Bone mineral density in young women with long-standing amenorrhea: limited effect of hormone replacement therapy with ethinylestradiol and desogestrel

To assess bone mineral density (BMD) at different skeletal sites in women with hypothalamic or ovarian amenorrhea and the effect of estrogen-gestagen substitution on BMD we compared BMD of 21 amenorrheic patients with hypothalamic or ovarian amenorrhea with that of a control population of 123 healthy women. All amenorrheic patients were recruited from the outpatient clinic of the Division of Gynecological Endocrinology at the University of Berne, a public University Hospital. One hundred and twenty-three healthy, regularly menstruating women recruited in the Berne area served as a control group. BMD was measured using dual-energy X-ray absorptiometry (DXA). At each site where it was measured, mean BMD was lower in the amenorrheic group than in the control group. Compared with the control group, average BMD in the amenorrheic group was 85% at lumbar spine (p < 0.0001), 92% at femoral neck (p < 0.02), 90% at Ward's triangle (p < 0.03), 92% at tibial diaphysis (p < 0.0001) and 92% at tibial epiphysis (p < 0.03). Fifteen amenorrheic women received estrogen-gestagen replacement therapy (0.03 mg ethinylestradiol and 0.15 mg desogestrel daily for 21 days per month), bone densitometry being repeated within 12-24 months. An annual increase in BMD of 0.2% to 2.9% was noted at all measured sites, the level of significance being reached at the lumbar spine (p < 0.0012) and Ward's triangle (p < 0.033). In conclusion BMD is lower in amenorrheic young women than in a population of normally menstruating, age-matched women in both mainly trabecular (lumbar spine, Ward's triangle, tibial epiphysis) and mainly cortical bone (femoral neck, tibial diaphysis).(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of nicotinic receptor-induced postsynaptic responses to luteinizing hormone-releasing hormone in bullfrog sympathetic ganglia via a Na+-dependent mechanism

Nicotine at very low doses (5–30 nM) induced large amounts of luteinizing hormone-releasing hormone (LHRH) release, which was monitored as slow membrane depolarizations in the ganglionic neurons of bullfrog sympathetic ganglia. A nicotinic antagonist, d-tubocurarine chloride, completely and reversibly blocked the nicotine-induced LHRH release, but it did not block the nerve-firing-evoked LHRH release. Thus, nicotine activated nicotinic acetylcholine receptors and produced LHRH release via a mechanism that is different from the mechanism for evoked release. Moreover, this release was not caused by Ca2+ influx through either the nicotinic receptors or the voltage-gated Ca2+ channels because the release was increased moderately when the extracellular solution was changed into a Ca2+-free solution that also contained Mg2+ (4 mM) and Cd2+ (200 μM). The release did not depend on Ca2+ release from the intraterminal Ca2+ stores either because fura-2 fluorimetry showed extremely low Ca2+ elevation (≈30 nM) in response to nicotine (30 nM). Moreover, nicotine evoked LHRH release when [Ca2+] elevation in the terminals was prevented by loading the terminals with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid and fura-2. Instead, the nicotine-induced release required extracellular Na+ because substitution of extracellular NaCl with N-methyl-d-glucamine chloride completely blocked the release. The Na+-dependent mechanism was not via Na+ influx through the voltage-gated Na+ channels because the release was not affected by tetrodotoxin (1–50 μM) plus Cd2+ (200 μM). Thus, nicotine at very low concentrations induced LHRH release via a Na+-dependent, Ca2+-independent mechanism.

Lys9 for Glu9 substitution in glucagon-like peptide-1(7-36)amide confers dipeptidylpeptidase IV resistance with cellular and metabolic actions similar to those of established antagonists glucagon-like peptide-1(9-36)amide and exendin (9-39)

The incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) has been deemed of considerable importance in the regulation of blood glucose. Its effects, mediated through the regulation of insulin, glucagon, and somatostatin, are glucose-dependent and contribute to the tight control of glucose levels. Much enthusiasm has been assigned to a possible role of GLP-1 in the treatment of type 2 diabetes. GLIP-l's action unfortunately is limited through enzymatic inactivation caused by dipeptidylpeptidase IV (DPP IV). It is now well established that modifying GLP-1 at the N-terminal amino acids, His7 and Ala8, can greatly improve resistance to this enzyme. Little research has assessed what effect Glu9-substitution has on GLP-1 activity and its degradation by DPP IV. Here, we report that the replacement of Glu9 of GLP-1 with Lys dramatically increased resistance to DPP IV. This analogue (Lys9)GLP-1, exhibited a preserved GLP-1 receptor affinity, but the usual stimulatory effects of GLP-1 were completely eliminated, a trait duplicated by the other established GLP-1-antagonists, exendin (9-39) and GLP-1 (9-36)amide. We investigated the in vivo antagonistic actions of (Lys9)GLP-1 in comparison with GLP-1(9-36)amide and exendin (9-39) and revealed that this novel analogue may serve as a functional antagonist of the GLP-1 receptor.

No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer

Background There is evidence that certain mutations in the double-strand break repair pathway ataxia-telangiectasia mutated gene act in a dominant-negative manner to increase the risk of breast cancer. There are also some reports to suggest that the amino acid substitution variants T2119C Ser707Pro and C3161G Pro1054Arg may be associated with breast cancer risk. We investigate the breast cancer risk associated with these two nonconservative amino acid substitution variants using a large Australian population-based case–control study. Methods The polymorphisms were genotyped in more than 1300 cases and 600 controls using 5' exonuclease assays. Case–control analyses and genotype distributions were compared by logistic regression. Results The 2119C variant was rare, occurring at frequencies of 1.4 and 1.3% in cases and controls, respectively (P = 0.8). There was no difference in genotype distribution between cases and controls (P = 0.8), and the TC genotype was not associated with increased risk of breast cancer (adjusted odds ratio = 1.08, 95% confidence interval = 0.59–1.97, P = 0.8). Similarly, the 3161G variant was no more common in cases than in controls (2.9% versus 2.2%, P = 0.2), there was no difference in genotype distribution between cases and controls (P = 0.1), and the CG genotype was not associated with an increased risk of breast cancer (adjusted odds ratio = 1.30, 95% confidence interval = 0.85–1.98, P = 0.2). This lack of evidence for an association persisted within groups defined by the family history of breast cancer or by age. Conclusion The 2119C and 3161G amino acid substitution variants are not associated with moderate or high risks of breast cancer in Australian women.

Drivers of technology substitution : successive generations of high tech products

Principal Topic High technology consumer products such as notebooks, digital cameras and DVD players are not introduced into a vacuum. Consumer experience with related earlier generation technologies, such as PCs, film cameras and VCRs, and the installed base of these products strongly impacts the market diffusion of the new generation products. Yet technology substitution has received only sparse attention in the diffusion of innovation literature. Research for consumer durables has been dominated by studies of (first purchase) adoption (c.f. Bass 1969) which do not explicitly consider the presence of an existing product/technology. More recently, considerable attention has also been given to replacement purchases (c.f. Kamakura and Balasubramanian 1987). Only a handful of papers explicitly deal with the diffusion of technology/product substitutes (e.g. Norton and Bass, 1987: Bass and Bass, 2004). They propose diffusion-type aggregate-level sales models that are used to forecast the overall sales for successive generations. Lacking household data, these aggregate models are unable to give insights into the decisions by individual households - whether to adopt generation II, and if so, when and why. This paper makes two contributions. It is the first large-scale empirical study that collects household data for successive generations of technologies in an effort to understand the drivers of adoption. Second, in comparision to traditional analysis that evaluates technology substitution as an ''adoption of innovation'' type process, we propose that from a consumer's perspective, technology substitution combines elements of both adoption (adopting the new generation technology) and replacement (replacing the generation I product with generation II). Based on this proposition, we develop and test a number of hypotheses. Methodology/Key Propositions In some cases, successive generations are clear ''substitutes'' for the earlier generation, in that they have almost identical functionality. For example, successive generations of PCs Pentium I to II to III or flat screen TV substituting for colour TV. More commonly, however, the new technology (generation II) is a ''partial substitute'' for existing technology (generation I). For example, digital cameras substitute for film-based cameras in the sense that they perform the same core function of taking photographs. They have some additional attributes of easier copying and sharing of images. However, the attribute of image quality is inferior. In cases of partial substitution, some consumers will purchase generation II products as substitutes for their generation I product, while other consumers will purchase generation II products as additional products to be used as well as their generation I product. We propose that substitute generation II purchases combine elements of both adoption and replacement, but additional generation II purchases are solely adoption-driven process. Extensive research on innovation adoption has consistently shown consumer innovativeness is the most important consumer characteristic that drives adoption timing (Goldsmith et al. 1995; Gielens and Steenkamp 2007). Hence, we expect consumer innovativeness also to influence both additional and substitute generation II purchases. Hypothesis 1a) More innovative households will make additional generation II purchases earlier. 1 b) More innovative households will make substitute generation II purchases earlier. 1 c) Consumer innovativeness will have a stronger impact on additional generation II purchases than on substitute generation II purchases. As outlined above, substitute generation II purchases act, in part like a replacement purchase for the generation I product. Prior research (Bayus 1991; Grewal et al 2004) identified product age as the most dominant factor influencing replacements. Hence, we hypothesise that: Hypothesis 2: Households with older generation I products will make substitute generation II purchases earlier. Our survey of 8,077 households investigates their adoption of two new generation products: notebooks as a technology change to PCs, and DVD players as a technology shift from VCRs. We employ Cox hazard modelling to study factors influencing the timing of a household's adoption of generation II products. We determine whether this is an additional or substitute purchase by asking whether the generation I product is still used. A separate hazard model is conducted for additional and substitute purchases. Consumer Innovativeness is measured as domain innovativeness adapted from the scales of Goldsmith and Hofacker (1991) and Flynn et al. (1996). The age of the generation I product is calculated based on the most recent household purchase of that product. Control variables include age, size and income of household, and age and education of primary decision-maker. Results and Implications Our preliminary results confirm both our hypotheses. Consumer innovativeness has a strong influence on both additional purchases (exp = 1.11) and substitute purchases (exp = 1.09). Exp is interpreted as the increased probability of purchase for an increase of 1.0 on a 7-point innovativeness scale. Also consistent with our hypotheses, the age of the generation I product has a dramatic influence for substitute purchases of VCR/DVD (exp = 2.92) and a strong influence for PCs/notebooks (exp = 1.30). Exp is interpreted as the increased probability of purchase for an increase of 10 years in the age of the generation I product. Yet, also as hypothesised, there was no influence on additional purchases. The results lead to two key implications. First, there is a clear distinction between additional and substitute purchases of generation II products, each with different drivers. Treating these as a single process will mask the true drivers of adoption. For substitute purchases, product age is a key driver. Hence, implications for marketers of high technology products can utilise data on generation I product age (e.g. from warranty or loyalty programs) to target customers who are more likely to make a purchase.