Involvement of dopamine D2 -like receptors in the antiepileptogenic effects of deep brain stimulation during kindling in rats.

AIMS: Deep brain electrical stimulation (DBS), as a potential therapy for drug resistive epileptic patients, has inhibitory action on epileptogenesis. In the present investigation, the role of dopamine D2 -like receptors in the antiepileptogenic action of DBS was studied. METHODS: Seizures were induced in adult rats by stimulating the perforant path in a semi-rapid kindling method. Five minutes after the last kindling stimulation, daily DBS was applied to the perforant path at the pattern of low frequency stimulation (LFS; 1 Hz; pulse duration: 0.1 ms; intensity: 50-150 µA; 4 trains of 200 pulses at 5 min intervals). Sulpiride (10 µg/1 µl, i.c.v.), a selective dopamine D2 -like receptor antagonist, was administered prior to the daily LFS application. RESULTS: Kindling stimulations increased cumulative daily behavioral seizure stages, daily afterdischarge duration (dADD), and population spike amplitude (PS) in dentate gyrus following perforant path stimulation, while applying LFS decreased the kindled seizures' parameters. In addition, kindling potentiated the early (at 10-50 ms inter-pulse interval) and late (at 150-1000 ms inter-pulse interval) paired-pulse inhibition and decreased the paired-pulse facilitation (at 70-100 ms inter-pulse interval). These effects were also inhibited by applying LFS. All inhibitory effects of LFS on kindling procedure were prevented by sulpiride administration. CONCLUSION: These data may suggest that LFS exerts its preventive effect on kindling development, at least partly, through the receptors on which sulpiride acts which are mainly dopamine D2 -like (including D2 , D3 , and D4 ) receptors.

Determinants of Prognosis in Triple-Negative Breast Cancer: Report from a Large Breast Cancer Registry.

BACKGROUND: The outcome of patients with triple-negative breast cancer (TNBC) is highly dependent on demographic factors and ethnicity. We aimed to evaluate the clinicopathological determinants of prognosis among women with TNBC using data from one of the largest breast cancer (BC) registries. METHODS: A total of 6145 patients with BC from our referral center were evaluated from 1995 to 2018, among whom 523 had TNBC. The baseline, menstrual and reproductive, treatment and pathology related characteristics were evaluated. RESULTS: Among TNBC patients, the rate of stage 3 and 4 BC (29.9% vs. 14.4% and 7.8% vs. 0% for stage 3 and 4, respectively; P<0.001), invasive ductal carcinoma (90.7% vs. 75.6%; P=0.004), nodal involvement (46.7% vs. 33.4%; P=0.026), mastectomy (57.3% vs. 37.8%; P=0.001) and axillary node dissection (76.7% vs. 59.8%; P=0.019) was significantly higher in the group that developed recurrence. Disease-free-survival was 80.6% (157.76 ± 9.48 months) and overall-survival was 90.1% (182.73 ± 3.28 months). For death, stage 3 BC (compared to stages 0 and 1 as base) showed a higher risk of earlier death (adjusted HR: 4.191, 95% CI=1.392-12.621; P=0.011). For recurrence, stage 3 BC (adjusted HR: 1.044, 95% CI=1.209-6.673; P=0.017) (compared to stages 0 and 1 as base) showed significantly higher risk for developing earlier recurrence. Moreover, those who had invasive ductal carcinoma (compared to other types of BCs) had a higher risk for developing earlier recurrence (adjusted HR: 3.307, 95% CI=1.191-0.724; P=0.012). CONCLUSION: BC stage plays a significant role in both earlier recurrence and earlier mortality among patients with TNBC.

Occupational eye dose to medical staff in various interventional cardiologic procedures: is the need for lead goggles the same in all groups of radiation workers?

Considering the increased use of interventional cardiologic procedures and concern about irradiation to the eyes, it is necessary to measure eye dose in radiation workers. The assessment of eye dose using collar dose is a routine but inaccurate method. Therefore this study was designed to measure eye dose in the radiation workers of various interventional cardiologic procedures. In this study eye dose was measured for left and right eyes in three groups of radiation workers in angiography ward of Afshar hospital in various procedures using TLD. Measurements were done separately for cardiologists, nurses and radio-technologists in 100 procedures. The nurses functioned as surgical assistants and were usually close to the table. The correlation of staff dose to exposure parameters was also investigated. Eye dose in physicians were higher than other staff in all procedures. Also the left eye dose was considerably higher than right one, especially for physicians. The median equivalent dose per procedure of left eye for physicians, nurses and radio-technologists were 7.4, 3.6, 1.4 µSv (PCI) and 3.2, 3.1, 1.3 µSv (Adhoc) and 3.2, 1.7, 1.1 µSv (CA), respectively. The annual left eye equivalent dose with (without) using lead goggles were 2.4 (15.3), 1.4 (2.2), 1.0 (1.1) mSv for physicians, nurses and radio-technologists, respectively. There were also a positive correlation between eye dose and KAP for procedures without lead goggles. The lead goggles showed lower protection effects for radio-technologists than other staff. Only 30% of physicians received a dose higher than 1/3 of the ICRP annual dose limit, therefor only physician eye dose should be monitored in catheterization labs.

Deep brain stimulation restores the glutamatergic and GABAergic synaptic transmission and plasticity to normal levels in kindled rats.

BACKGROUND: The precise effect of low frequency stimulation (LFS) as a newly postulated, anticonvulsant therapeutic approach on seizure-induced changes in synaptic transmission has not been completely determined. HYPOTHESIS: In this study, the LFS effect on impaired, synaptic plasticity in kindled rats was investigated. METHODS: Hippocampal kindled rats received LFS (4 trials consisting of one train of 200 monophasic square waves, 0.1 ms pulse duration, 1 Hz) on four occasions. LTP induction was evaluated using whole-cell recordings of evoked excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs respectively) in CA1 neurons in hippocampal slices. In addition, the hippocampal excitatory and inhibitory post-synaptic currents (EPSCs and IPSCs), and the gene expression of NR2A, GluR2 and γ2 were evaluated. RESULTS: LTP induction was attenuated in excitatory and inhibitory synapses in hippocampal slices of kindled rats. When LFS was applied in kindled animals, LTP was induced in EPSPs and IPSPs. Moreover, LFS increased and decreased the threshold intensities of EPSCs and IPSCs respectively. In kindled animals, NR2A gene expression increased, while γ2 gene expression decreased. GluR2 gene expression did not significantly change. Applying LFS in kindled animals mitigated these changes: No significant differences were observed in NR2A, γ2 and GluR2 gene expression in the kindled+LFS and control groups. CONCLUSION: The application of LFS in kindled animals restored LTP induction in both EPSPs and IPSPs, and returned the threshold intensity for induction of EPSCs, IPSCs and gene expression to similar levels as controls.

Effect of low frequency stimulation on impaired spontaneous alternation behavior of kindled rats in Y-maze test.

Epileptic seizures are characterized with cognitive disorders. In this study we investigated the effect of electrical low frequency stimulation (LFS), as a potential anticonvulsant agent, on kindled seizure-induced cognitive impairments. Animals were kindled through electrical stimulation of hippocampal CA1 area in a semi-rapid manner (12 stimulations/day). One group of animals received LFS 4 times at 0.5, 6.5, 24 and 30h following the last kindling stimulation. Applied LFS was consisted of 4 packages at 5min intervals. Each package contained 200 monophasic square wave pulses of 0.1ms duration at 1Hz. The Y-maze test was performed in all animals to measure the spontaneous alternation behavior. Kindled animals showed significant impairment in spontaneous alternation behavior compared to the control group. Application of LFS improved the observed impairment in spontaneous alternation behavior in kindled animals, so that there was no significant difference between kindled+LFS and control group. The observed improving effect of LFS was accompanied with a significant increase in calcineurin gene expression within the hippocampal area. Therefore, it may be postulated that application of LFS in kindled animals, which resulted in increment of calcineurin gene expression, can improve the seizure-induced impairment in spontaneous alternation behavior in Y-maze test.

Low-frequency electrical stimulation enhances the effectiveness of phenobarbital on GABAergic currents in hippocampal slices of kindled rats.

Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABAA receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital+LFS was investigated on GABAA-mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100µM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo. Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABAA currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital.

Combined sub-threshold dosages of phenobarbital and low-frequency stimulation effectively reduce seizures in amygdala-kindled rats.

Low-frequency stimulation (LFS) is a potential therapy utilized in patients who do not achieve satisfactory control of seizures with pharmacological treatments. Here, we investigated the interaction between anticonvulsant effects of LFS and phenobarbital (a commonly used medicine) on amygdala-kindled seizures in rats. Animals were kindled by electrical stimulation of basolateral amygdala in a rapid manner (12 stimulations/day). Fully kindled animals randomly received one of the three treatment choices: phenobarbital (1, 2, 3, 4 and 8 mg/kg; i.p.; 30 min before kindling stimulation), LFS (one or 4 packages contained 100 or 200 monophasic square wave pulses, 0.1-ms pulse duration at 1 Hz, immediately before kindling stimulation) or a combination of both (phenobarbital at 3 mg/kg and LFS). Phenobarbital alone at the doses of 1, 2 and 3 mg/kg had no significant effect on the main seizure parameters. LFS application always produced anticonvulsant effects unless applied with the pattern of one package of 100 pulses, which is considered as non-effective. All the seizure parameters were significantly reduced when phenobarbital (3 mg/kg) was administered prior to the application of the non-effective pattern of LFS. Phenobarbital (3 mg/kg) also increased the anticonvulsant actions of the effective LFS pattern. Our results provide an evidence of a positive cumulative anticonvulsant effect of LFS and phenobarbital, suggesting a potential combination therapy at sub-threshold dosages of phenobarbital and LFS to achieve a satisfactory clinical effect.

The effect of hydroalcoholic extract of Stachys lavandulifolia vahl on pregnant mice.

OBJECTIVES: Stachys lavandulifolia is commonly used for many health problems including anxiety. A couple of reports indicate that this plant might have an abortifacient effect on pregnant women. Here we examined this effect on pregnant mice. MATERIALS AND METHODS: Incremental doses of 0, 50, 100, 150 and 200 mg/kg of the extracts or normal saline (control group) were injected intraperitoneally to the pregnant mice between 7(th) to 12(th) days of pregnancy. On day 16, uterine tubes were resected and absorbed fetuses were counted. RESULTS: Our study showed that the different average of absorbed fetuses between treated and control groups is significant (P < 0.05). S. lavandulifolia changes the activity level of hypothalamus-pituitary gland-gonad axis due to flavonoid compounds. Also, S. lavandulifolia decreases progesterone concentration resulting in a significant difference between treated and control groups (P < 0.05) and gives rise to failure in fetus survival and consequently, abortion. The length and weight of fetuses decreased in treated groups and there was a significant difference between treated and control groups (P < 0.05). CONCLUSION: Owing to the possible abortive effect of Stachys lavandulifolia, it is highly recommended to use it cautiously during pregnancy.