Calcineurin inhibition with systemic FK506 treatment increases dendritic branching and dendritic spine density in healthy adult mouse brain

Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and recent data suggest that calcineurin activation mediates some of the neurotoxicity of the Alzheimer related neurotoxin Aβ. Immunosuppression via calcineurin inhibition with the compound FK506 is an important treatment for organ transplant patients. Here we use Golgi impregnation techniques, along with a new survival analysis-based statistical approach for analysis of dendritic complexity, to show that in healthy adult mice one week of treatment with FK506 affects both the branching patterns and dendritic spine density of cortical neurons. These results indicate that calcineurin inhibition leads to readily detectable changes in brain morphology, further implicating calcineurin related pathways in both the function and structure of the adult brain

Routinedaten aus der medizinischen Versorgung für die Notaufnahme-Surveillance: 1,5 Jahre Notaufnahme-Situationsreport

SUMO ist ein am Robert Koch-Institut entwickeltes und betriebenes System, welches Gesundheitsdaten für Public Health-Surveillance verarbeitet und bereitstellt. Der Notaufnahme-Situationsreport enthält Daten der Routinedokumentation aus einer Auswahl deutscher Notaufnahmen und bildet die aktuelle Inanspruchnahme dieser Notaufnahmen ab.SUMO is a system that has been developed and implemented at the Robert Koch Institute. It processes and provides health data for surveillance and public health research. The Emergency Department Situation Report presents data from the routine documentation of selected emergency departments in Germany, and shows the current utilisation of those emergency departments

Aberrant methylation of c-myc and c-fos protooncogenes and p53 tumor suppressor gene in myelodysplastic syndromes and acute non-lymphocytic leukemia

Purpose: Aberrant methylation, as an epigenetic phenomenon, may precede and regulate the expression of genes involved in transformation mechanisms that lead to leukemogenesis of hemopoietic cells. The genes involved mostly encode transcription factors and cell cycle specific inhibitors. The aim of this project was to study the DNA methylation pattern of c-myc, c-fos and p53 in myelodysplastic syndromes (MDS) and in acute non-lymphocytic leukemias (ANLL). Patients and methods: DNA was isolated from the monocyte cell layer harvested from bone marrow or peripheral blood samples of 44 patients suffering from MDS and ANLL. Genomic DNA was digested with methylation-specific enzymes, and was electrophoresed and hybridized with probes specift for human c-myc, c-fos and p53 genes. Results: In MDS, the c-myc gene in exons 2 and 3 was regionally hypomethylated, whereas exon 2 in ANLL was hypermethylated and exon 3 hypomethylated. The c-fos gene was hypomethylated in ANLL type 4 and presented aberrant hypomethylation in the different types of MDS. The p53 anti-oncogene appeared extensively hypomethylated in MDS. Conclusion: Aberrant DNA methylation pattern of the c-myc, c-fos and p53 tumor suppressor gene seems to be a primary event in the transformation process from myelodysplasia to acute leukemia, affecting their expression, and, consequently, altering the proliferation, differentiation or apoptosis of hemopoietic precursor cells. The p53 hypomethylation predisposes to critical mutations that enhance the transformation process of myelodysplasia to leukemia. The recognition of altered methylation of these genes in myelodysplasia may have prognostic implications and may lead to novel therapeutic modalities. © 2003 Zerbinis Medical Publications

A new genetic variant of hereditary apolipoprotein A-I amyloidosis: a case-report followed by discussion of diagnostic challenges and therapeutic options

Background: Hereditary amyloidosis refers to a wide spectrum of rare diseases with different causative mutations in the genes of various proteins including transthyretin, apolipoprotein AI and AII, gelsolin, lysozyme, cystatin C, fibrinogen Aα-chain, β2-microglobulin, apolipoprotein CII and CIII. Case presentation: Among hereditary amyloidosis subtypes, we describe here a specific case of Apolipoprotein AI amyloidosis (AApoAI), where the diagnosis began from an almost asymptomatic hepatomegaly followed by the development of primary hypogonadism. Baseline laboratory tests showed increased liver enzymes, while imaging tests revealed a suspected infiltrative liver disease. Patient underwent into liver biopsy and histological examination detected the presence of periodic acid-Schiff (−) and Congo-red (+) amorphous eosinophilic material within normal liver tissue. In the typing of amyloid by immunoelectron microscopy, the liver appeared heavily infiltrated by anti-apoAI (+) amyloid fibrils. Gene sequencing and mutational analysis revealed a single-base mutation at position c.251 T > C resulting in an amino acid substitution from leucine to proline in the mature ApoAI protein. This amino acid change led to lower cleavage and ApoAI deposition into the involved organs. Few years later, our patient remaining without treatment, came with symptoms consistent with primary hypogonadism but testicular involvement with ApoAI deposits could not be proven since the patient refused testicular biopsy. Based on this case, we recap the diagnostic challenges, the clinical manifestations, and the potential treatment options for this indolent hereditary amyloidosis subtype. Conclusions: This case-report enlarges the clinical picture of ApoAI-driven disease and its complex genetic background and in parallel suggests for a more systematic approach in any case with strong suspicion of hereditary amyloidosis. © 2019 The Author(s)

A new genetic variant of hereditary apolipoprotein A-I amyloidosis: a case-report followed by discussion of diagnostic challenges and therapeutic options

Background: Hereditary amyloidosis refers to a wide spectrum of rare diseases with different causative mutations in the genes of various proteins including transthyretin, apolipoprotein AI and AII, gelsolin, lysozyme, cystatin C, fibrinogen Aα-chain, β2-microglobulin, apolipoprotein CII and CIII. Case presentation: Among hereditary amyloidosis subtypes, we describe here a specific case of Apolipoprotein AI amyloidosis (AApoAI), where the diagnosis began from an almost asymptomatic hepatomegaly followed by the development of primary hypogonadism. Baseline laboratory tests showed increased liver enzymes, while imaging tests revealed a suspected infiltrative liver disease. Patient underwent into liver biopsy and histological examination detected the presence of periodic acid-Schiff (−) and Congo-red (+) amorphous eosinophilic material within normal liver tissue. In the typing of amyloid by immunoelectron microscopy, the liver appeared heavily infiltrated by anti-apoAI (+) amyloid fibrils. Gene sequencing and mutational analysis revealed a single-base mutation at position c.251 T > C resulting in an amino acid substitution from leucine to proline in the mature ApoAI protein. This amino acid change led to lower cleavage and ApoAI deposition into the involved organs. Few years later, our patient remaining without treatment, came with symptoms consistent with primary hypogonadism but testicular involvement with ApoAI deposits could not be proven since the patient refused testicular biopsy. Based on this case, we recap the diagnostic challenges, the clinical manifestations, and the potential treatment options for this indolent hereditary amyloidosis subtype. Conclusions: This case-report enlarges the clinical picture of ApoAI-driven disease and its complex genetic background and in parallel suggests for a more systematic approach in any case with strong suspicion of hereditary amyloidosis

TLR4/TIRAP polymorphisms are associated with progression and survival of patients with symptomatic myeloma

Myeloma cells thrive in an environment of sustained inflammation, which impacts the development and evolution of the disease, as well as drug resistance. We evaluated the impact of genetic polymorphisms in the Toll-like receptor 4 (TLR4) pathway, which have been implicated in different inflammatory responses in the outcomes of patients with symptomatic multiple myeloma (MM) who have received contemporary therapies. We found that the presence of single nucleotide polymorphisms (SNPs) in both the TLR4 and toll/interleukin-1 receptor (TIR)-associated protein (TIRAP) genes was associated with lower response to primary therapy mainly for patients who received immunomodulatory drugs but not in patients treated with bortezomib-based therapies. Furthermore, TIRAP SNP was associated with a significantly shorter progression-free survival and overall survival, independently of other prognostic factors, such as age, transplant, International Staging System stage, lactate dehydrogenase and cytogenetics. This is the first study to demonstrate the effect of SNPs in TLR4/TIRAP in MM. Our data indicate that genetic variability in the immune system may be associated with different responses to antimyeloma therapies and may be a critical component affecting the natural history of the disease, providing the basis for further investigation of the role of these pathways in myeloma. © 2016 John Wiley & Sons Ltd

Addition of cyclosporin-A to chemotherapy in secondary (post-MDS) AML in the elderly. A multicenter randomized trial of the Leukemia Working Group of the Hellenic Society of Hematology

In elderly patients with secondary leukemia, poor therapeutic response and low overall survival have been attributed mainly to age and to the primary resistance of leukemic cells to chemotherapy. Modulation of resistance has been attempted in different studies, but the results have been contradictory. We conducted an open, randomized multicenter clinical trial involving patients more than 60 years old with secondary leukemia preceded by a myelodysplastic syndrome. The induction chemotherapy regimen included idarubicin, cytarabine, and etoposide (group A); randomization involved simultaneous administration of cyclosporin-A per os (group B). Fifty-five patients were evaluated, 26 in group A and 29 in group B. Overall complete remission was achieved in 40% of the patients, 27% vs 52% in groups A and B, respectively (p=0.01). Leukemia-free survival was more favorable in patients who received cyclosporin-A, 12 vs 7 months for groups B and A, respectively (p=0.03). In a follow up period of 30 months, 7 out of 55 patients (13%) were alive, 4 of whom were in complete remission. Five out of the 7 alive patients were randomized in group B and had received cyclosporin-A. Treatment failure was higher in group A [19 of 26 patients (73%)] than in group B with CsA [14 of 29 patients (48%)] (p < 0.0001). Treatment-related toxicity/mortality was 13%. Modulation of drug resistance by CsA in elderly people suffering from secondary acute leukemia may improve the outcome of chemotherapy without increasing drug toxicity and treatment-related mortality