Transdermal hormone therapy and bone health

The clinical aftermath of the reporting of the initial findings of the Women’s Health Initiative (WHI) in 2002 was a profound reduction in the use of hormone therapies by menopausal women. This reduction led to a well documented increase in vasomotor symptoms and vaginal atrophy among those women who discontinued their hormone regimens. However, another adverse impact among these women, as well as many other menopausal women, is the well recognized increased likelihood of osteoporosis resulting from the decline in circulating estradiol levels associated with natural and surgical menopause. Although the use of non-hormonal drugs such as bisphosphonates has been shown to reduce the risk of fracture in women with osteoporosis, bisphosphonates have not been shown to reduce the risk of fracture in non-osteoporotic women. Indeed, only oral estrogen (as demonstrated in the WHI studies) has been shown to reduce the risk of fracture in osteoporotic and non-osteoporotic women. As non-oral hormone therapies have been shown to be as effective in treating vasomotor symptoms and vulvovaginal atrophy and to have a different (and perhaps more beneficial) physiological effect than oral regimens, it behooves us to assess the impact of non-oral hormone regimens on bone mineral density and fracture risk. Although there are no clinical trials that primarily assess the impact of non-oral regimens on fracture risk in menopausal women, numerous studies are consistent in demonstrating the positive impact of non-oral regimens in maintaining and increasing bone mineral density among users, even for those women using estrogen doses that are considered to be “too low” to have a beneficial impact on other menopausal symptoms

Estradiol valerate and dienogest: a new approach to oral contraception

Most combination oral contraceptives contain ethinyl estradiol and a progestin. A new and novel oral contraceptive formulation combines estradiol valerate (E2V) with dienogest (DNG) in a four-phase dosing regimen. 17β-estradiol is a naturally-occurring estrogen, and a contraceptive pill containing such an estrogen offers potential benefits with regard to metabolic side effects and adverse events. Dienogest is derived from 19-nortestosterone and exerts profound progestational effects on the endometrium, but it differs from other progestins in its class by its antiandrogenic activity. Estradiol valerate plus dienogest (E2V/DNG) is now available in a four-phasic regimen that integrates an estrogen stepdown and progestin stepup dosing approach along with a short two-day hormone-free interval. This regimen offers safe, reliable contraception and has been shown to be an effective treatment for heavy menstrual bleeding. Metabolic effects and adverse events appear similar to those reported with oral contraceptives containing ethinyl estradiol

Coherent State path-integral simulation of many particle systems

The coherent state path integral formulation of certain many particle systems allows for their non perturbative study by the techniques of lattice field theory. In this paper we exploit this strategy by simulating the explicit example of the diffusion controlled reaction $A+A\to 0$. Our results are consistent with some renormalization group-based predictions thus clarifying the continuum limit of the action of the problem.Comment: 20 pages, 4 figures. Minor corrections. Acknowledgement and reference correcte

Mesoscopic Full Counting Statistics and Exclusion models

We calculate the distribution of current fluctuations in two simple exclusion models. Although these models are classical, we recover even for small systems such as a simple or a double barrier, the same distibution of current as given by traditionnal formalisms for quantum mesoscopic conductors. Due to their simplicity, the full counting statistics in exclusion models can be reduced to the calculation of the largest eigenvalue of a matrix, the size of which is the number of internal configurations of the system. As examples, we derive the shot noise power and higher order statistics of current fluctuations (skewness, full counting statistics, ....) of various conductors, including multiple barriers, diffusive islands between tunnel barriers and diffusive media. A special attention is dedicated to the third cumulant, which experimental measurability has been demonstrated lately.Comment: Submitted to Eur. Phys. J.

X-ray absorption spectroscopy systematics at the tungsten L-edge

A series of mononuclear six-coordinate tungsten compounds spanning formal oxidation states from 0 to +VI, largely in a ligand environment of inert chloride and/or phosphine, has been interrogated by tungsten L-edge X-ray absorption spectroscopy. The L-edge spectra of this compound set, comprised of [W<sup>0</sup>(PMe<sub>3</sub>)<sub>6</sub>], [W<sup>II</sup>Cl<sub>2</sub>(PMePh<sub>2</sub>)<sub>4</sub>], [W<sup>III</sup>Cl<sub>2</sub>(dppe)<sub>2</sub>][PF<sub>6</sub>] (dppe = 1,2-bis(diphenylphosphino)ethane), [W<sup>IV</sup>Cl<sub>4</sub>(PMePh<sub>2</sub>)<sub>2</sub>], [W<sup>V</sup>(NPh)Cl<sub>3</sub>(PMe<sub>3</sub>)<sub>2</sub>], and [W<sup>VI</sup>Cl<sub>6</sub>] correlate with formal oxidation state and have usefulness as references for the interpretation of the L-edge spectra of tungsten compounds with redox-active ligands and ambiguous electronic structure descriptions. The utility of these spectra arises from the combined correlation of the estimated branching ratio (EBR) of the L<sub>3,2</sub>-edges and the L<sub>1</sub> rising-edge energy with metal Z<sub>eff</sub>, thereby permitting an assessment of effective metal oxidation state. An application of these reference spectra is illustrated by their use as backdrop for the L-edge X-ray absorption spectra of [W<sup>IV</sup>(mdt)<sub>2</sub>(CO)<sub>2</sub>] and [W<sup>IV</sup>(mdt)<sub>2</sub>(CN)<sub>2</sub>]<sup>2–</sup> (mdt<sup>2–</sup> = 1,2-dimethylethene-1,2-dithiolate), which shows that both compounds are effectively W<sup>IV</sup> species. Use of metal L-edge XAS to assess a compound of uncertain formulation requires: 1) Placement of that data within the context of spectra offered by unambiguous calibrant compounds, preferably with the same coordination number and similar metal ligand distances. Such spectra assist in defining upper and/or lower limits for metal Z<sub>eff</sub> in the species of interest; 2) Evaluation of that data in conjunction with information from other physical methods, especially ligand K-edge XAS; 3) Increased care in interpretation if strong π-acceptor ligands, particularly CO, or π-donor ligands are present. The electron-withdrawing/donating nature of these ligand types, combined with relatively short metal-ligand distances, exaggerate the difference between formal oxidation state and metal Z<sub>eff</sub> or, as in the case of [W<sup>IV</sup>(mdt)<sub>2</sub>(CO)<sub>2</sub>], add other subtlety by modulating the redox level of other ligands in the coordination sphere

Advantages of dynamic “closed loop” stable isotope flux phenotyping over static “open loop” clamps in detecting silent genetic and dietary phenotypes

In vivo insulin sensitivity can be assessed using “open loop” clamp or “closed loop” methods. Open loop clamp methods are static, and fix plasma glucose independently from plasma insulin. Closed loop methods are dynamic, and assess glucose disposal in response to a stable isotope labeled glucose tolerance test. Using PPARα−/− mice, open and closed loop assessments of insulin sensitivity/glucose disposal were compared. Indirect calorimetry done for the assessment of diurnal substrate utilization/metabolic flexibility showed that chow fed PPARα−/− mice had increased glucose utilization during the light (starved) cycle. Euglycemic clamps showed no differences in insulin stimulated glucose disposal, whether for chow or high fat diets, but did show differences in basal glucose clearance for chow fed PPARα−/− versus SV129J-wt mice. In contrast, the dynamic stable isotope labeled glucose tolerance tests reveal enhanced glucose disposal for PPARα−/− versus SV129J-wt, for chow and high fat diets. Area under the curve for plasma labeled and unlabeled glucose for PPARα−/− was ≈1.7-fold lower, P < 0.01 during the stable isotope labeled glucose tolerance test for both diets. Area under the curve for plasma insulin was 5-fold less for the chow fed SV129J-wt (P < 0.01) but showed no difference on a high fat diet (0.30 ± 0.1 for SV129J-wt vs. 0.13 ± 0.10 for PPARα−/−, P = 0.28). This study demonstrates that dynamic stable isotope labeled glucose tolerance test can assess “silent” metabolic phenotypes, not detectable by the static, “open loop”, euglycemic or hyperglycemic clamps. Both open loop and closed loop methods may describe different aspects of metabolic inflexibility and insulin sensitivity

TXNIP Regulates Peripheral Glucose Metabolism in Humans

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. METHODS AND FINDINGS: We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. CONCLUSIONS: TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM