Manuela Födinger

Most CD56+ Intestinal Lymphomas Are CD8+CD5− T-Cell Lymphomas of Monomorphic Small to Medium Size Histology

The expression of the natural killer (NK) cell marker CD56 has been reported to occur in NK cell lymphomas/leukemias and a small group of peripheral T-cell lymphomas but has not been studied extensively in primary intestinal non-B-cell lymphomas. Normal human jejunal intraepithelial lymphocytes (IELs) are mainly T-cell receptor (TCR)-alphabeta+CD3+CD8+CD5low and include an approximately 15% fraction of CD56+ cells that could be the cells of origin for CD56+ intestinal T-cell lymphoma (ITL). To test this hypothesis, 70 cases diagnosed as ITL were immunophenotyped, and 15 CD56+ cases (21%) were identified. The majority of the CD56+ lymphomas was of monomorphic small to medium-sized histology, shared the common phenotype betaF1+/-CD3epsilon/cyt+CD8+CD4-CD5-CD57-TIA-1+ and had clonally rearranged TCR gamma-chain genes. In contrast, the CD56- lymphomas were mainly composed of pleomorphic medium and large cells or had a morphology most consistent with anaplastic large-cell lymphoma and were mostly CD8-. These findings suggest that the majority of CD56+ intestinal lymphomas are morphologically and phenotypically distinct T-cell lymphomas most likely derived from activated cytotoxic CD56+CD8+ IELs. Some overlapping histological and clinical features between CD56+ and CD56- ITLs indicate that the former belong to the clinicopathological entity of ITL. The consistent expression of cytotoxic-granule-associated proteins introduces ITL (both CD56+ and CD56-) into the growing family of usually aggressive extranodal lymphomas of cytotoxic T-cell and NK-cell derivation. In contrast to putative NK-cell lymphoma of the sinonasal region, intestinal NK-cell lymphoma seems to be very rare.

C-reactive protein and body mass index independently predict mortality in kidney transplant recipients.

C‐reactive protein (CRP) is a risk factor for cardiovascular outcomes and mortality in the general population. To date, there are no prospective studies of the association between CRP and mortality or allograft loss in kidney transplant recipients (KTR). In 1995, 438 consecutive KTR were enrolled in this prospective study. Important information on demographic, clinical and immunological characteristics was collected at baseline, and CRP was measured using standard methods. Patients were then followed‐up for a median 7.8 years. Time‐to‐event analyses (univariate and multivariate Cox proportional hazards regression models) were used to study the main outcomes: all‐cause mortality and kidney allograft loss, defined as the earlier of return to dialysis, re‐transplantation, or death. From univariate analyses, we found that CRP ≥0.5 mg/dL was associated with a 83% greater mortality risk compared with lower levels of this inflammatory marker [hazard ratio (HR) = 1.83; 95% confidence interval (CI): 1.23–2.72; p = 0.003]. After multivariate adjustment, patients with a CRP ≥0.5 mg/dL had a 53% higher mortality risk compared with patients whose CRP was below that threshold (HR = 1.53; 95% CI: 1.01–2.31; p = 0.04). No associations between CRP and the risk of kidney allograft loss were detected. Furthermore, we were not able to detect any effect modification between CRP and body mass index on the outcomes under study. We conclude that CRP predicts all‐cause mortality, but not allograft loss in stable KTR.

Efficacy of folinic versus folic acid for the correction of hyperhomocysteinemia in hemodialysis patients

The effectiveness of intravenous folinic acid or intravenous folic acid for the treatment of hyperhomocysteinemia of hemodialysis patients is unknown. In a randomized, controlled, double-blind trial, 66 hemodialysis patients were administered either 15 mg of folic acid or an equimolar amount (16.1 mg) of folinic acid intravenously three times weekly. Normalization of total homocysteine (tHcy) plasma levels after 4 weeks of treatment was achieved in 10 patients (30.3%) in the folic-acid group and 6 patients (18.2%; P: = 0.389) in the folinic-acid group (normalization at any time during the study period in 39.4% and 33.3% of the patients; P: = 0.798). The relative reduction in tHcy plasma levels at week 4 was 32.2% in the folic-acid group and 34.1% in the folinic-acid group. A high baseline tHcy plasma concentration (P: = 0.00001), methylenetetrahydrofolate reductase (MTHFR) 677TT/1298AA genotype (P: = 0.03540), and low red blood cell folate concentrations (P: = 0.02285) were associated with a better relative response to treatment. Normalization of tHcy plasma levels was dependent on a lower baseline tHcy level (P: = 0.01976), younger age (P: = 0.00896), and MTHFR 677TT/1298AA or 677CT/1298AC genotypes (P: = 0.00208 and P: = 0.02320, respectively). A 4-week course of intravenous folinic acid is not superior to intravenous folic acid in reducing elevated tHcy plasma levels in hemodialysis patients. The response to treatment is predicted by tHcy plasma level, red blood cell folate content, and MTHFR genotype.

Molecular Genetics of Homocysteine Metabolism

Recent genetic studies have led to the characterization of molecular determinants contributing to the pathogenesis of hyperhomocysteinemia. In this article we summarize the current insights into the molecular genetics of severe, moderate and mild hyperhomocysteinemia. We will consider deficiencies of the trans-sulfuration enzyme cystathionine β-synthase (gene symbol: CBS), and the disturbances of the remethylation enzymes 5,10-methylenetetrahydrofolate reductase (gene symbol: MTHFR), methionine synthase (gene symbol: MTR), and the recently identified methionine synthase reductase (gene symbol: MTRR). Furthermore, we will focus on clinically important genetic polymorphisms which are highly prevalent and thus of potential general interest.

A case of smouldering mastocytosis with peripheral blood eosinophilia and lymphadenopathy

Systemic mastocytosis (SM) is a clonal hematologic disease showing abnormal growth and accumulation of mast cells (MC) in visceral organs with or without skin involvement. The clinical course in SM is variable. In fact, indolent and aggressive variants have been described. In addition, SM patients may acquire an associated hematologic clonal non-MC lineage disease (AHNMD). In some cases, hematologic parameters are indicative of slowly progressing SM although the clinical course remains indolent over years. These cases have been referred to as smouldering SM. We report on a smouldering patient presenting with typical skin lesions, hypercellular marrow with focal MC aggregates, persistent leukocytosis (20,000-30,000/microl) with eosinophilia (5-10%), marked lymphadenopathy, and splenomegaly. The C-KIT mutation Asp-816-Val confirmed the diagnosis of SM. The clinical picture remained stable during an observation period of 10 years without signs of progression to an AHNMD or a high grade MC disease. These data show that some patients with SM can remain in a clinically indolent smouldering state over years even when presenting with marked eosinophilia and lymphadenopathy.

Pathogenic Entamoeba histolytica: cDNA cloning of a histone H3 with a divergent primary structure

Entamoeba histolytica has an unusual nuclear structure characterized by a low degree of chromatin condensation and the absence of stainable metaphase chromosomes. Although nucleosome-like particles were observed, no information about histones was available so far. In this paper we describe a cDNA clone with significant homology to H3 histones that was isolated from a library of pathogenic E. histolytica. The complete cDNA encodes a 15-kDa polypeptide, which like the histone sequence from Volvox carteri is shorter by one residue than the human homologue. The amino acid sequence has only 69% identity with human H3.3 histone and 67% identity with the human H3.1 histone. This is the highest degree of sequence divergence observed for any eukaryote H3 histone sequence. Our results indicate that this divergence may contribute to the unusual chromatin structure of E. histolytica.

Stem Cell Factor-induced Bone Marrow Mast Cell Hyperplasia Mimicking Systemic Mastocytosis (SM): Histopathologic and Morphologic Evaluation with Special Reference to Recently Established SM-criteria

Although systemic mastocytosis (SM) is a well-defined hematologic neoplasm, it is sometimes difficult to discriminate between SM and a reactive mast cell (MC) hyperplasia. We describe a patient with aplastic anemia who was treated with recombinant stem cell factor (SCF). In response to SCF, the patient showed transient hematologic improvement and developed a marked increase in MC as well as a transient increase in serum tryptase. Histologic and immunohistochemical examination revealed a huge increase in MC in the bone marrow with focal infiltrates similar to SM. However, most of the SM-criteria were not met: First, MC showed normal cytomorphological characteristics without significant atypias (no cytoplasmic extensions, no oval nuclei, no hypogranulated cytoplasm). Furthermore, bone marrow MC were CD2- and CD25-negative and did not exhibit the C-KIT 2468 A → T mutation (Asp-816-Val). After discontinuation of SCF the MC hyperplasia resolved confirming its reactive nature. Based on our case and similar cases mimicking mastocytosis, it seems of importance to apply recently established SM criteria in order to discriminate between reactive MC hyperplasia and true mastocytosis with certainty.

Results of an ophthalmologic screening programme for identification of cases with Anderson-Fabry disease.

Purpose: Anderson-Fabry disease is an inherited lysosomal storage disease with a broad and unspecific range of symptoms, a painful course of disease and early death. The recent development of new enzyme therapy emphasises the need for early diagnosis and treatment of undiagnosed patients. One of the affected organs of Anderson-Fabry disease is the eye. Cornea verticillata – corneal opacities and corneal dystrophy – as well as tortuositas vasorum can occur in an early stage of the disease affecting almost all hemizygous men and more than 70% of heterozygous women. In order to identify unknown cases with Anderson-Fabry disease, we carried out a screening programme contacting Austrian ophthalmologists. Methods: All 658 Austrian ophthalmologists were asked to record patients with cornea verticillata as well as tortuositas vasorum – twice at an interval of 3 months. Results: 33% of the contacted ophthalmologists replied, identifying 5 patients suspected of having Anderson-Fabry disease. After additional examinations including tests for enzyme activities Anderson-Fabry disease was confirmed in 1 man. Conclusion: We have identified 1 case with Anderson-Fabry disease through our ophthalmology screening programme among a population of approximately of 8 million. Ophthalmologic screening programmes for ocular manifestations typical of Anderson-Fabry disease are limited because of the moderate visual affection in these patients. Nevertheless, considering the limited options to detect such cases otherwise, ophthalmologists have a major responsibility to identify patients with Anderson-Fabry disease on routine examinations.

Molecular genetics and development of mast cells: Implications for molecular medicine

For a long time the biology of mast cells has remained an enigma. During the past few decades, molecular research has filled many of the gaps in our understanding of this multifunctional cell type. Several concepts are now established about the origin and development of mast cells. However, the mechanisms leading to autonomous proliferation of mast cells in patients with indolent or aggressive mastocytosis still require further investigation. This article focuses on the recent advances in the field of mast cell development and abnormal mast cell proliferation, and reviews data from the most significant mouse models, which have provided the basis for many of these new insights.

Patterns of co-occurrence of three single nucleotide polymorphisms of the 5,10-methylenetetrahydrofolate reductase gene in kidney transplant recipients

Background  Recently, a new mutation of the 5,10‐methylenetetrahydrofolate reductase (MTHFR) encoding gene was first described (1793G > A). Only few reports have studied the prevalence of this polymorphism, especially in combination with other MTHFR mutations (677C > T, 1298A > C).