Young age at first pregnancy does protect against early onset breast cancer in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutation carriers

Purpose

Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.

Methods

Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan–Meier analyses were performed.

Results

2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30–39 years. Kaplan–Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002).

Conclusions

The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

     

Invasive Haemophilus influenzae type b disease in the Oxford region (1985-91)

For a seven year period (1985-91) clinical and epidemiological data were prospectively collected on children aged < 10 years with microbiologically confirmed invasive Haemophilus influenzae type b infection in the Oxford region to study the epidemiology of the disease and determine the potential impact of early primary immunisation in infants. Computer records of primary immunisations given to these cases were retrospectively analysed and, where necessary, hospital and general practitioner records were searched to determine the immunisation history. Over the seven year period, 416 cases of invasive H influenzae type b disease were reported. Widescale immunisation against H influenzae type b began in 1991 as part of a regional trial. The estimated annual incidence for invasive disease between 1985 and 1990 was 35.5 cases per 100,000 children aged less than 5 years; for H influenzae type b meningitis it was 25.1 per 100,000 children aged less than 5 years. The cumulative risks for invasive disease and meningitis by the fifth birthday were one in 560 and one in 800 respectively. The majority of disease (71%) occurred in children less than 2 years of age with the peak monthly incidences at 6 and 7 months of age. The overall mortality was 4.3% and 50% of these deaths occurred suddenly. Most (91%) of the children had received at least one primary immunisation against diphtheria, tetanus, and pertussis before H influenzae type b infection and there was only one case of parental refusal of immunisation. None had received H influenzae type b immunisation. Given a vaccine uptake of 90% by 5 months of age it is estimated that at least 82% of the H influenzae type b infections could have been prevented. Extrapolated nationally, 1150 cases of infection and 50 deaths could be prevented each year by routine primary immunisation.     

Atypical distribution of Pneumocystis carinii infiltrates during radiation therapy

Bilateral peripheral pulmonary infiltrates caused by Pneumocystis carinii developed in a patient undergoing mediastinal irradiation after chemotherapy for Hodgkin disease. The paramediastinal part of the lung included within the treatment port remained clear during the 2 1/2 weeks of radiation therapy. The distribution of the pneumocystis infiltrates was altered by the radiation, producing a pattern that is the "radiographic negative" of typical post-radiation therapy paramediastinal fibrosis.     

AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages

Background and aims

Advanced glycation end products (AGEs) induce cellular oxidative/endoplasmic reticulum stress and inflammation. We investigated its underlying mechanisms for atherogenesis focusing on regulation of ABCA1 protein decay in macrophages.

Lithium augments GM-CSA generation in canine cyclic hematopoiesis

Cyclic hematopoiesis in gray collie dogs can be cured by lithium treatment. We examined the mechanism of lithium's effect by developing an assay for the canine equivalent of GM-CSF (called GM-CSA). Phytohemagglutinin (PHA)-stimulated canine blood mononuclear cells produce GM-CSA in a dose-dependent manner; this GM-CSA stimulates more neutrophil-containing colonies than does endotoxin-treated dog serum. Production of GM-CSA by PHA-stimulated normal dog cells was not altered by lithium. However, cells from gray collies during their neutrophilic period increased their GM-CSA when lithium (2 mEq/L) was added to low doses of PHA, whereas neutropenic gray collie cells did not. These data suggest that lithium could modulate cyclic hematopoiesis by increasing intramedullary GM-CSA at the time when marrow neutrophilic progenitor cells are at their nadir.     

Recipient humoral immunity against leukoreduced allogeneic platelets is suppressed by aminoguanidine, a selective inhibitor of inducible nitric oxide synthase

Leukoreduced allogeneic platelet transfusions have been previously shown to initially stimulate an in vitro cellular cytotoxicity and subsequently Induce the formation of immunoglobulin G (IgG) antidonor alloantibodies. To further characterize these responses and determine if they are related, recipient BALB/c H-2d mice were treated with aminoguanidine (AMG), a selective inhibitor of inducible nitric oxide synthase (iNOS), and transfused weekly with 2 x 10(8) C57BL/6 H2b platelets. In control, non-AMG-treated mice, transfusion significantly (P < .01) increased serum levels of interferon-gamma (IFN-gamma) by day 1 posttransfusion (PT). IFN-gamma returned to pretransfusion levels by day 3 PT, and its production was not affected by AMG treatment. Serum interleukin-4 (IL-4), on the other hand, was undetectable before and during the transfusion protocol. By day 3 PT, recipient spleen cells could mediate in vitro anti-P815 (auto), anti-EL4 (allo), and anti-R1.1 (third-party MHC) cytotoxicity, and these responses were maximal by day 7 PT. Concurrently, a significant reduction in the vitro ability of recipient splenocytes to respond to Concanavalin A (ConA) was observed; this was not seen with lipopolysaccharide (LPS) stimulation. Elevated levels of NO2- were found in the ConA culture supernatants from transfused mice at day 3 PT. Serum antidonor alloantibodies were detected by the fifth platelet transfusion. AMG treatment of recipient mice significantly inhibited the transfusion. Induced cytotoxicity and ConA-stimulated NO2- production, and restored ConA-induced proliferation to normal levels. AMG appeared to selectively inhibit platelet-induced alloantibody production in that it did not affect antibody production induced by transfusions with 10(5) allogeneic leukocytes or by immunization with a foreign protein antigen, human gamma globulin, in adjuvant therapy. These results indicate that an in vivo AMG-sensitive mechanism is essential for recipients to initiate a humoral IgG immune response against allogeneic platelets.     

Hypermethylation of the 5' region of the calcitonin gene is a property of human lymphoid and acute myeloid malignancies

An abnormal increase in numbers of CCGG sites methylated in the 5' region of the human calcitonin (CT) gene occurred in tumor cell DNA samples from 90% (17 of 19) of patients with non-Hodgkin's T and B cell lymphoid neoplasms and in 95% (21 of 22) of tumor cell DNA samples from patients with acute nonlymphocytic leukemia (ANLL). The changes were not seen in patients with chronic myelogenous leukemia (0 of 9). The abnormal methylation patterns appear to be a property only of transformed or malignant cells since they were not found in DNA from nonneoplastic adult tissues including sperm, early myeloid progenitor cells, benign lymphoid hyperplasia, peripheral lymphocytes stimulated to divide, or early myeloid progenitor cells (obtained by immunoaffinity using anti-My-10 antibody), but they did appear after Epstein-Barr virus transformation of lymphocytes. Moreover, during the course of therapy in patients with ANLL, the hypermethylation pattern reflects the presence of the leukemic clone even in normal-appearing granulocytes derived from this clone. The increased methylation of the CT gene may then provide an important molecular marker for biologic events in human cell transformation or tumor progression and may prove clinically useful in monitoring patients with lymphoid and acute myelogenous neoplasms.     

Heterogeneity of the T-cell receptor delta gene indicating subclone formation in acute precursor B-cell leukemias

Precursor B-cell acute lymphoblastic leukemias (B-ALLs) have been shown to be oligoclonal at the Ig heavy-chain (IgH) gene level in up to 40% of cases by Southern blot hybridization. In contrast, oligoclonality as deduced from diversity of T-cell receptor (TcR)-delta gene rearrangements of the immature types (ie, V delta 2-D delta 3, D delta 2-D delta 3) has not been reported, so far. We detected oligoclonality characterized by the coexistence of different junctional regions of identical V delta 2-D delta 3 rearrangements in four childhood precursor B-ALLs. No variation was found in the IgH gene status. Therefore, we define these populations as subclones. Two leukemias displayed the variants in an unequal proportion. In the other two leukemias, for which similar quantities of the coexisting rearrangements were detected, single cell-nuclei polymerase chain reaction (PCR) showed two separate leukemic populations. Subclone formation could not be demonstrated by Southern blot hybridization, but was detectable after PCR amplification of the V delta 2-D delta 3 rearrangement and separation by polyacrylamide gel electrophoresis. The variants arose independently from each other, as deduced from their individual sequences. Using subclone-specific oligonucleotides for hybridization to amplified DNA obtained at diagnosis and during follow- up from bone marrow samples, we demonstrate, (1) specificity of all subclone-deduced probes, (2) that one residual leukemic cell can be detected in 10(4) to 10(5) normal mononuclear cells in a semiquantitative assay, and (3) that none of the subclones persisted after induction therapy. We propose that in a leukemic cell population, TcR-delta gene diversity arises after rearrangements of the IgH genes resulting in apparent clonality at the IgH gene level. However, cells are oligoclonal, if the TcR-delta gene rearrangements are considered. As various subclones may respond differently to chemotherapy, they may hamper the detection of minimal residual disease. Therefore, we use all subclone-specific oligonucleotides for hybridization to amplified DNA from follow-up samples.