Neuromodulatory effect of vardenafil on aluminium chloride/D-galactose induced Alzheimer's disease in rats: emphasis on amyloid-beta, p-tau, PI3K/Akt/p53 pathway, endoplasmic reticulum stress, and cellular senescence.

Dysregulation of protein homeostasis, proteostasis, is a distinctive hallmark of many neurodegenerative disorders and aging. Deleteriously, the accumulation of aberrant proteins in Alzheimer's disease (AD) is accompanied with a marked collapse in proteostasis network. The current study explored the potential therapeutic effect of vardenafil (VAR), a phosphodiesterase-5 inhibitor, in AlCl3/D-galactose (D-gal)-induced AD in rats and its possible underlying mechanisms. The impact of VAR treatment on neurobehavioral function, hippocampal tissue architecture, and the activity of the cholinergic system main enzymes were assessed utilizing VAR at doses of 0.3 mg/kg and 1 mg/kg. Additionally, the expression level of amyloid-beta and phosphorylated tau proteins in the hippocampus were figured out. Accordingly, VAR higher dose was selected to contemplate the possible underlying mechanisms. Intriguingly, VAR elevated the cyclic guanosine monophosphate level in the hippocampus and averted the repressed proteasome activity by AlCl3/D-gal; hence, VAR might alleviate the burden of toxic protein aggregates in AD. In addition, a substantial reduction in the activating transcription factor 6-mediated endoplasmic reticulum stress was demonstrated with VAR treatment. Notably, VAR counteracted the AlCl3/D-gal-induced depletion of nuclear factor erythroid 2-related factor 2 level. Moreover, the anti-senescence activity of VAR was demonstrated via its ability to restore the balance of the redox circuit. The modulation of phosphatidylinositol-3-kinase/protein kinase B/p53 pathway and the reduction of nuclear factor kappa B level, the key regulator of senescence-associated secretory phenotype mediators release, with VAR treatment were also elucidated. Altogether, these findings insinuate the possible therapeutic benefits of VAR in AD management.

Cabergoline versus calcium infusion in the prevention of ovarian hyperstimulation syndrome: a randomised controlled study.

The aim of this study was to compare the efficacy of calcium infusion versus cabergoline in the prevention of ovarian hyperstimulation syndrome (OHSS) in IVF patients at high risk for OHSS. One hundred and seventy patients who were stimulated using the long luteal GnRH agonist protocol and at high risk for developing OHSS were randomised in a 1:1 ratio to cabergoline group and calcium gluconate group. In cabergoline group, 0.5 mg of cabergoline was administered once daily p.o. for eight days starting on the day of HCG administration. In calcium gluconate group, intravenous calcium gluconate (10%, 10 ml in 200 ml of physiologic saline) was administered daily for four days starting on the day of ovum pickup. Six patients in cabergoline group and eight patients in calcium gluconate group developed moderate OHSS. One patient in each group developed severe OHSS. The incidence of moderate/severe OHSS was comparable between both groups (8.24% vs. 10.59%, p value = .599, OR = 0.76, 95% CI [0.269-2.138]). The implantation, clinical and ongoing pregnancy rates were similar in the two groups (16.91% vs. 15.84%, p = .771, 35.29% vs. 32.94%, p = .746, and 30.59% vs. 28.24%, p = .736, respectively). In conclusion, calcium infusion and cabergoline have comparable effectiveness in the prevention of OHSS. Both drugs are well tolerated, cheap and have no adverse effects on the reproductive outcomes of IVF cycle.Clinical trial registration: The trial was registered on clinical trials.gov database [NCT02875587].Impact StatementWhat is already known on this subject? The effectiveness of cabergoline in the prevention of OHSS in IVF patients at high risk for OHSS is confirmed by overwhelming scientific evidence. Calcium infusion is a novel strategy for prevention of OHSS. Few studies reported the use of calcium infusion in the prevention of OHSS. A retrospective study and a randomised controlled study revealed that calcium infusion reduces the incidence of OHSS. Moreover, a quasi-randomised study revealed that calcium infusion is as effective as cabergoline in the prevention of OHSS.What the results of this study add? Calcium infusion and cabergoline have comparable effectiveness in the prevention of OHSS. Both drugs are well tolerated, cheap and have no adverse effects on the reproductive outcomes of IVF cycle.What the implications are of these findings for clinical practice and/or further research? Calcium infusion should be used to minimise the incidence of OHSS in IVF patients at high risk for OHSS.

Effect of Prolonged GnRH Agonist Downregulation on ICSI Outcome in Patients With Endometriomas of Less Than 5 cm: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect of prolonged Gonadotropin releasing hormone (GnRH) agonist downregulation in patients with endometriomas of less than 5 cm on the outcome of the proceeding Intracytoplasmic sperm injection (ICSI) trial. METHODS: In a randomized controlled trial at a university teaching hospital, 90 patients indicated for ICSI and having unilateral single endometrioma of less than 5 cm in diameter were randomized into 2 groups. Group A (45 patients) received the standard long protocol; whereas group B (45 patients) received 3 consecutive Intramuscular (IM) injections of triptorelin 3.75 mg 28 days apart followed by the standard long protocol 28 days after the last injection. RESULTS: There were no significant differences in the clinical and hormonal characteristics between the 2 groups. All ICSI cycle characteristics including number of retrieved oocytes, fertilized oocytes, and transferred embryos were also not significantly different. However, patients who received prolonged GnRH agonist therapy showed significantly higher chemical ( P = .011), clinical ( P = .018), and ongoing ( P = .028) pregnancy rates. CONCLUSION: Prolonged GnRH agonist downregulation improves the pregnancy rates in patients with small endometriomas undergoing ICSI.

Tubal cytokine changes accompany the epithelial atypia of letrozole-stimulated ovaries.

Letrozole (LTZ), one of ovulation induction medications, is increasingly prescribed in many gynecological conditions. Although its hazardous effect on the ovarian surface epithelium (OSE) as well as tubal epithelium cells (TEC) has been previously studied, the associated changes occurring in the inflammatory cytokines have not been elucidated. Therefore, the objective of our study is to investigate these changes that may accompany LTZ-induced tubo-ovarian epithelial abnormalities. A total of 45 Sprague-Dawley rats were used in this study, divided equally into; control, LTZ6 and LTZ12 groups (received saline, 6 and 12 cycles LTZ i.p. respectively). Samples from ovaries (OVs) as well as fallopian tubes (FTs) were histologically studied for the associated changes. An increased proliferative activity, Ki67 immunoexpression and abnormal invaginations were observed in the OSE of LTZ6 group accompanied with occasional pseudostratification and loss of cilia of TEC. These changes became more pronounced in the LTZ12 where micropapillae, hyperchromasia, frequent deep invaginations, cysts of OSE as well as papillae and multilayering of TEC were noticed. The tubal level of IL-1ß, IL-6, TNF-α and serum MCP-1 progressively increased in LTZ6 and LTZ12 groups compared with the control group. The significant positive correlation observed between these cytokines in the LTZ6 group became stronger in the LTZ12 one. However, no significant changes in the tubal IL-10 and TGF-ß were detected. Therefore, further studies are required to consider these cytokines as objective markers to precisely assess severity of the associated epithelial changes particularly in long periods of stimulation.

Modulation of motor cortical excitability following rapid-rate transcranial magnetic stimulation.

OBJECTIVE: To investigate the effect of high frequency rTMS (25 Hz at 90-100% of resting motor threshold) on the excitability of the motor cortex of healthy human subjects. METHODS: Resting and active motor threshold, MEP recruitment curve (I/O curve), short interval intracortical inhibition (SICI) and facilitation (ICF), and the duration of the silent period (SP) were tested in the right first dorsal interosseous muscle (FDI) before and twice after the end of 1500 pulses in 16 normal young adult male volunteers. RESULTS: Twenty-five Hertz rTMS decreased motor thresholds, reduced the duration of the silent period and had a tendency to increase the slope of the I/O curve. Most of these effects lasted for the duration of the two post-testing sessions (at least 30 min) and had returned to normal by 2h. There were no significant effects on SICI/ICF. CONCLUSION: Twenty-five Hertz rTMS can produce a long lasting increase in cortical excitability in healthy subjects. SIGNIFICANCE: This method may prove useful for the study of normal human physiology and for therapeutic manipulation of brain plasticity.