HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic hemochromatosis

Abstract: Genetic hemochromatosis (GH) is closely associated with genes of the major histocompatibility complex (MHC) on chromosome 6. Recently, a candidate gene for GH, with structural similarities to MHC class I genes, designated HLA-H and presently named HFE, has been cloned. The HFE gene is localized telomeric to the MHC and several reports have indicated that the HFE gene is mutated in GH patients. In the present study we have analyzed the relationship of HFE gene variants and disease manifestation in GH patients and family members. Fifty-seven patients with GH, 73 family members and 153 healthy blood donors were studied for the amino acid dimorphism at codon 63 (His63Asp=H63D) and codon 282 (Cys282Tyr= C282Y) of the HFE gene. The codon 63 and 282 dimorphism were defined by PCR amplification of genomic DNA samples and restriction enzyme digestion using RsaI/SnaBI for C282Y and Bcll/Mbo 1 for H63D. Ferritin, transferrin serum levels and total iron-binding capacity were determined prior to therapeutic intervention. The Tyr-282 substitution occurred in 53 (93%) of patients compared with 8 (5.2%) of controls (OR=169, P >0.0001). Fifty-one (90%) patients were Tyr-282 homozygous. In contrast, the Asp-63 substitution was present in 5 (8.8%) of the patients compared with 34 (22%) of controls (OR=0.39, P =NS) with none of the patients being homozygous. In Tyr-282 homozygous GH patients serum ferritin levels, transferrin saturation, liver iron and liver iron index were elevated significantly compared to Tyr-282-negative patients, whereas no difference was observed between Tyr/Cys-282 heterozygous and Tyr-282-negative patients.     

Levels of quality management of blood transfusion services in Europe

The European blood legislation has defined several key quality elements to achieve Good Manufacturing Practice (GMP) in the field of blood transfusion. During the recent years, the blood legislation is in the process of implementation throughout its member states. Following the Directive 2002/98/EC, Directive 2005/62/EC has given further requirements for quality-management systems to be fulfilled by blood establishments. In addition, GMP/Good Laboratory Practice (GLP) and ISO standards are used inter alia by blood establishments. In order to support the implementation of the blood legislation, the European Public Health Work Plan (2005/2007) has cofunded two projects, led by the German Red Cross and supported by the European Blood Alliance, delivering a common European Standard Operating Procedure (SOP) methodology (EU-Q-Blood-SOP) and criteria and standards for the inspection of blood establishments (EUBIS). The EU-SOP manual will assist blood establishments in preparing for the inspection of their services related to the implementation of quality relevant elements required by the EU Directive 2002/98/EC and its technical annexes. The standards and criteria for inspection of blood establishments will cross-reference existing quality standards to the directive requirements and define requirements for the structure of quality-management systems based on the directive 2002/98/EC and its technical annexes. Based on these requirements, inspection standards and criteria are developed to assist in the independent assessment of quality systems established by individual blood establishments. These assessments are done in relation to the requirements defined by the European Union legislation on blood, in order to safeguard the quality of blood and to achieve continuous improvement of its quality throughout Europe.     

Seroepidemiology of HTLV-III (LAV) in the Federal Republic of Germany

Summary In 1984 10,281 sera were collected in the FRG and examined for antibodies to HTLV-III (LAV) with an enzyme-linked immunosorbent assay and confirmative tests. Of the German AIDS patients 81% have antibodies. Individuals belonging to AIDS risk groups, homosexuals, haemophiliacs and i.v. drug abusers, have antibody frequencies between 25%–72%. The detection of HTLV-III antibodies in blood donours indicates that the virus is being transmitted by blood transfusions.Abbreviations AIDS acquired immunodeficiency syndrome - LAS lymphadenopathy syndrome - ARC AIDS related complex - LAV lymphadenopathy associated virus - HTLV-III human T-lymphotropic virus type III - HBV hepatitis B virus     

Prospective randomized clinical study in general surgery comparing a new low molecular weight heparin with unfractionated heparin in the prevention of thrombosis

A prospective, randomized, controlled clinical trial was performed comparing the antithrombotic efficacy of the low molecular weight heparin LMWH 21–23, (Braun) with an unfractionated heparin in elective general surgical patients over an observation period of 7 postoperative days. A total of 230 patients were admitted: 103 (group I) received low molecular weight heparin and 100 (group II) low-dose unfractionated heparin treatment given subcutaneously. In group I 41 patients (46%) were operated on for malignant disease and in group II 54 patients (54%). Due to the large amount of great abdominal procedures the intra- and perioperative application of hydroxyethyl starch was allowed for volume substitution. None of the patients died due to fatal pulmonary embolism. In group I four patients revealed positive ¹²⁵I-labeled fibrinogen uptake (3.9%); two patients belonged to the hydroxyethyl starch subgroup. In group II five patients displayed a positive fibrinogen uptake (5%); two belonged to the hydroxyethyl starch subgroup. The results of the hemostaseological investigations (e.g., prothrombin time, activated partial thromboplastin time, thrombin clotting time, fibrinogen, antithrombin III, protein C, plasminogen, ₂-antiplasmin , tissue-type plasminogen activator, plasminogen activator inhibitor) revealed no statistically significant differences between groups I and II or their subgroups, although a tendency to prolonged clotting times was observed. The antifactor Xa activity values, however, displayed a statistically significant difference between the two groups (P < 0.05). The antifactor Xa activity measured up to 0.16 U/ml for the low molecular weight heparin (group I) and 0.05 U/ml for the unfractionated heparin (group II) in the postoperative period. Major bleeding complications were not encountered in this study. Fundamental for the low incidence of thrombosis, the additive administration of hydroxyethyl starch appeared in almost one-third of the patients in both study groups.Abbreviations APTT activated partial thromboplastin time - aXa anti-factor Xa - DVT deep venous thrombosis - FUT ¹²⁵I-labeled fibrinogen uptake test - HES hydroxyethyl starch - LMWH low molecular weight heparin - PE pulmonary embolism - UFH unfractioned heparin     

Historical perspective: history of spinal surgery

The surgical treatment of spinal disorders did not develop before the 1970s of the last century. Previously limited technical possibilities and the danger of infections spinal surgery could not spread wider. This article reviews the history of spinal surgery from first trials as mentioned in the papyrus Smith in 1550 B.C. in Egypt to advanced techniques of today.     

Identification of 32 novel mutations in the factor VIII gene in Indian patients with hemophilia A

Seventy-five unrelated hemophilia A patients from India were analyzed for factor VIII gene defects. Intron 22 inversion was identified in 22 patients and intron 1 inversion in 2 patients. In the remaining 51 patients without inversions screening the FVIII gene by denaturing high performance liquid chromatography (DHPLC) revealed 42 different mutations in 44 unrelated subjects. These included 14 missense, 7 nonsense, 9 splice site, 8 deletional, 3 insertional mutations and one indel mutation. Of these, 32 were novel gene alterations. The hotspots included intron 22 inversion, CpG and adenine runs.     

Esophageal lichen planus: Current knowledge,challenges and future perspectives

Lichen planus (LP) is a frequent, chronic inflammatory disease involving the skin, mucous membranes and/or skin appendages. Esophageal involvement in lichen planus (ELP) is a clinically important albeit underdiagnosed inflammatory condition. This narrative review aims to give an overview of the current knowledge on ELP, its prevalence, pathogenesis, clinical manifestation, diagnostic criteria, and therapeutic options in order to provide support in clinical management. Studies on ELP were collected using PubMed/Medline. Relevant clinical and therapeutical characteristics from published patient cohorts including our own cohort were extracted and summarized. ELP mainly affects middle-aged women. The principal symptom is dysphagia. However, asymptomatic cases despite progressed macroscopic esophageal lesions may occur. The pathogenesis is unknown, however an immune-mediated mechanism is probable. Endoscopically, ELP is characterized by mucosal denudation and tearing, trachealization, and hyperkeratosis. Scarring esophageal stenosis may occur in chronic courses. Histologic findings include mucosal detachment, T-lymphocytic infiltrations, epithelial apoptosis (Civatte bodies), dyskeratosis, and hyperkeratosis. Direct immuno-fluorescence shows fibrinogen deposits along the basement membrane zone. To date, there is no established therapy. However, treatment with topical steroids induces symptomatic and histologic improvement in two thirds of ELP patients in general. More severe cases may require therapy with immunosuppressors. In symptomatic esophageal stenosis, endoscopic dilation may be necessary. ELP may be regarded as a precancerous condition as transition to squamous cell carcinoma has been documented in literature. ELP is an underdiagnosed yet clinically important differential diagnosis for patients with unclear dysphagia or esophagitis. Timely diagnosis and therapy might prevent potential sequelae such as esophageal stenosis or development of invasive squamous cell carcinoma. Further studies are needed to gain more knowledge about the pathogenesis and treatment options.     

Autologous transplantation of CD133 selected hematopoietic progenitor cells in a pediatric patient with relapsed leukemia

A pediatric patient with very early meningeal relapse of his CD34(+) CD133(-) pre-B-ALL was transplanted with 2.5 x 10(6)/kg CD133 selected autologous progenitor cells. Enrichment of CD133(+) cells resulted in a purity of 92.3 +/- 3.5% CD133(+). Hematopoietic engraftment with >1.0 x 10(9)/l neutrophils and >50 x 10(9)/l platelets was reached within 13 and 24 days, respectively. At a follow-up of 11(1/2) months after autologous transplantation, the patient is in complete remission. To our knowledge, the successful transplantation with a CD133 selected graft is the first one to be reported worldwide. CD133 selected cells may serve as an alternative in the case of CD34(+) malignancy.