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Biomedical subjects

K Lange

Publications and source records attributed to K Lange.

At least 19 recordsLinked to original sources
PubMed2007

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2-/- mice.

BACKGROUND AND PURPOSE: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator. EXPERIMENTAL APPROACH: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) and ALDH-2-/- mice. Activity of the cGMP-dependent kinase-I (reflected by levels of phosphorylated VAsodilator Stimulated Phosphoprotein, P-VASP) was quantified by Western blot analysis, mitochondrial dehydrogenase activity by HPLC. Following incubation of isolated mitochondria with PETN, PETriN-chromophore and PEDN, metabolites were quantified using chemiluminescence nitrogen detection and mass spectrometry. KEY RESULTS: Compared to WT, vasorelaxation in response to PETN, PETriN and GTN was attenuated about 10fold in ALDH-2-/- mice, identical to WT vessels preincubated with inhibitors of ALDH-2. Reduced vasodilator potency correlated with reduced P-VASP formation and diminished biotransformation of the tetranitrate- and trinitrate-compounds. None of these findings were observed for PEDN, GDN and PEMN. CONCLUSIONS AND IMPLICATIONS: Our results support the crucial role of ALDH-2 in bioactivating highly reactive nitrates like GTN, PETN and PETriN. ALDH-2-mediated relaxation by organic nitrates therefore depends mainly on the number of nitrate groups. Less potent nitrates like PEDN, GDN and PEMN are apparently biotransformed by other pathways.

Aldehyde Dehydrogenase↗
PubMed2006

[Eating disorders and diabetes mellitus].

Adolescent and young women with type 1 diabetes mellitus demonstrate a more than random coincidence with bulimia nervosa. However, the prevalence of eating disorders that do not fulfil the criteria of bulimia nervosa is also raised in women of this age group yet without diabetes mellitus. The comorbidity of type 1 diabetes and an eating disorder poses a risk factor in the development of diabetic follow-up diseases. Patients with an eating disorder and type 1 diabetes are characterized by an insufficient metabolic control and the early development of diabetic complications such as a retinopathy. The binge eating disorder, according to research aspects initially a new eating disorder entity, may especially be observed in overweight and obesity. Even if a binge eating disorder in persons with a type 2 diabetes does not occur more frequently than in those metabolically healthy persons, it does depict a risk factor for an accelerated weight gain which as rule involves an increase of insulin resistance.

Comorbidity↗
PubMed2005

Fishing for pleiotropic QTLs in a polygenic sea.

The application of factor analysis to human genetics has the potential to discover the coordinated control of multiple traits by common environment, common polygenes, or a single major gene. Classical factor analysis explains the covariation among the components of a random vector by approximating the vector by a linear transformation of a small number of uncorrelated factors. In the current paper we show how factor analysis dovetails with the classical variance decompositions of biometrical genetics. To explore the relationships between related quantitative variables, and avoid complicated positive definiteness constraints, we employ Cholesky and factor analytic decompositions. We derive an ECM algorithm and a competing quasi-Newton algorithm for estimating parameters by maximum likelihood and propose tactics for selecting initial parameter values. We also show how parameter asymptotic standard errors under these parameterizations propagate to asymptotic standard errors of the underlying variance components. Our genetic analysis program Mendel, which now incorporates the program Fisher, has performed well on a variety of data sets. We illustrate our methods, algorithms, and models on two data sets: a bivariate quantitative genetic example using total finger ridge count data and a multivariate linkage example using insulin resistance data.

Algorithms↗
PubMed2004

[Diabetes in childhood: everyday burden and professional consequences for parents].

BACKGROUND AND OBJECTIVE: To investigate the burden and the financial and professional consequences for mothers and fathers after the onset of diabetes in their child in relationship to age at onset and family structure. PATIENTS AND METHODS: All families of children with an age at onset < 14 years and a diabetes duration < 10 years treated at four large pediatric diabetes centers received a structured questionnaire (burden of diabetes, professional position and career development, financial consequences for both parents, demographic data). RESULTS: 580 families with 583 children with type 1 diabetes (46 % girls, diabetes duration 5.0 +/- 3.2 years, age at onset 6.9 +/- 3.9 years) participated. 42 % of the children had an age at onset below 6 years. 11 % had single parents. Before the onset of diabetes in their children 93 % of the fathers worked full-time, thereafter 4 % changed their employment. Mothers worked at onset full-time in 22 % and part-time in 38 %; thereafter 31 % reduced their working time or stopped working. 33 % of the mothers reported handicaps in their professional career development, especially those with a child with age at onset below 6 years (44 %). Negative financial consequences were present in 44 % of the families. The day to day burden on a scale from 1 to 5 decreased both in mothers and in fathers with increasing age at onset. The individual burden was higher in mothers (3.6 +/-1.1) than in fathers (2.8 +/- 1.1) (p = 0.000). CONCLUSIONS: Initiatives to reduce the burden on families with a child with diabetes are urgently needed. Particularly the social and professional integration of mothers with younger children at diabetes onset need to be improved through support measures outside the family.

Adolescent↗
PubMed2003

[Mycosis fungoides in childhood and adolescence with clonal T-cell receptor gamma gene rearrangement. Two cases].

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) characterized by its typical progress in three stages: the patch-, the plaque- and the tumour-stage. The incidence of mycosis fungoides rises with age and the average age at presentation is about 50. Children and adolescents are rarely affected and there are only few reports in the literature. We report a 12- and a 15-year-old boy showing refractory skin lesions not typical for mycosis fungoides. The histo- and immunohistological investigations and the detection of clonal T-cell receptor gamma gene rearrangements confirmed the diagnosis of early onset mycosis fungoides in both cases.

Adolescent↗
PubMed2003

Health-related quality of life in chronic pancreatitis: a psychometric assessment.

BACKGROUND: Measurement properties of a generic instrument to assess health-related quality of life in patients with chronic pancreatitis have not been described. METHODS: We assessed the health-related quality of life in 314 patients with chronic pancreatitis using the generic Medical Outcomes Study Short Form-36 Health Survey. Data were compared with age- and gender-matched general population norms and the psychometric properties of the instrument were evaluated. RESULTS: Patients with chronic pancreatitis reported considerably worse scores on all Short Form-36 scales compared with the general population. Decrements were most pronounced in role limitations caused by physical (-29%) and emotional health problems (-20%), and general health perceptions (-19%). Test-retest reliability coefficients were > or = 0.82 for all subscales and internal consistency coefficients ranged from 0.78 to 0.92. Floor effects were negligible for all but the two role subscales, but there were substantial ceiling effects for five of the eight subscales. Construct validity was supported by the findings that the Short Form-36 discriminated well between patients of different age, burden of chronic illness and severity of symptoms. CONCLUSIONS: Patients with chronic pancreatitis experience substantial deteriorations in health-related quality of life compared with the general population. The Short Form-36 proved to be a feasible, reliable and valid measure for descriptive studies of patients with chronic pancreatitis, but ceiling effects may limit its usefulness as an outcome measure in the assessment of treatment effects.

Adult↗
PubMed2003

Aberrant immunophenotypes of mantle cell lymphomas.

Mantle cell lymphomas (MCL) are characterized by cytomorphological criteria, a distinct immunophenotype and a characteristic chromosomal aberration (t(11;14)). In morphological variants of MCL the immunohistochemical constellation with CD5-positivity and CD23-negativity is a helpful and decisive diagnostic aid to differentiate MCL from other B-cell-lymphomas, e.g. lymphocytic lymphomas (B-CLL). In this study the morphological, immunophenotypical, and genetical features of 50 MCL were analysed. Five cases revealed an aberrant immunophenotype with lacking expression of CD5 (n = 3) and positive reactivity to CD23 (n = 2) while cyclin D1 expression could be demonstrated in all 5 cases. These constellations show that there is, besides morphological subgroups, a small group of MCL with aberrant immunophenotypes, which has to be taken into account in the differential diagnosis to lymphocytic lymphoma and other lymphomas.

Aged↗
PubMed2003

Increase of bone marrow lymphocytes in systemic mastocytosis: reactive lymphocytosis or malignant lymphoma? Immunohistochemical and molecular findings on routinely processed bone marrow biopsy specimens.

AIMS: To clarify the nature (reactive or neoplastic) of lesional, perifocally aggregated lymphocytes in bone marrow infiltrates of systemic mastocytosis (SM), the histopathology of which can resemble malignant lymphoma with focal bone marrow involvement, particularly low grade malignant B cell lymphoma of lymphoplasmacytic immunocytoma subtype, which frequently exhibits increased mast cell (MC) numbers. METHODS: Thirteen cases of SM and three of lymphoplasmacytic immunocytoma with predominant focal bone marrow infiltration were investigated. Immunostaining of formalin fixed, paraffin wax embedded bone marrow specimens was performed using antibodies against CD2, CD5, CD20, CD23, and CD25; kappa and lambda immunoglobulin light chains; and MC markers chymase, tryptase, and CD117 (KIT). Monoclonal rearrangements of IgH and TCRgamma were studied using seminested polymerase chain reaction (PCR). c-kit point mutation Asp816-Val was detected by PNA mediated PCR clamping and hybridisation probes. RESULTS: The lymphocytic clusters in SM contained nearly equal numbers of mature T and B cells, the latter with no coexpression of aberrant antigens, such as CD5 or CD23. Most MCs in SM cases constantly coexpressed tryptase, CD25, and CD117. No monoclonal rearrangements were seen for IgH or TCRgamma. In contrast, B cells from immunocytomas showed light chain restriction and monoclonal rearrangement for IgH, confirming their neoplastic nature. c-kit point mutation Asp816-Val was found in ten of 13 SM cases, but in none of the three immunocytomas. CONCLUSIONS: Focal accumulations of lymphocytes in the bone marrow of SM are reactive in nature and could be termed lymphocytosis. A diagnosis of SM-AHNMD/immunocytoma should not be made.

B-Lymphocytes↗
PubMed2003

Nitrogen removal from digester supernatant via nitrite--SBR or SHARON?

Separate biological elimination of nitrogen from the digester supernatant of a municipal wastewater treatment plant (WWTP) was investigated in pilot and full-scale plants. Denitrification mainly via nitrite was achieved in a sequencing batch reactor (SBR) and a continuous flow reactor (CSTR or SHARON). Suppression of nitrite oxidation in the SBR was feasible at short aerobic/anaerobic intervals allowing for immediate denitrification of the produced nitrite. Nitrate production could also be stopped by exposing the biomass to anaerobic conditions for 11 days. Temporarily high concentrations (up to 80 gNH3-Nm(-3)) of free ammonia could not be considered as the major reason for inhibiting nitrite oxidation. In a full-scale SBR plant 90% of the nitrogen load was denitrified in a total hydraulic retention time (HRT) of 1.6 days and with a sludge age between 15 and 20 days. Ethanol and methanol were used for denitrification. The specific average substrate consumption was 2.2 gCOD(dosed) g(-1)N(removed) with an effective biomass yield of 0.2 gCOD(biomass) g(-1)COD(dosed). No dosing with base was required. In the SHARON process full nitrogen elimination was achieved only with a total HRT greater than 4 days at 29 degrees C. The overall costs were estimated at 1.4 euros kg(-1)N(removed) for the SBR and 1.63 euros kg(-1)N(removed) in SHARON mode, respectively. The SHARON process is simple in operation (CSTR) but the tank volume has to be significantly greater than in SBR.

Bacteria, Aerobic↗
PubMed2003

[Overexpression of NPM-ALK induces different types of malignant lymphomas in IL-9 transgenic mice].

Anaplastic large cell lymphoma (ALCL) comprises approximately 25 % of all non-Hodgkin lymphomas in children and young adults. 40% of these tumours have a translocation t(2;5)(p23;q35), which fuses the nucleophosmin gene (NPM) to the anaplastic lymphoma kinase gene (ALK) resulting in a hybrid protein which contributes to the pathogenensis of ALCL. To further analyse the transforming activity in an animal model, a cDNA encoding the protein product, NPM-ALK, was incorporated into a retrovirus construct and introduced into mouse bone marrow progenitors by infection. In a bone marrow gene transfer and transplantation protocol the hematopoietic compartments of lethally irradiated IL-9 transgenic mice were reconstituted with npm-alk infected progenitor cells. IL-9 transgenic mice were chosen, because IL-9, a pleiotropic T helper 2 cytokine, is expressed in most cases of human ALCL and was shown to have an oncogenic potential at least on T cells. Reconstituted mice developed NPM-ALK positive lymphomas including lymphoblastic lymphomas of T-cell type (T-LB), mature and immature plasmacytoma (PZ) and plasmoblastic/anaplastic diffuse large B-cell lymphoma after 10-30 weeks. The combined overexpression of NPM-ALK and IL-9 exerts cooperative oncogenic activity in the transformation of murine lymphoid cells leading to accelerated and enhanced development of T-LB. Many animals developed plasmacytic/plasmoblastic neoplasms, of which the most aggressive tumours share many features with human anaplastic/plasmoblastic diffuse large B-cell lymphoma.

Animals↗
PubMed2002

Remission of a cutaneous Mycosis fungoides after topical 5-ALA sensitisation and photodynamic therapy in a patient with advanced HIV-infection.

BACKGROUND: Treatment of Mycosis fungoides (MF) in HIV-infected patients is controversially discoursed. Photodynamic therapy (PDT) after topical sensitization with 5-aminolevulinic acid (5-ALA) is a new and effective modality for treatment of skin malignancies. OBJECTIVE: In this report we describe, what is, to our knowledge, the first case of a patient with MF through advanced HIV-infection, successfully experiencing topical 5-ALA sensitization and PDT. METHODS: 5-ALA ointment was applied to plaques and held in occlusion for 4 hours. PDT was applied using the PDT 1200 irradiation source (Waldmann Medizintechnik System) with 180 J/cm superset 2. RESULTS: Complete remission of MF was achieved, after two completed cycles of photodynamic therapy. CONCLUSION: MF lesions in the presended case showed a high response to 5-ALA sensitization and PDT. This modality appeared to be very effective in treatment of MF in a HIV-infected patient and could be a valuable treatment option for cutaneous T-cell lymphoma in HIV-infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Donor-derived soluble MHC antigens plus low-dose cyclosporine induce transplantation unresponsiveness independent of the thymus by down-regulating T cell-mediated alloresponses in a rat transplantation model.

BACKGROUND: In vitro, soluble MHC (sMHC) antigens modulate and induce apoptosis in alloreactive and antigen-specific T cells, demonstrating their potency to regulate T cell-mediated immune responses. However, their efficacy to regulate immunological responses in vivo remains unclear. Here, we report that repetitive intraperitoneal injection of recombinant Lewis rat-derived MHC class I antigens in Dark Agouti (DA) rats modulates alloreactivity. METHODS: RT1.A1 (Lewis derived) genes were cloned into mammalian expression vectors, and RT1.Aa (DA derived) genes were used to transfect a rat myeloma cell line. RT1.A1 molecules were injected intraperitoneally in DA recipients that subsequently underwent transplantation with Lewis-derived cardiac allografts. RESULTS: Soluble class I antigens were secreted by the transfected cells and were shown to be heterodimeric, peptide-loaded, and conformationally folded. Injection of donor-derived soluble MHC significantly reduced the ability of recipient animals to mount a cytotoxic T-cell response to donor-derived tissue. More interestingly, this treatment significantly prolonged donor-graft survival and allowed 60% of treated animals to develop graft tolerance (>120 days), when donor sMHC were combined with a single subtherapeutic dosage of cyclosporine. Thymectomy of recipient animals before transplantation did not interfere with induction of peripheral tolerance. CONCLUSIONS: Donor-derived sMHC are potential tolerogens for down-regulating the cytotoxic T-cell response of animals that undergo transplantation. Thus, these data provide for the first time a rationale for the application of directly injected sMHC in vivo to down-regulate immunological responses and aid the induction of graft tolerance.

Animals↗
PubMed2001

Quantitative-trait-locus analysis of body-mass index and of stature, by combined analysis of genome scans of five Finnish study groups.

In recent years, many genomewide screens have been performed, to identify novel loci predisposing to various complex diseases. Often, only a portion of the collected clinical data from the study subjects is used in the actual analysis of the trait, and much of the phenotypic data is ignored. With proper consent, these data could subsequently be used in studies of common quantitative traits influencing human biology, and such a reanalysis method would be further justified by the nonbiased ascertainment of study individuals. To make our point, we report here a quantitative-trait-locus (QTL) analysis of body-mass index (BMI) and stature (i.e., height), with genotypic data from genome scans of five Finnish study groups. The combined study group was composed of 614 individuals from 247 families. Five study groups were originally ascertained in genetic studies on hypertension, obesity, osteoarthritis, migraine, and familial combined hyperlipidemia. Most of the families are from the Finnish Twin Cohort, which represents a population-wide sample. In each of the five genome scans, approximately 350 evenly spaced markers were genotyped on 22 autosomes. In analyzing the genotype data by a variance-component method, we found, on chromosome 7pter (maximum multipoint LOD score of 2.91), evidence for QTLs affecting stature, and a second locus, with suggestive evidence for linkage to stature, was detected on chromosome 9q (maximum multipoint LOD score of 2.61). Encouragingly, the locus on chromosome 7 is supported by the data reported by Hirschhorn et al. (in this issue), who used a similar method. We found no evidence for QTLs affecting BMI.

Body Height↗
PubMed2001

Regulation of glucose uptake in differentiated cells.

Glucose uptake into the cell is mediated by a family of glycosylated membrane proteins, called glucose transporters (GTs) that are able to facilitate passive hexose transfer across the lipid plasma membrane. The tissue-specific transporter isoforms generally differ in their affinity to the natural substrate D-glucose according to the specific functions of the respective organ. The mechanisms by which external and internal signals regulate glucose uptake into the cells belong to one of the most extensively studied fields of cell physiology. However, in spite of significant progress in identifying the involved molecular components and signaling pathways, the final cellular mechanism responsible for the short-term regulation of glucose uptake is still a matter of intense debate. The widely accepted translocation hypothesis, which explains transport regulation by exo- and endocytic modulation of the number of GTs in the plasma membrane, insufficiently accounts for the whole insulin-induced transport stimulation and is insufficient to integrate the wide variety of different transport-modulating signals in differentiated tissue cells into a common mechanistic concept. Some time ago, a novel type of glucose transport regulation has been proposed prevailing in differentiated tissue cells. This mechanism depends on the presence of glucose transporters on microvilli of differentiated cells. The basic framework for this theory was provided by a recently presented novel concept of ion channel regulation via microvillar structures [Lange, K. (1999): Microvillar Ca++ signaling: A new view on an old problem. J. Cell. Physiol. 180, 19-35; Lange, K. (2000): Regulation of cell volume via microvillar ion channels. J. Cell. Physiol. 185, 21-35; Lange, K. (2000): Microvillar ion channels - Cytoskeletal regulation of ion fluxes. J. Theor. Biol. 206, 561-584], earlier studies on glucose transport regulation and a number actual biochemical findings. Here, a survey on both concepts is given and the ability of the novel mechanism of microvillar transport regulation to integrate a large body of experimental data into the common concept of cellular regulation via microvillar pathways is discussed.

Adipocytes↗
PubMed2001

[Congenital hearing loss in children. 2: Genetic hearing loss].

Molecular genetic tests enable a differentiated view of patho-physiological correlation of sensori-neural hearing impairment. On the basis of 4791 records of the German Central Registry on Childhood Hearing Loss (Deutsches Zentralregister für kindliche Hörstörungen (DZH)) it was shown that 35% of all permanent hearing impairment in Germany is caused genetically and 20% are acquired. The proportion of indistinct etiology remains at 45%. The number of children who have a hearing impairment by birth is also vague. It has to be expected that approximately 5% of these children develop a hearing impairment afterwards albeit its genetic determination. In 4791 cases a syndromal phenotype was assumed in 8.9%. Practical advice is given for clinical routine diagnostics with pragmatic suggestions and some distinct syndromes are described. Hitherto identified deafness genes reveal their role in pathological auditory function. Future diagnostic and therapeutic strategies are outlined on the basis of molecular genetic methods.

Abnormalities, Multiple↗