Pagrindiniai šios temos aspektai yra nervų – raumenų ligos, jų klasifikacija bei asmenų sergančių nervų – raumenų ligomis specialieji poreikiai, jų tenkinimo lygis. Nervų – raumenų ligos arba neuroraumeninės ligos – tai grupė skirtingų ligų, kurių metu pažeidžiami raumenys. Specialių poreikių žmogui svarbu ne tenkinti tuos poreikius, bet atsižvelgti į poreikius, prisitaikyti prie galimybių ir sudaryti sąlygas fiziškai, dvasiškai bręsti. Neįgalieji mūsų visuomenės nariai turi išskirtines fizines ir psichologines ypatybes ir specialiuosius poreikius, kurie iškyla neįgaliesiems siekiant lygių galimybių dalyvauti fizinio ugdymo, neįgaliųjų sporto, rekreacinės ir buitinės veiklos srityse. Specialiųjų poreikių įvairovę lemia skirtingos negalių rūšys (fizinės, regėjimo, klausos, intelekto) ir funkcijos pažeidimo laipsnis. Darbo aktualumas: Lietuvos sergančiųjų nervų – raumenų ligomis asociacijos (LSNRLA) duomenimis nėra atlikta tyrimų, apibendrinančių žmonių sergančių nervų ������ raumenų ligomis specialiųjų poreikių tenkinimo lygį ne tik Kauno mieste, bet ir visoje Lietuvoje. Yra labai svarbu išaiškinti neįgalių asmenų specialiuosius poreikius, ko pasekoje būtų galima pagerinti šių žmonių gyvenimo kokybę. Tyrimo objektas: žmonių, sergančių nervų – raumenų ligomis, specialieji poreikiai. Tyrimo tikslas: ištirti žmonių, sergančiųjų nervų – raumenų ligomis specialiuosius poreikius ir jų tenkinimą Kauno mieste. Tyrimo uždaviniai: 1) nustatyti žmonių, sergančių nervų – raumenų... [toliau žr. visą tekstą] / The main aspects of this theme are the nervous - muscular complaints, its classification, and the special needs of the people who suffer from nervous - muscular complaints and the level of how these needs are satisfied. Nervous – muscular complaints or neuromuscular diseases are the group of different illnesses that affects muscle. It is important for the human being that suffers from this kind of illness not only to satisfy his special needs but also to pay respect to these needs, help adapt to the opportunities and allow him/her to mature physically and spiritually. The disabled have exceptional physical and psychological qualities and needs that arise when disabled people pursue equal opportunities to participate in physical nurture, recreational and daily living area and sport activities. The variance of special needs is determined by the different types of disablement (physical, visual, auditory, intellectual) and the level of functional lesion. Relevance: Considering the information of Lithuanian association of people who suffer from neuromuscular complaints, there is no other research generalizing the level of how special needs of disabled people are satisfied in Kaunas city and Lithuania. It is very important to evaluate the special needs of disabled people, to improve quality of life. Objective: Special needs of the disabled who suffer from nervous-muscular complaints. Goals: · Identify and compare type of mobility independence considering of age and... [to full text]

Muscle wasting is a significant complication of many diseases including diabetes mellitus, renal and liver failure, HIV/AIDS, and cancer. Sustained loss of skeletal muscle can severely impair a patient's quality of life and often results in poor tolerance and responsiveness to disease treatments. The increased protein breakdown observed during muscle atrophy has been attributed to accelerated activity of the ubiquitin-proteasome pathway, but the precise mechanisms by which this activation stimulates muscle protein loss are poorly understood. Previous work showed that the deubiquitinating enzyme USP19 is upregulated in rat skeletal muscle in various forms of muscle wasting, including streptozotocin induced diabetes, cancer, and dexamethasone treatment. 1 To further explore the role of USP19 in muscle wasting, siRNA-mediated depletion of the enzyme was carried out in L6 myotubes. Knockdown of USP19 resulted in more rapid differentiation of myoblasts into myotubes, with a greater extent of myoblast fusion. It also produced tubes that were visibly larger than those formed by myoblasts transfected with a control siRNA. At the molecular level, silencing of USP19 increased the amount of myosin heavy chain (MHC) and tropomyosin proteins. It also increased levels of MHC transcript, suggesting that USP19 acts at the level of gene transcription or mRNA stability rather than protein degradation. USP19 may mediate its effects on muscle-specific gene expression through the myogenic transcription factor myogenin, since depletion of USP19 increased protein and mRNA levels myogenin but did not affect protein levels of the related transcription factor Myf5. Moreover, the increased tropomyosin and MHC observed upon USP19 knockdown could be abolished when myogenin was simultaneously depleted using siRNA. Collectively, these results suggest that USP19 functions to inhibit the synthesis of key muscle proteins and may therefore be a promising target for the treatment of muscle atrophy.

Knee function was evaluated by knee score, activity level, clinical findings and performance tests, muscle size by computerized tomography (CT), morphology by light (LM) and electron microscopy (EM), muscle function by electromyography (EMG) and isokinetic performance in 29 patients with chronic anterior cruciate ligament (ACL) tear. Preoperatively CT disclosed a significant mean atrophy of the quadriceps and nonsignificant changes of the other muscle areas of the injured leg. Morphology of m vastus lateralis of the injured leg was normal in more than half of the biopsies preoperatively, the rest showed signs of nonoptimal activation. Significant decreases in all isokinetic parameters were noticed together with significantly decreased EMG of the quadriceps muscle of the injured leg. Âfter surgical reconstruction the knees were immobilized in a cast for 6 weeks at either 30° or 70° of knee flexion. After cast removal CT showed significant decreases of all areas which also remained after training. The 30° group showed larger fibres (intracellular oedema) and more frequent morphological abnormalities than the 70° group. Fourteen weeks postoperatively the patients were allocated to either a combination of isometric and progressive resistance training or isokinetic training for 6 weeks. CT showed slightly larger areas at 20 weeks postoperatively than at 6 weeks. Morphological abnormalities were still prominent at 20 weeks postoperatively. Maximum isokinetic knee extensor mechanical output and endurance were markedly decreased at 14 weeks postoperatively but both improved progressively during the one year rehabilitation, mostly during the intensive 6 week training period but irrespective of training programme used. Fatiguability/endurance level improved over the preoperative level. Muscular work/integrated EMG was stable while EMG/t increased indicating neuromuscular relearning. The clinical result at 28 months foliowup was excellent or good in 93% of the patients and clinical stability improved in 66%. Independent upon primary knee immobilization angle or training programmes no differences could be demonstrated with respect to stability, range of motion, function or isokinetic mechanical output. Isokinetic performance was still significantly lower in the injured compared to the noninjured leg and not significantly different from the preoperative values. Morphology, only 6 cases, showed abnormalities similar to preoperative findings. In conclusion, the reason for the decreased maximum and total knee extensor performance in these patients with ACL tears is suggested to be nonoptimal activation of normal functioning muscle fibres depending on changes in knee joint receptor afferent inflow. No differences concerning the markedly improved postoperative clinical result could be seen between the different treatment modalities used. A nonoptimal muscular activation might explain the still decreased isokinetic performance present at followup. / <p>S. 1-40: sammanfattning, s. 43-137: 5 uppsatser</p> / digitalisering@umu.se

Vaginal atrophy symptoms such as dryness, irritation, and itching, are common after menopause. Vaginal estrogen therapy is the most effective treatment but not appropriate for all women. Women with estrogen-responsive breast cancer treated with aromatase inhibitor (AI) treatment, suppressing estrogen levels, often suffer from more pronounced vaginal atrophy symptoms. However, vaginal estrogen treatment is not recommended, leaving them without effective treatment options. The aim of this thesis was to study the effect of long-term anti-estrogen therapy on circulating estrogen levels and biochemical factors in vaginal mucosa in relation to morphological changes and clinical signs of vaginal atrophy. Circulating estrogen levels were analyzed by use of mass spectrometry and radioimmunoassay. Immunohistochemistry was used to study vaginal proliferation and steroid hormone receptors in vaginal mucosa. Vaginal gene expression was studied by use of microarray technology and bioinformatic tools, and validated by use of quantitative real-time PCR and immunohistochemistry. An estrogenic regulation of aquaporins and a possible role in vaginal dryness was investigated in vaginal mucosa and in Vk2E6E7 cells. Aromatase inhibitor-treated women had higher than expected estradiol and estrone levels but still significantly lower than other postmenopausal women. Aromatase was detected in vaginal tissue, the slightly stronger staining in vaginal mucosa from AI-treated women, suggest a local inhibition of vaginal aromatase in addition to the systemic suppression. Vaginal mucosa from AI-treated women had weak progesterone receptor, and strong androgen receptor staining intensity. Low estrogen levels lead to low expression of genes involved in cell adhesion, proliferation, and differentiation as well as weak aquaporin 3 protein immunostaining. The higher than expected estrogen levels in AI-treated women suggest that estrogen levels might previously have been underestimated. Systemic estrogen suppression by treatment with AIs, and possibly also by local inhibition of vaginal aromatase, results in reduced cell adhesion, proliferation, differentiation, and weak aquaporin 3 protein staining. Low proliferation and poor differentiation leads to fewer and less differentiated superficial cells affecting epithelial function and possibly also causing vaginal symptoms. Aquaporin 3 with a possible role in vaginal dryness, cell proliferation, and differentiation should be further explored for the development of non-hormonal treatment options for vaginal symptoms.

Research suggests that the cerebellum is involved in cognition, but its exact role is unclear. The efficiency theory posits that the cerebellum supports processing speed. Other researchers argue that the cerebellum is functionally heterogeneous, and damage to lobes of the cerebellum causes selective loss of cognitive functions. This study sought to determine whether selective impairment in motor, verbal fluency, or processing speed occurred depending on the lobe of the cerebellum that was lesioned. Lesion mapping was used to measure lesion size and volumetric methods were used to measure atrophy in 25 adult survivors of cerebellar tumors. Participants had too a high degree of heterogeneous cerebellar lesions and accompanying atrophy to explore specialization. However, total cerebellar atrophy negatively impacted written and oral processing speed to a greater degree than total cerebellar lesion size. Younger ages at diagnosis and radiation therapy were associated with greater cerebellar atrophy.

Congenital myopathies are a rare and heterogeneous group of diseases. They are primarily characterised by skeletal muscle weakness and disease-specific pathological features. They harshly limit ordinary life and in severe cases, these myopathies are associated with early death of the affected individuals. The congenital myopathies investigated in this thesis are nemaline myopathy and myofibrillar myopathy. These diseases are usually caused by missense mutations in genes encoding myofibrillar proteins, but the exact mechanisms by which the point mutations in these proteins cause the overall weakness remain mysterious. Hence, in this thesis two different nemaline myopathy-causing actin mutations and one myofibrillar myopathy-causing myosin-mutation found in both human patients and mouse models were used to investigate the cascades of molecular and cellular events leading to weakness. I performed a broad range of functional and structural experiments including skinned muscle fibre mechanics, small-angle X-ray scattering as well as immunoblotting and histochemical techniques. Interestingly, according to my results, point mutations in myosin and actin differently modify myosin binding to actin, cross-bridge formation and muscle fibre force production revealing divergent mechanisms, that is, gain versus loss of function (papers I, II and IV). In addition, one point mutation in actin appears to have muscle-specific effects.  The presence of that mutant protein in respiratory muscles, i.e. diaphragm, has indeed more damaging consequences on myofibrillar structure than in limb muscles complexifying the pathophysiological mechanisms (paper II). As numerous atrophic muscle fibres can be seen in congenital myopathies, I also considered this phenomenon as a contributing factor to weakness and characterised the underlying causes in presence of one actin mutation. My results highlighted a direct muscle-specific up-regulation of the ubiquitin-proteasome system (paper III). All together, my research work demonstrates that mutation- and muscle-specific mechanisms trigger the muscle weakness in congenital myopathies. This gives important insights into the pathophysiology of congenital myopathies and will undoubtedly help in designing future therapies.

Spinal muscular atrophy is an autosomal recessive genetic disease that results from the loss and/or degeneration of alpha motor neurons in the lower part of the spinal cord. With ~ 1 in 6000 live births per year being affected, this disease is the second leading cause of infant death and is caused by the loss or decrease of the Survival of Motor Neuron protein (SMN). While a lot is known about the role that SMN plays in the cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), it remains a crucial question in the field to gain a better understanding of what specific/distinct function(s) SMN might have in motor neurons. We have identified novel interactions between SMN and two RNA-binding proteins (RBPs) known to be components of axonal RNA granules. More specifically, we demonstrated that SMN interacts with HuD and SERBP1 in a direct fashion in foci-like structures along neurites of motor neuron-derived cells. We have also demonstrated that the SMN/HuD interaction is required for the localization of HuD into RNA granules in neurites of motor neuron-derived cells. Furthermore, I have shown that SERBP1 is down-regulated in the absence of normal levels of SMN and, most importantly, that over-expression of SERBP1 can rescue SMA-like neuronal defects using a cell culture model of the disease. These findings may help shed light on the non-canonical molecular pathway(s) involving SMN and RBPs in motor neurons and underscores the possible therapeutic benefits of targeting these RBPs in the treatment of SMA.

Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. Whether TSA specifically targets the upregulation of the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice is unclear. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-Smn mediated pathway. Daily intraperitoneal injection of TSA from postnatal day 12 to 25 was performed in the Smn2B/- mice and littermate controls. Previous work from our laboratory demonstrated that treatment with TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/-mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Here, we have shown that TSA treatment does not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. Further, qPCR analysis revealed no changes in the level of Smn transcripts in the brain or spinal cord of TSA-treated SMA mice. Similarly, western blot analysis revealed no significant increase in Smn protein levels in the brain, spinal cord, hind limb muscle, heart muscle, or the liver of TSA treated Smn2B/- mice. However, TSA has beneficial effects in the muscles of Smn2B/- mice and improves motor behavior and myofiber size. TSA improves muscle development by enhancing the activity of myogenic regulatory factors independent of the Smn gene. The beneficial effect of TSA is therefore likely through an Smn-independent manner. Identification of these protective pathways will be of therapeutic value for the treatment of SMA.

The concept of age has undergone a shift from a non-specific measure of chronological age, to an identification of underlying biological, psychological and functional factors leading to age-related changes over time. Loss of neurons (atrophy) and cognitive decline in healthy aging fit well in to this age paradigm. The aging brain is thought to undergo functional shifts in information processing in response to atrophy, which is conceptualised as a “Compensation Hypothesis” of cognitive aging. Using behavioural (reaction time, variability measures, and accuracy on the n-back task of working memory), structural (stereological cortical volume estimates) and functional (functional Magnetic Resonance Imaging) approaches, this study documents decreased whole brain, prefrontal and dorsolateral prefrontal cortex volumes in older individuals. Further, slower, less accurate, and more variable performance on the n-back task in older participants was accompanied by a posterior-to-anterior shift in processing, confirming the Compensation Hypothesis of cognitive aging. The behavioural data combined with structural and functional findings, suggest an aging brain that neuropsychologically compensates over time by paradoxically placing further processing demands on a structurally compromised dorsolateral prefrontal cortex. This produces adequate but slower, more variable, and less accurate performance compared to younger brains; compensation occurs in age, but is not complete. Decision making research has pointed to the important role of emotion in judgement, and has implicated the orbitofrontal cortex as critical for this processing modality. The structural data in this study showed preferentially less volume in the dorsolateral prefrontal cortex, but maintained cortical volume in the orbitofrontal cortex with age. Younger individuals took longer and maintained their accuracy with increasing complexity during the n-back task, with older participants decreasing their accuracy but not to the level of chance with increasing task complexity. As such, decision making on the n-back task may have shifted with age from the pure processing power of the structurally compromised dorsolateral prefrontal cortex to increasing reliance on emotionally-guided decision making inputs mediated by the intact orbitofrontal cortex resulting in adequate but not fully compensated performance in older people. These findings are discussed in relation to evolutionary pressures on the human working memory system, Hume’s concepts of reason and the passions, and to the emerging field of neuroeconomics. / Graduate

Skeletal muscle (SM) atrophy complicates many illnesses, diminishing quality of life and increasing disease morbidity, health resource utilization and health care costs. In animal models of muscle atrophy, loss of SM mass results predominantly from ubiquitin-mediated proteolysis and ubiquitin ligases are the key enzymes that catalyze protein ubiquitination. We have previously shown that ubiquitin ligase Nedd4-1 is up-regulated in a rodent model of denervation-induced SM atrophy and the constitutive expression of Nedd4-1 is sufficient to induce myotube atrophy in vitro, suggesting an important role for Nedd4-1 in the regulation of muscle mass. In this study we generate a Nedd4-1 SM specific-knockout mouse and demonstrate that the loss of Nedd4-1 partially protects SM from denervation-induced atrophy confirming a regulatory role for Nedd4-1 in the maintenance of muscle mass in vivo. Nedd4-1 did not signal downstream through its known substrates Notch-1, MTMR4 or FGFR1, suggesting a novel substrate mediates Nedd4-1’s induction of SM atrophy.