Biomedical subjects
Publications and source records attributed to H Wolf.
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Without vitamin D supplementation, the majority of infants seems to be at risk of vitamin D-deficiency rickets. On the other hand, routine vitamin D supplementation of breast-fed infants is not recommended by all authors. In this paper we give an overview of vitamin D metabolism and vitamin D regulation in newborns, which may differ in a certain way from the regulation in adults. Based on this, minimal and optimal requirements for vitamin D in newborns and infants is determined. Furthermore, the paper aims at defining dosages and conditions that are at risk of vitamin D intoxication.
Contrary to type IV contact dermatitis, histochemical studies of immunological mechanisms in type I contact dermatitis are rare. To analyse the immunohistochemical kinetics of immediate type I reactions we followed up prick-test reactions to individual specific allergens in 5 atopics with respiratory allergy (group I) and in 4 patients with proven type I contact dermatitis (group II). Punch biopsies (diameter 6 mm) were taken 20 minutes, 6, 24 and 72 h after prick testing. Histological investigations were performed on paraffin-embedded tissue; immunohistochemical studies were done one frozen tissue with a panel of monoclonal antibodies applying the alkaline-phosphatase-anti-alkaline-phosphatase-complex method. In type I contact dermatitis a moderate lympho-monocytic dermal infiltrate appeared, which increased until 72 hrs after testing. In contrast, the immediate allergic reactions of group I revealed only mild lympho-monocytic infiltration in all proven sequential biopsies. No quantitative differences concerning the immunohistochemical pattern of OKM-1, OKM-5, Leu-2a and Leu-3a were observed between the two groups. Group II showed an increase in HLA DR, OKT6, anti-IgE- and anti-IL-2-receptor immunoreactivity whereas group I exhibited only moderate or no immunoreactivity. A dendritic anti-IgE-staining pattern, most probably on Langerhans cells, was only observed in the epidermis of group II patients. A pathogenetic concept of IgE-mediated type I contact dermatitis is presented and possible relationships with atopic dermatitis are discussed.
Following computer-assisted analysis of the amino acid sequence of various HIV-1 isolates, we synthesized a series of oligopeptides derived from variable and conserved regions of the envelope protein complex gp120/gp41. The peptides were used in ELISA tests for their reactivity with human antisera from HIV-1 positive individuals; patients with clinically manifested AIDS showed only a rather limited reaction, predominantly with two peptides (p102-112, p316-326), which is in contrast to sera from HIV-1 positive asymptomatic individuals, whose sera were reactive with almost all peptides. Using consecutive sera of the same patients, decreasing antibody titers to defined epitopes could be shown to occur during the development of AIDS. Cellular immune response recognition was analyzed in T-cell proliferation assays by [3H]thymidine incorporation. One peptide localized in a conserved region clearly induced proliferation of T-cells. Those data were combined to a map of the functions localized in the various regions of the HIV-1 envelope proteins.
The role of urinary cytology in detection and follow-up of urinary bladder tumours is still evolving. However, considerable variations in the accuracy of detecting bladder tumours exist in published work on the subject. In this study the influence of concomitant urothelial atypia on urinary cytology was investigated. Further, the correlation of grading between cytology and tumour histology was examined, and finally the role of urinary cytology as a prognostic factor was investigated. 102 comparative studies of simultaneously achieved precystoscopic voided urine samples, tumour histology and 8 pre-selected site biopsies were available from patients having a Ta, T1 or T2 bladder tumour. The overall numbers of positive cytology were found to be 64%, but correcting for false positives caused by concomitant urothelial atypia the numbers were reduced to 55% (p less than 0.01). A considerable higher ability to detect high-grade than low-grade tumours was found. Correlation between grading of tumour histology and cytology was found to be only 50%. Patients were followed for 3 years. From the results of pre-cystoscopic cytology it was possible to define a low-risk group and a high-risk group. Patients with negative cytology had very low risk of future invasive tumour recurrence whereas all patients with grade III-IV cytologic changes were found to harbour either a grade III tumour or carcinoma in situ, both conditions predictive of aggressive tumour course.
Improvement in survival of patients with bladder cancer has despite much effort in optimizing treatment schedules been limited (21). Patients seem to present with a bladder tumour that has a biological potential which it is difficult to alter by treatment. Bladder tumours seem either to possess or lack the biological potential for invasion. Non-invasive (Ta) bladder tumours do not kill the patient, and survival of patients with invasive tumours is localized to the bladder or present with regional and/or distant metastases (26).
Transabdominal ultrasonography can detect bladder tumours down to 5 mm in diameter, and in combination with urine cytology it is a potential alternative to cystoscopy for control of bladder tumour patients. This modality was compared with cystoscopy in 260 investigations on patients with previous non-invasive tumours. Of 153 negative ultrasonographies 55 (21%) were false negative, overlooking 15 tumours above 5 mm (including 5 flat papillomatous areas), 30 tumours 5 mm or less and 10 flat dysplastic lesions (diagnostic sensitivity 64%). In 14 of the false negative ultrasonographies urine cytology was abnormal, increasing the combined diagnostic sensitivity to 73%. Most overlooked tumours above 5 mm were in bladder neck, anterior wall and dome. Of 89 positive ultrasonographies 15 were false positive (diagnostic specificity 83%). Two patients developed invasive tumours in the study period. One was detected by ultrasound and urine cytology, the other - a flat muscle invasive tumour - was not. Ultrasonography plus urine cytology is only acceptable for control of patients with very little risk of invasive and few non-invasive recurrences, i.e. patients with previous Ta, grade I or II transitional cell tumours and no recurrences after 1 or 2 control cystoscopies.
With the purpose of studying DNA replication activity and location in normal and malignant tissue, bladder tumours were induced in ten rats by the intravesical installation of N-Nitroso-N-Methyl-Urea. Ten rats were installed with the NMU solvent and served as controls. The animals were injected intraperitoneally with 1 mg bromodeoxyuridine/100 g weight one hour prior to sacrifice. An indirect immunoperoxidase method using mouse monoclonal anti-bromodeoxy-uridine antibody was used on tissue sections of normal urothelium and bladder tumours to visualize labelled nuclei. Labelling indices were calculated and correlated to the grade of atypia. We found that normal urothelium had very little proliferative activity. The labelling index of tumours increased with increasing grade of atypia, being highest in invasive tumours. Only cells located to the basal cell layer were labelled in normal and grade I urothelium. In grade II and III tumours labelled cells were found in the intermediate cell layer as well as in the basal cell layer. Areas of squamous metaplasia showed high labelling indices, however the proliferative cells were restricted to the basal cell layer. The bromodeoxyuridine labelling index thus increases with increasing grade of atypia.
This review summarizes studies from our and other laboratories attempting to define the molecular and clonotypic origin of autoantibodies that typify systemic autoimmune diseases such as lupus and rheumatoid arthritis. Comparative restriction fragment length polymorphism (RFLP) studies investigating the immunoglobulin (Ig) germline gene organization in lupus-prone strains of mice suggested that the disease can develop in different Ig heavy (H) and light (L) chain haplotypes, and that the Ig germline genes in lupus mice are probably normal. Analysis of the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice revealed that similar, and in some instances even identical, gene segments are expressed in autoantibodies and in antibodies to exogenous antigens, and that anti-self and anti-non-self responses are encoded by the same, or at least an overlapping germline gene repertoire. A large variety of Ig variable (V), diversity (D), and joining (J) gene segments can encode autoantibodies with different specificities, and both germline genes and somatically-mutated genes can be expressed in such antibodies.
Latency of Epstein-Barr virus infection may be generated by surviving immortalized B cells or by continuous re-infection. EBV-positive B-cell tumors have been found following bone-marrow transplantation (BMT) and were of donor type in the few cases investigated. We established a B-cell line from the bone marrow of a patient in complete remission following allogeneic BMT for aplastic anemia 18 months post-grafting. Differences in sex and isoenzymes allowed an exact determination of chimerism in our case. While the patient showed persistent complete chimerism of all cell lineages, cells grown in culture were of recipient type. They expressed B-cell markers, showed a monoclonal rearrangement of the immunoglobulin genes and carried EBV-associated antigens. As direct preparations of cells from the patient did not contain detectable recipient-type cells, it appeared likely that small numbers of EBV-transformed B cells of the recipient survived for long periods in this patient. For the development of secondary B-cell neoplasms in vivo, additional patho-physiological steps like severe graft versus host disease or T-cell suppression are obviously required because the patient was still free of lymphoma 3 years post-grafting.
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Immunohistochemistry has led to the finding of an expression of ABO-related blood group antigens in normal and malignant bladder urothelium which is different from that found on erythrocytes from the same individual. This includes a loss of blood group ABO expression in malignant urothelium, and the expression of Leb antigens in normal and malignant cells from individuals with Le(a+b-) and Le(a-b-) erythrocytes. To elucidate the mechanism of this blood group antigen expression in urothelium we have analyzed the activity of the specific glycosyltransferases encoded by the ABO, Se, H, Le, and X blood group genes in normal and malignant urothelium. Biopsies of normal urothelium were obtained from 22 individuals and biopsies of urothelial tumors from 20 individuals. The tissue donors were typed for ABO, Lewis, and secretor status on erythrocytes and saliva. The biopsies were disaggregated to single cell suspensions, and the activity of the individual glycosyltransferases was determined as pmol of labeled sugar incorporated by oligosaccharide acceptors per 100,000 cells. The A (alpha-3-N-acetyl-D-galactosaminyl) and B (alpha-3-D-galactosyl) gene-specified transferases showed no activity in malignant cells, whereas all other enzymes examined were expressed in both normal and malignant cells. Secretors and nonsecretors showed the same alpha-2-L-fucosyltransferase activity in both normal and malignant cells, whereas the alpha-3-L-fucosyltransferase was reduced (P less than 0.02) in malignant cells from Lewis positive individuals. The Lewis gene-encoded alpha-4-L-fucosyltransferase showed a similar activity in Lewis positive and negative individuals. These results indicate that the disappearance of A and B blood group antigens in bladder tumors and the expression of Leb antigens in normal and malignant cells from individuals with Le(a+b-) and Le(a-b-) erythrocytes are due to corresponding differences in glycosyltransferases. The results indicate that the ABO, H, Se, and Le genes are subjected to a tissue-dependent differential expression.
The total non-Hodgkin's lymphoma-population treated between 1978 and 1986 by means of radiotherapy or combined chemo/radiotherapy was analysed as to primary extranodular manifestation. 39 cases, 16 women and 23 men, were observed (stage IE 12, stage IIE 22 and stage IIIE 5). Immunoblastic (10), lymphoblastic (9) and centroblastic (6) lymphomas are the most frequent with respect to histology. Gastroenteron (16) and otorhinolaryngological region (13) are in the lead with regard to localisation. 5-year-survival-rates are determined in dependence on clinical stage: IE 65.8%, IIE 39.2% (low, connected with the proportion of high-malignant histology) and IIIE 25.0%. The 5-year-survival-rate of primary gastrointestinal manifestation amounted to 51.5%. With respect to aetiopathogenesis of primary extranodular lymphomas gut-, mucosa- and bronchial-associated lymphoid tissue, aberrant lymph-nodes and the influence of viral- and immunologic factors seem to be important.
Quantitative DNA measurements and estimates of blood group-related carbohydrate antigen expression have been used as predictive parameters in transitional cell carcinomas (Ca). To obtain an accurate quantitative characterization of cellular subpopulations on the basis of these parameters, the authors developed a dual-parameter flow cytometric method using a fluorescence-activated cell sorter. With this method single-cell suspensions from 26 transitional cell carcinomas were analyzed by means of propidium iodide (red fluorescence) as DNA ligand, and peanut agglutinin (PNA), wheat germ agglutinin (WGA), and anti-blood group A antibody (aBGA) as carbohydrate ligands. The latter ligands were visualized directly or indirectly by FITC (green fluorescence). The carbohydrate ligand binding was correlated to the DNA content of cell populations in the way that aneuploid populations showed a higher PNA binding (P less than 0.0002) and a lower WGA (P less than 0.01) and aBGA (P less than 0.04) binding than did diploid cell populations. The binding of PNA to aneuploid populations could be further increased (P less than 0.004) by neuraminidase treatments. Thus, aneuploid cells express both neuraminic acid substituted and unsubstituted PNA receptors. The carbohydrate ligand binding was cell cycle-dependent, as it was reduced (less than 0.008) in the G2-M phase. A low WGA (P less than 0.004) or aBGA (P less than 0.02) binding was correlated to tissue invasion. Immunohistochemistry with the carbohydrate ligands showed a good correlation between aBGA (P less than 0.0005) and PNA (P less than 0.004) binding to tumor cells and flow cytometric assay of these, as well as a correlation (P less than 0.003) between cellular location of WGA receptors and flow cytometric assay of these. It seems that dual-parameter flow cytometry represents an important tool in the characterization of bladder tumors.
Unstimulated IFN- and IL2-stimulated (NK) cell activities were investigated in patients with breast cancer who had received either local radiotherapy alone or adjuvant chemotherapeutic treatment with CMF combined with radiotherapy 12 to 18 months previously. When tested against the primarily NK-sensitive K562 cell line, patients who had received adjuvant chemotherapeutic treatment with CMF were shown to have a significantly decreased unstimulated and IFN-stimulated NK cell activity, as compared to both patients after radiotherapy only (P less than 0.002) and P less than 0.005, respectively) and healthy control persons (P less than 0.05). The former group of patients also had a significantly decreased IFN-stimulated NK cell activity, when tested against the primarily NK-insensitive Chang hepatoma cell line, as compared to patients after radiotherapy only (P less than 0.005) and healthy controls (P less than 0.05). Moreover, patients after radiotherapy only proved to have a significantly increased unstimulated (P less than 0.01) and IFN-stimulated NK cell activity (K562: P less than 0.05; Chang hepatoma cell line: P less than 0.05), as compared to healthy control individuals. In contrast, no difference in IL2-stimulated NK cell activity was detected. The investigation for the expression of CD3 and/or Leu 19 antigens as phenotypic markers of cells with non-MHC restricted cytotoxicity showed a significantly lower percentage of cells with the CD3+ phenotype in patients with breast cancer, irrespective of the chosen post-operative treatment, as compared to healthy controls (P less than 0.01). Finally, patients with breast cancer who had received radiotherapy only had a significant trend towards an increased percentage of CD3+/Leu 19+ PMNC, as compared to both patients after CMF treatment (P less than 0.05) and healthy controls (P less than 0.025). We conclude that patients with breast cancer vary on a long-term basis in their NK activity and in the phenotype of their PMNC depending on their post-operative adjuvant management.
During antirejection treatment with antithymocyte globulin (ATG), a 48-year-old male kidney graft recipient was erroneously given 30 mg/kg ATG on day 5 of the treatment course. Clinically, the patient presented with abdominal pain, profuse diarrhea, and fever. Initially, the platelet count dropped to 94 x 10(3)/microliters and showed a further decrease to 65 x 10(3)/microliters 2 days thereafter. Plasmapheresis carried out about 12 h after the end of ATG infusion resulted in a decrease in serum levels of total rabbit immunoglobulin as well as the antibody fraction reactive with human T lymphocytes. Within 10 days after the discontinuation of ATG treatment, the relative and absolute number of the T-cell subpopulations, which had disappeared from the circulation at the time of antirejection therapy, returned to normal values. In addition, at this time both platelet and lymphocyte counts were again found to be in the normal range. Kidney function had recovered from the rejection crisis such that the patient could be discharged 26 days posttransplantation.
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