Timing ovulation for intrauterine insemination with a GnRH antagonist

BACKGROUND: We aimed to assess the efficacy of a GnRH antagonist in intrauterine insemination (IUI) cycles to increase number of mature ovulatory follicles and pregnancy rates. METHODS: Prospective randomized study. Women (18-38 years old) with primary/secondary infertility were included. Eighty-two patients were randomly assigned to controlled ovarian stimulation (COS) consisting of rFSH + GnRH antagonist or rFSH alone. RESULTS: A non-significant increase in the total amount of rFSH was seen in the GnRH antagonist group (707+/-240 IU) with respect to the control group (657+/-194 IU). The number of mature follicles (> or =16 mm) was significantly higher in the GnRH antagonist group than in the control group (2.4+/-1.4 versus 1.7+/-1.2, P<0.05). Pregnancy rates were significantly increased in the group of patients receiving the GnRH antagonist (38%) compared to the control group (14%). The only non-single pregnancy (triplets) occurred in the antagonist group. CONCLUSIONS: In this preliminary study, adding the GnRH antagonist to the COS protocol for IUI cycles significantly increased pregnancy rates. Nevertheless, these results may not be associated directly with the antagonist itself but with the fact that more mature ovulatory follicles are present by the day of the hCG. Finally, the risk for multiple gestations needs to be carefully evaluated.     

Analysis of the role of the PAC1 receptor in neutrophil recruitment, acute-phase response, and nitric oxide production in septic shock

Infections caused by Gram-negative bacteria constitute one of the major causes of septic shock, which results from the inability of the immune system to limit bacterial spread during the ongoing infection. In the last decade, it has been demonstrated that vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two endogenous immunopeptides, which together with three G protein-coupled receptors (VPAC1, VPAC2, and PAC1) exert a significant, therapeutic effect attenuating the deleterious consequences of septic shock by balancing pro- and anti-inflammatory factors. We have recently shown PAC1 receptor involvement in vivo as an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide-induced production of proinflammatory interleukin-6. The present study deepens in the protective role of PAC1 receptor in septic shock, elucidating its involvement in the modulation of neutrophil recruitment and in the expression of different molecular sensors such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, fibrinogen, serum amyloid A, and nitric oxide as important, systemic players of the development of septic shock. Our results, using a mice deficient in PAC1 and a PAC1 antagonist, show that VIP and PACAP as well as the PAC1 receptor are involved in neutrophil recruitment in different target organs, in adhesion molecules expression, and in coagulation-related molecule fibrinogen synthesis. Thus, this study provides some important insights with respect to the involvement of PAC1 into the complexities of sepsis and represents an advantage for the design of more specific drugs complementing standard intensive care therapy in severe sepsis, confirming VIP and PACAP as candidates for multitarget therapy of septic shock.     

Evidence that orexins A and B stimulate insulin secretion from rat pancreatic islets via both receptor subtypes

Orexins are recently identified neuropeptides that appear to play a role in the regulation of energy homeostasis and arousal. They bind to and activate two closely related G protein-coupled receptors (OXR1 and OXR2), previously described as orphans. In this study we examined involvement of orexins in regulation of insulin secretion from rat pancreatic islets utilizing an in situ perfused pancreas and isolated pancreatic islet models. By means of RT-PCR we found that both OXR1 and OXR2 are expressed in rat pancreatic islets. Furthermore, the expression levels of OXR1 were higher than OXR2. In both experimental models applied, orexins A and B (1, 10 and 100 nmol/l) concentration dependently stimulated insulin secretion at two different glucose concentrations (6.66 or 26.4 mmol/l), with orexin A being more potent than orexin B. This study demonstrates that orexins A and B modulate insulin secretion in vitro.     

Functional neural stem cells derived from adult bone marrow

Pluripotent hematopoietic cells from adult bone marrow may give rise not only to neurons, oligodendrocytes and astrocytes after transplantation into newborn brains, but also to neural stem cells (NSC). These NSC localize to both the ventricular epithelium and subventricular zone, persist in the transplanted brain, and may generate neurospheres 1 month after transplant, which after in vitro expansion differentiate into the different neural lineages. Furthermore, the bone marrow-derived NSC differentiate in vivo into functional oligodendrocytes and neurons following demyelinating lesions, thus, demonstrating the ability of adult bone marrow progenitors to generate self-renewing, functional neural stem cells, validating this approach as an alternative source of long-lasting neural stem cells with therapeutic implications in neurodegenerative diseases.     

The COX-2 inhibitor, rofecoxib, ameliorates dextran sulphate sodium induced colitis in mice

Objective: We have evaluated the efficacy of the selective cyclo-oxygenase (COX)-2 inhibitor, rofecoxib, for the prevention of experimental colitis.Material and methods: To induce colitis BALB/c mice received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Rofecoxib (2.5–10 mg/kg body weight, p.o.) was administered throughout the treatment period with DSS. Colitis was quantified by a clinical damage score, colon length, weight loss, stool consistency and rectal bleeding. Inflammatory response was assessed by neutrophil infiltration, determined by histology and myeloperoxidase (MPO) activity. Interleukin (IL)-1, prostaglandin (PG)E₂ and PGD₂ levels in colon mucosa and the immunohistochemical expression of COX-1 and –2 were also studied.Results: The COX-2 inhibitor ameliorated severe colitis, reduced the degree of inflammation through reduction of neutrophil infiltration and IL-1 levels. PGE₂, and PGD₂ synthesis were significantly reduced in DSS-treated groups. Indeed, treatment with rofecoxib diminished the lost of COX-1 caused by DSS in the crypt epithelium whereas expression of COX-2 remained unaffected.Conclusions: Rofecoxib is protective in acute DSS – induced colitis, probably by reducing neutrophil infiltration, inhibiting up-regulation of IL-1 and returning to normal COX-1 expression in the inflamed colonic mucosa.Received 19 April 2004; returned for revision 17 June 2004; accepted by I. Ahnfelt-Rønne 23 November 2004     

Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS). EAE and MS are characterized by CNS inflammation, demyelination and neurodegeneration. The inflammatory response occurring within the CNS leads to glial activation, dysfunction and death, as well as axonal damage and neurological deficit. Although the pathogenic mechanisms involved in EAE/MS are not well understood, accumulating data suggest that oxidative stress plays a major role in lesion development, and contributes to axonal dysfunction and degeneration. Metallothionein-I and -II are anti-inflammatory, neuroprotective, antioxidant proteins expressed during EAE and MS, in which they might play a protective role. The present study aimed to describe the expression profile of a group of inflammatory, neurodegenerative and tissue repair markers as well as metallothioneins during proteolipid protein-induced EAE, and to establish the time-relationships these molecules had during EAE. Interestingly, we found two marker expression profiles. In the first, marker expression increased as clinical signs worsened and reverted to baseline expression during recovery; in the second, marker expression increased at a later point during relapse, peaked at highest clinical score, and remained elevated throughout recovery. Of note, metallothionein expression was found to be related to the second profile, which would suggest that metallothionein proteins are implicated in the clinical recovery of EAE and perhaps these antioxidant proteins may provide therapeutic benefits in MS.     

Effects of hormonal replacement with androgens and estrogens on male sexual behavior and plasma levels of these steroids in gonadectomized golden hamsters (Mesocricetus auratus)

Because the endocrine control of sexual behavior in male hamsters remains controversial, this study analyzed the influence of different androgens and estrogens in the regulation of masculine, sexual behavior (MBS). Aromatizable androgens: androstenedione (A) and testosterone (T), a non-aromatizable androgen: 5α-dihydrotestosterone (DHT), as well as estrogens (E₂ and E₁) alone or in combination with DHT, were administered in gonadectomized, sexually experienced males, for 3 weeks. In addition, plasma levels of these steroids were determined. Gonadectomy completely suppressed masculine sexual behavior (MSB) after 4 weeks. Both A and T replacements restored all the sexual behavior parameters in castrated hamsters by the 3rd week of treatment, with A being more potent in restoring all copulatory series and maintaining all MSB parameters, including long intromissions. Castrated males treated with DHT showed little interest in the female and did not display any copulatory behavior. Gonadectomized males treated with estrogens alone showed active anogenital investigation and displayed some mounts, but did not ejaculate. Males treated with estrogens combined with DHT had longer latencies and less number of ejaculations than males treated with aromatizable androgens. Long intromissions were observed only in males treated with T or A. Plasma levels of A were significantly higher than T levels in intact males. In males treated with A both androgens and estrogens were present in plasma. These results support the notion that aromatizable androgens, mainly A, but not non-aromatizable androgens or even estrogens in combination with DHT, play a relevant role in the endocrine regulation of MSB in the golden hamster.