Biomedical subjects
Publications and source records attributed to M Hummel.
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Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April 2002, we conducted a multicentre phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m(2) of rituximab. The mean follow-up time is 24.2 months. Histology was distributed in 10 diffuse large cell-, 2 marginal zone-, 1 Burkitt-like lymphoma, 1 Hodgkin-like PTLD and 3 polymorphic lymphoproliferations. Therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. Rituximab proved to be well tolerated and effective in the treatment of PTLD.
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The aim of the present study was to evaluate the penetration depth (PD) and the thickness of the oxygen inhibition layer (OIL) of a fissure sealant (Helioseal, Vivadent) and various adhesives (Heliobond, Excite, Vivadent; Resulcin, Merz; Solobond M, Voco; Prompt L-Pop, 3M-Espe) applied to enamel lesions in vitro. From 27 bovine teeth 54 enamel specimens were prepared and covered with nail varnish (control) thus obtaining three windows for treatment. After demineralisation (pH 5.0, 14 d) two of the windows were etched with phosphoric acid (20%, 5 s), whereas the third area served as control. The specimens were divided randomly into six groups (n = 9) and the respective adhesive was applied (90 s), either once or twice. Light-curing followed each application. Enamel slabs (perpendicular to the surface) were cut and studied after infiltration with a fluorescent low-viscous resin using confocal microscopy (CLSM). The image of the lesion was divided into two areas with different grey values. Lesion depths were calculated (ImageJ) from the surface to that point in the lesion where the grey value clearly changed to a darker grey value. The zone with the darker grey values marked the front of demineralisation. Mean lesion depths (+/- SD) after demineralisation were measured at 105 (+/- 21) microm. After single application, Resulcin [89 (+/- 22)%] and Helioseal [98 (+/- 6)%] had almost completely penetrated the lesion. Heliobond [126 (+/- 33)%] and Excite [184 (+/- 40)%] penetrated even deeper than the defined lesion. For Excite double application decreased the OIL significantly (p = 0.03; adjusted paired t-test). Adhesives are capable to penetrate artificial initial enamel lesions completely. Follow-up studies are needed to confirm this effect for natural lesions.
Cocaine-induced behavioral sensitization is a complex phenomenon involving a number of neuromodulator and neurotransmitter systems. To specifically investigate the role of the micro opioid receptor (MOR) in cocaine-induced behavioral sensitization in mice, both genetic and pharmacological approaches were undertaken. MOR-1 deficient mice of varying backgrounds (C57BL/6J, 129S6, F1 hybrid 129S6xC57BL/6J and 129S6xC57BL/6J) and wild-type C57BL/6J mice exposed continuously to naltrexone, an opioid receptor antagonist, received single daily injections of saline or cocaine for 10 days. All mice received a single cocaine challenge 7 days following the last saline or cocaine injection to test for the expression of sensitization. The locomotor-stimulating and sensitizing effects of cocaine observed in MOR-1 wild-type mice were absent in MOR-1 knockout mice maintained on the mixed 129S6xC57BL/6J background. In contrast, MOR-1 deficient mice developed on a C57BL/6J background showed an accentuated sensitivity to cocaine-induced locomotion. Cocaine's psychomotor activating effects were more pronounced in the MOR-1 C57BL/6J knockouts injected daily with cocaine than in the MOR-1 wild-type mice. Similar locomotor-stimulating and sensitizing effects were found in both F1 hybrid 129S6xC57BL/6J MOR-1 wild-type and MOR-1 knockout mice, while the 129S6 strain showed an overall indifference to cocaine. That is, both the locomotor-stimulating and sensitizing effects of cocaine were absent in both MOR-1 wild-type and MOR-1 knockout mice maintained on the 129S6 background. Lastly, the locomotor-stimulating and sensitizing effects of cocaine were attenuated in C57BL/6J wild-type mice exposed continuously to naltrexone. Collectively, these data support a role for opioidergic involvement in cocaine-influenced behavior in mice. Moreover, MORs appear to differentially modulate a sensitized response to cocaine in different strains of mice as delineated by MOR-1 gene deletion and pharmacological antagonism.
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BACKGROUND: The role of B cells and macrophages in microvascular disease after heart transplantation remains controversial. METHODS: Out of a total of 809 endomyocardial biopsies without evidence of acute cellular rejection (n = 422, 72 females and 350 males, median age 46 years), 393 without evidence of the quilty phenomenon were investigated zero to ten years after heart transplantation. Vascular reaction (endothelial cell swelling and vessel wall thickening) was graded by H&E staining, and immunohistochemistry was performed for T cells (clone UCHL1), B cells (clone L26) and macrophages (clone KP1) and evaluated semi-quantitatively (light microscopy x 200). RESULTS: Positive reaction for T cells and macrophages as well as evidence of endothelial cell swelling decreased with time after heart transplantation. Positive reactions for B cells were less frequent and increased slightly during the observation time, while vessel wall thickening dominated the last observation interval between the fourth and tenth years. Severity of vascular reaction was independent of immunohistochemical evidence of B cells or macrophages. CONCLUSIONS: While activation of the humoral and the non-specific immunological system is common after heart transplantation, microvascular alterations seem to develop independently of these findings.
AIMS: To determine anxiety in parents of children undergoing testing for islet autoantibodies. SUBJECTS AND METHODS: Children of parents with Type 1 diabetes (T1DM) were tested at birth, age 9 months, 2 years and 5 years for islet autoantibodies. Families were informed about islet autoantibody status in the child after each visit. The psychological impact of islet autoantibody testing was assessed in parents before and after the 5 years visit. Anxiety was measured using a subscale of the State-Trait-Anxiety Inventory (STAI) and structured single-item questions. Four hundred and sixty-three parents were evaluated before blood drawing and 317 parents at notification of islet autoantibody status. RESULTS: Before blood withdrawal, anxiety was increased in mothers and in particular in mothers of islet autoantibody-positive offspring compared with a normative control group. At notification of islet antibody status, anxiety significantly decreased in parents of islet autoantibody-negative offspring, and increased in parents of islet autoantibody-positive offspring. Blood withdrawal was considered a burden for parents and offspring (15% and 48%, respectively). Most parents from islet autoantibody-negative and -positive offspring wished to know the diabetes risk of their child (95% and 100%, respectively) and were glad to be informed about their child's islet antibody status (97% and 87%). CONCLUSIONS: Overall, islet autoantibody testing in early childhood reduces anxiety in T1DM families. The increased anxiety associated with islet autoantibody-positive status suggests, however, that testing should be performed in centres which can provide accurate risk information and counselling if required.
Composite lymphomas are defined as two unrelated, morphologically and genetically distinct lymphomas occurring at the same point in time within the same tissue or organ. Since their original definition, several composite lymphomas have been reported exclusively based on morphological grounds. However, with the application of immunohistological and molecular biological techniques it has become evident that many so called "composite" lymphomas do not fulfil the necessary criteria, because they merely represent two different morphological phenotypes of the same malignant clone. This report describes the manifestation of a true composite lymphoma within a single cervical lymph node, which is composed of a cutaneous T cell lymphoma and a classic Hodgkin lymphoma of B cell type--a very rare finding indeed.
Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common clinical variants of cutaneous T cell lymphoma. Although thought to be closely related to mature T helper cells, the relation between the neoplastic cells in MF and SS is still not fully clarified. This report describes a patient with complete remission of SS under treatment with extracorporeal photophoresis (ECP), who subsequently developed typical plaques of MF and large cell lymphoma (LCL). Serial polymerase chain reaction analyses confirmed identical T cell receptor beta and gamma gene rearrangements in SS, MF, and LCL, and complete disappearance of the circulating malignant T cell clone from the peripheral blood after ECP. These findings indicate that the neoplastic cells in SS, MF, and LCL are derived from a common precursor T cell, despite the change in clinical phenotype.
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AIM/HYPOTHESIS: Type 1 diabetes (T1D) is an autoimmune disease with multiple susceptibility genes. The aim of this study was to determine whether combining IDDM1/HLA and IDDM2/ insulin( INS) 5' variable number of tandem repeat locus (VNTR) genotypes improves T1D risk assessment. METHODS: Patients with T1D (n=488), control subjects (n=846), and offspring of parents with T1D (n=1122) were IDDM1 and IDDM2 genotyped. Offspring were followed for islet autoantibodies and T1D from birth until the age of 2 to 12 years. RESULTS: Compared to the I/I INS VNTR genotype, the I/III and III/III genotypes reduced T1D risk conferred by IDDM1/HLA in all HLA genotype categories of the case-control cohort by 1.6-fold to three-fold. The highest T1D risk was associated with INS VNTR class I/I plus HLA DR3/DR4-DQ8 (20.4% in patients, 0.6% in control subjects) or HLA DR4-DQ8/DR4-DQ8 (6.3% in patients, 0.2% in control subjects). In the offspring, HLA DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 conferred increased risk for early development of islet autoantibodies (14.6% and 12.9% by age 2 years). Offspring with these high risk IDDM1 genotypes plus the INS VNTR class I/I genotype (n=71; 6.3%) had the highest risk of developing islet autoantibodies (21.8% by age 2 years vs 8.9% in offspring with high risk IDDM1 plus INS VNTR class I/III or III/III genotypes, p<0.05) and T1D (8.5% by age 6 years vs 4.3%). Offspring who developed autoantibodies to multiple antigens had increased frequencies of both high risk IDDM1 and IDDM2 genotypes (p<0.0001), whereas offspring who developed autoantibodies to GAD only had increased frequencies of high risk IDDM1 and protective IDDM2 genotypes, suggesting that IDDM2 influences the autoimmune target specificity. CONCLUSION/INTERPRETATION: Combining IDDM1 and IDDM2 genotyping identifies a minority of children with an increased T1D risk.
BACKGROUND: Studies of outcome in cardiac transplantation have focused primarily on identifying patient- and donor-related factors associated with patient mortality. Less consideration has been given to the impact of the transplant center. This study was undertaken to assess variability in heart transplantation outcome in Eurotransplant centers to provide a framework for auditing. METHODS AND RESULTS: In a 2-year period, 1,401 adult patients underwent heart transplantation in 45 centers. The 1-year patient survival rate was 76% (95% CI, 74%-78%) with a range of 0% to 100% at the center level. The risk-adjusted center effect on mortality was estimated by calculating a standardized difference between the observed number of deaths 1 year after transplantation and the expected number of deaths based on the case mix. By assessing within- and between-center variations with empirical Bayes (EB) methods, after adjustment for all registered prognostic factors, an improved estimate of the true center effect was obtained. Compared with the standard risk-adjusted center effect method, fewer outlying centers were identified with the EB method. CONCLUSION: EB methods, because they are known to incorporate more information from the data, enable a more precise and realistic portrayal of heart transplant centers' performances, compared with other risk-adjusted center effect methods. In the context of auditing procedures, EB methods should preferably be used for the identification of centers that deviate significantly from quality standards.
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In order to integrate evolutionary concepts into lymphoma research we mapped features of classic Hodgkin lymphoma (a disease which has been recently described to be derived from germinal center B-cells) onto a phylogenetic tree of vertebrates. Secondly, we matched the phylogenetic occurrence of classic Hodgkin lymphoma to the changes in the lymphoid organ structure during vertebrate evolution. According to our analysis, classic Hodgkin lymphoma evolved exclusively at the developmental stage of mammals. Interestingly the appearance of Hodgkin lymphoma is correlated to the evolution of germinal centers in mammals. This lends some credit to the hypothesis that genes specific to the germinal center reaction are involved in the pathogenesis of Hodgkin lymphoma. However, as evolution did not stop at the developmental stage of the mammalian stem-species, to a certain extent species with specific differences of classic Hodgkin lymphoma can be expected. One such difference is that classic Hodgkin lymphoma occurs with a significantly higher frequency in humans than in all other mammals. This could be partially due to Epstein-Barr virus (EBV) infection in approximately 40%-50% of Hodgkin disease cases, that is associated with an expression of the EBV-encoded oncogen LMP-1. In conclusion we propose that the mapping of lymphoma related characteristics onto a phylogenetic tree is a valuable new tool in lymphoma research.
In this study we have analyzed bacterial lipopolysaccharide (LPS) induced genes in hemocytes of the Lepidopteran species Galleria mellonella using subtractive hybridization, followed by suppressive PCR. We have found genes that show homologies to molecules, such as gloverin, peptidoglycan recognition proteins and transferrin known to be involved in immunomodulation after bacterial infection in other species. In addition, a few molecules previously not described in the innate immune reactions were detected, such as a RNA binding molecule and tyrosine hydroxylase. Furthermore, the full-length cDNA of a LPS-induced molecule with six toxin-2-like domains is described to be a promising candidate to further elucidate the relationship between toxin- and defensin-like domains in arthropod host defense.
Defects in nine sarcomeric protein genes are known to cause hypertrophic cardiomyopathy (HCM). Mutation types and frequencies in large cohorts of consecutive and unrelated patients have not yet been determined. We, therefore, screened HCM patients for mutations in six sarcomeric genes: myosin-binding protein C3 (MYBPC3), MYH7, cardiac troponin T (TNNT2), alpha-tropomyosin (TPM1), cardiac troponin I (TNNI3), and cardiac troponin C (TNNC1). HCM was diagnosed in 108 consecutive patients by echocardiography (septum >15 mm, septal/posterior wall >1.3 mm), angiography, or based on a state after myectomy. Single-strand conformation polymorphism analysis was used for mutation screening, followed by DNA-sequencing. A total of 34 different mutations were identified in 108 patients: 18 mutations in MYBPC3 in 20 patients [intervening sequence (intron) 7 + 1G > A and Q1233X were found twice], 13 missense mutations in MYH7 in 14 patients (R807H was found twice), and one amino acid change in TPM1, TNNT2, and TNNI3, respectively. No disease-causing mutation was found in TNNC1. Cosegregation with the HCM phenotype could be demonstrated for 13 mutations (eight mutations in MYBPC3 and five mutations in MYH7). Twenty-eight of the 37 mutation carriers (76%) reported a positive family history with at least one affected first-grade relative; only eight mutations occurred sporadically (22%). MYBPC3 was the gene that most frequently caused HCM in our population. Systematic mutation screening in large samples of HCM patients leads to a genetic diagnosis in about 30% of unrelated index patients and in about 57% of patients with a positive family history.