Charcot-Marie-Tooth neuropathy type 1A combined with Duchenne muscular dystrophy

We report a 24-year-old male with an unusual combination of two inherited neuromuscular disorders – Charcot-Marie-Tooth (CMT) disease type 1A and Duchenne muscular dystrophy (DMD). A phenotypic presentation of this patient included features of both these disorders. Nerve conduction studies revealed demyelinating peripheral neuropathy. Electromyography showed a profound myogenic pattern. The serum creatine kinase level was highly elevated. Muscle biopsy revealed a dystrophic picture with deficient dystrophin immunostaining. CMT1A duplication on chromosome 17p11.2 was found. The frame-shift mutation c.3609–3612delTAAAinsCTT (p.K1204LfsX11) was detected in the dystrophin gene by analysing mRNA isolated from the muscle tissue. The patient inherited both these mutations from his mother. The combination of CMT1A and DMD has not been reported as yet.     

Haarfarbe und Haarfarbstoffe

Ohne Zusammenfassung     

Clinical approach to normal intraocular pressure glaucoma

Normal intraocular pressure (IOP) glaucoma is a clinical condition characterized by pathologic optic nerve excavation and visual field impairment, defined as optic neuropathy with certain features of a disease known as glaucoma. Glaucomatous optic nerve lesion is characterized by optic disk excavation or depression, however, this feature may greatly vary. The level of IOP is considered only one of the multiple risk factors involved in the disease development. In normal IOP glaucoma, papillary lesions and visual field impairments may differ from those occurring in primary open-angle glaucoma. In modern ophthalmology, the terminology has been modified, so the term low IOP glaucoma has been replaced by the term normal IOP glaucoma. It is now believed that various factors play a role in the development of glaucomatous optic neuropathy in normal IOP glaucoma and show variable interference depending on IOP level. Additional studies are needed to define these interactions and their impact on the mechanism of glaucomatous excavation. This will hopefully pave the way to new therapeutic approaches and help in clinical decisions concerning the prognosis and treatment of individual patients.     

Screening for chlamydia trachomatis in military personnel by urine testing

Summary In order to determine the infection rate ofChlamydia trachomatis in young males in Austria an epidemiological study was performed on 335 male Austrian soldiers attending the military hospital for a health check-up procedure. Three hundred twenty-nine (98.2%) of the screened males were clinically asymptomatic. Chlamydial diagnosis was established by testing first catch urine (FCU). Urine sediment was tested by an enzyme immunosorbent assay (EIA) and by a direct immunofluorescent test (DIF test). Positive results in both tests were defined true positives. In 41 (12.2%) of all the 335 soldiers a genital chlamydial infection could be demonstrated by a positive result of the sediment of the FCU in both tests. 93% of the positive results in the DIF test could be confirmed by the EIA whereas only 77% of the positive EIA tests were also positive in the DIF test. Data on genital symptoms and the history of sexually transmitted diseases (STDs) as well as information about sexual relationships were available from all persons included in the study and did not differ between chlamydia positive and negative ones. The study demonstrates a high infection rate withC. trachomatis in mostly asymptomatic young males when using FCU for chlamydial diagnosis. Due to the discrepancy between the EIA and the DIF test, positive results of the sediment of FCU in the EIA test should be confirmed by the DIF test to eliminate false positive cases.

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Screening auf Chlamydia trachomatis im Urin bei Militärpersonal

Zusammenfassung Um bei vorwiegend asymptomatischen männlichen Jugendlichen die Infektionsrate mitChlamydia trachomatis zu bestimmen, wurde im Rahmen einer Routinekontrolle in einem Militärspital eine Chlamydienuntersuchung bei insgesamt 335 Soldaten durchgeführt. Neben der Diagnose vonC. trachomatis wurden Daten über klinische Beschwerden, die Zahl früherer genitaler Kontaktinfektionen sowie über das Sexualverhalten der untersuchten Personen erhoben. Die Chlamydiendiagnostik erfolgte durch die Antigenbestimmung des Harnsediments mittels Enzymimmunassay (EIA) und direkter Immunfluoreszenz (DIF). Der Nachweis vonC. trachomatis im Harnsediment war bei 41 (12,2%) Männern durch ein positives Resultat in beiden Testverfahren möglich. 93% der im DIF-Test positiven Ergebnisse stimmten mit jenen im EIA überein, während nur 77% der positiven Resultate des EIA im DIF-Test bestätigt werden konnten. 98,2% der untersuchten Männer waren klinisch asymptomatisch, chlamydien-positive Personen unterschieden sich weder im Sexualverhalten noch in der Zahl früherer Infektionen von jenen mit negativem Chlamydienergebnis. Die erhobenen Daten weisen auf eine hohe Zahl klinisch asymptomatischer Chlamydieninfektionen bei vorwiegend jungen Männern hin. Aufgrund der diskrepanten Ergebnisse positiver Resultate in beiden Testverfahren sollte ein Antigennachweis im EIA aus dem Harnsediment durch den DIF-Test bestätigt werden. Der Nachweis einer Chlamydieninfektion aus dem Harnsediment kann lediglich dann empfohlen werden, wenn die Gewinnung von Patientenmaterial aus dem Urethralsekret nicht möglich ist.

     

The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML).

The International Prognostic Scoring System (IPSS) for myelodysplastic syndrome (MDS) is based upon weighted data on bone marrow (BM) blast percentage, cytopenia, and cytogenetics, separating patients into four prognostic groups. We analyzed the value of the IPSS in 142 children with de novo MDS and 166 children with juvenile myelomonocytic leukemia (JMML) enrolled in retro- and prospective studies of the European Working Group on childhood MDS (EWOG-MDS). Survivals in MDS and JMML were analyzed separately. Among the criteria considered by the IPSS score, only BM blasts <5% and platelets >100 x 10(9)/l were significantly associated with a superior survival in MDS. In JMML, better survival was associated with platelets >40 x 10(9)/l, but not with any other IPSS factors including cytogenetics. In conclusion, the IPSS is of limited value in both pediatric MDS and JMML. The results reflect the differences between myelodysplastic and myeloproliferative diseases in children and adults.     

Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors

While the field of cancer genetics has enjoyed a great deal of attention among cancer researchers in the last few decades, the appreciation of cancer epigenetics is more recent, -owing to the fact that epigenetic mechanisms have emerged as key mechanisms in cancer development. All critical changes in cancer cells, such as silencing of tumour-suppressor genes, activation of oncogenes and defects in DNA repair, are caused not only by genetic but also by epigenetic mechanisms. Epigenetic events can affect many steps in tumour development; therefore, better understanding of epigenetic mechanisms is fundamental to our ability to successfully prevent, diagnose and treat cancer. Various environmental and dietary agents and lifestyles are suspected to be implicated in the development of a wide range of human cancers by eliciting epigenetic changes, though the contribution of epigenetic mechanisms to a given human cancer type and the precise targets of epigenetic alterations during cancer development are largely unknown. The major obstacle in establishing a relationship between epigenetic changes and exposure to dietary, lifestyle and environmental factors and cancer is the fact that studies are typically too small and lack statistical power to identify the interactions between epigenetic changes and exposures. Tremendous advances in our understanding of basic epigenetic mechanisms and rapid progress that is being made in developing new powerful technologies, such as those for sensitive and quantitative detection of epigenetic changes as well as for genome-wide analysis (epigenomics), hold great promise that these issues may be addressed in near future. Therefore, experimental evidence on the precise role of epigenetic changes induced by environment, diet and lifestyle is eagerly awaited.     

Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling. (Blood. 2005;105:410-419)      

Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood

Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: {"type":"clinical-trial","attrs":{"text":"NCT00662090","term_id":"NCT00662090"}}NCT00662090)     

DNA hypermethylation is associated with invasive phenotype of malignant melanoma

Tumor cell invasion is one of the key processes during cancer progression, leading to life-threatening metastatic lesions in melanoma. As methylation of cancer-related genes plays a fundamental role during tumorigenesis and may lead to cellular plasticity which promotes invasion, our aim was to identify novel epigenetic markers on selected invasive melanoma cells. Using Illumina BeadChip assays and Affymetrix Human Gene 1.0 microarrays, we explored the DNA methylation landscape of selected invasive melanoma cells and examined the impact of DNA methylation on gene expression patterns. Our data revealed predominantly hypermethylated genes in the invasive cells affecting the neural crest differentiation pathway and regulation of the actin cytoskeleton. Integrative analysis of the methylation and gene expression profiles resulted in a cohort of hypermethylated genes (IL12RB2, LYPD6B, CHL1, SLC9A3, BAALC, FAM213A, SORCS1, GPR158, FBN1 and ADORA2B) with decreased expression. On the other hand, hypermethylation in the gene body of the EGFR and RBP4 genes was positively correlated with overexpression of the genes. We identified several methylation changes that can have role during melanoma progression, including hypermethylation of the promoter regions of the ARHGAP22 and NAV2 genes that are commonly altered in locally invasive primary melanomas as well as during metastasis. Interestingly, the down-regulation of the methylcytosine dioxygenase TET2 gene, which regulates DNA methylation, was associated with hypermethylated promoter region of the gene. This can probably lead to the observed global hypermethylation pattern of invasive cells and might be one of the key changes during the development of malignant melanoma cells.