Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl) ethylenediamine]dichloroplatinum(II)-complexes, Part II: Biological properties

The activity of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine] dichloroplatinum(II)-complexes (1-PtCl2,R,S; 2-PtCl2, R,R/S,S; 3-PtCl2, R,R; 4-PtCl2, S,S) on several tumor models (MDA-MB 231 breast cancer cell line; P 388 leukemia, mouse; L 1210 leukemia, mouse; L 5222 leukemia, rat; Ehrlich ascites tumor, mouse--wildtype; cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.) is described. For comparison the analogous [1,2-bis(4-hydroxyphenyl)ethylendiamine]dichloroplatinum (II)-complexes (5-PtCl2, R, S; 6-PtCl2, R,R/S,S; 7-PtCl2, R,R; 8-PtCl2, S,S) and cisplatin are used. 1-PtCl2 to 4-PtCl2 (OH in 3,3'-positions) show their maximum antitumor effect at lower doses than 5-PtCl2 to 8-PtCl2 (OH in 4,4'-positions). 2-PtCl2 and 6-PtCl2 (R,R/S,S) are more active than 1-PtCl2 and 5-PtCl2 (R,S). 4-PtCl2 and 8-PtCl2 (S,S) are superior to 3-PtCl2 and 7-PtCl2 (R,R). On the L 5222 leukemia 2-PtCl2 (R,R/S,S), 4-PtCl2 (S,S) and 8-PtCl2 (S,S) markedly surpass cisplatin. Strong effects are produced by 2-PtCl2 to 4-PtCl2 on the Ehrlich ascites tumor (wildtype, cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.). The combination of 4-PtCl2 with cisplatin results in a weakly synergistic effect.     

Response to immunization against polio after allogeneic marrow transplantation.

Long-term immunity to poliovirus and immunization response to inactivated poliovirus vaccine (IPV) were studied in 55 patients who underwent allogeneic bone marrow transplantation (BMT). Antibodies were determined by neutralization assays. Patients were studied before, at 12 months after BMT and at 12 months after immunization with IPV. Thirty-seven patients were seropositive to all poliovirus types at 12 months after BMT. At least a four-fold decrease in antibody level was recorded between BMT and 12 months later in 55%, 41%, and in 45% of the patients to poliovirus types 1, 2, and 3, respectively. Nineteen patients were immunized with one dose of trivalent IPV. Eight patients (42%), seven patients (36%), and four patients (21%) responded with at least a four-fold antibody titer increase to poliovirus type 1, 2, and 3, respectively. Twenty-nine patients were primarily immunized with three IPV doses. The response rates were 52%, 48% and 48% to poliovirus types 1, 2, and 3, respectively. The immunization responses were similar in patients who did or did not have chronic GVHD. Reimmunization of allogeneic BMT recipients against poliovirus is necessary and a three dose schedule is needed to obtain an adequate immunization response.     

DNA repair synthesis in individuals with and without a family history of cancer

The influence of family history on DNA repair synthesis, unscheduledDNA synthesis (UDS), was assessed in volunteers with or withouta family history of cancer. UDS, following treatment of mononuclearleukocytes with N-acetoxy-2-acetylaminofluorene, was measuredas the incorporation of [³H] into DNA in the presence of hydroxyurea.The positive family history group (n=71) had an average of 2.4first-degree relatives with cancer, defined as any major cancer,excluding skin cancer: 31 participants reported that canceroccurred in both their parents. The ‘no family history’comparison group (n=29) had no family history of cancer throughthe second degree. There was a significant reduction in UDSin cells from individuals with family history, compared to thosewith no family history (P>0.002). This relationship was notexplained by factors known to influence UDS, such as age, smokingor hypertension. We conclude that reduced UDS in mononuclearleukocytes is associated with a family history of any majorcancer, and is not confined to a history of cancer of any singleorgan site. This conclusion is further supported by the observationthat individuals (n=13) with parents who had an earlier onsetof cancer (<60 years) also had a significantly lower DNArepair synthesis than those (n=18) whose parents had later diagnosisof cancer (>60 years).     

Patients seeking symmetrical recontouring for “Perceived” deformities in the width of the face and skull

This article describes plastic surgery patients who sought symmetrical recontouring of the width of the face and skull. The basic demographic and personality characteristics of these facial width deformity (FWD) patients and the surgical procedures performed on them are discussed. Details of the surgical and psychological management of three representative cases are given. Speculative conclusions regarding the general characteristics of the FWD population are offered. Suggestions are proposed for a combined surgical-medical psychotherapeutic collaboration in managing these patients.     

Prospective comparison of hip fracture treatment: 856 cases followed for 4 months in The Netherlands and Sweden

In a prospective multicenter study 1115 hip fracture patients were registered in Rotterdam (The Netherlands), Sundsvall and Lund (Sweden). The patients had similar background parameters with a mean age of 78 years, about half of them living alone and just above 80 percent coming from independent living

For cervical fracture, hemiarthroplasty was the predominating treatment in Rotterdam (n 169), whereas osteosynthesis was used in Sundsvall (screws n 135) and Lund (hook-pins n 148). The mean (median) hospitalization time was 32 (20) days in Rotterdam, 16 (12) days in Sundsvall, and 17 (10) days in Lund. Discharge to independent living varied from 53 percent in Lund to 72 percent in Sundsvall. Functional outcome (walking ability and ADL capacity) was at 4 months similar in all groups, but at 2 weeks was lower in Rotterdam. Mortality at 2 weeks / 1 month 14 months was in Rotterdam 4/9/20, in Sundsvall 2/4/13, and in Lund 01311 0 percent.

Trochanteric fractures were treated by screwplate in Rotterdam (n 146) and Lund (n 78), and by Ender nails in Sundsvall (n 11 7). The mean (median) hospitalization time was in Rotterdam 39 (29) days, in Sundsvall 24 (1 5) days and in Lund 19 (11) days. Discharge to independent living varied from 41 percent in Lund to 57 percent in Sundsvall. Functional outcome was similar between the groups. Mortality at 2 weeks / 1 month 14 months was in Rotterdam 2/6/14, in Sundsvall 611 2/19 and in Lund 12/12/18 percent.

Thus, our study has shown that it is possible to perform a prospective multicenter study involving different European countries. The functional out- come after 4 months was very consistent between the centers studied, irrespective of choices made concerning operation method and rehabilitation routines. However, a difference in mortality within these first postoperative months was found, which seems attributable to the operation procedure.     

Assoziation der chronischen Urtikaria mit Helicobacter pylori-induzierter Antrum-Gastritis

Zusammenfassung Trotz der H?ufigkeit der Erkrankung liegen nur wenige gesicherte Erkenntnisse über die ?tiologie der chronischen Urtikaria vor. Bei 10 Patienten, bei denen keine anderweitige Ursache für die Erkrankung ermittelt werden konnte, führten wir eine Gastroskopie durch. Bei 8 der 10 Patienten konnte eine Besiedlung der Magenschleimhaut mit Helicobacter pylori gesichert werden. Die Urtikaria heilte innerhalb weniger Tage bei allen Patienten ab, nachdem wir eine Therapie mit Amoxicillin und Omeprazol einleiteten. Eingegangen am 6. Februar 1995 Angenommen am 12. Mai 1995     

Surface proteins of Streptococcus agalactiae and related proteins in other bacterial pathogens

Streptococcus agalactiae (group B Streptococcus) is the major cause of invasive bacterial disease, including meningitis, in the neonatal period. Although prophylactic measures have contributed to a substantial reduction in the number of infections, development of a vaccine remains an important goal. While much work in this field has focused on the S. agalactiae polysaccharide capsule, which is an important virulence factor that elicits protective immunity, surface proteins have received increasing attention as potential virulence factors and vaccine components. Here, we summarize current knowledge about S. agalactiae surface proteins, with emphasis on proteins that have been characterized immunochemically and/or elicit protective immunity in animal models. These surface proteins have been implicated in interactions with human epithelial cells, binding to extracellular matrix components, and/or evasion of host immunity. Of note, several S. agalactiae surface proteins are related to surface proteins identified in other bacterial pathogens, emphasizing the general interest of the S. agalactiae proteins. Because some S. agalactiae surface proteins elicit protective immunity, they hold promise as components in a vaccine based only on proteins or as carriers in polysaccharide conjugate vaccines.     

Toxicity and adaptive immune response to intracellular transgenes delivered by helper-dependent vs. first generation adenoviral vectors

The host immune response to intracellular transgenes delivered by helper-dependent (HDV) vs. first generation (FGV) adenoviral vectors has been relatively unstudied. Previous studies showed short-term correction of bovine and murine argininosuccinate synthetase (ASS) deficiency after first generation adenoviral-mediated liver gene therapy. To determine whether the host adaptive immune response against the intracellular transgene human ASS (hASS) contributed to loss of gene expression in this setting, the same vector (FGV-CAG-hASS) was injected into Rag-/- (immunodeficient) mice. As in wild-type C57BL/6 (B6) mice, Rag-/- mice also showed significant loss of hASS expression and vector by week 4 post-injection, with concomitant elevation of liver enzymes and disruption of liver architecture. Therefore, direct toxicity due to vector rather than adaptive immune response against hASS primarily accounted for loss of expression with FGVs. In contrast to hASS, beta-galactosidase is strongly immunogenic and activates the host adaptive immune response. Loss of transgene expression was observed in B6 mice with either a FGV or a HDV expressing beta-galactosidase. However, the drop in gene expression observed with the HDV was primarily due to the adaptive immune response, since both beta-galactosidase expression and vector genome were sustained in immunodeficient mice treated with HDV. As expected, with weakly immunogenic hASS, vector genome and hASS expression were sustained with a HDV in spite of ubiquitous expression of the transgene. Therefore, viral gene expression is a primary determinant of intermediate and chronic toxicities at day 3 and week 4 post-injection. However, even in the absence of viral gene expression, strongly immunogenic intracellular transgenes can stimulate clearance of transduced hepatocytes.     

Which donor should be chosen for hematopoietic stem cell transplantation among unrelated HLA-A, -B, and -DRB1 genomically identical volunteers?

The aim of this study was to identify significant prognostic factors by using unrelated genomically HLA-A, -B and -DRB1-identical donors. Such data could help to choose the best donor. We studied 136 consecutive patients with hematologic malignancies and a median age of 32 years (range, 0-55 years) who received hematopoietic stem cell transplantation. Bone marrow grafts were given to 83 and peripheral blood stem cells to 53 patients. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 30% and of chronic GVHD was 54%. At 5 years, the overall transplant-related mortality (TRM) was 34%, and patient survival was 50%. In Cox multivariate analysis, 32 potential risk factors were analyzed. Monoclonal antibody OKT-3 during conditioning was correlated with grade II to IV acute GVHD, chronic GVHD, and TRM. HLA-DP mismatch was associated with poor TRM and poor survival. Cytomegalovirus-seropositive patients with a seronegative donor had a decreased leukemia-free survival. Five-year TRM was 14% with no risk factor, 38% with 1 risk factor, and 87% with 2 risk factors. The 5-year survival was 72%, 48%, and 30% with 0, 1, and 2 risk factors, respectively. We concluded that unrelated hematopoietic stem cell transplantation may be improved if an optimal donor and immunosuppression are chosen.