accessible human HF invites preclinical and clinical testing of novel hypotheses generated with this approach.

Age-related carbonyl stress and erythrocyte membrane protein carbonylation

Reactive carbonyl species (RCS) have been widely used as indicators of oxidative stress. However, the associations of carbonyl stress with aging process and biochemical alteration of erythrocyte are still poorly understood. Fresh blood samples in vacutainer tubes containing sodium heparinate were obtained from 874 volunteers who were divided into young, adult and old groups based on their age. Plasma RCS and thiols concentrations between different age groups and erythrocyte membrane protein carbonylation in the adult group were detected within 24h of the blood sampling. Results showed that the plasma thiols concentration decreased gradually during aging process, and the p-values between all three groups are less than 0.05. The plasma RCS concentration in different age groups showed a nonlinear association with age. The levels in the young group were slightly higher than the adult group (not significant) and lower than the old group (p < 0.01). The protein carbonylation of erythrocyte membrane was positively correlated with plasma RCS concentration (p < 0.01), but not plasma thiols concentration. We conclude that higher levels of RCS, not lower levels of thiols, in plasma are a direct risk factor for the protein carbonylation of erythrocyte membrane. Owing to the decrease of thiols levels and increase of RCS levels during aging process, a shift from RCS-related redox allostasis to carbonyl stress would contribute to age-related biological dysfunction and even aging process.

Does “Psychological Dysfunction” Mean Anything? A Critical Essay on Pathology Versus Agency

Any effort to discuss or study psychopathology (by any name) must decide how to distinguish between psychopathology and narratively comprehensible reactions to adverse circumstances of life. A pathology framework, which views the distressed individual as acted on by impersonal forces, is incompatible with an agential framework, which views the individual as the protagonist in a unique story. Although the Diagnostic and Statistical Manual of Mental Disorders ( DSM) recognizes this issue, it addresses it by postulating that “primary mental disorder” results from a “psychological dysfunction” and non—culturally sanctioned reactions to life events indicate mental disorder. In this essay, the authors examine whether the concept of “psychological dysfunction” can withstand an analogy to that of biological dysfunction. They also examine the DSM’s view that “culture” has already prepared an official evaluation of any reaction to the vicissitudes of life. They conclude that the DSM has failed to convincingly distinguish between psychopathology and reactions to life’s vicissitudes. They suggest that the DSM’s insistence on separating people’s feelings and actions from their own unique circumstances and context amounts to a moral, not scientific enterprise. The study of how people fare in living should abandon the concept of mental disorder and related terms.

The evolution of misbelief

From an evolutionary standpoint, a default presumption is that true beliefs are adaptive and misbeliefs maladaptive. But if humans are biologically engineered to appraise the world accurately and to form true beliefs, how are we to explain the routine exceptions to this rule? How can we account for mistaken beliefs, bizarre delusions, and instances of self-deception? We explore this question in some detail. We begin by articulating a distinction between two general types of misbelief: those resulting from a breakdown in the normal functioning of the belief formation system (e.g., delusions) and those arising in the normal course of that system's operations (e.g., beliefs based on incomplete or inaccurate information). The former are instances of biological dysfunction or pathology, reflecting "culpable" limitations of evolutionary design. Although the latter category includes undesirable (but tolerable) by-products of "forgivably" limited design, our quarry is a contentious subclass of this category: misbeliefs best conceived as design features. Such misbeliefs, unlike occasional lucky falsehoods, would have been systematically adaptive in the evolutionary past. Such misbeliefs, furthermore, would not be reducible to judicious - but doxastically noncommittal - action policies. Finally, such misbeliefs would have been adaptive in themselves, constituting more than mere by-products of adaptively biased misbelief-producing systems. We explore a range of potential candidates for evolved misbelief, and conclude that, of those surveyed, only positive illusions meet our criteria.

Functional impact of biological rhythm disturbance in bipolar disorder

Bipolar disorder (BD) is characterized by frequent recurrence, incomplete recovery, cognitive dysfunction and poor functioning. Impairment lingers in the interepisodic period and mechanisms leading to this dysfunctional state are not fully comprehended. To our knowledge the association of biological rhythm dysfunction with functioning in BD has not been assessed directly. The objective of this study was to measure and quantify the impact of rhythm dysfunction on interepisodic functioning in BD. We also tested the association between executive functioning and sleep and rhythm problems. Eighty-one outpatients with BD and 79 matched control subjects were consecutively recruited. Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and biological rhythms with the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). A subsample had their executive functioning assessed with the Wisconsin Card Sorting Test (WCST). Patients and control subjects were well matched. Functioning and rhythm scores were correlated in patients and control subjects. The BRIAN score was the strongest predictor of functioning in the regression model. Biological rhythms partially mediated the impairment associated with bipolar disorder. The rhythm score was also associated with executive functioning. Biological rhythm dysfunction was a potent predictor of functioning in interepisodic patients with bipolar disorder; it may also mediate much of the disorder-induced disability. These results further the notion that biological rhythms may be interesting targets for diverse interventions aiming to improve functioning and prevent relapse in interepisodic bipolar disorder.

S.08.03 Arc/Arg3.1 synthesis and control of LTp consolidation in the adult dentate gyrus in vivo

Primary neuronal cultures are widely used to elucidate fundamental aspects of neuronal anatomy, physiology, cell biology, and neuronal dysfunction in animal models of disease. However, preparation of primary neuronal cultures from rodent embryos is labor-intensive, and it is often difficult to produce high-quality cultures consistently in a single laboratory, and to compare results between laboratories. To overcome these issues, cryopreservation can be used to obtain more standardized, high-quality banks of neuronal cultures.In this study, we present a simplified cryopreservation method for rodent primary hippocampal and cortical neurons from embryonic day 18.5 fetuses, using DMSO-containing traditional cell freezing medium.Cryopreserved neurons stored for more than 1 year in liquid nitrogen were assessed by cell imaging, as well as biochemical signaling transduction and gene expression in response to pharmacological treatments. Cryopreserved neuronal cultures were comparable to freshly prepared cultures in terms of: (1) neuronal viability, (2) neuronal morphology and maturation, (3) functional synapse formation, (4) stimulus responsiveness. These results indicate that DMSO-cryopreserved neurons are equivalent to freshly prepared neurons both developmentally and functionally.Our method is simple and does not require special reagents or equipment.Introduction of the cryopreserved neurons as a standard laboratory practice has the potential to increase the robustness and reproducibility of findings between laboratories and reduce the number of animals used in research.

Food for thought: autophagic vacuolar myopathies

Most paediatricians are familiar with the terms lysosomal storage disorders (LSDs) and neuromuscular disorders (NMDs), and these disease entities seem to have little in common. Here, I am giving a...

Disability and diagnosis: should role impairment be eliminated from DSM/ICD diagnostic criteria?

Disability and diagnosis: should role impairment be eliminated from DSM/ICD diagnostic criteria?