Gertrud Unfried

Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade.

Expression of inducible nitric oxide synthase (iNOS) by tumor cells has been suggested to abrogate metastasis in several tumor models, whereas constitutive NOS expression correlated positively with tumor grade in human breast carcinoma. Whether or not expression of one of the various NOS isoforms could predict the prognosis of breast cancer, however, has not been established. In the present report we investigated the cellular distribution of NOS isoforms in a series of benign and malignant breast tumors and in normal breast tissue. Immunohistochemistry revealed that in samples of benign disease the number of iNOS + epithelial cells or total epithelial cells was 69 ± 16% (n=50). In samples of grade II invasive ductal breast carcinomas the number of iNOS+ tumor cells or total tumor cells was 62 ± 20 (n=40), compared to 12 ± 9 (n=40) in samples of grade III carcinomas (P < 0.0001). iNOS protein was also identifiable in most of the epithelial cells of normal breast tissue (n=4). In contrast, eNOS protein was restricted to vascular endothelial cells in all of the specimens studied. Since the presence of tumor cell iNOS protein is inversely related to the tumor’s metastatic potential, we conclude that endogenous tumor cell mediated iNOS expression might have an inhibitory effect on the metastatic process in breast cancer.

Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage

OBJECTIVE To identify associations or interrelations between carriage of the methylenetetrahydrofolate reductase (MTHFR) C677T, the MTHFR A1298C, the factor V Leiden G1691A, the factor II prothrombin G20210A, the human platelet antigen (HPA) 1 C12548T, and the apolipoprotein (APO) B R3500Q polymorphisms and idiopathic recurrent miscarriage (IRM). DESIGN Prospective case control study. SETTING Academic research institution. PATIENT(S) One hundred forty-five women with a history of three or more consecutive pregnancy losses before 20 weeks gestation and 101 healthy postmenopausal women with at least two live births and no history of pregnancy loss. INTERVENTION(S) Peripheral venous punctures. MAIN OUTCOME MEASURE(S) Multiplex polymerase chain reaction was performed to identify the different alleles of six candidate genetic risk factors for IRM (MTHFR C677T, MTHFR A1298C, factor V Leiden G1691A, factor II prothrombin G20210A, HPA 1 C12548T, and the APO B R3500Q). RESULT(S) Allele and genotype frequencies of all polymorphisms were not significantly different between the study and the control groups. Also, no significant associations occurred between combinations of polymorphisms and the occurrence of IRM. CONCLUSION(S) Our data fall short of showing any significant association between single polymorphisms of the MTHFR, the Factor V Leiden, the Factor II Prothrombin, the HPA 1 and APO B genes or combinations of these polymorphisms and the occurrence of IRM.

Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage

Abstract Objective: Proinflammatory cytokines have been described as etiologic factors in idiopathic recurrent miscarriage. We investigated the relation between idiopathic recurrent miscarriage and polymorphisms in the gene encoding for the interleukin 1 receptor antagonist, an indigenous modulator of proinflammatory immune response. Design: Prospective case control study. Setting: Academic research institution. Patient(s): One hundred five women with a history of three or more consecutive pregnancy losses before 20 weeks of gestation and 91 healthy, postmenopausal controls with at least two live births and no history of pregnancy loss. Intervention(s): Peripheral venous puncture. Main Outcome Measure(s): Polymerase chain reaction was performed to identify the different alleles of the gene encoding for interleukin 1 receptor antagonist. Result(s): Allele frequencies among women with idiopathic recurrent miscarriage and controls were 0.34 and 0.11, respectively, for the polymorphic allele 2 ( P =.002; odds ratio: 7.4, confidence interval: 2.9–10.8) and .05 and .05, respectively, for the polymorphic allele 3 ( P =.6; odds ratio: 1.3, confidence interval: 0.8–2.3). Allele 2 was present in homozygous form in 9% of women with idiopathic recurrent miscarriage. In contrast, 1% of the control women were homozygous for this allele ( P Conclusion(s): These data support a role for allele 2 of the gene encoding for interleukin 1 receptor antagonist as genetic determinant of idiopathic recurrent miscarriage.

Interleukin–1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage

OBJECTIVE Proinflammatory cytokines have been described as etiologic factors in idiopathic recurrent miscarriage. We investigated the relation between idiopathic recurrent miscarriage and polymorphisms in the gene encoding for the interleukin 1 receptor antagonist, an indigenous modulator of proinflammatory immune response. DESIGN Prospective case control study. SETTING Academic research institution. PATIENT(S) One hundred five women with a history of three or more consecutive pregnancy losses before 20 weeks of gestation and 91 healthy, postmenopausal controls with at least two live births and no history of pregnancy loss. INTERVENTION(S) Peripheral venous puncture. MAIN OUTCOME MEASURE(S) Polymerase chain reaction was performed to identify the different alleles of the gene encoding for interleukin 1 receptor antagonist. RESULT(S) Allele frequencies among women with idiopathic recurrent miscarriage and controls were 0.34 and 0.11, respectively, for the polymorphic allele 2 (P=.002; odds ratio: 7.4, confidence interval: 2.9--10.8) and.05 and.05, respectively, for the polymorphic allele 3 (P=.6; odds ratio: 1.3, confidence interval: 0.8--2.3). Allele 2 was present in homozygous form in 9% of women with idiopathic recurrent miscarriage. In contrast, 1% of the control women were homozygous for this allele (P<.001; odds ratio: 13.5, confidence interval: 7.5--21.8). CONCLUSION(S) These data support a role for allele 2 of the gene encoding for interleukin 1 receptor antagonist as genetic determinant of idiopathic recurrent miscarriage.

Endothelial Nitric Oxide Synthase Gene Polymorphism in Women with Idiopathic Recurrent Miscarriage

BACKGROUND Lack of endothelium-derived nitric oxide is associated with vasospasm and vascular infarction. We investigated the relationship between idiopathic recurrent miscarriage and a polymorphism of the gene encoding endothelial nitric oxide synthase (NOS3). METHOD In a prospective case-control study, 105 women with idiopathic recurrent miscarriage and 91 healthy controls were investigated. We used the polymerase chain reaction to identify the different alleles of a 27 base pair tandem repeat polymorphism in intron 4 of the NOS3 gene. RESULTS The wild type B allele was identified on 329 out of 392 chromosomes (frequency 0.84). The polymorphic A allele was present on 63 chromosomes (frequency 0.16). The genotype frequencies were as follows: 68% (B/B), 31% (A/B) and.5% (A/A). The distribution of genotype frequencies was significantly different between the study and control groups for allele A/B heterozygotes (NOS3(A/B)) (36.7 versus 23.8%, P = 0.03, OR 1.6, 95% CI 1.1--3.8). Only one individual was homozygous for the A allele (NOS3(A/A)). She was in the study group. Between women with primary and secondary recurrent miscarriages, no statistically significant difference between the distribution of NOS3(A/B) genotypes (28 versus 34%) was observed. CONCLUSIONS These data support a role for the NOS3 gene as a genetic determinant of the risk of idiopathic recurrent miscarriage.