Biomedical subjects
Publications and source records attributed to H Ludwig.
Three of four patients with chronic myelogenous leukemia in blast crisis were found to express the multidrug resistance (MDR1) gene in their blast cells. Expression of the MDR1 gene may contribute to the poor response of these patients to chemotherapy.
The in vivo migration of [111In]oxine-labeled peripheral mononuclear cells (PMNC) was studied in 20 patients with various lymphatic malignancies and palpable enlarged lymph nodes. The maximal labeling dose of 10 microCi (0.37 MBq) [111In]oxine/10(8) PMNC was found not to adversely influence either cell viability or lymphocyte proliferation in vitro. For in vivo studies, 1.5 X 10(9) PMNC were gained by lymphapheresis and reinjected intravenously after radioactive labeling, 150 microCi (5.55 MBq). The labeling of enlarged palpable lymph nodes was achieved in three out of three patients with Hodgkin's disease and in five out of five with high-malignant lymphoma, whereas three out of seven patients with low malignant lymphoma and no patient with chronic lymphatic leukemia had positive lymph node imaging. We thus conclude that PMNC retain their ability to migrate after [111In]oxine labeling and that these cells traffic to involved lymph nodes of some, but not all hematologic malignancies.
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The incidence of cervical cancer is decreasing, wherever screening programs are offered and accepted. Pathogenetic factors for dysplasia and cervical cancer among others are coital activity in early adolescence, promiscuity and low economic status. More than 80 percent of severe cervical dysplasias as a precancerous stage show the oncogenic potential of a sexually transmitted disease. The prognosis of cervical cancer widely depends on the stage found at the time of first detection. The staging procedure which then follows needs gynecological experience and skill. Clinical staging with methods auxiliary to inspection, colposcopy and palpation is still the most common method and remains to be the basis of the international data treasure of the Annual Report of FIGO, although clinical methods and even CT and MRI are insufficient for the evaluation of pelvic and/or paraaortic lymphnode metastases. To overcome the imperfection of clinical staging, surgical procedures are recommended to complete before any therapeutic decision is made, at least in cases thought to be operable. Radical hysterectomy with pelvic lymphadenectomy in stages Ib and IIa is the method of choice in most modern centers of gynecologic oncology. However, radiotherapy is still prevalent in all stages of cervical cancer as the most common therapy around the world. Further development in 5-years survival figures is expected to profit from supporting screening programs in risk populations or from expansions of already existing programs rather than from further modifications of the therapeutic modalities, already highly specialized.
Thirty-three previously untreated patients with multiple myeloma were randomized to either a combination of recombinant interferon-alpha-2C (rIFN-alpha-2C) plus vincristine/melphalan/cyclophosphamide and prednisone (VMCP) or VMCP chemotherapy alone. The combined regimen effected 67% responses and 26% minor responses, while 35 and 47% of VMCP-treated patients had a pathologically documented remission, respectively. Despite the somewhat earlier achievement and duration (12.0 vs. 8.0 months) of objective response, and the marginal survival benefit observed in the rIFN-alpha-2C + VMCP treatment arm, a significant improvement in therapeutic gain by adding a biologic response modifier to conventional first-line polychemotherapeutic drug treatment in myeloma patients has not yet been achieved. The combined regimen was well tolerated without unusual or unexpected toxic effects.
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In 2 out of 29 patients suffering from the myeloproliferative syndrome a lack of thromboxane conversion by platelets from exogenous arachidonic acid was discovered. In one patient PGE2 (30.9%) and 12-HETE (12-Hydroxyeicosatetraenoic acid) (42.8%) were formed instead, whilst in the other patient 12-HETE (72.9%) was the main metabolic product. In both the patients, serum and plasma TXB2, as well as malondialdehyde, were quite low. It is claimed that this phenomenon is due to the expression of a pathological population of platelets related to the disease.
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Overall activation volumes for multistep reactions are not usually pressure independent. The present investigation gives a quantitative description of this effect under Theory. Simple relations are obtained which can easily be applied to experimental data and which allow more insight into the dynamics of enzyme reactions. This is demonstrated under Experimental Application for the conversion of fumarate to L-malate catalyzed by the enzyme fumarase. The volume profile of this reaction indicates a pulsation of the enzyme molecule during catalysis. The appendix discusses the question whether Eyring's transition-state theory is an appropriate basis for investigations of this kind.
Gamma-camera imaging after injection of radiolabelled autologous leucocytes can be very helpful in the diagnosis, localization and further clinical treatment of inflammatory diseases. We present a technique allowing sterile separation of white blood cells and labelling with 99mTc-phytate or -oxine and with 111In-oxine, -oxine sulphate or -tropolone. The method is non-invasive and the radiation dose amounts to less than 80 mrad using 100 microCi 111Indium. The use of radiolabelled granulocytes is of particular diagnostic value in patients with septicaemia of unknown origin. Whole body scanning allows not only visualization of enhanced splenic uptake in septicaemia, but also localization of an inflammatory process. Preferential indications for a diagnostic approach using radiolabelled granulocytes are inflammatory abdominal processes which cannot easily be documented by means of other non-invasive techniques, such as inflammatory bowel disease (Crohn's diseases and ulcerative colitis), arthritic processes and abscesses of the liver and spleen, as well as subphrenic and retroperitoneal abscesses. Untreated osteomyelitis can be located with the help of labelled granulocytes, but in patients treated with antibiotics a false negative result is obtained in approximately 50% of cases for as yet unknown reasons, even in the presence of a still active osteomyelitic process.
During the infection cycle of herpes simplex virus polypeptides appear as immediate early, early and late proteins. We classified the 65 K DNA binding protein as an early (beta-) protein by comparing its detectibility with that of two well defined proteins the ICP 4 (known as immediate early protein) and the ICP 8 (known as early protein).
No significant testing in screening or early diagnosis of cancer is possible at present. Tumor markers of different origin are useful in the search for occult locoregional recurrence, metastatic disease, or early detection of progression irrespective of localization. The comparative analysis of tumor markers for follow-up is mandatory. Estrogen- and progesterone-receptor assays for prognostic evaluation in endometrial and breast carcinoma, and in some cases of ovarian tumors, should complete any pretherapeutic step. There is a possible link with epidermal-growth factor (EGF) with regard to uncontrolled growth of tumors in hormone-dependent (target) organs.
A library of subgenomic fragments of bovine herpesvirus type 2 (BHV-2) DNA was constructed in the expression cloning vector lambda gt11 and screened with monoclonal antibodies to the glycoprotein gb BHV-2, which is homologous to glycoprotein gB (gB-1) of herpes simplex virus type 1 (HSV-1). Lambda gt11 clones containing gB BHV-2-specific sequences were used to identify lambda EMBL3 vectors with DNA inserts which contained the complete gB BHV-2 gene. Nucleotide sequencing revealed that the gB BHV-2 gene is highly conserved compared to gB-1. The amino acid sequences and the predicted secondary structures of both glycoproteins are very similar. Two further open reading frames (ORF) in close vicinity to the gene encoding gB BHV-2 showed considerable homology to HSV-1 genes. They code for the major DNA-binding protein (dbp) of BHV-2 and a putative 72-kDa polypeptide. The gene of the latter protein corresponding to ICP18.5 of HSV-1 is interspersed between the ORFs of gB BHV-2 and the dbp of BHV-2. All three genes map in the unique long region of the genome. Their homology and the colinear arrangement compared to HSV-1 indicate a close relationship between the two viruses.
Bovine herpesvirus 2 (BHV-2) specifies a glycoprotein of 130 kDa (gB BHV-2) which shows extensive homology to glycoprotein B (gB-1) of herpes simplex virus 1 (HSV-1). The BHV-2-specific 130-kDa glycoprotein is able to induce cross-reacting antibodies, some of which even cross-neutralize HSV-1. In order to determine the genome localization of gB BHV-2 and in order to identify conserved antigenic domains in both glycoproteins, we established libraries of subgenic fragments of BHV-2 and HSV-1 DNA in the prokaryotic expression vector lambda gt11 and screened them with cross-reacting monoclonal antibodies which allowed us to identify recombinant lambda gt11 clones expressing gB fusion protein. Nucleotide sequencing of inserted DNA fragments within these recombinant lambda gt11 clones revealed that they originated from the carboxy-terminal part of the major DNA-binding proteins (dbp) of BHV-2 (dbp BHV-2) and its counterpart ICP8 in HSV-1. Antisera raised against the beta-galactosidase fusion protein of recombinant phage lambda-113/2 coding for an 84 amino acid (aa) polypeptide originating from dbp BHV-2 neutralized infectivity of BHV-2 and HSV-1 in the presence of complement and precipitated [3H] glucosamine-labeled gB BHV-2 and gB-1. This antiserum also reacts with ICP8 and presumably with dbp BHV-2. Two hypotheses are discussed to explain this unexpected result: (i) epitopes in the carboxy-terminal part of gB BHV-2 and gB-1 are similar to antigenic determinants in the amino-terminal region of the gBs, thus providing cross-reacting antibody-binding sites; (iii) during gene expression a carboxy-terminal part of dbp BHV-2 and ICP8 genes might be spliced to the amino-terminal region of the glycoproteins gB BHV-2 and gB-1.
Previous preliminary studies had shown that caprine herpesvirus (BHV-6) infections exist in many countries where goats play an economical role. The extensive serum survey made in Greece reveals that the virus must be widespread because more than 50% of the goats have antibodies. The bucks were found to have a higher evidence of infections than the female goats. The kids possessing maternal antibodies became seronegative at the age of 4 months and new antibodies appeared at the age of 7-8 months. Observations in 2 closed goat herds showed that the virus does not spread during the mating and lactating period. Neutralization titres increased or new infections in seronegative animals occurred after the summer when breeding took place. The virus is present in a latent state and recurrent infections are assumed to occur. In spite of that all our efforts to isolate the virus were unsuccessful, even after experimental immunosuppression.
Isolates of equine herpesvirus type 1 (EHV-1) originating from affected antelope and cattle were compared with reference EHV-1 and EHV-4 isolates and were characterized. Based on cross-neutralization, DNA restriction profiles and blot-hybridization data these isolates could be characterized as EHV-1. One isolate (from an antelope) with a different restriction profile showed significant DNA homology with EHV-1, partial homology with EHV-4, and little or no homology with EHV-2 and HSV-1 DNAs. Blot hybridization revealed differences in DNA restriction fragments located at the termini of two isolates and size heterogeneity in the unique long/internal repeat junction fragment (UL/IR) of one isolate.
Envelope proteins of bovine herpesvirus type 2 (BHV-2) and herpes simplex virus types 1 and 2 (HSV-1, -2) share cross-reacting determinants. Monoclonal antibodies directed against epitopes of a 130K glycoprotein of BHV-2 detect determinants on the surface of infected cells and react either with cytoplasmic or nuclear antigens. Biological and biochemical characterization of the proteins recognized by these antibodies revealed that the BHV-2 specific 130K glycoprotein and the gB of HSV share common epitopes. Some of them are involved in the neutralization of HSV and BHV-2.