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1.  Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma 
Oncology Letters  2016;11(6):4134-4138.
Signal transducer and activator of transcription-3 (STAT3) drives endometrial carcinogenesis, while signaling via gap junctions gets weakened during cancer progression. Connexin 26 (Cx26), Cx43 and STAT3 were immunohistochemically evaluated in 78 endometrioid adenocarcinomas: Nuclear expression of STAT3 positively correlated with cytoplasmic immunoreactivity to Cx43 (P=0.004, r=0.318) and Cx26 (P=0.006, r=0.309). STAT3 correlated with Cx43 (P=0.022, r=0.411) and Cx26 (P=0.008 r=0.466) in G1 tumors. A statistically significant linkage remained in G2 cancers between STAT3 and Cx43 (P=0.061, r=0.262) and Cx26 (P=0.016, r=0.331); however, no correlations were observed in G3 tumors. STAT3 was significantly associated with Cx 43 (p=0.003, r=0.684) and Cx26 (p=0.049, r=0.500) in estrogen receptor (ER) negative adenocarcinomas. STAT3 did not correlate with Cx43 in ER positive adenocarcinomas; however, STAT3 expression remained correlated with Cx26 expression (P=0.035, r=0.268). In progesterone receptor negative tumors STAT3 was significantly associated with Cx43 (P=0.035, r=0.451) and Cx26 (P<0.0001, r=0.707). However, in PgR positive adenocarcinomas STAT3 correlated with Cx43 (P=0.03, r=0.290) but not with Cx26. Thus, it appears that hormone dependent acceleration of cancer growth breaks the association between STAT3 and Cx expression. These associations become weaker as the tumors dedifferentiate from G1 to G3 endometrioid adenocarcinomas. The present study provides evidence that the loss of correlation between STAT3 and selected Cx proteins occurs in tumors with more aggressive behavior.
PMCID: PMC4888192  PMID: 27313754
STAT3; connexin 32; connexin 43; estrogen and progesterone receptors; endometrioid adenocarcinoma
2.  Primary follicular non-Hodgkin's lymphoma of the ureter: A case report and literature review 
Oncology Letters  2016;11(6):3939-3942.
Ureteral cancer is a rare type of neoplasm, with the most prevalent forms including squamous cell carcinoma, transitional cell carcinoma and adenocarcinoma. Ureteral lymphoma is particularly uncommon, and forming a pre-operative diagnosis of the disease is often difficult. The current study describes the case of a 31-year-old man presenting with a space-occupying lesion located in the left lower ureter. Follicular non-Hodgkin's lymphoma was diagnosed via intraoperative frozen section and post-operative pathological analysis. The affected ureteric segment was excised, and the ureter was repaired by end-to-end anastomosis with insertion of a double-J tube for internal drainage. The patient was followed up for 10 months and presented with no signs of recurrence. The current study affirms the importance of pathological examination in the differential diagnosis of ureteral neoplasms and the selection of an appropriate treatment.
PMCID: PMC4888145  PMID: 27313721
follicular lymphoma; ureter; non-Hodgkin's lymphoma
3.  miR-494 inhibits ovarian cancer cell proliferation and promotes apoptosis by targeting FGFR2 
Oncology Letters  2016;11(6):4245-4251.
MicroRNAs (miRs) have been reported to be key regulators in numerous types of cancer. The aim of the present study was to investigate the role of miR-494 in ovarian cancer. Expression of miR-494 was analyzed in ovarian cancer tissues and cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-494 mimic or negative control was transiently transfected into A2780 and SKOV3 cell lines. A cell counting kit-8 assay was performed to assess the effects of miR-494 on cell proliferation, and flow cytometry was used to evaluate the apoptotic rate. The target gene of miR-494 was detected by luciferase assay. Expression of fibroblast growth factor receptor 2 (FGFR2) was identified using RT-qPCR and western blotting. In the present study, decreased expression of miR-494 was observed in ovarian cancer samples and cell lines. Overexpression of miR-494 inhibited ovarian cancer cell proliferation by inducing apoptosis. Additional investigation indicated that FGFR2 was a direct target of miR-494. Taken together, the results of the present study suggested that miR-494 suppressed ovarian cancer cell proliferation by inducing apoptosis via targeting FGFR2.
PMCID: PMC4888167  PMID: 27313773
microRNA-494; proliferation; apoptosis; fibroblast growth receptor 2; ovarian cancer
4.  Microsurgical management of pediatric ependymomas of the fourth ventricle via the trans-cerebellomedullary fissure approach: A review of 26 cases 
Oncology Letters  2016;11(6):4099-4106.
In the present study, the microsurgical management of 26 ependymomas of the fourth ventricle in children via the trans-cerebellomedullary fissure (CMF) approach was reviewed and evaluated. Clinical data were obtained from 26 ependymomas of the fourth ventricle treated with microsurgery using the trans-CMF approach from March 2006 to September 2010 at the Department of Neurosurgery of The First Affiliated Hospital of China Medical University (Shenyang, China). These data were collected and analyzed. Suboccipital median posterior fossa craniotomy and trans-CMF approach were performed in all cases for the microsurgical removal of the tumors. An additional incision was performed in the inferior medullary velum of 5 patients, in order to obtain adequate exposure of the tumors. As a result, all tumors were well exposed during surgery. Gross total resection (GTR) was achieved in 22 cases, near total resection (NTR) in 3 cases and subtotal resection (STR) in 1 case. All excised tumors were pathologically confirmed. No mortality occurred intraoperatively, and no patient presented with mutism or any other surgery-related complications. One patient suffered from postoperative hydrocephalus and received ventriculoperitoneal shunting, which relieved the symptoms. Over the 3.0–7.5-year follow-up period (mean, 4.8 years), tumor relapse occurred in 1 case with GTR, 2 cases with NTR and 1 case with STR. In total, 3 patients succumbed to tumor relapse and 4 were lost to follow-up. According to the literature and the clinical experience of the present authors, the trans-CMF approach provides safe and sufficient access to the fourth ventricle without the requirement of an incision in the inferior vermis. This approach prevents damage to the normal cerebellum and improves the surgical outcome. Tumor removal, restoration of cerebrospinal fluid circulation and preservation of brainstem function are factors that should be taken into consideration during surgery. For patients with residual tumors, adjuvant radiotherapy and/or chemotherapy may be beneficial.
PMCID: PMC4888166  PMID: 27313748
cerebellomedullary fissure; fourth ventricle; ependymoma; microsurgery
5.  Reduced expression of the WW domain-containing oxidoreductase in human hematopoietic malignancies 
Oncology Letters  2016;11(6):4083-4088.
The role of the WW domain-containing oxidoreductase (WWOX) gene in multiple types of solid human cancers has been documented extensively thus far. Recently, we investigated the in vitro effects of WWOX overexpression and observed marked growth arrest in human leukemia cells; however, the clinical characterization of WWOX in leukemia remains poorly investigated. The present study evaluated the WWOX expression profiles of 182 patients with leukemia of different types and 5 leukemic cell lines, using reverse transcription-polymerase chain reaction and immunofluorescence analysis. The results found that WWOX mRNA and WWOX protein expression was significantly reduced or absent in the leukemia cases and cell lines compared with paired controls. The WWOX-positive rate was also lower in the leukemia cases compared with the rate of the normal controls. Notably, the WWOX level was reduced in newly diagnosed and relapsed cases, or in chronic myelogenous leukemia in the blastic phase, yet elevated in remission samples. Moreover, WWOX-negative cases exhibited WWOX expression restoration following induced remission. These findings suggest that WWOX may contribute to the occurrence and development of leukemia, and that it has potential to be a good biomarker or predictor for leukemia therapy.
PMCID: PMC4888223  PMID: 27313745
WW domain-containing oxidoreductase; expression; leukemia; hematopoietic malignancies; clinical characterization
6.  Knockdown of β-catenin by siRNA influences proliferation, apoptosis and invasion of the colon cancer cell line SW480 
Oncology Letters  2016;11(6):3896-3900.
The aim of the present study was to explore the effect of knocking down the expression of β-catenin by small interference (si)RNA on the activity of the Wnt/β-catenin signaling pathway, and the proliferation, apoptosis and invasion abilities of the human colon cancer cell line SW480. For that purpose, double-stranded siRNA targeting β-catenin (β-catenin-siRNA) was synthesized and transfected into SW480 cells. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect the messenger (m)RNA and protein levels of β-catenin in SW480 cells. To detect cell proliferation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed, while cell apoptosis and caspase-3 activity were detected by flow cytometry and caspase-3 activity assay, respectively. Matrigel invasion assay was performed to detect the influence of siRNA-mediated gene silencing on the invasion and metastasis of SW480 cells in vitro. The results of RT-PCR and western blot analysis demonstrated that, compared with the blank control, negative control and liposome groups, β-catenin-siRNA transfected SW480 cells had significantly decreased mRNA and protein levels of β-catenin. In addition, following β-catenin-siRNA transfection, the proliferation of SW480 cells was significantly lower than that of the blank control, negative control and liposome groups, while the apoptosis rate increased in β-catenin-siRNA transfected cells, compared with the aforementioned groups. Invasion assay showed that, following β-catenin-siRNA transfection, the number of SW480 cells infiltrating through the Matrigel membrane was significantly lower than that of the blank control, negative control and liposome groups. Following β-catenin-siRNA transfection, the caspase-3 activity in SW480 cells was lower than that in the blank control, negative control and liposome groups. These results indicate that siRNA-mediated silencing of β-catenin could inhibit the proliferation and invasion of SW480 cells and induce apoptosis, thus providing novel potential strategies for the clinical treatment of colon cancer, and may serve as a novel target for cancer therapy.
PMCID: PMC4888144  PMID: 27313713
β-catenin gene; colorectal cancer; RNA interference; cell proliferation; apoptosis
7.  Treatment of brain metastases of renal cell cancer with combined hypofractionated stereotactic radiotherapy and whole brain radiotherapy with hippocampal sparing 
Oncology Letters  2016;11(6):3777-3781.
Renal cell cancer patients with brain metastatic disease generally have poor prognosis. Treatment options include surgery, radiotherapy, targeted therapy or best supportive care with respect to disease burden, patient preference and performance status. In the present case report the radiotherapy technique combining whole brain radiotherapy with hippocampal sparing (hippocampal avoidance whole brain radiotherapy HA-WBRT) and hypofractionated stereotactic radiotherapy (SRT) of the brain metastases is performed in a patient with metastatic renal cell carcinoma. HA-WBRT was administered to 30 Gy in 10 fractions with sparing of the hippocampal structures and SRT of 21 Gy in 3 fractions to brain metastases which has preceded the HA-WBRT. Two single arc volumetric modulated arc radiotherapy (VMAT) plans were prepared using Monaco planning software. The HA-WBRT treatment plan achieved the following results: D2=33.91 Gy, D98=25.20 Gy, D100=14.18 Gy, D50=31.26 Gy. The homogeneity index was calculated as a deduction of the minimum dose in 2% and 98% of the planning target volume (PTV), divided by the minimum dose in 50% of the PTV. The maximum dose to the hippocampus was 17.50 Gy and mean dose was 11.59 Gy. The following doses to organs at risk (OAR) were achieved: Right opticus Dmax, 31.96 Gy; left opticus Dmax, 30.96 Gy; chiasma D max, 32,76 Gy. The volume of PTV for stereotactic radiotherapy was 3,736 cm3, with coverage D100=20.95 Gy and with only 0.11% of the PTV being irradiated to dose below the prescribed dose. HA-WBRT with SRT represents a feasible technique for radiotherapy of brain metastatic disease, however this technique is considerably demanding on departmental equipment and staff time/experience.
PMCID: PMC4888132  PMID: 27313693
brain metastases; renal cell cancer; stereotactic radiotherapy; stereotactic radiosurgery; whole brain radiotherapy; hippocampal-avoidance whole brain radiotherapy
8.  CT findings of sclerosing stromal tumor of the ovary: A report of two cases and review of the literature 
Oncology Letters  2016;11(6):3817-3820.
Sclerosing stromal tumor (SST) of the ovary, which was first described by Chalvardjian and Scully in 1973, is a rare ovarian neoplasm, occurring predominantly in young women. The most common clinical symptom in patients with SST is menstrual irregularities. Microscopically, the tumor is characterized by the presence of pseudo-lobulated cellular areas, with a prominent tendency to sclerosis, marked vascularity and pronounced variation in cellular size and shape. In the current study, 2 cases of SST of the ovary are presented. These cases were confirmed by imaging, surgical and histological examination. No adjuvant therapy was administered to the patients and the two patients were disease-free with no imaging findings of recurrence or metastasis 24 months following surgery.
PMCID: PMC4888134  PMID: 27313700
ovary; sclerosing stromal tumor; computed tomography
9.  Hypogonadism and erectile dysfunction in myotonic dystrophy type 1 
Acta Myologica  2013;32(2):106-109.
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It affects many organs and systems besides muscle. Aim of this study was to assess frequency of erectile dysfunction (ED) and hypogonadism, the correlation between them and the impact of ED on quality of life (QoL) in patients with DM1. A series of 25 men (aged from 22 to 58 years) with a diagnosis of DM1 was analyzed. Muscular Impairment Rating Scale (MIRS) was used to assess severity of muscular involvement. Erectile function was assessed using the short form of the International Index of Erectile Function test (IIEF-5). Levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were assessed. All patients completed the Serbian version of the SF-36 questionnaire as a measure of health-related QoL. ED was present in 18 (72%) of patients. Seven (28%) patients were euogonadic, 16 (64%) had compensated hypogonadism and 2 (8%) had primary hypogonadism. ED was somewhat more common in patients with hypogonadism (78% vs. 57%). Mental composite score of SF-36 was lower in patients with ED (p<0.05). Our results showed that 72% of men with DM1 had ED and hypogonadism. Studies with larger number of subjects are needed to resolve cascade of events that lays behind ED in DM1. Development of therapeutic strategies may have positive impact on QoL. Substitutive therapy with androgens may be benefitial.
PMCID: PMC3866901  PMID: 24399868
myotonic dystrophy type 1; erectile dysfunction; hypogonadis
10.  Long-term ventilation of patients with Duchenne muscular dystrophy: experiences at the Neuromuscular Centre Ulm 
Acta Myologica  2012;31(3):170-178.
The various measures used to treat the symptoms of Duchenne muscular dystrophy (DMD), i.e. medication with steroids, early operation on contractures and spine deformities as well as cardiac diagnostics and therapy, should always be accompanied by careful monitoring of the patient's respiratory status. Therapy for respiratory failure, in particular long-term ventilation, is now generally accepted as essential for DMD patients. The provision of assisted ventilation has made a decisive contribution to the quality of life for older patients and the stigma hitherto attached to it as being merely a means of keeping a patient comfortable towards the end of life has now been dispelled. Even outside the hospital, assisted ventilation has become routine. These days it is not uncommon for patients on assisted ventilation to have their life extended by 10 years or more.
Non-invasive ventilation is sufficient if used concomitantly with coughing aids. Before undergoing orthopaedic surgery the patient' s respiratory status has to be carefully assessed in order to minimize the risk of perioperative complications. Feeding and swallowing problems may develop if the patient has a scoliosis of the cervical spine region, even if he has had thoraco-lumbar spine surgery. There is still insufficient awareness of this potential problem in relation to respiratory care.
Interdisciplinary collaboration between hospitals, general practitioners, muscle and respiratory centres, as well as advocacies and self-help groups is vital. The administration of aids to support DMD patients is now facilitated by guidelines drawn up by several centres of excellence. Here we mainly describe the historic development of respiratory care at the Ulm Neuromuscular Centre.
PMCID: PMC3631799  PMID: 23620648
Duchenne muscular dystrophy; respiratory failure; non-invasive ventilation; increased survival
11.  The role of fibrosis in Duchenne muscular dystrophy 
Acta Myologica  2012;31(3):184-195.
Muscular dystrophies such as Duchenne muscular dystrophy (DMD) are usually approached as dysfunctions of the affected skeletal myofibres and their force transmission. Comparatively little attention has been given to the increase in connective tissue (fibrosis) which accompanies these muscular changes. Interestingly, an increase in endomysial tissue is apparent long before any muscular degeneration can be observed. Fibrosis is the result of a reactive or reparative process involving mechanical, humoral and cellular factors. Originating from vulnerable myofibres, muscle cell necrosis and inflammatory processes are present in DMD. Muscular recovery is limited due to the limited number and capacity of satellite cells. Hence, a proactive and multimodal approach is necessary in order to activate protective mechanisms and to hinder catabolic and tissue degrading pathways.
Several avenues are discussed in terms of potential antifibrotic therapy approaches. These include pharmaceutical, nutritional, exercise-based and other mechanostimulatory modalities (such as massage or yoga-like stretching) with the intention of exerting an anti-inflammatory and antifibrotic effect on the affected muscular tissues. A preventive intervention at an early age is crucial, based on the early and seemingly non-reversible nature of the fibrotic tissue changes. Since consistent assessment is essential, different measurement technologies are discussed.
PMCID: PMC3631802  PMID: 23620650
Duchenne muscular dystrophy; fibrosis; endo- and perimysium; extracellular matrix; TGF-β1; myostatin; antifibrotic therapy
12.  Risk assessment and genetic counseling in families with Duchenne muscular dystrophy 
Acta Myologica  2012;31(3):179-183.
The Duchenne Muscular dystrophy (DMD) is the most frequent muscle disorder in childhood caused by mutations in the Xlinked dystrophin gene (about 65% deletions, about 7% duplications, about 26% point mutations and about 2% unknown mutations). The clinically milder Becker muscular dystrophy (BMD) is allelic to DMD. About 33% of all patients are due to de novo mutations and germ line mosaicism is frequently observed. While in earlier studies equal mutation rates in males and females had been reported, a breakdown by mutation types can better explain the sex ratio of mutations: Point mutations and duplications arise preferentially during spermatogenesis whereas deletions mostly arise in oogenesis.
With current analytical methods, the underlying mutation can be identified in the great majority of cases and be used for carrier detection. However, in families with no mutation carrier available, the genetic model to be used for counselling of relatives can be quite complex.
PMCID: PMC3631803  PMID: 23620649
Duchenne muscular dystrophy; Becker muscular dystrophy; dystrophin gene; molecular genetic diagnosis; genetic model; germ line mosaicism
13.  Next generation sequencing (NGS) strategies for the genetic testing of myopathies 
Acta Myologica  2012;31(3):196-200.
Next generation sequencing (NGS) technologies offer the possibility to map entire genomes at affordable costs. This brings the genetic testing procedure to a higher level of complexity. The positive aspect is the ease to cope with the complex diagnosis of genetically heterogeneous disorders and to identify novel disease genes. Worries arise from the management of too many DNA variations with unpredictable meaning and incidental findings that can cause ethical and clinical dilemmas. The technology of enrichment makes possible to focus the sequencing to the exome or to a more specific DNA target. This is being used to provide insights into the genetics underlying Mendelian traits involved in myopathies and to set up cost-effective diagnostic tests. This huge potential of the NGS applications makes likely that these will soon become the first approach in genetic diagnostic laboratories.
PMCID: PMC3631804  PMID: 23620651
Next generation sequencing; NGS; neuromuscular disorders
14.  Right atrial preference pacing algorithm in the prevention of paroxysmal atrial fibrillation in myotonic dystrophy type 1 patients: a long term follow-up study 
Acta Myologica  2012;31(2):139-143.
Atrial Preference Pacing (APP) is a pacemaker (PM) algorithm that works by increasing the atrial pacing rate to achieve continuous suppression of a spontaneous atrial rhythm and prevent supraventricular tachyarrhythmias. We have previously shown that atrial preference pacing may significantly reduce the number and the duration of AF episodes in myotonic dystrophy type 1 (DM1) patients who are paced for standard indications.
However, the role that APP therapies play in the prevention of AF in a long-term period remains still unclear. Aim of the present prospective study was to evaluate whether this beneficial effect is maintained for 24-months follow-up period.
To this aim, 50 patients with Myotonic Dystrophy type 1 who underwent dual-chamber PM implantation for first- and second- degree atrioventricular block, were consecutively enrolled and followed for 2 years. One month later the stabilization period, after the implantation, they were randomized to APP algorithm programmed OFF or ON for 6 months each, using a cross-over design, and remained in the same program for the second year. The results showed that while the number of AF episodes during active treatment (APP ON phases) was lower than that registered during no treatment (APP OFF phases), no statistically significant difference was found in AF episodes duration between the two phases. Furthermore, during the APP OFF and APP ON phases, the percentage of atrial pacing was 0 and 99%, respectively, while the percentage of ventricular pacing did not show differences statistically significant (11 vs. 9%, P = 0.2). Atrial premature beats were significantly higher during APP OFF phases than during APP ON phases. Lead parameters remained stable over time and there were no lead-related complications. Based on these 24-months follow-up data, we can conclude that, in DM1 patients who underwent dual-chamber PM implantation, APP is an efficacy algorithm for preventing paroxysmal AF even in long term periods.
PMCID: PMC3476853  PMID: 23097606
myotonic dystrophy; atrial preference pacing; atrial fibrillation
15.  Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients 
Acta Myologica  2012;31(2):121-125.
Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.
The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).
The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23-38.6) in patients who could benefit of mechanical ventilation.
This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age.
PMCID: PMC3476854  PMID: 23097603
Duchenne; survival; cardiomyopathy
16.  Survival in Duchenne muscular dystrophy 
Acta Myologica  2012;31(2):117-120.
To determine the survival in a population of German patients with Duchenne muscular dystrophy.
Patients and methods:
Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected.
67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 % to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years.
Conclusion and clinical relevance:
our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients.
PMCID: PMC3476855  PMID: 23097602
duchenne muscular dystrophy; survival; ventilation
17.  TARDBP mutations are not a frequent cause of ALS in Finnish patients 
Acta Myologica  2012;31(2):134-138.
In previous studies 1-3 % of ALS patients have TARDBP mutations as the cause of the disease. TARDBP mutations have been reported in ALS patients in different populations but so far there are no studies on the frequency of TARDBP mutations in Finnish ALS patients. A cohort of 50 Finnish patients, 44 SALS and 6 FALS patients, were included in the study. Genomic DNA was extracted from venous blood or muscle tissue and a mutation analysis of TARDBP was performed. No definitely pathogenic mutations could be identified in TARDBP in our patient cohort. However, two previously unknown variations were found: one silent mutation in exon 2 and one relatively deep intronic single nucleotide insertion in intron 5. In addition, two previously known non-pathogenic polymorphisms in intron 5 were detected. The size of our cohort is obviously not large enough to conclusively exclude TARDBP mutations as a very rare cause of ALS in Finland. However, based on our results TARDBP mutations do not appear to be a frequent cause of familial or sporadic ALS in Finland.
PMCID: PMC3476858  PMID: 23097605
Amyotrophic lateral sclerosis; mutation screening; TARDBP
18.  ClC1 chloride channel in myotonic dystrophy type 2 and ClC1 splicing in vitro 
Acta Myologica  2012;31(2):144-153.
Myotonic dystrophy type 2 (DM2) is caused by CCTG-repeat expansions. Occurrence of splicing and mutations in the muscle chloride channel gene CLCN1 have been reported to contribute to the phenotype. To examine the effect of CLCN1 in DM2 in Germany, we determined the frequency of a representative ClC1 mutation, R894X, and its effect on DM2 clinical features. Then, we examined CLCN1 mRNA splice variants in patient muscle functionally expressed the most abundant variant, and determined its subcellular localization. Finally, we established a cellular system for studying mouse clcn1 pre-mRNA splicing and tested effects of expression of (CCUG)18, (CUG)24 and (AAG)24 RNAs. The R894X mutation was present in 7.7% of DM2 families. DM2 R894X-carriers had more myotonia and myalgia than non-carriers. The most abundant CLCN1 splice variant in DM2 (80% of all transcripts) excluded exons 6-7 and lead to a truncated ClC1236X protein. Heterologous ClC1236X expression did not yield functional channels. Co-expression with ClC1 did not show a dominant negative effect, but a slightly suppressive effect. In C2C12 cells, the clc1 splice variants generated by (CCUG)18-RNA resembled those in DM2 muscle and differed from those generated by (CUG)24 and (AAG)24. We conclude that ClC1 mutations exert gene dose effects and enhance myotonia and pain in DM2 in Germany. Additionally, the ClC1236X splice variant may contribute to myotonia in DM2. Since splice variants depend on the types of repeats expressed in the cellular C2C12 model, similar cell models of other tissues may be useful for studying repeatdependent pathogenetic mechanisms more easily than in transgenic animals.
PMCID: PMC3476861  PMID: 23097607
PROMM; myotonic dystrophy; chloride channel
19.  The impact of permanent muscle weakness on quality of life in periodic paralysis: a survey of 66 patients 
Acta Myologica  2012;31(2):126-133.
The periodic paralyses are hereditary muscle diseases which cause both episodic and permanent weakness. Permanent weakness may include both reversible and fixed components, the latter caused by fibrosis and fatty replacement. To determine the degree of handicap and impact of permanent weakness on daily life, we conducted a 68-question online survey of 66 patients over 41 years (mean age, 60 ± 14 years). Permanent weakness occurred in 68%, muscle pain in 82% and muscle fatigue in 89%. Eighty-three percent of patients reported themselves as moderately to very active between ages 18-35. At the time of the survey only 14% reported themselves as moderately to very active. Contrary to the literature, only 21% of patients reported decreased frequency of episodic weakness with increased age. Sixty-seven percent had incurred injuries due to falls. Mobility aids were required by 49%. Strength increased in 49% of patients receiving professional physiotherapy and in 62% performing self-managed exercise routines. A decline of strength was observed by 40% with professional and by 16% with self-managed exercise routine, suggesting that overworking muscles may not be beneficial. There is an average of 26 years between age at onset and age at diagnosis indicating that diagnostic schemes can be improved. In summary our data suggests that permanent muscle weakness has a greater impact on the quality of life of patients than previously anticipated.
PMCID: PMC3476862  PMID: 23097604
periodic paralysis; myopathy; paramyotonia congenita
20.  A novel N440K sodium channel mutation causes myotonia with exercise-induced weakness - exclusion of CLCN1 exon deletion/duplication by MLPA 
Acta Myologica  2011;30(2):133-137.
We report a 4-generation Turkish family with 10 affected members presenting with myotonia and potassium- and exerciseinduced paralytic attacks. The clinical presentation was neither typical for the chloride channel myotonias Thomsen and Becker nor for the separate sodium channel myotonia entities potassiumaggravated myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis. It is best described by a combination of potassium-aggravated myotonia and hyperkalemic periodic paralysis. We excluded exonic chloride channel mutations including CLCN1 exon deletion/duplication by MLPA. Instead we identified a novel p.N440K sodium channel mutation that is located at the inner end of segment S6 of repeat I. We discuss the genotype phenotype relation.
PMCID: PMC3235863  PMID: 22106717
chloride channel myotonia Thomsen and Becker; sodium channel myotonia; hyperkalemic periodic paralysis; potassiumaggravated myotonia; paramyotonia congenita; CLCN1; MLPA
21.  Dysferlinopathy course and sportive activity: clues for possible treatment 
Acta Myologica  2011;30(2):127-132.
LGMD2B is a frequent proximo-distal myopathy with rapid evolution after age 20. Exacerbating factors may be physical exercise and inflammation. There is very little information about the effect of sportive activity in LGMD2B, since eccentric exercise frequently results in muscle damage. LGMD2B has often an onset with myalgia and MRI imaging (STIR-sequences) shows myoedema. In a prolonged observational study of a series of 18 MM/LGMD2B patients we have studied the pattern of clinical and radiological evolution. The disease has an abrupt onset in the second decade and most patients perform sports before definite disease onset. On the basis of Gardner-Medwin and Walton scale, grade 4 is reached two years faster in patients who performed sports (over 1000 hours). Other considerations regarding pathogenetic mechanism and response to treatment show a poor response to immunosuppressive treatment of muscle inflammation. Preventing a strenuous physical activity should be recommended in patients with high CK and diagnosed or suspected to have dysferlin deficiency.
PMCID: PMC3235880  PMID: 22106716
dysferlin; pathogenesis; physical exercise; sport activity
22.  The Microglial-Motoneuron dialogue in ALS 
Acta Myologica  2011;30(1):4-8.
Neuroinflammation is a pathological hallmark of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), and is characterized by activated microglia at sites of neuronal injury. In ALS. neurons do not die alone; neuronal injury is noncell- autonomous and depends upon a well-orchestrated dialogue between motor neurons and microglia. Evidence from transgenic models expressing mutant superoxide dismutase 1 (SOD) suggests that the dialogue between motor neurons and microglia initially protects motor neurons. However, with increasing stress and injury within motor neurons, induced by the presence of misfolded proteins such as mSOD1, mitochondrial function and axoplasmic flow are impaired and endoplasmic reticulum stress is induced; misfolded proteins themselves or alternate signals are released from motor neurons and activate microglia. Activated microglia, in turn, switch from anti-inflammatory and neuroprotective to proinflammatory and neurotoxic. Neurotoxic signaling from motor neurons promotes microglial release of reactive oxygen species and pro-inflammatory cytokines further enhancing motor neuron stress and cell injury and initiating a self-propagating cycle of motor neuron injury and cell death. A greater understanding of how to restore the imbalance between neuroprotection and cytotoxicity will depend upon a greater understanding of the motor neuron-microglial dialogue.
PMCID: PMC3185827  PMID: 21842586
Microglia; Motoneurons; ALS
23.  Sporadic-inclusion body myositis (s-IBM) is not so prevalent in Istanbul/Turkey: a muscle biopsy based survey 
Acta Myologica  2011;30(1):34-36.
In a muscle biopsy based study, only 9 out of 5450 biopsy samples, received from all parts of greater Istanbul area, had typical clinical and most suggestive light microscopic sporadic-inclusion body myositis (s-IBM) findings. Two other patients with and ten further patients without characteristic light microscopic findings had referring diagnosis of s-IBM. As the general and the ageadjusted populations of Istanbul in 2010 were 13.255.685 and 2.347.300 respectively, the calculated corresponding ‘estimated prevalences' of most suggestive s-IBM in the Istanbul area were 0.679 X 10-6 and 3.834 X 10-6. Since Istanbul receives heavy migration from all regions of Turkey and ours is the only muscle pathology laboratory in Istanbul, projection of these figures to the Turkish population was considered to be reasonable and an estimate of the prevalence of s-IBM in Turkey was obtained.
The calculated ‘estimated prevalence' of s-IBM in Turkey is lower than the previously reported rates from other countries. The wide variation in the prevalence rates of s-IBM may reflect different genetic, immunogenetic or environmental factors in different populations.
PMCID: PMC3185828  PMID: 21842592
Sporadic inclusion body myositis; s-IBM; prevalence; myopathy
24.  HIV-related neuromuscular diseases: nemaline myopathy, amyotrophic lateral sclerosis and bibrachial amyotrophic diplegia 
Acta Myologica  2011;30(1):29-31.
The human immunodeficiency virus (HIV) causes diverse disorders of the brain, spinal cord and peripheral nerves. Rarely, polymyositis and myoglobinuria are seen. Two other neuromuscular syndromes in people with HIV antibodies are nemaline myopathy and bibrachial amyotrophic diplegia, a form of motor neuron disease. The associations between these diseases and the possibility that HIV infection could be a risk factor for either amyotrophic lateral sclerosis (ALS) itself or other motor neuron diseases are investigated.
PMCID: PMC3185829  PMID: 21842590
HIV-Related Neuromuscular Diseases; nemaline myopathy; amyotrophic lateral sclerosis; bibrachial amyotrophic diplegia
25.  Continuous muscle activity, Morvan's syndrome and limbic encephalitis: ionic or non ionic disorders? 
Acta Myologica  2011;30(1):32-33.
The early pathophysiologic study showed increasing evidence that autoimmunity is implicated in the pathogenesis of neuromyotonia. Antibodies to voltage gated potassium channel were detected in the serum of patients who had peripheral nerves hyperexcitability and also Morvan's disease or limbic encephalitis. These discoveries offered new approaches to treatments.
Recently, antibodies previously attributed to VGKC recognise 2 surface antigens LGI1 and CASPR2 into the VGKC complex. Finally, VGKC antibodies are directed to 2 proteins the first one is a key hippocampic protein containing pre and post synaptic proteins. The second one CASPR2 is an hippocampic and paranodal protein.
There clinical significance is different: hyperexcitability, limbic encephalitis without thymoma for LGI1, hyperexcitability, Morvan limbic encephalitis and frequent thymoma for CASPR2.
In conclusion, the term NMT - LE - VGKC should be changed to NMT- LE with LGI1 and CASPR2 antibodies and classified as auto immune synaptic disorders. Mutations in genes encoding both these proteins are found in hereditary epilepsy and other syndromes. Various potassium channelopathies are closely linked to Morvan's syndromes. A new classification of antibodies will be necessary.
PMCID: PMC3185830  PMID: 21842591
Neuromyotonia; autoimmunity; Isaac's Syndrome

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