Jerzy T. Marcinkowski

Skeletal muscle pathology in Huntington's disease

Huntingtons disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments.

The influence of gender on phenotype and disease progression in patients with Huntington's disease

INTRODUCTION Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder. The aim of this study is to determine whether gender plays a role in the phenotypic expression and progression of HD. METHODS 1267 patients with HD (636 women) from the Registry project of the EHDN were included. A cross-sectional analysis (ANCOVA) controlling for differences in age at onset, disease burden, disease duration, smoking status, alcohol abuse, depression and the number of years of education, was performed to evaluate if there were differences between men and women in UHDRS motor, function and cognitive scores. Additionally, analyses on follow-up data using linear mixed models with the same covariates were performed to test for gender-related differences in progression. RESULTS Baseline features did not differ between genders, with the exception of a higher frequency of past and current depression among women, and a higher number of years of education as well as more frequent alcohol abuse and smoking among men. In the cross-sectional ANCOVA analyses of patients with a mid-age HD onset, women showed worse scores than men in the functional domain (TFC, P = 0.001; UHDRS functional, P = 0.033), UHDRS motor (P = 0.033). The longitudinal analyses showed a faster rate of progression in women in the functional assessment (P = 0.025), the motor assessment (P = 0.032) and the independence scale (P = 0.008). CONCLUSIONS These results suggest a complex gender effect on the phenotypical presentation and the rate of disease progression in HD, with slightly more severe phenotype and faster rate of progression in women in especially the motor and functional domains.

HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements

For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes.

The Relationship of Purpose in Life and Hope in Shaping Happiness Among Patients with Cancer in Poland

The authors investigated the relationship of purpose of life, and hope in the happiness and life satisfaction of patients with cancer during or following cancer treatment. Fifty cancer patients were interviewed during recovery in two Warsaw medical centers. The primary measures used were Purpose in Life Test, Herth Hope Index, Happiness and Social Well-Being tools by Czapiński, and the Cantril Ladder of Satisfaction with Life, as well as medical and demographic measures. Purpose in life was correlated with measures of happiness, and satisfaction with life. Hope was correlated with current happiness, and four measures of satisfaction with life. Patients who had cancer longer, that is, duration of disease, showed lower scores for purpose in life, and number of friends. The longer the time of cancer treatment, the lower were patients’ scores for desire for life. Purpose in life and hope were positively correlated with eleven measures of happiness and satisfaction in life. The cancer variables negatively correlated with loss of friends and six variables of happiness, and satisfaction in life, suggesting the impact that having cancer treatment had on patients’ lives. Psychological support in the cancer center was helpful to patients in and out of treatment.

Do Existential Variables Mediate Between Religious-Spiritual Facets of Functionality and Psychological Wellbeing

Religiosity has been related to psychological wellbeing outcomes. Although this relationship is primarily based on studies of church attendance or prayer and wellbeing, more recent work has focused on the potential mechanisms that may mediate the religion-wellbeing findings. One of the major function of religion is finding of meaning of life and improving hope. Recent studies have indicated that hope and meaning of life are the potential variables mediate between religion and wellbeing. It was hypothesized that one pathway through which religiosity may exert its positive influence on psychological wellbeing is through finding meaning of life and improving hope. One study was conducted examining the relationships among spiritual experiences, hope, meaning of life and psychological wellbeing operationalized as satisfaction with life, positive affect and negative affect. The following research tools were used: Daily Spiritual Experiences Scale, Purpose in Life Test, Hearth Hope Index, Cantril Ladder, Positive and Negative Affect Schedule. Meaning of life and hope were noticed to mediate between spiritual experiences and satisfaction with life as well as between spiritual experiences and positive affect. Spiritual experiences were not related to negative affect. Both meaning of life and hope predicted negative affect. This study found meaning of life and hope to be an important factors in the religion-wellbeing relationship and related to positive psychological outcomes, including improved satisfaction with life and positive affect as well as reduced negative affect.

A study of molecular changes relating to energy metabolism and cellular stress in people with Huntington’s disease: looking for biomarkers

Huntington’s disease (HD) is a neurodegenerative disorder characterized by a progressive motor and cognitive decline and the development of psychiatric symptoms. The origin of molecular and biochemical disturbances in HD is a mutation in the HTT gene, which is autosomally dominantly inherited. The altered huntingtin protein is ubiquitously expressed in the CNS, as well as in peripheral tissues. In this study we measured the metabolism changes in gene transcription in blood of HD gene carriers (premanifest and manifest combined) versus 28 healthy controls. The comparison revealed statistically significant Global Pattern Recognition Fold Change (FC) for 6 mRNA transcripts, reflecting an increase of: MAOB (FC = 3.07; p = 0.0005) which encodes an outer mitochondrial membrane-bound enzyme called monoamine oxidase type B; TGM2 (FC = 1.8; p = 0.02) encoding a transglutaminase 2 that mediates cellular stress; SLC2A4 (FC = 1.64; p = 0.02) solute carrier family 2 (facilitated glucose transporter) member 4; branched chain ketoacid dehydrogenase kinase (BCKDK) (FC = 1.34; p = 0.02); decrease of LDHA (FC = −1.16; p = 0.03) lactate dehydrogenase A; and brain-derived neurotrophic factor (BDNF) (FC = −2,11; p = 0.03). These distinguished changes coincided with HD progress. The analyses of gene transcription levels in sub-cohorts confirmed these changes and also revealed 28 statistically significant FCs of gene transcripts involved in ATP production and BCAA metabolism.

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy.

Huntingtons disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of re-synthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.

Assessing physical activity and sedentary lifestyle behaviours for children and adolescents living in a district of Poland. What are the key determinants for improving health

INTRODUCTION Adequate levels of physical activity throughout an individuals life ensure an optimal state of health. Only 30% of adolescents and 10% of adults perform sufficient physical activity to facilitate proper physical, psychological/mental and emotional development. OBJECTIVE Determining physical activity behaviour in children and adolescents through surveying the opinions of school pupils and parents, in order to lend support for optimised educational programmes designed to promote healthy lifestyle behaviour, as well as establishing consistent answers. MATERIALS AND METHODS A randomised survey was conducted on two groups of n=1100 pupil subjects, each attending elementary or secondary school, with the former in Classes 5 and 6, whereas the latter were aged between 16-19 years old; in both instances parents were also included in the survey. All subjects came from the Kalisz District in western-central Poland, and were divided into those living in the city of Kalisz and those in the surrounding rural areas. RESULTS It was found that 87%, 96% and 89% of elementary, middle and secondary school pupils, respectively, participated in Physical Education (PE) lessons. The numbers of pupils who daily, or almost daily, spent time on a computer, were 52%, 60% and 70%, respectively, for elementary, middle and secondary schools, and likewise 70%, 62% and 48% for watching TV. CONCLUSIONS It is vital that education programmes with a focus on a healthy lifestyle are introduced and targeted at teenagers in order to promote physical activity during the crucial time of the bodys development. The period of maturing into adulthood is particularly crucial for acquiring the right knowledge, convictions, skills and attitudes that help shape a pro-healthy lifestyle in later years.

Trends in smoking among secondary school and high school students in Poland, 2009 and 2011

OBJECTIVES To determine the age and the most common circumstances for smoking initiation along with smoking rates and to evaluate smoking trends for secondary and high school students in Poland during 2009 and 2011. MATERIAL AND METHODS In 2009, a pilot study was conducted in districts of Poland on high school students and their parents. For statistical analysis, correctly completed questionnaires from 999 students and 667 parents were qualified for use. After the pilot study, a nationwide study of secondary school students and their parents was also conducted in 2009. For statistical analysis, correctly completed questionnaires were used from 9360 students and 6951 from their parents. The research tool was a questionnaire developed by the Chief Sanitary Inspectorate. These studies were then compared to the nationwide research study from 2011. Questionnaires were obtained from a survey of 3548 students from secondary schools and 4423 of those from high schools. RESULTS Smoking initiation usually begins at ages 12-15 years. Rates of secondary school student smoking at least once in their lifetime were about the same level in the surveyed years (2009 - 9%, 2011 - 11%), whereas rates of high school student smoking increased (2009 - 15%, 2011 - 24%). Moreover, 34% of secondary school student smoked less than once a week, whereas in 2009, only 8% of students had done so. For high school students, a 1/2 smoked every day; similar to 2009. Students usually smoked in parks, on streets or any other open space areas. CONCLUSIONS From analyzing the smoking trends over the survey period it can be concluded that the problem of smoking increases with respondent age. Int J Occup Med Environ Health 2017;30(5):763-773.

A Becker myotonia patient with compound heterozygosity for CLCN1 mutations and Prinzmetal angina pectoris

Becker myotonia is a recessive muscle disease with prevalence of > 1:50,000. It is caused by markedly reduced function of the chloride channel encoded by CLCN1. We describe a Polish patient with severe myotonia, transient weakness, and muscle cramps who only responds to lidocaine. In addition, the patient has Prinzmetal angina pectoris and multiple lipomatosis. He is compound heterozygeous for a novel p.W303X and a frequent p.R894X CLCN1 mutation. CLCN1 exon number variation was excluded by MLPA. His son with latent myotonia was heterozygeous for p.R894X. We discuss the potential relations of the three rare diseases and the inheritance of p.R894X.