Damage to the gastric mucosa by free radicals.
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Animals↗
Biomedical subjects
H Stein
Publications and source records attributed to H Stein.
Renin inhibitors. Improvements in the stability and biological activity of small peptides containing novel Leu-Val replacements.
We have designed a novel class of potent (0.3-7 nM) renin inhibitors which contain a dihydroxyethylene replacement for what is formally the Leu10-Val11 amide bond. Good potency (0.6 nM), water solubility (greater than 10 mg/ml at 37 degrees C), stability toward degradation by chymotrypsin (t1/2 = 820 min), and in vivo activity in a primate model (15% drop in mean arterial pressure in association with complete inhibition of plasma renin activity) are properties which have been incorporated into compound 10, an interesting new agent to be used in the study of hypertension.
Animals↗
Phenotypical characterization of the cells invading pancreatic islets of diabetic BB/OK rats: effect of interleukin 2 receptor-targeted immunotherapy.
We investigated immunohistochemically the phenotypes of mononucleated cells invading pancreatic islets of diabetic BB/OK rats in comparison to the diabetes-resistant parental strain, and 12 and 120 days after a temporary treatment (10 days) with a monoclonal antibody (1 mg/kg b.w.) directed against interleukin 2 receptor (IL 2R) combined with a subtherapeutic dose of cyclosporin A (1.5 mg/kg b.w.). Using a panel of monoclonal antibodies (OX-19, OX-8, W3/25, KI-M2R, OX-6, OX-17, ART-18) and the alkaline phosphatase anti-alkaline phosphatase system to visualize the bound primary antibodies, we observed an even distribution of mononucleated cells across the endocrine pancreas at a "background" level when obtained from diabetes-resistant parental rat strain. Diabetic BB/OK rats, characterized by a moderate hyperglycemia and a marked decrease of pancreatic insulin content, displayed a remarkable accumulation of mononucleated cells in the endocrine pancreas. Morphometric studies revealed an increase of all phenotypes investigated, nearly all mononucleated cells expressed class II histocompatibility antigens (OX-6+, OX-17+) and the number of cells expressing the IL 2R (ART-18+) was markedly enhanced. Sixty-seven percent of the immunotherapeutically treated BB/OK rats normalized plasma glucose and enhanced pancreatic insulin content. The successfully treated animals are characterized by a decrease of cells invading pancreatic islets (OX-19+, OX-8+, W3/25+, KI-M2R+), a decrease of class II histocompatibility antigen and IL 2R expression. The number of IL 2R cells is also diminished in the endocrine pancreas of unsuccessfully treated BB rats.
Animals↗
Comments on Hodgkin's disease: the Sternberg-Reed cell by P. Bucsky.
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Cell Transformation, Neoplastic↗
Unique display of a pathologic karyotype in Hodgkin's disease by Reed-Sternberg cells.
The clonality of Reed-Sternberg cells is still a matter of controversy. In Hodgkin's disease, these cells rarely constitute more than 2% of all cells in tissue biopsies of lymph node lesions, the rest being a large collection of various reactive cells. To determine in which cells the abnormal karyotype occurs, we studied two patients with Hodgkin's disease by a cytogenetic method allowing simultaneous analysis of cell morphology, immunologic phenotype, and karyotype in the same mitotic cell. The Ber-H2 (CD30) and Leu-M1 (CD15) monoclonal antibodies were used to identify mitotic Reed-Sternberg cells. In 24-48-hour cultures of lymph node cells from Hodgkin's lesions, there was a mixture of cells with an abnormal clonal karyotype and a normal karyotype. The abnormal clonal karyotype was restricted to Ber-H2- and Leu-M1-positive cells, i.e., the Reed-Sternberg cells. In keeping with these findings, most of the clonal atypical karyotypes occurred in kappa- and lambda-positive large cells, i.e., Reed-Sternberg cells. Mitotic cells with T markers (CD3,4,8) or B markers (CD22) had the normal karyotype. There were no mitoses in cells expressing the antigens recognized by Leu11 (CD16) or Leu11 + Leu7. These findings provide strong evidence suggesting that in Hodgkin's disease only the Reed-Sternberg cells possess a clonal karyotypic abnormality and thus are most probably the only neoplastic component in Hodgkin's disease.
Adult↗
Renin inhibitors. Dipeptide analogues of angiotensinogen utilizing a dihydroxyethylene transition-state mimic at the scissile bond to impart greater inhibitory potency.
The synthesis of diol-containing renin inhibitors has revealed that a simple vicinal diol functionality corresponding to the scissile Leu-Val bond in human angiotensinogen is capable of imparting inhibitory activity at a comparable or higher level than either the corresponding aldehyde or hydroxymethyl functionality (compare inhibitors 2a-c or 3a-c). This finding has led to the further optimization of a series of small transition-state analogue inhibitors by the inclusion of a second hydroxyl group in the Leu-Val surrogate to give compounds that inhibited human renin in the 200-700-pM range (e.g. 43, 45, 63, 66). The magnitude of effect of the second hydroxyl group on potency is not only dictated by the absolute stereochemistry of the diol but also by the side chain of the P1 residue. Molecular modeling of the diol-containing inhibitors suggests that one of the hydroxyl groups hydrogen bonds to Asp 32 and Asp 215, while the second hydrogen bonds to Asp 215. These diol inhibitors are extremely selective for human renin over the related enzymes cathepsin D, pepsin, and gastricsin. At high concentrations, compounds containing a leucine or phenylalanine rather than a histidine at the P2 position gave only minor amounts of inhibition of the other enzymes. Inhibitor 43 suppressed plasma renin activity completely and lowered mean blood pressure in monkeys after both intravenous and intraduodenal administration, but the blood pressure drop lasted less than 1 h. Monitoring the blood levels of 43 by enzyme inhibition assay after intraduodenal administration to monkeys or oral administration to rats revealed low absorption and rapid clearance. While intratracheal administration to dogs gave approximately 50% bioavailability, rapid clearance was still a problem. After examination of inhibitor 45 in a sensitive primate model in which monkeys were rendered both hypertensive and hyperreninemic, the effects on lowering systolic but not diastolic pressure were apparent even after 22 h postdosing. Details on the synthesis, in vitro structure-activity relationships, molecular modeling, in vivo activity, and metabolism of these inhibitors are described.
Angiotensinogen↗
New inhibitors of human renin that contain novel Leu-Val replacements. Examination of the P1 site.
Stereoselective syntheses of several nonpeptide sulfidoethanol fragments that function as Leu10-Val11 (P1-P1') scissile bond replacements in human angiotensinogen are presented. These fragments are prepared from a variety of amino acids with formal P1 side chains varying in size and lipophilicity by converting them to their corresponding N-protected aminoalkyl epoxide 5 followed by ring opening with isopropyl mercaptan. The coupling of these fragments to either Boc-Phe-Ala-OH or Boc-Phe-His-OH produces inhibitors of human renin, 6 and 7, respectively, which are compared to a series of dipeptide-aldehyde inhibitors, 4, by molecular modeling and biochemical methods. Qualitatively, histidine-containing (P2) inhibitors 7 possess greater inhibitory potency than their corresponding alanine (P2) analogues 6, which are more potent than the corresponding aldehydic inhibitors from series 4. Within a given series, inhibitors with the cyclohexylmethyl P1 side chain are more potent than the benzyl analogues, which in turn are more potent than cyclohexyl or isobutyl derivatives. Inhibitors with parger P1 side chains (e.g. adamantylmethyl and benzhydryl) are much less active. The inhibitory potency of these compounds against human renin is discussed in terms of specific interactions with the enzyme.
Amino Acid Sequence↗
Some observations on the use of computerised tomography in Legg-Calve-Perthes' disease.
The use of computerised tomography in the assessment of hip pathologies in children is an uncommonly used modality. To date, we were unable to find any definite work on the use of CAT scan investigations in LCPD. Ten children with Legg-Calve-Perthes' disease were reassessed by two-plane AP and lateral radiographs and by computerised tomography. The findings strongly suggest that computerised axial tomography is an important modality capable of providing more detailed information on the distorted anatomy, magnitude and severity of the disruptive process in the femoral head. This modality demonstrated the presence of fragmentation and cyst formation in the femoral head even if two-plane radiographs appeared to be normal.
Child↗
Monoclonal antibodies in the diagnosis of Hodgkin's disease. The search for a rational panel.
A novel, comprehensive panel of monoclonal antibodies was tested in a large series of routinely processed lymph node biopsy specimens from patients with Hodgkin's disease (69 cases), with the object of developing either definitive or adjunctive diagnostic criteria. B- and T-cell lymphomas and reactive states that could mimic Hodgkin's disease were also assessed with the same monoclonal antibody panel. In addition to the popularly used anti-Leu-M1 (CD15), the panel included the recently produced Ber-H2 (CD30) antibody, which detects a formalin-resistant epitope of the Ki-1 antigen. The other monoclonal antibodies were directed against epithelial membrane antigen (Dako-EMA) and leukocyte common antigen (Dako-LC) (CD45), as well as B-cell (LN-1 and LN-2) and T-cell (MT1) associated antigens. The results showed clear phenotypic separation of nodular lymphocyte predominant subtype of Hodgkin's disease from other subtypes. The lymphocytic and histiocytic cells of nodular lymphocyte predominant Hodgkin's disease were reactive for LN-1 (all cases) and anti-EMA (most cases) but negative for anti-Leu-M1 and Ber-H2. Within the other subtypes--i.e. nodular sclerosis and mixed cellularity--nearly all Reed-Sternberg cells and Hodgkin's cells were positive for both anti-Leu-M1 and Ber-H2. Ber-H2 monoclonal antibody was observed to react more frequently with Reed-Sternberg cells and Hodgkin's cells in Bouin's- or formalin-fixed tissues. Pleomorphic T-cell lymphomas, which could mimic Hodgkin's disease on morphology, created the same problem on phenotypic analysis. However, MT1 identified a significant proportion of T-cell lymphomas with Reed-Sternberg-like cells, having proven negative for Reed-Sternberg cells and Hodgkin's cells in Hodgkin's disease. Thus, a combination of anti-Leu-M1, Ber-H2, anti-EMA, LN-1, and MT1 monoclonal antibodies appears at present to be the most useful panel for the diagnosis and the differential diagnosis of Hodgkin's disease.
Antibodies, Monoclonal↗
Immunocytochemical evaluation of the percentage of proliferating cells in pathological bone marrow and peripheral blood samples with the Ki-67 and anti-bromo-deoxyuridine monoclonal antibodies.
The monoclonal antibody Ki-67, directed against a nuclear antigen expressed by dividing cells in all the phases of cell cycle except G0 and early G1, was used in combination with an anti-BrdU monoclonal antibody, reacting selectively with cells in S-phase, for assessing the percentage of proliferating cells in bone marrow and peripheral blood samples from patients with lymphoma, leukaemia and multiple myeloma. Immunocytochemical labelling of proliferating cells was performed on marrow frozen sections and/or cytospins using an immunoalkaline phosphatase (APAAP) technique that made it possible to obtain proliferative index measurements in a few hours in contrast to the 3-7 d needed with tritiated thymidine. In the 54 marrow lymphoma cases studied a highly significant correlation was observed between the proportion of Ki-67 (+) cells and the separation into low- and high-grade malignant lymphomas according to the Kiel classification. In patients with multiple myeloma at the first diagnosis, the percentage of Ki-67 (+) cells was low (6-10%). In contrast, a high percentage of Ki-67 (+) cells (40-50%) was observed in a young adult with multiple myeloma, in a patient who first presented at the clinical observation with an extradural mass and in three patients who developed extramedullary masses several years after the initial diagnosis of myeloma. In acute lymphoblastic leukaemias of common type the mean value of Ki-67 labelling was 31.3%. Because of their simplicity and rapidity, immunocytochemical techniques may be expected to replace autoradiography and flow cytometry for the detection of proliferating cells in haematological samples.
Antibodies, Monoclonal↗
Detection of cytomegalovirus by in situ hybridisation and immunohistochemistry using new monoclonal antibody CCH2: a comparison of methods.
In situ hybridisation, immunohistochemistry, and morphological analysis for the detection of cytomegalovirus (CMV) were compared in routinely processed tissue sections from a patient with acquired immune deficiency syndrome (AIDS) and widespread CMV infection. Both in situ hybridisation and immunohistochemistry with the monoclonal antibody CCH2 labelled all "owl's eye" cells intensely and, in addition, nuclei of some morphologically normal cells. Quantitative evaluation of the results showed that in situ hybridisation and immunohistochemistry with CCH2 were considerably more sensitive than purely morphological analysis, particularly in tissues with only a few cells infected by CMV. It is further shown that immunohistochemistry with CCH2 detected a higher figure of CMV infected cells than in situ hybridisation. In conclusion, both in situ hybridisation and immunohistochemistry are rapid, sensitive, and specific methods for CMV detection. For routine purposes, however, immunohistochemistry seems to be more suitable.
Acquired Immunodeficiency Syndrome↗
[Coexpression of cytokeratin, desmin, and neurofilaments in malignant tumors].
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Desmin↗
[Immunological demonstration of estrogen and progesterone receptors in testicular Leydig cell tumors].
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Humans↗
Coexpression of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptor by anaplastic large cell lymphomas. Diagnostic value in so-called malignant histiocytosis.
A group of 63 cases of anaplastic large cell lymphomas (variants of diffuse large cell lymphomas often diagnosed as "malignant histiocytosis") was characterized on both morphologic criteria and expression of epithelial membrane antigen (EMA) and Ki-1 antigen (CD30). On the basis of the reactivity of these tumors with anti-EMA and anti-Ki-1 antibodies, four subtypes could be distinguished. In the majority of cases (n = 49), neoplastic cells coexpressed EMA and Ki-1 antigens. Nineteen of these cases were tested for IL-2R, and all were positive (Type I, EMA+, Ki-1+, IL-2R+). In the second group (n = 5), the neoplastic cells expressed EMA but not the Ki-1 antigen. These cases were not tested for the presence of IL-2R (Type II, EMA+, Ki-1-, IL-2R?). There were tumors with similar morphology expressing only Ki-1 antigen (Type III, EMA-, Ki-1+, IL-2R-) or negative for both EMA and Ki-1 antigens (Type IV, EMA-, Ki-1-, IL-2R-). EMA appeared to occur predominantly on activated cells, as has been previously shown for Ki-1 antigen. Analysis using monoclonal antibodies to T-cell, B-cell, or macrophage-associated differentiation antigens showed that these tumors were heterogeneous in terms of cell lineage. Tumors coexpressing EMA, Ki-1, and IL-2R (Type I), were most commonly of T-cell origin (n = 12); the remainder in this type expressed B-cell markers (n = 4), a mixed B/T phenotype (n = 2), or no clear phenotype (n = 9). By contrast, tumors of Types II, III, and IV were mainly from B-cell origin (n = 6) or showed a mixed B/T phenotype (n = 1). Despite the fact that a significant proportion of these cases were initially classified morphologically as "malignant histiocytosis," only 3 of the 63 cases were possibly of histiocytic origin. These results confirm that true malignant histiocytosis is rare and that most tumors with histologic features currently regarded as being consistent with this diagnosis are lymphocytic in origin and express activation antigens such as EMA, Ki-1 antigen, and IL-2R.
Antibodies↗
Detection of viral DNA by in situ hybridization using bromodeoxyuridine-labeled DNA probes.
Detection of viral DNA in infected tissues is demonstrated by in situ nucleic acid hybridization employing bromodeoxyuridine (BrdUrd)-labeled probes. BrdUrd is used alternatively to biotinylated nucleotides in the preparation of DNA probes and, after hybridization, developed with a monoclonal anti-BrdUrd antibody and the alkaline phosphatase-anti-alkaline phosphatase technique. The sensitivity using both BrdUrd- and biotin-labeled probes is similar. Furthermore, the simultaneous detection of viral coinfections will be possible by means of this technique in conjunction with biotin-labeled DNA probes.
Bromodeoxyuridine↗
Nuclear and cytoplasmic distribution of cellular myb protein in human haematopoietic cells evidenced by monoclonal antibody.
A monoclonal antibody was used for analysing the expression of the cellular myb (c-myb) protein in a variety of established human tumor cell lines and its decrease after induction of differentiation. Differentiated resting human T-cells and B-cells do not express detectable amounts of c-myb protein. However, upon mitogenic stimulation in vitro T-cells exhibit strong expression of the c-myb protein as demonstrated by immunocytochemical staining and indirect immunoprecipitation. In contrast to the transformed T-lymphoblastic cell line Molt-4, where c-myb protein is a nuclear antigen, it was found in proliferating normal T-cells almost exclusively distributed in the cytoplasm. Screening of a total of 70 fresh human malignant lymphomas by immunohistochemical staining indicates the presence of the c-myb protein primarily in non-Hodgkin's lymphomas with a large growth fraction, i.e. precursor cell-derived lymphoblastic lymphomas of B-cell type and T-cell type (9/10, 3/4, respectively) and anaplastic large cell Ki-1 lymphomas (5/9), which originate from activated lymphoid cells. The c-myb protein was located predominantly in the nucleus and in some cases additionally in the cytoplasm. The different subcellular locations suggest a dual functional role. While nuclear localisation is exhibited by transformed haematopoietic cells, cytoplasmic localisation appears to be characteristic for proliferating normal T-cells and points to a second property of the c-myb protein other than interaction with DNA.
Animals↗
[Differentiation pathways of normal and malignant cells of the lymphatic system].
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Antigens, Differentiation↗
[Cutaneous B cell lymphoma in chronic Borrelia burgdorferi infection. Report of 2 cases and a review of the literature].
Low-grade malignant B-cell lymphomas of the skin can be distinguished from lymphadenosis benigna cutis (Bäfverstedt) by immunohistological methods developed in the last few years. Its coexistence with Borrelia burgdorferi infection can be shown by clinical and serological findings. In the chronic stage of this infection, lymphocytic cell infiltrations consistent with histological and immunohistological findings of malignant B-cell lymphoma can be found. Predominantly at the extremities, multiple plaque-shaped or nodular lesions are seen, showing a follicular pattern in their periphery. The tumors do not respond to antibiotic therapy. They regress totally after X-ray treatment, but local recurrences are rather common. They show a long persistent course with only slow progression and seem to be of low-grade malignancy independent from the cytological findings. In most cases the tumors remain limited to the skin and to one anatomical site; nevertheless, the development of systemic involvement has been reported. We present two cases of malignant B-cell lymphoma of the skin in patients with chronic B. burgdorferi infection. Both cases showed the typical clinical and histological features of this entity. Similar reports from the literature indicate close relationships with the chronic stage of Borrelia infection, with the simultaneous presence of acrodermatitis chronica atrophicans as an indicator. We conclude that an elevated titer indicating Borrelia infection is an important finding for the diagnosis and prognosis of this particular type of cutaneous B-cell lymphoma.
Aged↗