Role of IP-10 to Predict Clinical Progression and Response to IL-6 Blockade With Sarilumab in Early COVID-19 Pneumonia. A Subanalysis of the SARICOR Clinical Trial.

Background: The Clinical Trial of Sarilumab in Adults With COVID-19 (SARICOR) showed that patients with coronavirus disease 2019 (COVID-19) pneumonia and increased levels of interleukin (IL)-6 might benefit from blockade of the IL-6 pathway. However, the benefit from this intervention might not be uniform. In this subanalysis, we sought to determine if other immunoactivation markers, besides IL-6, could identify which subgroup of patients benefit most from this intervention.

Early Use of Sarilumab in Patients Hospitalized with COVID-19 Pneumonia and Features of Systemic Inflammation: the SARICOR Randomized Clinical Trial.

The objective of this study was to investigate the efficacy and safety of early treatment with sarilumab, added to standard of care (SOC), in hospitalized adults with COVID-19. Methods included phase II, open-label, randomized, controlled clinical trial of hospitalized patients with COVID-19 pneumonia and interleukin (IL)-6 levels ≥ 40 pg/mL and/or d-dimer > 1,500 ng/mL. Participants were randomized (1:1:1) to receive SOC (control group), SOC plus a single subcutaneous dose of sarilumab 200 mg (sarilumab-200 group), or SOC plus a single subcutaneous dose of sarilumab 400 mg (sarilumab-400 group).

Immunoguided Discontinuation of Prophylaxis for Cytomegalovirus Disease in Kidney Transplant Recipients Treated With Antithymocyte Globulin: A Randomized Clinical Trial.

Background: Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy.

Understanding the regulation of pituitary progesterone receptor expression and phosphorylation.

Administration of human FSH (hFSH) during the diestrus phase in cyclic rats is followed by a reduction in the preovulatory LH surge. This inhibitory action of FSH involves a decrease in the stimulatory effect of gonadotrope progesterone receptor (PR) activation, in a ligand-dependent (progesterone) and -independent (GNRH) manner. PR activation and action are mandatory for LH surge, and are dependent on the phosphorylation of serine (Ser) residues.

Estrogen receptor (ESR) 2 partially offsets the absence of ESR1 in gonadotropes of pituitary-specific Esr1 knockout female mice.

Estrogen receptor 1 and 2 (ESR1 and 2) mediate estrogen (E) action on gonadotrope function. While much is known about the effects of ESR1 on the gonadotrope, there is still some controversy regarding the effects of ESR2. To investigate the role of ESR2 in the gonadotrope, 45-day-old female mice of two different genotypes were used: wild type (WT) and pituitary (gonadotropes and thyrotropes)-specific Esr1 knockout (KO).

Involvement of rat gonadotrope progesterone receptor in the ovary-mediated inhibitory action of FSH on LH synthesis.

Rat ovaries stimulated with human follicle-stimulating hormone (hFSH) overexpress a factor that attenuates the LH surge in the rat: the putative gonadotropin surge-attenuating factor (GnSAF). A reduced gondadotrope progesterone receptor (PR) phosphorylation/activation is likely to be the main causative factor involved in GnSAF bioactivity on LH release. Besides, GnSAF reduces LH synthesis as well as LH secretion, and it is not known whether PR is involved in the inhibitory action of GnSAF on LH synthesis.

Immunoneutralization of inhibin in cycling rats increases follicle-stimulating hormone secretion, stimulates the ovary and attenuates progesterone receptor-dependent preovulatory luteinizing hormone secretion.

Passive immunization against inhibin with an anti-inhibin serum (AIS) during the diestrous phase in cycling rats increased follicle-stimulating hormone secretion, stimulated the ovaries and reduced the magnitude of the luteinizing hormone (LH) surge in the afternoon of proestrus. The involvement of gonadotrope progesterone receptor (PR) expression/action in the inhibitory effects of the follicle-stimulating hormone-dependent putative ovarian factor gonadotropin surge-attenuating factor on preovulatory LH secretion was studied in the absence of circulating free inhibin. Proestrous pituitaries from rats injected with AIS or a non-immune serum (NIS) were studied for determination of PR-AB and PR-B mRNAs by RT-PCR and PR-B and PR-A isoform proteins by Western blot.

Activation of estrogen receptor-alpha induces gonadotroph progesterone receptor expression and action differently in young and middle-aged ovariectomized rats.

Background: We attempted to define the effect of estrogen receptor (ER)alpha activation on gonadotroph progesterone receptor (PR) expression (mRNA and protein) and action (GnRH-stimulated and GnRH self-priming) in short- and long-term ovariectomized (OVX) rats.

Methods: Two weeks or 1 year after OVX, rats were injected over 3 days with 125 microg/kg of estradiol benzoate (EB), 7.5 mg/kg of the selective ERalpha agonist propylpyrazole triol (PPT), or 15 mg/kg of the selective ER modulator tamoxifen (TX).

Ovarian stimulation with FSH in the rat reduces proestrous GnRH-dependent LH secretion through a dual mechanism: inhibition of LH synthesis and release.

Administration of human follicle-stimulating hormone (hFSH) to female rats during diestrus phase attenuates the spontaneous luteinizing hormone (LH) surge in proestrous afternoon. The inhibition of LH secretion is associated with a decreased pituitary LH content in intact, but not in ovariectomized rats injected with 25mug estradiol benzoate (EB). This suggests that the mechanism of action of the putative non-steroidal ovarian bioactive FSH-dependent gonadodotropin surge attenuating factor (GnSAF) might, in addition, involve a reduction in LH synthesis.

Ovarian stimulation with FSH reduces phosphorylation of gonadotrope progesterone receptor and LH secretion in the rat.

Administration of human FSH (hFSH) to cyclic rats during the dioestrous phase attenuates progesterone receptor (PR)-dependent events of the preovulatory LH surge in pro-oestrus. The increased bioactivity of the putative ovarian gonadotropin surge inhibiting/attenuating factor induced by hFSH treatment is not associated with a decrease in PR protein expression, and the possibility of its association at a PR posttranslational effect has been raised. The present experiments aimed to analyse PR phosphorylation status in the gonadotrope of rats with impaired LH secretion induced by in vivo hFSH injection.

Morphological effects of oestradiol-17beta, and selective oestrogen receptor alpha and beta agonists on luteinising hormone-secreting cells in tamoxifen-treated ovariectomised rats.

To investigate the role played by the different rat gonadotroph oestrogen receptor (ER) pools in the effects of oestradiol-17beta (E2) on gonadectomy cells, two-week ovariectomised (OVX) rats were used. The basic experimental group of rats was injected with 3 mg of the selective ER modulator tamoxifen (TX) on days 15-20 after OVX. Groups of TX-treated OVX rats were additionally injected on days 18-20 after OVX with 10 microg oestradiol benzoate (EB), 1 mg of the selective ERalpha agonist propylpyrazole triol (PPT), or 1 mg of the selective ERbeta diarylpropionitrile (DPN).

The ovary-mediated FSH attenuation of the LH surge in the rat involves a decreased gonadotroph progesterone receptor (PR) action but not PR expression.

Hyperstimulation of ovarian function with human FSH (hFSH) attenuates the preovulatory surge of LH. These experiments aimed at investigating the mechanism of ovarian-mediated FSH suppression of the progesterone (P(4)) receptor (PR)-dependent LH surge in the rat. Four-day cycling rats were injected with hFSH, oestradiol benzoate (EB) or vehicle during the dioestrous phase.

The integrated action of oestrogen receptor isoforms and sites with progesterone receptor in the gonadotrope modulates LH secretion: evidence from tamoxifen-treated ovariectomized rats.

The specific role of each oestrogen receptor (ER) isoform (alpha and beta ) and site (nucleus and plasma membrane) in LH release was determined in ovariectomized (OVX) rats injected over 6 days (days 15-20 after OVX) with a saturating dose (3 mg/day) of tamoxifen (TX), a selective ER modulator with nuclear ERalpha agonist actions in the absence of oestrogen. This pharmacological effect of TX was demonstrated by the fact that it was blocked by the selective ERalpha antagonist methyl-piperidinopyrazole. Over the past 3 days of the 6-day TX treatment, rats received either 25 microg/day oestradiol benzoate (EB), 1.

Oestradiol-17beta inhibits tamoxifen-induced LHRH self-priming blocking hormone-dependent and ligand-independent activation of the gonadotrope progesterone receptor in the rat.

In the rat, administration of tamoxifen (TX) in the absence of oestrogen (E) induces LHRH self-priming, the progesterone receptor (PR)-dependent property of LHRH that increases gonadotrope responsiveness to itself. The oestrogen-dependent PR can be phosphorylated/activated by progesterone (P4) and, in the absence of the cognate ligand, by intracellular LHRH signals, particularly cAMP/protein kinase A. We have recently found that oestradiol-17beta (E2), acting on a putative membrane estrogen receptor-alpha in the gonadotrope, inhibits this agonist action of TX.

A paradoxical inhibitory effect of oestradiol-17beta on GnRH self-priming in pituitaries from tamoxifen-treated rats.

Two-week ovariectomized (OVX) rats were injected over three days with 25 microg oestradiol benzoate (EB), 3 mg tamoxifen (TX) and 0.2 ml oil and their pituitaries were harvested for incubation experiments. Pituitaries from EB- and TX-treated OVX rats exhibited GnRH self-priming when incubated with their corresponding ligand.

Tamoxifen but not other selective estrogen receptor modulators antagonizes estrogen actions on luteinizing hormone secretion while inducing gonadotropin-releasing hormone self-priming in the rat.

Selective estrogen receptor modulators (SERMs) are compounds which may function as agonists or antagonists depending upon the target tissue. This study compares the actions of different SERMs on luteinizing hormone (LH) secretion, and on gonadotropin-releasing hormone (GnRH) self-priming in the rat. To do this, 4-day cyclic rats were injected twice, on day 2 (metestrus) and day 3 of the estrous cycle, with one of the following SERMs: 0.