Additive anticonvulsant effects of agmatine and lithium chloride on pentylenetetrazole-induced clonic seizure in mice: involvement of α₂-adrenoceptor

After 60 years, lithium is still the mainstay in the treatment of mood disorders and widely used in clinic. In addition to its mood stabilizer effects, lithium also shows some anticonvulsant properties. Similar to lithium, agmatine also plays a protective role in the CNS against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on α(2)-adrenoceptors. So, we designed this study: 1) to investigate whether agmatine and lithium show an additive effect against clonic seizures induced by pentylenetetrazole; 2) to assess whether this additive effect is mediated through the α(2)-adrenoceptor or not. In our study, acute administration of a single effective dose of lithium chloride (30 mg/kg, i.p.) increased the seizure threshold. Pre-treatment with low and, per se, non-effective doses of agmatine (1 and 3mg/kg) potentiated a sub-effective dose of lithium (10mg/kg). Interestingly, the anticonvulsant effects of these effective combinations of lithium and agmatine were prevented by pre-treatment with low and non-effective doses of yohimbine [α(2)-adrenoceptor antagonist] (0.1 and 0.5mg/kg). On the other hand, clonidine [α(2)-adrenoceptor agonist] augmented the anticonvulsant effect of a sub-effective combination of lithium (5mg/kg i.p.) and agmatine (1mg/kg) at relatively low doses (0.1 and 0.25mg/kg). In summary, our findings demonstrate that agmatine and lithium chloride exhibit additive anticonvulsant properties which seem to be mediated through α(2)-adrenoceptor.     

The Immunosuppressive Activity of Polymeric Micellar Formulation of Cyclosporine A<Emphasis Type="Italic">: In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Studies

We have previously developed micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and delivery of cyclosporine A (CsA). These micelles were able to reduce the renal uptake and nephrotoxicity of CsA. The purpose of the current study was to test the efficacy of polymeric micellar formulation of CsA (PM-CsA) in suppressing immune responses by either T cells or dendritic cells (DCs). The performance of PM-CsA was compared to that of the commercially available formulation of CsA (Sandimmune®). Our results demonstrate that PM-CsA could exert a potent immunosuppressive effect similar to that of Sandimmune® both in vitro and in vivo. Both formulations inhibited phenotypic maturation of DCs and impaired their allostimulatory capacity. Furthermore, both PM-CsA and Sandimmune® have shown similar dose-dependent inhibition of in vitro T cell proliferative responses. A similar pattern was observed in the in vivo study, where T cells isolated from both PM-CsA-treated and Sandimmune®-treated mice have shown impairment in their proliferative response and IFN-γ production at similar levels. These results highlight the potential of polymeric micelles to serve as efficient vehicles for the delivery of CsA.     

Analysis of plasminogen activator inhibitor-1, integrin beta3, beta fibrinogen, and methylenetetrahydrofolate reductase polymorphisms in Iranian women with recurrent pregnancy loss

Citation
Jeddi‐Tehrani M, Torabi R, Zarnani AH, Mohammadzadeh A, Arefi S, Zeraati H, Akhondi MM, Chamani‐Tabriz L, Idali F, Emami S, Zarei S. Analysis of plasminogen activator inhibitor‐1, integrin beta3, beta fibrinogen and methylenetetrahydrofolate reductase polymorphisms in Iranian women with recurrent pregnancy loss. Am J Reprod Immunol 2011; 66: 149–156 Problem To identify the associations of the plasminogen activator inhibitor‐1 (PAI‐1) ?675 4G/5G, beta fibrinogen (BF) ?455G/A, integrin beta 3 (ITGB3) 1565T/C, and methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C polymorphisms with recurrent pregnancy loss (RPL). Method of study Polymerase chain reaction and restriction fragment length polymorphism (PCR‐RFLP) were performed to assess the frequency of five candidate genetic risk factors for RPL, and the frequencies of the polymorphisms were calculated and compared between case and control groups. Results The BF ?455G/A, MTHFR 677C/T, and 1298A/C polymorphisms were found to be positively, and ITGB3 1565T/C polymorphism negatively, associated with RPL. Homozygosity but not heterozygosity for PAI‐1 ?675 4G/5G polymorphism was significantly higher in patients with RPL than in the control group. The presence of both mutations of MTHFR genes highly increased the risk of RPL. Conclusion The data highlight the importance of thrombophilia screening in patients with RPL.     

Etomidate use in severe sepsis and septic shock patients does not contribute to mortality

Use of etomidate in severe sepsis and septic shock has been challenged in recent literature due to its link to adrenal insufficiency and suspected increased mortality. We hypothesized that etomidate does not contribute to mortality in this patient population. A retrospective chart review of 230 intubated, severe sepsis/septic shock patients at two university tertiary care referral centers was conducted for patients receiving treatment between 12/2001 and 10/2009. The primary endpoint was in-hospital mortality. Additional investigated variables included the use of corticosteroids, hospital and intensive care unit (ICU) length of stay, mechanical ventilation days and patient demographics. One hundred seventy-three patients received etomidate and fifty-seven patients received either no medication or an alternative drug. Use of etomidate in this patient cohort did not worsen mortality. Mortality in the etomidate group was 43.9% (76/173). Mortality in the non-etomidate cohort was 45.6% (26/57) (p = 0.48). APACHE II scores were 22 ± 7.2 and 23 ± 7.1 for the etomidate group and the non-etomidate group, respectively, (p = 0.36). There was no significant difference in mortality between etomidate and non-etomidate cohorts in this study. This large retrospective multi-center study further supports the safety of etomidate use in severe sepsis and septic shock.     

Cationic polymer‐mediated small interfering RNA delivery for P‐glycoprotein down‐regulation in tumor cells

BACKGROUND:

Among the treatment options that have been developed for cancer, chemotherapy remains 1 of the leading clinical approaches. Chemotherapy can usually control tumor growth at the onset of disease, but its effectiveness becomes limited by the overexpression of transporter proteins responsible for drug efflux, leading to multidrug resistance (MDR). To overcome this obstacle, the authors explored the feasibility of down‐regulating the main drug transporter, P‐glycoprotein (P‐gp), by using nonviral small interfering RNA (siRNA) delivery as means to enhance the accumulation of chemotherapeutic agents in drug‐resistant cancer cells.

METHODS:

Several cationic carriers capable of siRNA complexation were investigated for P‐gp down‐regulation in the MDA435/LCC6 cell line and, consequently, increased cellular uptake of the chemotherapeutic agents doxorubicin and paclitaxel.

RESULTS:

Efficient siRNA delivery into tumor cells was demonstrated particularly using a palmitic‐acid substituted poly(L‐lysine), with no apparent differences in siRNA delivery between the wild type (WT)‐expressing and P‐gp‐expressing phenotype (MDR1) of the cells. Efficient siRNA delivery led to approximately 40% to 50% P‐gp suppression (based on the average expression level of the protein), an approximately 3‐fold increased DOX uptake, and increased cytotoxicity in MDR1 cells.

CONCLUSIONS:

The authors concluded that effective siRNA delivery with nonviral carriers can reduce the level of P‐gp on cell surfaces and enhance the efficiency of chemotherapeutic agents in vitro. Cancer 2010. © 2010 American Cancer Society.     

Differential expression of nucleostemin,a stem cell marker,and its variants in different types of brain tumors

Nucleostemin (NS) is implicated in the control of stem and cancer cell proliferation. In the present study, we have examined the expression of NS and its spliced variants in various brain tumors. Total RNA was extracted from 59 brain tumor samples, and the expression of different NS spliced variants was measured by semi‐quantitative RT‐PCR. The subcellular distribution of NS protein in brain tumors was further examined by immunohistochemistry. Furthermore, to decipher the potential involvement of NS in brain tumorogenesis, its expression was knocked‐down by means of RNA interference (RNAi) in two malignant glioma (U‐87MG and A172), one astrocytoma (1321N1) and one medulloblastoma (DAOY) cell lines. The alterations in cell‐cycle progression of the treated cells were then analyzed by flow cytometry. Our data revealed that NS and its variants are widely expressed in different types of brain tumors. Among the NS spliced variants, variant “1” and variant “3” were detected in the majority of tumor samples, whereas variant “2” was only detectable in few samples. Moreover, the intensity of the expression was correlated with the grade of the tumors (P < 0.05). Accordingly, the expression was much higher in glial tumors compared to that of meningiomas. As expected, a nucleolar/nucleoplasmic localization of NS protein was observed in the examined tumor samples. RNAi results revealed a significant reduction of NS expression along with a moderate blockade of the cell cycle in G₂/M and S phases of NS‐siRNA treated cells. All in all, our data suggest a potential role for NS in tumorogenesis of brain cancers. © 2010 Wiley‐Liss, Inc.     

Effects of salpingectomy during abdominal hysterectomy on ovarian reserve: a randomized controlled trial

Background

The aim of this study was to investigate the effect of salpingectomy on ovarian function by measuring AMH.

Methods

This study was a balanced, single-center, double-blind, randomized, controlled trial in Ruin Tan Arash Hospital, Tehran, between May 2013 and November 2014. A total of 30 patients undergoing elective abdominal hysterectomy were randomized into two groups, 15 with salpingectomy and 15 without salpingectomy. The primary objective of this study was to compare mean difference of anti-Mullerian hormone (AMH) between two groups. The secondary outcomes measured were follicle-stimulating hormone (FSH), operative time, and blood loss.

Results

Serum AMH levels decreased at 3 months after hysterectomy in all patients (pre AMH 1.32 ± (0.91); post AMH 1.05 ± (0.88), P < 0.001), the salpingectomy group (pre AMH 1.44 ± (0.94); post AMH 1.13 ± (0.86), P < 0.001), and no salpingectomy group (pre AMH 1.2 ± (0.9); post AMH 0.97 ± (0.92), P < 0.001). The rate of decline of AMH levels after surgery did not differ between the two groups (25% (17–33%) vs. 26% (15–36%), P = 0.23) among the women with salpingectomy versus without salpingectomy, respectively. There was no difference in the mean operative time (mean difference 0.33, 95% CI ??22.21 to 22.86, P < 0.92), mean blood loss (mean difference ??0.66, 95% CI ??15.8 to 14.46, P < 0.97), and post FSH (mean difference 0.34, 95% CI ??1.2 to 1.88, P < 0.65) between both groups.

Conclusions

Salpingectomy with abdominal hysterectomy is a safe treatment that does not have a deleterious effect on ovarian reserve.

Trial registration

Iranian Registry of Clinical Trials, IRCT2014123118866N4 (www.IRCT.ir)