Cognitive functioning and its heritability in bipolar I disorder

Bipolar I disorder is a severe psychiatric disorder characterized by episodic mood alterations that can be manic, depressive or mixed. Bipolar disorder seems to be highly genetic, but the etiology of this complex disorder has remained elusive. In recent years, studies have found that euthymic patients with bipolar disorder may have impairments particularly in executive functioning, verbal learning and memory. These impairments may be present also among some of the relatives of these patients, who may be vulnerable to the disorder. Using neuropsychological variables as endophenotypes, i.e. intermediate phenotypes between genes and the phenotypes, has been suggested to aid search for the etiological background of the disorder, but evidence is sparse on whether these variables fulfill the criteria for endophenotypes. The present thesis is part of the Genetic Epidemiology and Molecular Genetics of Severe Mental Disorders in Finland project. The specific aim was to investigate whether neuropsychological test variables would indicate genetic liability to the disorder and could therefore be regarded as endophenotypes. Thus, cognitive functions and their heritability were studied in bipolar I disorder patients and in their unaffected first-degree relatives from a population-based sample of families, comparing them to a population-based control group. In order to add homogeneity to the subgroups of bipolar disorder patients and their relatives, cognitive functions and their heritability were further studied in a group of families affected by bipolar I disorder only (bipolar families) and another group of families affected by both bipolar I disorder and schizophrenia or schizoaffective disorders (mixed families). Finally, the effect of processing speed on other cognitive functions was investigated. The study showed that especially executive functioning and processing speed fulfilled the endophenotype criteria. Impairments in these functions were found in bipolar patients and in their relatives irrespective of other severe psychopathology in the family. These functions were highly heritable in these families. Study also showed that generalized impairment in verbal memory may associate more with bipolar disorder than to vulnerability to other psychotic disorders, and be more related to fully developed disease; impairments in verbal learning and memory were found only in patients, and they were not found to be highly heritable. Finally, the most potential endophenotype, i.e. processing speed, seemed to contribute to a range of other cognitive dysfunctions seen in bipolar disorder patients. Processing speed, in particular, has also been shown to be a valid endophenotype in subsequent association analyses in psychiatric genetics in Finland and internationally. Information concerning cognitive impairments and their association with the psychosocial consequences of bipolar disorder is important in planning treatment. It is also important to understand and acknowledge that patients may have cognitive impairments that affect their everyday life. Psychosocial interventions and neuropsychological rehabilitation may supplement other conventional treatments for bipolar patients.

Determinants of Cognitive Impairment in Old Age and Their Genetic Architecture

Cognitive health is of central importance for independent and balanced old age, while memory disorders represent the leading cause of intensive and long-term care among the Finnish elderly. The aims of this study were to analyse the effect of height, body mass index, weight change, metabolic conditions and coffee drinking in midlife on cognitive performance in old age among a sample of 2606 Finnish twins aged 65 years or older who had participated in a telephone interview to assess their cognitive status. Since coffee drinking associates with several metabolic conditions and Finns are known to be the greatest consumers of coffee in the world, the heritability and stability of coffee drinking was analysed in the whole Older Finnish Twin Cohort (n=10716). In order to investigate the association between height and cognitive performance in a population with more supportive childhood living conditions, a total of 2161 Danish twins were included in this study. A greater height was found to clearly associate with better cognitive performance in Finnish subjects, but less so among the Danish sample, which may reflect the childhood environmental differences between these cohorts. In the Finnish subjects, there was greater variance in cognitive performance among shorter subjects, and environmental factors were found to play a greater role in their cognitive performance, whereas the cognitive performance of taller participants was mainly explained by genetic factors. Midlife metabolic variables that were found to be significantly associated with a poorer cognitive performance in old age included a higher body mass index and three metabolic conditions: cardiovascular disease, hypertension and, most significantly of all, diabetes. Moreover, both weight gain and loss, even to a lesser degree than suggested previously, were found to be associated with poorer cognition. Furthermore, evidence of a causal relationship between midlife cardiovascular disease and cognitive performance in old age was demonstrated among discordant twin pairs. Conversely, no effect of coffee drinking in midlife on cognitive performance in old age was observed, although coffee drinking was demonstrated to be stable in the study population. The heritability of coffee drinking was found to differ across sexes and age groups, being 51% in men and 52% in women in the whole study population. This study supports the contention that cognitive performance in old age reflects the effects of multiple genetic and environmental exposures, including their complex interactions during the life-span. The demonstrated associations and evidence of a causal pathway between potentially preventable exposures and poorer cognitive performance highlight the importance of preventive medicine.

Therapeutic change in interaction

A process of change within a single case of cognitive-constructivist therapy is analyzed by means of conversation analysis (CA). The focus is on a process of change in the sequences of interaction, which consist of the therapist’s conclusion and the patient’s response to it. In the conclusions, the therapist investigates and challenges the patient’s tendency to transform her feelings of disappointment and anger into self-blame. Over the course of the therapy, the patient’s responses to these conclusions are recast: from the patient first rejecting the conclusion, to then being ambivalent, and finally to agreeing with the therapist. On the basis of this case study, we suggest that an analysis that focuses on sequences of talk that are interactionally similar offers a sensitive method to investigate the manifestation of therapeutic change. It is suggested that this line of research can complement assimilation analysis and other methods of analyzing changes in a client’s talk.

The role of p73 in cancer – a pathway towards more effective cancer therapy

The p53-family consists of three transcription factors, p53, p73 and p63. The family members have similar but also individual functions connected to cell cycle regulation, development and tumorigenesis. p53 and p73 act mainly as tumor suppressors. During DNA damage caused by anticancer drugs or irradiation, p53 and p73 levels are upregulated in cancer cells leading to apoptosis and cell cycle arrest. p53 is mutated in almost 50 per cent of the cancers, causing the cancer cells unable to undergo cell death. Instead, p73 is rarely mutated in cancer cells and because of that could be more viable target for anticancer therapy. The network surrounding the regulation of p73 is extensive and has several potential targets for cancer therapy. One of the most studied is Itch ligase, the negative regulator of p73 levels. Gene therapy directed towards knockdown of Itch ligase is a potential approach but in need for more in vivo proof. p73 has two isoforms, transactivating TA-forms and dominant-negative ΔN-forms. The specific regulation of these isoforms could also offer a possible way for more effective cancer treatment. The literature work includes information of structures, isoforms, functions and possible therapeutic targets of p73. Also the main therapeutic approaches to date are introduced. The experimental part is based on transfection and cytotoxicity studies done e.g. in pancreatic cancer cells (Mia PaCa-2, PANC1, BxPc-3 and HPAC). The aim of the experimental work was to optimize the conditions for effective transfection with DAB16 dendrimer nanoparticles and to measure the cytotoxicity of plain dendrimers and DAB16-pDNA complexes. Also the protein levels of p73 and Itch ligase were measured by Western blotting. The work was done as a part of a bigger project, which was aiming to down regulate Itch ligase (negative regulator of p73) by siRNA/shRNA. Tranfection results were promising, showing good transfection efficacy with DAB16 N/P30 in pancreatic cancer cells (except in BxPc-3). Pancreatic cancer cells showed recovery in 3 days after they were exposed to plain dendrimer solution or to DAB16-pDNA. Measurement of protein levels by Western blotting was not optimal and the proposals for the improvement regarding e.g. the gels and the extracted protein amounts have been done.

Combination antiretroviral therapy -associated lipodystrophy : insights into pathogenesis and treatment

Introduction: Combination antiretroviral therapy (cART) has decreased morbidity and mortality of individuals infected with human immunodeficiency virus type 1 (HIV-1). Its use, however, is associated with adverse effects which increase the patients risk of conditions such as diabetes and coronary heart disease. Perhaps the most stigmatizing side effect is lipodystrophy, i.e., the loss of subcutaneous adipose tissue (SAT) in the face, limbs and trunk while fat accumulates intra-abdominally and dorsocervically. The pathogenesis of cART-associated lipodystrophy is obscure. Nucleoside reverse transcriptase inhibitors (NRTI) have been implicated to cause lipoatrophy via mitochondrial toxicity. There is no known effective treatment for cART-associated lipodystrophy during unchanged antiretroviral regimen in humans, but in vitro data have shown uridine to abrogate NRTI-induced toxicity in adipocytes. Aims: To investigate whether i) cART or lipodystrophy associated with its use affect arterial stiffness; ii) lipoatrophic SAT is inflamed compared to non-lipoatrophic SAT; iii) abdominal SAT from patients with compared to those without cART-associated lipoatrophy differs with respect to mitochondrial DNA (mtDNA) content, adipose tissue inflammation and gene expression, and if NRTIs stavudine and zidovudine are associated with different degree of changes; iv) lipoatrophic abdominal SAT differs from preserved dorsocervical SAT with respect to mtDNA content, adipose tissue inflammation and gene expression in patients with cART-associated lipodystrophy and v) whether uridine can revert lipoatrophy and the associated metabolic disturbances in patients on stavudine or zidovudine based cART. Subjects and methods: 64 cART-treated patients with (n=45) and without lipodystrophy/-atrophy (n=19) were compared cross-sectionally. A marker of arterial stiffness, heart rate corrected augmentation index (AgIHR), was measured by pulse wave analysis. Body composition was measured by magnetic resonance imaging and dual-energy X-ray absorptiometry, and liver fat content by proton magnetic resonance spectroscopy. Gene expression and mtDNA content in SAT were assessed by real-time polymerase chain reaction and microarray. Adipose tissue composition and inflammation were assessed by histology and immunohistochemistry. Dorsocervical and abdominal SAT were studied. The efficacy and safety of uridine for the treatment of cART-associated lipoatrophy were evaluated in a randomized, double-blind, placebo-controlled 3-month trial in 20 lipoatrophic cART-treated patients. Results: Duration of antiretroviral treatment and cumulative exposure to NRTIs and protease inhibitors, but not the presence of cART-associated lipodystrophy, predicted AgIHR independent of age and blood pressure. Gene expression of inflammatory markers was increased in SAT of lipodystrophic as compared to non-lipodystrophic patients. Expression of genes involved in adipogenesis, triglyceride synthesis and glucose disposal was lower and of those involved in mitochondrial biogenesis, apoptosis and oxidative stress higher in SAT of patients with than without cART-associated lipoatrophy. Most changes were more pronounced in stavudine-treated than in zidovudine-treated individuals. Lipoatrophic SAT had lower mtDNA than SAT of non-lipoatrophic patients. Expression of inflammatory genes was lower in dorsocervical than in abdominal SAT. Neither depot had characteristics of brown adipose tissue. Despite being spared from lipoatrophy, dorsocervical SAT of lipodystrophic patients had lower mtDNA than the phenotypically similar corresponding depot of non-lipodystrophic patients. The greatest difference in gene expression between dorsocervical and abdominal SAT, irrespective of lipodystrophy status, was in expression of homeobox genes that regulate transcription and regionalization of organs during embryonal development. Uridine increased limb fat and its proportion of total fat, but had no effect on liver fat content and markers of insulin resistance. Conclusions: Long-term cART is associated with increased arterial stiffness and, thus, with higher cardiovascular risk. Lipoatrophic abdominal SAT is characterized by inflammation, apoptosis and mtDNA depletion. As mtDNA is depleted even in non-lipoatrophic dorsocervical SAT, lipoatrophy is unlikely to be caused directly by mtDNA depletion. Preserved dorsocervical SAT of patients with cART-associated lipodystrophy is less inflamed than their lipoatrophic abdominal SAT, and does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal SAT is in expression of transcriptional regulators, homeobox genes, which might explain the differential susceptibility of these adipose tissue depots to cART-induced toxicity. Uridine is able to increase peripheral SAT in lipoatrophic patients during unchanged cART.

Kielellinen erityisvaikeus : oirekuva ja familiaalisuus potilasasiakirjojen perusteella

Goals. Specific language impairment (SLI) has a negative impact on child s speech and language development and interaction. Disorder may be associated with a wide range of comorbid problems. In clinical speech therapy it is important to see the child as a whole so that the rehabilitation can be targeted properly. The aim of this study was to describe the linguistic-cognitive and comorbid symptoms of children with SLI at the age of five, as well as to provide an overwiew of the developmental disorders in the families. The study is part of a larger research project, which will examine paths of development and quality of life of children with SLI as young adults. Methods. The data consisted of patient documents of 100 5-year old children, who were examined in Lastenlinna mainly at 1998. Majority of the subjects were boys, and children s primary diagnosis was either F80.1 or F80.2, which was most common, or both. The diagnosis and the information about the linguistic-cognitive status and comorbid symptoms were collected from reports of medical doctors and experts of other fields, as well as mentions related to familiality. Linguistic-cognitive symptoms were divided into subclasses of speech motor functions, prosessing of language, comprehension of language and use of language. Comorbid symptoms were divided into subclasses of interaction, activity and attention, emotional and behavior problems and neurologic problems. Statistical analyses were based mainly on Pearson s Chi Square test. Results and conclusions. Problems in language processing and speech motor functions were most common of the linguistic-cognitive symptoms. Most of the children had symptoms from two or three symptom classes, and it seemed that girls had more symptoms than boys. Usually children did not have any comorbid symptoms, or had them from one or three symptom classes. Of the comorbid symptoms the most prevalent ones were problems in activity and attention and neurological symptoms, which consisted mostly of motoric and visuomotoric symptoms. The most common of the comorbid diagnoses was F82, specific developmental disorder of motor function. According to literature children with SLI may have problems in mental health, but the results of this study did not confirm that. Children with diagnosis F80.2 had more linguistic-cognitive and comorbid symptoms than children with diagnosis F80.1. The cluster analyses based on all the symtoms revealed four subgroups of the subjects. Of the subjects 85 percent had a positive family history of developmental disorders, and the most prevalent problem in the families was delayed speech development. This study outlined the symptom profile of children with SLI and laid a foundation for the future longitudinal study. The results suggested that there are differences between linguistic-cognitive symptoms of boys and girls, which is important to notice especially when assessing and diagnosing children with SLI.

Bacteriophage therapy for Staphylococcus aureus bacteremia in streptozotocin-induced diabetic mice

The protective effect of bacteriophage was assessed against experimental Staphylococcus aureus lethal bacteremia in streptozotocin (STZ) induced-diabetic and non-diabetic mice. Intraperitoneal administrations of S. aureus (RCS21) of 2 x 10(8) CFU caused lethal bacteremia in both diabetic and non-diabetic mice. A single administration of a newly isolated lytic phage strain (GRCS) significantly protected diabetic and nondiabetic mice from lethal bacteremia (survival rate 90% and 100% for diabetic and non-diabetic bacteremic groups versus 0% for saline-treated groups). Comparison of phage therapy to oxacillin treatment showed a significant decrease in RCS21 of 5 and 3 log units in diabetic and nondiabetic bacteremic mice, respectively. The same protection efficiency of phage GRCS was attained even when the treatment was delayed up to 4 h in both diabetic and non-diabetic bacteremic mice. Inoculation of mice with a high dose (10(10) PFU) of phage GRCS alone produced no adverse effects attributable to the phage per se. These results suggest that phages could constitute valuable prophylaxis against S. aureus infections, especially in immunocompromised patients. (C) 2010 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Dietary habits and obesity: the role of emotional and cognitive factors

In post-industrialised societies, food is more plentiful, accessible and palatable than ever before and technological development has reduced the need for physical activity. Consequently, the prevalence of obesity is increasing, which is problematic as obesity is related to a number of diseases. Various psychological and social factors have an important influence on dietary habits and the development of obesity in the current food-rich and sedentary environments. The present study concentrates on the associations of emotional and cognitive factors with dietary intake and obesity as well as on the role these factors play in socioeconomic disparities in diet. Many people cognitively restrict their food intake to prevent weight gain or to lose weight, but research on whether restrained eating is a useful weight control strategy has produced conflicting findings. With respect to emotional factors, the evidence is accumulating that depressive symptoms are related to less healthy dietary intake and obesity, but the mechanisms explaining these associations remain unclear. Furthermore, it is not fully understood why socioeconomically disadvantaged individuals tend to have unhealthier dietary habits and the motives underlying food choices (e.g., price and health) could be relevant in this respect. The specific aims of the study were to examine 1) whether obesity status and dieting history moderate the associations of restrained eating with overeating tendencies, self-control and obesity indicators; 2) whether the associations of depressive symptoms with unhealthier dietary intake and obesity are attributable to a tendency for emotional eating and a low level of physical activity self-efficacy; and 3) whether the absolute or relative importance of food choice motives (health, pleasure, convenience, price, familiarity and ethicality) contribute to the socioeconomic disparities in dietary habits. The study was based on a large population-based sample of Finnish adults: the participants were men (N=2325) and women (N=2699) aged 25-74 who took part in the DILGOM (Dietary, Lifestyle and Genetic Determinants of Obesity and Metabolic Syndrome) sub-study of the National FINRISK Study 2007. The participants weight, height, waist circumference and body fat percentage were measured in a health examination. Psychological eating styles (the Three-Factor Eating Questionnaire-R18), food choice motives (a shortened version of the Food Choice Questionnaire), depressive symptoms (the Center for Epidemiological Studies Depression Scale) and self-control (the Brief Self-Control Scale) were measured with pre-existing questionnaires. A validated food frequency questionnaire was used to assess the average consumption of sweet and non-sweet energy-dense foods and vegetables/fruit. Self-reported total years of education and gross household income were used as indicators of socioeconomic position. The results indicated that 1) restrained eating was related to a lower body mass index, waist circumference, emotional eating and uncontrolled eating, and to a higher self-control in obese participants and current/past dieters. In contrast, the associations were the opposite in normal weight individuals and those who had never dieted. Thus, restrained eating may be related to better weight control among obese individuals and those with dieting experiences, while among others it may function as an indicator of problems with eating and an attempt to solve them. 2) Emotional eating and depressive symptoms were both related to less healthy dietary intake, and the greater consumption of energy-dense sweet foods among participants with elevated depressive symptoms was attributable to the susceptibility for emotional eating. In addition, emotional eating and physical activity self-efficacy were both important in explaining the positive association between depressive symptoms and obesity. 3) The lower vegetable/fruit intake and higher energy-dense food intake among individuals with a low socioeconomic position were partly explained by the higher priority they placed on price and familiarity and the lower priority they gave to health motives in their daily food choices. In conclusion, although policy interventions to change the obesogenic nature of the current environment are definitely needed, knowledge of the factors that hinder or facilitate people s ability to cope with the food-rich environment is also necessary. This study implies that more emphasis should be placed on various psychological and social factors in weight control programmes and interventions.

Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy

The current standard of care for hepatitis C virus (HCV) infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only similar to 50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects.

Bayesian Decentralized Spectrum Sensing in Cognitive Radio Networks

This paper considers the problem of spectrum sensing, i.e., the detection of whether or not a primary user is transmitting data by a cognitive radio. The Bayesian framework is adopted, with the performance measure being the probability of detection error. A decentralized setup, where N sensors use M observations each to arrive at individual decisions that are combined at a fusion center to form the overall decision is considered. The unknown fading channel between the primary sensor and the cognitive radios makes the individual decision rule computationally complex, hence, a generalized likelihood ratio test (GLRT)-based approach is adopted. Analysis of the probabilities of false alarm and miss detection of the proposed method reveals that the error exponent with respect to M is zero. Also, the fusion of N individual decisions offers a diversity advantage, similar to diversity reception in communication systems, and a tight bound on the error exponent is presented. Through an analysis in the low power regime, the number of observations needed as a function of received power, to achieve a given probability of error is determined. Monte-Carlo simulations confirm the accuracy of the analysis.

Spectral Sensing of Adaptive Frequency Hopping Signal for Cognitive Radio

The issue of dynamic spectrum scene analysis in any cognitive radio network becomes extremely complex when low probability of intercept, spread spectrum systems are present in environment. The detection and estimation become more complex if frequency hopping spread spectrum is adaptive in nature. In this paper, we propose two phase approach for detection and estimation of frequency hoping signals. Polyphase filter bank has been proposed as the architecture of choice for detection phase to efficiently detect the presence of frequency hopping signal. Based on the modeling of frequency hopping signal it can be shown that parametric methods of line spectral analysis are well suited for estimation of frequency hopping signals if the issues of order estimation and time localization are resolved. An algorithm using line spectra parameter estimation and wavelet based transient detection has been proposed which resolves above issues in computationally efficient manner suitable for implementation in cognitive radio. The simulations show promising results proving that adaptive frequency hopping signals can be detected and demodulated in a non cooperative context, even at a very low signal to noise ratio in real time.