Cancer of the colon in an egg donor: policy repercussions for donor recruitment

This paper describes the tragic case of a young woman who died of cancer of the colon after successfully donating eggs to her younger sister. Although there is no direct link between her operation and the subsequent development of bowel carcinoma, this case imparts a feeling of unease when seen in conjunction with other cases reported during the last few years. It is a reminder that little is known of the long-term consequences of some aspects of assisted conception. Women undergoing ovarian stimulation for themselves or a matched recipient have the right to be advised, in an agreed format, that there is some concern about unproven potential risks from the stimulatory drugs. The safety of egg donors must assume priority over all other considerations, including lack of donors or any moral position. The recent decision by the Human Fertilisation and Embryology Authority (HFEA) to withdraw any form of payment or recompense to egg donors does not seem to us to be based on a balance of scientific advances, patient needs and the ethics of gamete supply. They state that the intention to withdraw payments was implicit in the 1990 Human Fertilisation and Embryology (HFE) Act. However the Act was based on the Warnock report made 6 years earlier. Even in 1990 ovum donation was uncommon and fertility drugs had not yet caused any unease. The Act provided the HFEA with discretionary powers to issue directions so that the future policies would be consistent with any emerging new medical evidence. It is imperative that the HFEA provide convincing evidence on how the current policy of payment to donors harms society, donors or recipients, and how in the UK the new policy will improve medical practice in assisted conception. Successful pilot studies must precede the implementation of any new policy. Failure to do this could cause irreversible harm to the practice of assisted conception using donor gametes, which will ultimately be against the basic aims of the 1990 HFE Act.      

Investigation of three new mouse mammary tumor cell lines as models for transforming growth factor (TGF)-β and Neu pathway signaling studies: identification of a novel model for TGF-β-induced epithelial-to-mesenchymal transition

Introduction  

This report describes the isolation and characterization of three new murine mammary epithelial cell lines derived from mammary tumors from MMTV (mouse mammary tumor virus)/activated Neu + TβRII-AS (transforming growth factor [TGF]-β type II receptor antisense RNA) bigenic mice (BRI-JM01 and BRI-JM05 cell lines) and MMTV/activated Neu transgenic mice (BRI-JM04 cell line).     

Response to influenza virus vaccination in vertical HIV infection

OBJECTIVE: To assess the antibody response to influenza vaccine of children vertically infected with HIV. DESIGN: Prospective study in HIV infected children vaccinated during the winter of 1994-5. SETTING: Family HIV clinic at St Mary's Hospital, Paddington. SUBJECTS: 25 children, aged 1-11 years, vertically infected with HIV. MAIN OUTCOME MEASURES: Responses to influenza antigens (H1N1-A/Taiwan/1/86, H3N2-A/Shandong/9/93, B/Panama/45/ 90) were tested by haemagglutination inhibition. Antibody responses were assessed according to clinical symptoms and immune function, stratified according to the 1994 revised classification for HIV infection in children. RESULTS: 23 children (92%) had either very low or no detectable antibody before vaccination. New protective antibody responses were made by 10 children (40%): in seven to a single antigen, in two to two antigens, and in one to all three antigens. For each antigen there was an overall small increase in the mean geometric titre of antibody produced, but this only reached a protective level for antigen H1N1 and for children with minimal symptoms. Less symptomatic children were significantly more likely to produce a protective antibody response to influenza vaccination. No association was found between immune function, as measured by CD4 count, and vaccine response. CONCLUSIONS: Only vaccination of the least symptomatic HIV infected children against influenza is likely to be effective. This will not only protect them against influenza, but will also protect other more immunosuppressed and vulnerable members of their families.     

Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice

Angiotensin II (Ang II) acts mainly on two receptor subtypes: AT1 and AT2. Most of the known biological actions of Ang II are mediated by AT1 receptors; however, the role of AT2 receptors remains unclear. We tested the hypothesis that the cardioprotective effects of AT1 receptor antagonists (AT1-ant) after myocardial infarction (MI) are partially mediated by activation of AT2 receptors; thus in AT2 receptor gene knockout mice (AT2-/Y), the effect of AT1-ant will be diminished or absent. MI was induced by ligating the left anterior descending coronary artery. Four weeks later, AT2-/Y and their wild-type littermates (AT2+/Y) were started on vehicle, AT1-ant (valsartan, 50 mg/kg per day), or ACE inhibitor (enalapril, 20 mg/kg per day) for 20 weeks. Basal blood pressure and cardiac function as well as remodeling after MI did not differ between AT2+/Y and AT2-/Y. AT1-ant increased ejection fraction and cardiac output and decreased left ventricular diastolic dimension, myocyte cross-sectional area, and interstitial collagen deposition in AT2+/Y, and these effects were significantly diminished in AT2-/Y. ACE inhibitors improved cardiac function and remodeling similarly in both strains. We concluded that (1) activation of AT2 during AT1 blockade plays an important role in the therapeutic effect of AT1-ant and (2) the AT2 receptor may not play an important role in regulation of cardiac function, either under basal conditions after MI remodeling or in the therapeutic effect of ACE inhibitors.     

"Early-peak" carbon monoxide production in certain erythropoietic disorders

The "early-labeled" peak (ELP) of 14CO excretion following injection of glycine-2-14C was used to study erythropoiesis in a patient with sideroblastic anemia and in four subjects with myeloproliferative disorders. The ELP was greatly enlarged in all patients, as compared with a normal volunteer. The contour of the peaks from the hematologically abnormal subjects suggested the presence of increased erythroid heme degradation. In the patient with sideroblastic anemia, all hours of the early peak were significantly reduced after transfusion. This was interpreted to mean that even the earliest or "nonerythroid" phase of the peak is influenced by erythropoietic activity, at least under conditions of erythropoietic stress.     

Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart

Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.     

Role of the B1 kinin receptor in the regulation of cardiac function and remodeling after myocardial infarction

Kinins exert cardioprotective effects via 2 G-protein-coupled receptors, B1 and B2. Using B1 kinin receptor gene knockout mice (B1-/-), we tested the hypotheses that the B1 receptor plays an important role in preservation of cardiac function, whereas lack of B1 may accelerate cardiac remodeling and dysfunction after myocardial infarction, and that B2 receptors may compensate for lack of B1, whereas blockade of B2 receptors in B1-/- mice may cause further deterioration of cardiac function and remodeling. Female B1-/- mice and wild-type controls (C57BL/6J, B1+/+) underwent sham surgery or myocardial infarction and were treated with either vehicle or B2-antagonist (icatibant, 500 microg/kg per day, subcutaneous) for 8 weeks. We found that in sham myocardial infarction, B1-/- mice had a larger left ventricular diastolic chamber dimension both initially and at 4 to 8 weeks compared with B1+/+. Left ventricular mass and myocyte size were also larger in B1-/- with sham operation than in B1+/+, although cardiac function did not differ between strains. After myocardial infarction, cardiac remodeling and function were similar in both strains, although B1-/- mice tended to have lower blood pressure. Blockade of B2 receptors tended to worsen cardiac remodeling and dysfunction in B1-/- but not in B1+/+. These results may suggest that B2 receptors play an important role in compensating for lack of B1 receptors in mice with myocardial infarction. Dual blockade of both B1 and B2 eliminates this compensation, leading to further deterioration of cardiac dysfunction and remodeling after myocardial infarction.     

Relationship of Height to Site‐Specific Fracture Risk in Postmenopausal Women

Height has been associated with increased risk of fracture of the neck of femur. However, information on the association of height with fractures at other sites is limited and conflicting. A total of 796,081 postmenopausal women, who reported on health and lifestyle factors including a history of previous fractures and osteoporosis, were followed for 8 years for incident fracture at various sites by record linkage to National Health Service hospital admission data. Adjusted relative risks of fracture at different sites per 10‐cm increase in height were estimated using Cox regression. Numbers with site‐specific fractures were: humerus (3036 cases), radius and/or ulna (1775), wrist (9684), neck of femur (5734), femur (not neck) (713), patella (649), tibia and/or fibula (1811), ankle (5523), and clavicle/spine/rib (2174). The risk of fracture of the neck of femur increased with increasing height (relative risk [RR] = 1.48 per 10‐cm increase, 99% confidence interval [CI] 1.39–1.57) and the proportional increase in risk was significantly greater than for all other fracture sites (p_{heterogeneity} < 0.001). For the other sites, fracture risk also increased with height (RR = 1.15 per 10 cm, CI 1.12–1.18), but there was only very weak evidence of a possible difference in risk between the sites (p_{heterogeneity} = 0.03). In conclusion, taller women are at increased risk of fracture, especially of the neck of femur. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).