The Mare as a Model for Luteinized Unruptured Follicle Syndrome: Intrafollicular Endocrine Milieu.

Luteinized unruptured follicle (LUF) syndrome is a recurrent anovulatory dysfunction that affects up to 23% of women with normal menstrual cycles and up to 73% with endometriosis. Mechanisms underlying the development of LUF syndrome in mares were studied to provide a potential model for human anovulation. The effect of extended increase in circulating LH achieved by administration of recombinant equine LH (reLH) or a short surge of LH and decrease in progesterone induced by prostaglandin F2α (PGF2α) on LUF formation (Experiment 1), identification of an optimal dose of COX-2 inhibitor (flunixin meglumine, FM; to block the effect of prostaglandins) for inducing LUFs (Experiment 2), and evaluation of intrafollicular endocrine milieu in LUFs (Experiment 3) were investigated. In Experiment 1, mares were treated with reLH from Day 7 to Day 15 (Day 0=ovulation), PGF2α on Day 7, or in combination. In Experiment 2, FM at doses of 2.0 or 3.0 mg/kg every 12 h and human chorionic gonadotropin (hCG) (1500 IU) were administered after a follicle ≥32 mm was detected. In Experiment 3, FM at a dose of 2.0 mg/kg every 12 h plus hCG was used to induce LUFs and investigate the intrafollicular endocrine milieu. No LUFs were induced by reLH or PGF2α treatment; however, LUFs were induced in 100% of mares using FM. Intrafollicular PGF2α metabolite, PGF2α, and PGE2 were lower and the ratio of PGE2:PGF2α was higher in the induced LUF group. Higher levels of intrafollicular E2 and total primary sex steroids were observed in the induced LUF group along with a tendency for higher levels of GH, cortisol, and T; however, LH, PRL, VEGF-A, and NO did not differ between groups. In conclusion, this study reveals part of the intrafollicular endocrine milieu and the association of prostaglandins in LUF formation, and indicates that the mare might be an appropriate model for studying the poorly understood LUF syndrome

The Mare as a Model for Luteinized Unruptured Follicle Syndrome: Intrafollicular Endocrine Milieu.

Luteinized unruptured follicle (LUF) syndrome is a recurrent anovulatory dysfunction that affects up to 23% of women with normal menstrual cycles and up to 73% with endometriosis. Mechanisms underlying the development of LUF syndrome in mares were studied to provide a potential model for human anovulation. The effect of extended increase in circulating LH achieved by administration of recombinant equine LH (reLH) or a short surge of LH and decrease in progesterone induced by prostaglandin F2α (PGF2α) on LUF formation (Experiment 1), identification of an optimal dose of COX-2 inhibitor (flunixin meglumine, FM; to block the effect of prostaglandins) for inducing LUFs (Experiment 2), and evaluation of intrafollicular endocrine milieu in LUFs (Experiment 3) were investigated. In Experiment 1, mares were treated with reLH from Day 7 to Day 15 (Day 0=ovulation), PGF2α on Day 7, or in combination. In Experiment 2, FM at doses of 2.0 or 3.0 mg/kg every 12 h and human chorionic gonadotropin (hCG) (1500 IU) were administered after a follicle ≥32 mm was detected. In Experiment 3, FM at a dose of 2.0 mg/kg every 12 h plus hCG was used to induce LUFs and investigate the intrafollicular endocrine milieu. No LUFs were induced by reLH or PGF2α treatment; however, LUFs were induced in 100% of mares using FM. Intrafollicular PGF2α metabolite, PGF2α, and PGE2 were lower and the ratio of PGE2:PGF2α was higher in the induced LUF group. Higher levels of intrafollicular E2 and total primary sex steroids were observed in the induced LUF group along with a tendency for higher levels of GH, cortisol, and T; however, LH, PRL, VEGF-A, and NO did not differ between groups. In conclusion, this study reveals part of the intrafollicular endocrine milieu and the association of prostaglandins in LUF formation, and indicates that the mare might be an appropriate model for studying the poorly understood LUF syndrome

Dominant follicle growth patterns and associated endocrine dynamics in anovulatory and ovulatory waves in women

Growth patterns and associated endocrine profiles were compared between dominant anovulatory (ADF) and ovulatory follicles (OvF) developing from different waves within and between menstrual cycles in women. Follicular mapping profiles of 49 healthy women of reproductive age and blood samples were obtained every 1–3 days during one interovulatory interval. Sixty-three dominant follicles were classified into wave 1 (W1ADF; n = 8) and wave 2 (W2ADF; n = 6) anovulatory follicles and wave 2 (W2OvF; n = 33) and wave 3 (W3OvF; n = 16) ovulatory follicles. Comparisons were made between W1ADF and W2ADF, W2ADF and W2OvF, and W2OvF and W3OvF. The waves were numbered 1, 2, or 3 based on when the waves emerged relative to the preceding ovulation. W1ADF emerged closer to the preceding ovulation, and W2ADF emerged in the late luteal or early follicular phase. The interval from emergence to maximum diameter was shorter for W2ADF than W1ADF and for W3OvF than W2OvF. Selection of W3OvF occurred at a smaller diameter compared to W2OvF. W1ADF regressed at a faster rate than W2ADF. Also, W1ADF were associated with lower mean follicle stimulating hormone (FSH) and higher mean estradiol than W2ADF. In contrast, W3OvF were associated with higher FSH and luteinizing hormone (LH) compared to W2OvF. However, W2OvF were associated with higher progesterone than W3OvF. This study contributes to the understanding of the physiologic mechanisms underlying selection of the dominant follicle, ovulation, and pathophysiology of anovulation in women, as well as optimization of ovarian stimulation protocols for assisted reproduction

BPS states in M-theory and twistorial constituents

We provide a complete algebraic description of BPS states in M-theory in terms of primary constituents that we call BPS preons. We argue that any BPS state preserving $k$ of the 32 supersymmetries is a composite of (32-k) BPS preons. In particular, the BPS states corresponding to the basic M2 and M5 branes are composed of 16 BPS preons. By extending the M-algebra to a generalized D=11 conformal superalgebra $osp(1|64)$ we relate the BPS preons with its fundamental representation, the D=11 supertwistors.Comment: 4 pages. Refs. updated, two cosmetic changes, to appear in PR

Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study

Mikolajczyk RT, Stanford JB, Ecochard R. Multilevel model to assess sources of variation in follicular growth close to the time of ovulation in women with normal fertility: a multicenter observational study. Reproductive Biology and Endocrinology. 2008;6(1): 61.Background: To assess the amount of variability in ovarian follicular growth rate and maximum follicular diameter related to different centers, women and cycles of the same women in a multicenter observational study of follicular growth. Methods: Secondary analysis of a prospective cohort study from eight centers in Europe. There were 533 ultrasound examinations in 282 cycles of 107 women with normal fertility. A random effects model with center, woman and cycle as hierarchical units of variation was used to analyze mean follicular diameter on days preceding ovulation. Results: Follicular growth did not differ by center. There was homogenous growth across women and cycles, and the maximum follicular diameter before ovulation varied substantially across cycles but not across women. Many (about 40%) women had small maximum follicular diameter on the day before ovulation (<19 mm). Pre-ovulatory cycle length was not related to maximum follicular diameter. Conclusion: In normal fecundity, there is a substantial variation in maximum follicular diameter from cycle to cycle based on variation in the duration of follicular development, but the variation could not be explained by different characteristics of different women. Explanation of variation in follicular growth has to be found on the cycle level

G-Structures, Fluxes and Calibrations in M-Theory

We study the most general supersymmetric warped M-theory backgrounds with non-trivial G-flux of the type R^{1,2} x M_8 and AdS_3 x M_8. We give a set of necessary and sufficient conditions for preservation of supersymmetry which are phrased in terms of G-structures and their intrinsic torsion. These equations may be interpreted as calibration conditions for a static ``dyonic'' M-brane, that is, an M5-brane with self-dual three-form turned on. When the electric flux is turned off we obtain the supersymmetry conditions and non-linear PDEs describing M5-branes wrapped on associative and special Lagrangian three-cycles in manifolds with G_2 and SU(3) structures, respectively. As an illustration of our formalism, we recover the 1/2-BPS dyonic M-brane, and also construct some new examples.Comment: 40 pages; v2: one reference added, typos correcte

Interplay of energy dependent astrophysical neutrino flavor ratios and new physics effects

We discuss the importance of flavor ratio measurements in neutrino telescopes, such as by measuring the ratio between muon tracks to cascades, for the purpose of extracting new physics signals encountered by astrophysical neutrinos during propagation from the source to the detector. The detected flavor ratios not only carry the energy information of specific new physics scenarios which alter the transition probabilities in distinctive ways, but also the energy dependent flavor composition at the source. In the present work, we discuss the interplay of these two energy dependent effects and identify which new physics scenarios can be distinguished from the detected flavor ratios as a function of astrophysical parameters. We use a recently developed self-consistent neutrino production model as our toy model to generate energy dependent source flavor ratios and discuss (invisible) neutrino decay and quantum decoherence as specific new physics examples. Furthermore, we identify potentially interesting classes of sources on the Hillas plot for the purpose of new physics searches. We find that sources with substantial magnetic fields 10^3 Gauss <= B <= 10^6 Gauss, such as Active Galactic Nuclei (AGN) cores, white dwarfs, or maybe gamma-ray bursts, have, in principle, the best discrimination power for the considered new physics scenarios, whereas AGN jets, which typically perform as pion beam sources, can only discriminate few sub cases in the new physics effects. The optimal parameter region somewhat depends on the class of new physics effect considered.Comment: 34 pages, 10 figures, 1 table. Discussion on statistics added, minor clarifications. Final version published in JCA

Supersymmetric string model with 30 kappa--symmetries in an extended D=11 superspace and 30/ 32 BPS states

A supersymmetric string model in the D=11 superspace maximally extended by antisymmetric tensor bosonic coordinates, $\Sigma^{(528|32)}$, is proposed. It possesses 30 $\kappa$-symmetries and 32 target space supersymmetries. The usual preserved supersymmetry-$\kappa$-symmetry correspondence suggests that it describes the excitations of a BPS state preserving all but two supersymmetries. The model can also be formulated in any $\Sigma^{({n(n+1)\over 2}|n)}$ superspace, n=32 corresponding to D=11. It may also be treated as a `higher--spin generalization' of the usual Green--Schwarz superstring. Although the global symmetry of the model is a generalization of the super--Poincar\'e group, ${\Sigma}^{({n(n+1)\over 2}|n)}\times\supset Sp(n)$, it may be formulated in terms of constrained OSp(2n|1) orthosymplectic supertwistors. We work out this supertwistor realization and its Hamiltonian dynamics. We also give the supersymmetric p-brane generalization of the model. In particular, the $\Sigma^{(528|32)}$ supersymmetric membrane model describes excitations of a 30/32 BPS state, as the $\Sigma^{(528|32)}$ supersymmetric string does, while the supersymmetric 3-brane and 5-brane correspond, respectively, to 28/32 and 24/32 BPS states.Comment: 23 pages, RevTex4. V2: minor corrections in title and terminology, some references and comments adde

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches