Aromatase inhibitors in ovarian stimulation

The selective estrogen receptor modulator, clomiphene citrate (CC), has been the principal drug used for induction of ovulation in women with polycystic ovarian syndrome (PCOS). CC is associated with adverse side effects and low pregnancy rates attributed to long-lasting estrogen receptor depletion. Anastrozole and letrozole are potent, non-steroidal, reversible aromatase inhibitors, developed for postmenopausal breast cancer therapy. We hypothesized that aromatase inhibitors could mimic the action of CC in reducing estrogen negative feedback on follicle stimulating hormone (FSH) secretion, without depleting estrogen receptors. In a series of preliminary studies, we reported the success of aromatase inhibition in inducing ovulation in anovulatory women with PCOS. Moreover, we showed that concomitant use of aromatase inhibitors resulted in a significant reduction of the FSH dose needed for controlled ovarian hyperstimulation. We suggest that aromatase inhibitors act through an increase in endogenous gonadotropin secretion as well as through increased intraovarian androgen levels that may increase ovarian FSH receptors. Recently, we demonstrated the safety of aromatase inhibitors in pregnancy outcome studies examining spontaneous pregnancy loss, multiple pregnancy rates and congenital anomalies compared to a control group of infertility patients treated with CC.     

Hypertension Is a Conditional Factor for the Development of Cardiac Hypertrophy in Type 2 Diabetic Mice

Background

Type 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice.

Methods

Thereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n = 9–10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation.

Results

Vehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice.

Conclusions

Collectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling.     

Seasonal variability in otariid energetics: implications for the effects of predators on localized prey resources

Otariids, like other wild mammals, contend with a wide variety of energetic demands across seasons. However, due to the cryptic behaviors of this marine group, few studies have been able to examine longitudinal energetic costs or the potential impact of these costs on seasonal or annual prey requirements. Here we evaluated the changes in energy demand and intake of female California sea lions (Zalophus californianus) during reproductive (n=2 sea lions) and nonreproductive (n=3) periods. Monthly measurements included resting metabolic rate, blood hormone levels, body condition (blubber thickness and body mass), and caloric intake for adult sea lions throughout molting, late pregnancy, lactation, and postweaning. We found that maintenance energy demands decreased from 32.0 to 23.1 MJ d(-1) before pupping, remaining stable at 19.4+/-0.6 MJ d(-1) during lactation and postweaning. Energy intake rates to meet these demands showed marked changes with activity level and the reproductive cycle, reaching a peak intake of 3.6 times baseline levels during lactation. Translating this into prey demands, we find that 20,000 reproductively active females on San Nicolas Island rookeries would maximally require 4,950 metric tons of Pacific whiting during a month of the breeding season. This localized impact is reduced significantly with postbreeding dispersal and demonstrates the importance of considering spatial and temporal factors driving the energetic requirements of predators when designing marine protected areas.     

Environmental consequences of deltamethrin residues in cattle feces in an African agricultural landscape

Pyrethroid insecticides are widely used to control ectoparasites of livestock, particularly ticks and biting flies. Their use in African livestock systems is increasing, driven by the need to increase productivity and local food security. However, insecticide residues present in the dung after treatment are toxic to dung‐inhabiting insects. In a semiarid agricultural habitat in Botswana, dung beetle adult mortality, brood ball production, and larval survival were compared between untreated cattle dung and cattle dung spiked with deltamethrin, to give concentrations of 0.01, 0.1, 0.5, or 1 ppm. Cattle dung‐baited pitfall traps were used to measure repellent effects of deltamethrin in dung on Scarabaeidae. Dung decomposition rate was also examined. There was significantly increased mortality of adult dung beetles colonizing pats that contained deltamethrin compared to insecticide‐free pats. Brood ball production was significantly reduced at concentrations of 1 ppm; larval survival was significantly reduced in dung containing 0.1 ppm deltamethrin and above. There was no difference in the number of Scarabaeidae attracted to dung containing any of the deltamethrin concentrations. Dung decomposition was significantly reduced even at the lowest concentration (0.01 ppm) compared to insecticide‐free dung. The widespread use of deltamethrin in African agricultural ecosystems is a significant cause for concern; sustained use is likely to damage dung beetle populations and their provision of environmentally and economically important ecosystem services. Contaminated dung buried by paracoprid (tunneling) beetles may retain insecticidal effects, with impacts on developing larvae below ground. Lethal and sublethal effects on entire dung beetle (Scarabaeidae) communities could impair ecosystem function in agricultural landscapes.     

Preliminary experience with subcutaneous human ovarian cortex transplantation in the NOD-SCID mouse.

Xenogeneic transplantation of ovarian cortex into an immunodeficient animal host may be an approach toward fertility preservation for young female patients undergoing cancer therapy. Our objective was to evaluate the development of follicles in human ovarian cortex placed s.c. in non-obese diabetic-severe combined immune deficiency (NOD-SCID) mice (n = 54). The following variables were compared: 1) male versus female mice as hosts, 2) intact versus pituitary down-regulated mice, and 3) warm versus cold tissue transport. After 2 wk, 37 of 50 (74%) of the human xenografts contained follicles. At 12 wk after transplantation, exogenous gonadotropin stimulation resulted in follicle growth in 19 of 37 (51%) of the grafts, including the development of antral follicles, which could be palpated and visualized through the mouse skin. Significantly more developing follicles were identified in male versus female mice (13 of 17 vs. 6 of 20, respectively; p = 0.013) after stimulation. No difference was found between intact and pituitary down-regulated mice as hosts. Follicular survival was significantly increased by warm versus cold tissue transport. Our results suggest that s.c. ovarian cortex xenografting into NOD-SCID mice is feasible. Primordial follicles in ovarian xenografts retain their developmental potential and form antral follicles following gonadotropin stimulation.     

Acute lymphoblastic leukemia (ALL) antigens detected with antisera to E rosette-froming and non-E rosette-forming ALL blasts.

Based on the presence or absence of erythrocyte receptors(E) a T cell marker, acute lymphocytic leukemia (ALL), can be divided into E+ALL and E-ALL. We studied cell surface antigens on blasts from 12 children with untreated ALL: eight with E-ALL and four with E+ALL. Heterologous antisera were raised against thymus cells, E+ and E-ALL blasts, appropriately absorbed and tested by immunofluorescence and a radiolabeled antibody assay with normal and leukemic lymphoid cells. By both methods, anti-thymus and anti-E+ALL sera reacted with human thymocytes. Specific binding of anti-E+ALL serum to T antigens was indicated by the fact that a single absorption with thymocytes abolished its binding to allogenic thymocytes, and the reactivity of anti-E+ALL serum with thymus, blood and bone marrow lymphocytes was similar to that of anti-thymus serum. After exhaustive absorption with blood leukocytes, anti-E+ALL and E-ALL sera were negative against normal lymphocytes and bone marrow cells from children with ALL in remission. Anti-thymus and anti-E+ALL sera reacted with blasts from patients with E+ALL, but not with E-ALL. In contrast, anti-E+ALL serum reacted with 40 to 96% of blasts from all children with E-ALL, whereas of the four patients with E+ALL, two were negative and two had the lowest percentage of immunofluorescent cells (10 to 22%). These results were confirmed with the radiolabeled antibody assay. Patients with active E-ALL had cells bearing E-ALL antigen(s) in the peripheral blood and bone marrow, but the number of immunofluorescent cells was lower in blood. Cells reactive with anti-E-ALL serum did not react with thymus cells, blood lymphocytes, remission bone marrow cells, Raji cells, PWM and PHA-induced blasts and CLL cells bearing mIg (uk). These data suggest that the antigen detected on E-ALL blasts by anti-E-ALL serum is neither a HLA-related nor a cell differentiation antigen. Thus, by using antiserum to E+ALL blasts, we have confirmed the presence of a T cell-specific antigen(s) on E+ALL cells. This antiserum did not recognize other leukemia-associated antigens common to E+ and E-ALL. We have also demonstrated an antigen(s) which is regularly expressed on E-ALL blasts and is either not detectable or is present in a lower proportion of E+ALL blasts.     

A multi-recombination model for the mtDNA rearrangements seen in maize cmsT regenerated plants

Regeneration of plants from maize cytoplasmic male sterile type T (cmsT) callus tissue culture promotes, in some instances, genetic variability in their mitochondrial genomes. These mutations have been analyzed in various cmsT regenerated plants that have or have not regained the male fertile phenotype. A unique multi-recombination model explains the various mitochondrial genome rearrangements. First, recombination involving two different sets of direct repeats gives rise to subgenomic recombinant circles. Second, intermolecular recombination between some selected subgenomes gives rise to a new rearranged master chromosome. The consequence of these events is the formation of a new master chromosome containing sequence deletions and duplications when compared to the progenitor. This new mitochondrial genome seems stable, although it does not contain the entire genetic complexity of the progenitor.     

Detection of a Luteovirus in Groundnut Rosette Diseased Groundnuts (Arachis hypogaea) by Enzyme-linked Immunosorbent Assay and Immunoelectron Microscopy

In groundnut rosette diseased groundnut plants collected near Zaria, Nigeria, a luteovirus was detected by ELISA and ISEM. In ELISA only beet western yellows virus antiserum reacted, while in ISEM luteovirus particles were trapped by antisera beet western yellows virus, potato leafroll virus, pea leafroll virus and barley yellow dwarf virus. The data are in agreement with the interpretation that the assistor of groundnut rosette virus is possibly a member of the luteovirus group.