Dorota Sienkiewicz

Duchenne muscular dystrophy: current cell therapies:

Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed.

Quality of Life in Children and Adolescents With Cerebral Palsy and Myelomeningocele

The aim of this study was to compare health-related quality of life in children with cerebral palsy and with myelomeningocele. Fifty-seven children with spastic cerebral palsy and 34 patients with myelomeningocele aged 5-16 years were included in the study. Their mothers completed standardized measures on the Revidierter Kinder Lebensqualitätsfragebogen (KINDL-R) parent questionnaire. The 2 groups were demographically comparable. The children with cerebral palsy were classified more frequently into levels II (n = 24) and III (n = 18) of the Gross Motor Function Classification System. Other patients were classified into levels IV (n = 5) and V (n = 10). Three patients with myelomeningocele were community walkers, 10 could walk with assistive devices, and 21 used a wheelchair. Lesion level was thoracic in 13 patients, lumbar in 17, and sacral in 4. Twenty-nine patients (85.3%) with myelomeningocele had hydrocephalus, and 27 had a shunt. Parents in the both studied groups reported similar overall quality of life of their children in the dimensions of physical and emotional well-being, self-esteem, family, friends, and school. No significant correlations between the quality-of-life scores and age, walking ability, and mental development of the studied groups were found.

Assessment of risk factors for osteoporosis and fractures in children with meningomyelocele

PURPOSE Our objective was to assess bone and muscular mass in children with meningomyelocele (MMC), and to analyze risk factors for osteoporosis and fractures based on densitometric examination. MATERIAL AND METHODS The study group included 30 patients (15 girls and 15 boys) with MMC, aged 6-17 years, treated in the Department of Pediatric Rehabilitation, University Hospital. Physiotherapeutic assessment and laboratory tests (serum parathormone, alkaline phosphatase levels, calcium, and phosphate levels, and urine calcium levels) were performed. Densitometry was measured by dual energy X-ray absorptiometry using a Lunar DPX-L apparatus. Lean mass (fat-free tissue content) and fat mass (% fat content) was evaluated. RESULTS Femur fractures were the most common 12/30 (40%); 5/30 (17%) of the children with MMC had multiple fractures. The incidence of fractures correlated significantly with BMI and body fat content (p = 0.03) Children with MMC and fractures had a tendency toward higher BMI, despite the same absolute value of body mass, compared to those without fractures. Body fat levels were higher in MMC patients with fractures than in those without fractures (BMI R = 0.393, p = 0.03). Children with MMC and fractures had significantly higher 24 h calcuria values, despite normal renal function indices (p = 0.03). CONCLUSIONS Low-energetic fractures in MMC children may result from metabolic disturbances that are a consequence of excessive renal calcium loss or excessive fatty tissue content.

Schizencephaly as a cause of spastic cerebral palsy

PURPOSE The objective was to investigate the clinical features of schizencephaly in children with spastic cerebral palsy. MATERIAL AND METHODS The present study included 180 children with cerebral palsy, spastic tetraplegia, diplegia, and hemiplegia. All magnetic resonance (MR) scans were obtained using a 1.5 T MR scanner with the use of a standard circularly polarized head coil. RESULTS Significant abnormalities relevant to cerebral palsy were evident on MRI in 95%. Periventicular leukomalacia was detected more frequently in children with spastic diplegia than in other patients. Cerebral atrophy was found more often in tetraplegic patients. Porencephalic cysts were detected more often in children with spastic hemiplegia. Congenital brain anomalies were evident in 20 (11.1%) children with spastic cerebral palsy. Twelve patients had schizencephaly with cerebral palsy. Children with spastic diplegia and tetraplegia had bilateral schizencephaly; patients with spastic hemiplegia only had unilateral schizencephaly. Most patients with schizencephaly had epilepsy. CONCLUSIONS Schizencephaly occurred more often in patients with spastic hemiplegia. Early detection of brain abnormalities in children with cerebral palsy may help in the prognosis and in the introduction of appropriate therapy.

Effect of Periodic Granulocyte Colony-Stimulating Factor Administration on Endothelial Progenitor Cells and Different Monocyte Subsets in Pediatric Patients with Muscular Dystrophies.

Muscular dystrophies (MD) are heterogeneous group of diseases characterized by progressive muscle dysfunction. There is a large body of evidence indicating that angiogenesis is impaired in muscles of MD patients. Therefore, induction of dystrophic muscle revascularization should become a novel approach aimed at diminishing the extent of myocyte damage. Recently, we and others demonstrated that administration of granulocyte colony-stimulating factor (G-CSF) resulted in clinical improvement of patients with neuromuscular disorders. To date, however, the exact mechanisms underlying these beneficial effects of G-CSF have not been fully understood. Here we used flow cytometry to quantitate numbers of CD34+ cells, endothelial progenitor cells, and different monocyte subsets in peripheral blood of pediatric MD patients treated with repetitive courses of G-CSF administration. We showed that repetitive cycles of G-CSF administration induced efficient mobilization of above-mentioned cells including cells with proangiogenic potential. These findings contribute to better understanding the beneficial clinical effects of G-CSF in pediatric MD patients.

Potential beneficial effects of granulocyte colony-stimulating factor therapy for spastic paraparesis in a patient with kyphoscoliosis: a case report.

Congenital kyphosis and kyphoscoliosis are much less common than congenital scoliosis and more serious because these curves can progress rapidly and can lead to spinal cord compression and paraplegia. A 15-year-old boy presented with congenital kyphoscoliosis along with spastic paraparesis (American Spinal Injury Association Impairment Scale grade C). We examined the safety and effectiveness of a low dose of analog granulocyte colony-stimulating factor (G-CSF) in this patient. G-CSF 5 µg/kg was given subcutaneously, daily for 5 days per month for 3 months. Laboratory tests, including blood, biochemical tests, and CD34+ cells (marker hematopoietic progenitor cells) were performed, in addition to clinical examination. Clinical examination revealed an increase of muscle strength in the upper limbs and decrease spasticity in the lower limbs between baseline and day 90 and day 180. We found no serious adverse event, drug-related platelet reduction, or splenomegaly. Leukocyte levels remained below 21,000/µL. CD34+ increased significantly at day 5 of G-CSF administration. Low-dose G-CSF was safe and well tolerated by the patient. A significant increase in muscle strength in this patient with spastic paraparesis after 3 months of treatment may indicate beneficial effects of G-CSF factor in this disorder. These results are inspiring and warrant further studies.

Efficacy and the Safety of Granulocyte Colony-Stimulating Factor Treatment in Patients with Muscular Dystrophy: A Non-Randomized Clinical Trial

Introduction The current standard treatment for patients with Duchenne muscular dystrophy (DMD) involves corticosteroids. Granulocyte colony-stimulating factor (G-CSF) induces the proliferation of satellite cells and myoblasts and, in turn, muscle regeneration. Beneficial effects of G-CSF were also described for skeletal muscle disorders. Aim We assessed the safety and effects of using G-CSF to promote muscle strength in patients with DMD. Materials and methods Inclusion criteria were as follows: patients aged 5–15 years with diagnosed with DMD confirmed by genetic test or biopsy. Fourteen patients were treated with steroids, and their use was not changed in this study. Diagnoses were confirmed by genetic tests: deletions were detected in 11 patients and duplications in 5 patients. Nineteen 5- to 15-year-old patients diagnosed with DMD—9 were in wheelchairs, whereas 10 were mobile and independent—completed an open study. Participants received a clinical examination and performed physiotherapeutic and laboratory tests to gage their manual muscle strength, their isometric force using a hand dynamometer, and aerobic capacity [i.e., 6-min walk test (6MWT)] before and after therapy. Each participant received G-CSF (5 µg/kg/body/day) subcutaneously for five consecutive days during the 1st, 2nd, 3rd, 6th, and 12th month. Laboratory investigations that included full blood count and biochemistry were performed. Side effects of G-CSF treatment were assessed during each visit. During each cycle of G-CSF administration in the hospital, rehabilitation was also applied. All patients received regular ambulatory rehabilitation. Results The subcutaneous administration of G-CSF improved muscle strength in participants. We recorded a significant increase in the distance covered in the 6MWT, either on foot or in a wheelchair, increased muscle force in isometric force, and a statistically significant decrease in the activity of the muscle enzyme creatine kinase after nearly every cycle of treatment. We observed no side effects of treatment with G-CSF. Conclusion Our findings suggest that G-CSF increases muscle strength in patients with DMD, who demonstrated that G-CSF therapy is safe and easily tolerable.

The clinical signs and risk factors of non-ambulatory children with cerebral palsy

The aim of the study was to analyze the risk factors and clinical picture of cerebral palsy in non-ambulatory children. The study included 133 children (77 boys and 56 girls) with cerebral palsy aged 6– 17 years. The patients remained under the care of the Outpatient Clinic and Department of Pediatric Rehabilitation of the Medical University of Bialystok. Ninety-eight of the studied patients had spastic tetraplegia, 14 diplegia and 21 hemiplegia. The average duration of pregnancy was 35.21 ± 1.32 weeks, the mean Apgar score was 4.31 ± 3.60 and the mean birth weight was 2448.3 ± 384.7 g. The patients exhibited the following types of motor dysfunctions: spasticity was found in 91 (68.9%) of the patients, hypotonia in 24 (18.2%), extrapyramidal symptoms in 13 (9.8%) and ataxia in 4 (3.0%) cases. More than3/4 (79%) of the children were classified as level V on the Gross Motor Functional Classification System (GMFCS) scale, and 21% as level IV. All the children had mental retardation: 10 (7.5%) mild, 45 (33.3%) moderate and 78 (58.6%) severe. Most children (69.2%) with cerebral palsy did not speak, although 41 (30.8%) managed to utter single words and sentences. More than half (64.6%) required assistance in order to eat, whereas 47 (35.4%) had to be fed. Nearly half (44%) of the patients suffered from epilepsy. Periventricular leukomalacia and atrophy of the cerebral cortex were the most frequent findings on magnetic resonance imaging. Low birth weight, a low Apgar score, and preterm birth were factors that had a negative impact on the ability of children with cerebral palsy to ambulate independently. Spasticity of the lower limbs, mental retardation, lack of speech development and inability to eat without assistance, as well as changes observed on magnetic resonance imaging were also factors determining lack of independent walking.

Recombinant Granulocyte Colony-Stimulating Factor Increases Muscle Strength in Neuromuscular Disorders

To the Editor: Granulocyte-colony stimulating factor is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. A human recombinant form of granulocyte colonystimulating factordfilgrastimdis commonly used to treat neutropenia after chemotherapy. The healing process of an injured muscle can be divided into three different phases.1 The first phase, or the necrosisdegeneration and inflammation phase, occurs within the firstminutes and continues for up to 2weeks after injury. The second phase, or the regeneration repair phase, begins in the firstweek after injuryandpeaks at 14days. Finally, scar-tissue formation (third phase) takes place during week 2 and increases over time for up to 4weeks after injury. Furthermore, the time between injury and initiation of the proliferation is affected by several factors and metabolic state of the muscle. Filgrastim induces also neurogenesis, exerts antiapoptotic effects in neurons and muscles, and has anti-inflammatory properties.2 Recent studies have demonstrated that granulocyte colony-stimulating factor has regenerating and repairing functions in skeletal-muscle regeneration therapy.3 It has been also demonstrated that, after injuries that crush the muscles, the injection of granulocyte-colony stimulating factor daily improves muscular regeneration. The findings that stem cells other than satellite cells could also contribute to muscle regeneration led to studies moving away from using satellite cells/myoblasts, towards atypical stem cells.4 Filgrastim can potentially be used for the treatment of spinal cord injury, stroke, and neurodegenerative diseases.5 Recently, we examined the safety and effectiveness of filgrastim in a 15-year-old boy with facioscapulohumeral dystrophy and in a 15-year-old boy with congenital kyphoscoliosis along with spastic paraparesis. Filgrastim 5 mg/kg was given subcutaneously daily for 5 days/month for 3 months.5 Laboratory tests, CD34þ cells, and electromyography were performed. Clinical examination revealed a significant increase of muscle strength in the lower and upper limbs in the patient with facioscapulohumeral dystrophy between baseline and day 90, and day 180. A significant increase of muscle strength in the upper limbs in the patient with spastic paraparesis was observed.

Effects of granulocyte colony-stimulating factor therapy for osteogenesis imperfecta: a case report

__________________________________________________________________________________________ Introduction: Osteogenesis imperfecta (OI) is a genetic disorder of increased bone fragility and low bone mass. OI type IV. Materials and methods: We examined the safety and effectiveness of a low dose of analog granulocyte colony-stimulating factor (G-CSF) in a 15-year-old girl OI type IV. G-CSF 5 μg/kg was given subcutaneously, for 5 days/month for 3, 6 and 12 months. Laboratory tests, including blood, biochemical tests were performed, in addition to clinical examination. Results: Clinical examination revealed an increase of muscle strength in the upper and lower limbs between base line and day 6 and 12 months. We found no serious adverse events. Leukocyte levels remained below 38,000/μL. Low dose G-CSF was safe and well tolerated by the patient. Conclusions: A significant increase in muscle strength in this patient may indicate beneficial effects of G-CSF factor in this disorder. These results are inspiring and warrant further studies.