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sábado, 28 de julio de 2012

Disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis

Progesterone (P) is an endogenous anticonvulsant hormone. P is being evaluated as a treatment for epilepsy, traumatic brain injury, and other complex neurological conditions.

Preclinical and clinical studies suggest that P appears to interrupt epileptogenic events.

However, the potential disease-modifying effect of P in epileptogenic models is not widely investigated.

In this study, we examined the effects of P on the development of hippocampus kindling in female mice.

In addition, we determined the role of progesterone receptors (PR) in the P’s effect on the kindling epileptogenesis utilizing PR knockout (PRKO) mice. P, at 25 mg/kg, did not affect seizures and did not exert sedative/motor effects in fully-kindled mice. P treatment (25 mg/kg, twice daily for 2 weeks) significantly suppressed the rate of development of behavioral kindled seizure activity evoked by daily hippocampus stimulation in wild-type (WT) mice, indicating a disease-modifying effect of P on limbic epileptogenesis.

There was a significant increase in the rate of ‘rebound or withdrawal’ kindling during drug-free stimulation sessions following abrupt discontinuation of P treatment.

A washout period after termination of P treatment prevented such acceleration in kindling.

PRKO mice were kindled significantly slower than WT mice, indicating a modulatory role of PRs in seizure susceptibility.

P’s effects on early kindling progression was partially decreased in PRKO mice, but the overall (~2-fold) delay in the rate of kindling for the induction of stage 5 seizures was unchanged in PRKO mice. Moreover, the acute anticonvulsant effect of P was undiminished in fully-kindled PRKO mice.

These studies suggest that P exerts disease-modifying effects in the hippocampus kindling model at doses that do not significantly affect seizure expression and motor performance, and the kindling-retarding effects of P may occur partly through a complex PR-dependent and PR-independent mechanism.
Keywords: Progesterone, epileptogenesis, kindling, disease-modifying, neurosteroid, progesterone receptor, seizure

1. Introduction

Epilepsy is a chronic condition characterized by recurrent unprovoked seizures. Epilepsy affects about 3 million people in the United States, including 1 million women that are of childbearing age (Engel et al., 2007). Antiepileptic drugs (AEDs) are the mainstay for the treatment of epilepsy. Despite the availability of over two dozen AEDs, about one-third of people with epilepsy show seizures that are not controlled to even the best available treatment. Many people with epilepsy need long-term drug therapy that is often associated with debilitating side effects and drug interactions. Presently, there is no specific drug for curing epilepsy (Jacobs et al., 2009). The mechanisms underlying development of epilepsy are not very well understood. The term ‘epileptogenesis’ is used to describe the complex plastic changes in the brain that, following a precipitating insult or injury, convert a normal brain into a brain debilitated by recurrent seizures (Pitkänen et al., 2009). There is a desperate need for drugs that truly prevent the development of epilepsy (‘antiepileptogenic agents’) or alter its natural course to delay the appearance or severity of epileptic seizures (‘disease-modifying agents’). A number of clinical trials show a lack of antiepileptogenic efficacy of AEDs, including phenytoin and carbamazepine, in patients at high risk for developing epilepsy (Temkin, 2001).
The kindling model of epileptogenesis has provided a conceptual framework for developing prophylactic treatment to prevent the onset of epilepsy or stop its progression (Goddard et al., 1969; McNamara et al., 1992). Kindling is the most widely used model to screen for drugs with disease-modifying efficacy (Löscher, 2002), although it is difficult to find a human correlate of this process because kindling does not lead to epilepsy. However, the lack of antiepileptogenic efficacy of phenytoin and carbamazepine in patients is highly consistent with studies in the kindling model (Wada et al., 1978; Albertson et al., 1984; Silver et al., 1991). Previous studies have shown that only a few drugs, including valproate, exert true antiepileptogenic or disease-modifying effects in the kindling model in that kindling acquisition is significantly retarded after termination of drug treatment (Silver et al., 1991; McNamara et al., 1992). Several newer AEDs such as topiramate, lamotrigine, and lacosamide have been evaluated for disease-modifying activity, but these AEDs had limited or weak efficacy (Walker et al., 2002; Nissinen et al., 2004). Despite levetiracetam’s robust efficacy on the kindling epileptogenesis (Löscher et al., 1998), it did not produce either antiepileptogenic or disease-modifying effects in a post-status epilepticus (SE) model of epilepsy (Brandt et al., 2007). These studies lead to the conclusion that the conventional AEDs do not exert a true antiepileptogenic effect. The mechanisms involved in epileptogenesis after injury involve an interaction of acute and delayed anatomic, molecular, and physiological events that are both complex and multifaceted (Walker et al., 2002). Hence, pharmacotherapies should be targeted at the multiple factors that contribute to the epileptogenic cascade, to maximize the likelihood of a successful prevention.
Progesterone (P) is an appealing hormone for prophylactic interventions on epilepsy development, due to its multifunctional modulatory actions in the brain. P is an endogenous anticonvulsant hormone. P has long been known to have antiseizure activity in animal models (Selye 1942; Craig, 1966; Kokate et al., 1999; Frye and Scalise, 2000; Reddy et al., 2004), and in clinical studies (Bäckström et al., 1984; Herzog, 1995; 1999). Therefore, women with epilepsy are prone to seizures in response to decreased levels of P during perimenstrual periods (Herzog et al., 1997; Reddy, 2009). Presently P is being evaluated in an NIH-sponsored, multicenter clinical trial as a treatment for epilepsy in women (Herzog et al., 2008). Indeed, the incidence of epilepsy is generally lower in women than in men (Hauser et al., 1993; Christensen et al., 2005; McHugh and Delanty, 2008). This gender difference could be caused by ovarian hormones such as P. Although P is known to inhibit stimulation-evoked seizures in kindling models (Holmes and Weber, 1984; Mohammad et al., 1998; Lonsdale et al., 2006), P has not been investigated widely for its potential disease-modifying effect in epileptogenic models. In the amygdala kindling model, P has been shown to impair epileptogenesis in male rats (Holmes and Weber, 1984; Edwards et al., 2001).
Previous studies have shown that P supports the normal development of neurons, and that it reduces the extent of brain damage after traumatic brain injury (TBI) (Roof et al., 1994; Cutler et al., 2005; 2007). It has been observed in animal models that females have reduced susceptibility to TBI and this protective effect has been hypothesized to be caused by increased circulating levels of P in females (Roof and Hall, 2000; Meffre et al., 2007). A number of additional studies have confirmed that P has neuroprotective effects (Gibson et al., 2008). Promising results have also been reported in human clinical trials. Recently, two clinical studies have evaluated P as a treatment for moderate to severe TBI (Wright et al., 2007; Xiao et al., 2008). P is highly efficacious in reducing disability and death in TBI. P has neuroprotective properties in acute models of ischemic injury, stroke, and astroglial dysfunction (Koenig et al., 1995; Jiang et al., 1996; He et al., 2004).
P targets multiple molecular and cellular mechanisms relevant to epileptogenesis, and therefore, P may be a natural disease-modifying agent. P’s cellular actions are mediated by the progesterone receptors (PRs), which are expressed in the hypothalamus, neocortex, hippocampus and limbic areas (Brinton et al., 2008). P is an intermediate precursor for the synthesis of neurosteroids (Reddy, 2009). P’s antiseizure activity is mediated mainly by its conversion to allopregnanolone, a neurosteroid and positive modulator of GABA-A receptors with broad-spectrum antiseizure properties (Belelli et al., 1989; Kokate et al., 1999; Frye et al., 2002; Kaminski et al., 2004; Reddy et al., 2004). Neurosteroids have unique binding sites on GABA-A receptors (Gee et al., 1995; Hosie et al., 2006). They modulate both synaptic and extrasynaptic GABA-A receptors and their modulatory action is highly sensitive at δ-subunit-containing extrasynaptic GABA-A receptors (Herd et al., 2007). Moreover, neurosteroids can modulate PRs via intracellular metabolism to analogs that bind to PRs (Rupprecht et al., 1993). P may modulate signaling cascades of inflammation, apoptosis, neurogenesis and synaptic plasticity (Patel, 2004; Vezzani, 2005; Stein and Sayeed, 2010), and therefore, P may exert disease-modifying effects on epileptogenesis.
In this study, we investigated the disease-modifying effects of P on hippocampus kindling epileptogenesis in female mice. In addition, we sought to determine the role of the PR in P’s effect on kindling development using PR knockout (PRKO) mice. Our results indicate that P has disease-modifying effects that may occur through a complex mechanism.

2. Materials and Methods

2.1. Animals

Adult female mice (3–5 months old) weighing approximately 25–30 g were used in the study. The generation of PR WT (+/+) and PRKO (−/−) mice by a PR null mutation has been described previously (Lydon et al., 1995; Reddy et al., 2004). PRKO mice lack both the PR-A and PR-B isoforms that are transcribed by the PR gene. These mice were maintained in a hybrid C57BL6/129SV background. Animals were housed separately, four to a cage and were fed mouse chow and water ad libitum. Genotype was confirmed by PCR using mouse tail genomic DNA (Reddy et al., 2005). Animals were not checked for ovarian cycle stages due to chronic experimental (kindling) protocol that lasted longer than the 5-day cycle. However, changes in seizure susceptibility are not evident among phases of the estrous cycle in kindled animals (Wahnschaffe and Löscher, 1992). All procedures were performed in strict compliance with the NIH Guide for the Care and Use of Laboratory Animals, under a protocol approved by the Institutional Animal Care and Use Committee.

2.2. Hippocampus kindling

The kindling epileptogenesis was induced by daily hippocampus stimulations (Rogawski et al., 2001; Reddy et al., 2004). Mice were anesthetized by intraperitoneal injections of ketamine (100 mg/kg) and xylazine (20 mg/kg), and a stimulation-recording bipolar electrode (Plastic-One, Inc.) was stereotaxically implanted in the right ventral hippocampus (2.9 mm posterior, 3.0 mm lateral, and 3.0 mm below dura) and anchored with dental acrylic to three screws. After a postoperative recovery period of at least 1 week, the electrographic afterdischarge (AD) threshold was determined by application of a 1s train of 1 ms biphasic rectangular pulses at 60 Hz beginning at 25 µA. Additional stimulations increasing by 25 µA were given at 5 min intervals until an electrographic AD lasting at least 5 s was detected using the digital EEG system (Astro-Med, West Warwick, RI). Kindling stimulations (1-ms pulses, 60 Hz frequency, 1s duration) were applied following standard protocol, consisting of a once-daily stimulation at 125% of AD threshold using an isolated pulse stimulator (A-M Systems). Stimulations were delivered daily until stage 5 seizures were elicited on three consecutive days. The AD duration was acquired from the hippocampal electrode using Axoscope 8.0 software (Axon Instruments). Behavioral seizures were rated according to the Racine’s scale (1972), as modified for the mouse: stage 0, no response or behavior arrest; stage 1, chewing or head nodding; stage 2, chewing and head nodding (wet dog shakes); stage 3, forelimb clonus; stage 4, bilateral forelimb clonus and rearing; stage 5, falling.

2.3. Drug treatment and kindling studies

The overall experimental protocol for drug treatment and kindling stimulations is illustrated in Fig.1. In the kindling development study (protocol #1), P (25 mg/kg) was injected subcutaneously, 30-min prior to stimulation sessions each morning, on days 1 to 14. Animals received a second dose in the evening. [P has a very short half-life, <0.5 h, therefore, multiple doses are needed to maintain adequate plasma levels]. Stimulations were applied daily during P treatment and during the P-free (withdrawal) period. This treatment design has been utilized for testing drugs against kindling development (Dürmüller et al., 1994; Rogawski et al., 2001). In the second study (protocol #2), animals received P treatment (25 mg/kg, s.c., twice daily) for 14 days, followed by a 1-week washout period. Animals were stimulated during P treatment and again after the washout period. Stock solutions of P (Steraloids, Inc.) for injection were made in 15% β-cyclodextrin solution, and additional dilutions were made using normal saline. Control animals received vehicle injections. β-Cyclodextrin alone, at concentrations as high as 50%, failed to affect kindled seizures. Stimulation was continued on a daily basis, seven days per week during drug-treatment sessions and drug-free sessions. Kindling stimulation was continued until stage 5 seizures were elicited on three consecutive days. In a separate group of WT and PRKO mice, kindling stimulation was delivered daily (five days per week) without drug treatment until stage 5 seizures elicited on three consecutive days. These mice were used for drug testing when they consistently exhibited stage 5 seizures with stimulation, which is considered the “fully kindled” state. To examine the ability of P to suppress the expression of kindled seizures, the kindled mice underwent a 3-day test protocol. On day 1, they were verified to exhibit stage 5 seizures. On day 2, a subcutaneous P injection was administered 30 min prior to stimulation. On day 3, the animals were stimulated again without P pretreatment. During each test session, the behavioral seizure score and the afterdischarge duration were recorded as indices of drug efficacy.
Fig. 1

Fig. 1

Study design

2.4. Sedation/motor impairment test

Evaluation for sedation/motor impairment was carried out using an inverted screen test that determines an animal’s ability to support its own body weight by grasping a grid (Coughenour et al., 1977). Thirty minutes after the P injection, mice were placed on a horizontally oriented grid (consisting of parallel 1.5-mm-diameter rods situated 1 cm apart), and the grid was inverted. Animals that fell from the grid within 10 s were scored as positive for sedation/motor impairment. Vehicle-treated mice never fell from the grid within 10 s.

2.5. Estimation of P and allopregnanolone levels

Mice were anesthetized with isoflurane, and 0.5 ml carotid blood was collected in heparinized tubes. The plasma was separated by centrifugation at 12,000g for 10 min and stored at −20°C. The concentration of allopregnanolone was quantified by liquid chromatography-mass spectrometry as described previously (Reddy et al., 2004). Briefly, a 200 µl plasma sample was added to a tube containing evaporated internal standard. The steroid and internal standard were extracted with 4 ml of hexane. Each sample was analyzed using the atmospheric pressure chemical ionization technique under acidic conditions. Plasma concentrations of P were analyzed by an immunoassay (Antech GLP). The detection limit of the assay was <0.2 ng/ml.

2.6. Data analysis

Group data was expressed as the mean ± standard error of the mean (SEM); differences in seizure stages between groups were compared with the nonparametric Kruskal-Wallis test followed by the Mann-Whitney U-test. Comparison of means of the afterdischarge duration between groups was made with one-way analysis of variance, followed by the unpaired two-tailed Student’s t-test. Comparison of the mean percentage inhibition of seizure stage and afterdischarge duration in fully kindled animals was made by the Wilcoxon signed ranks test and the paired two-tailed Student’s t-test, respectively. In all statistical tests, the criterion for statistical significance was p<0.05.

3. Results

3.1. Effect of P on seizure expression and motor performance

To determine the optimum dose of P for testing against hippocampus kindling development, the activity of P in suppressing against kindled seizures was evaluated in fully-kindled WT mice. As shown in Fig.2, P suppressed the expression of behavioral seizures and reduced the AD duration at high dose (100 mg/kg) but did not significantly affect seizure activity at low doses (25 mg/kg). Impairment in motor performance, assessed as time on an inverted screen bar, occurred in mice receiving 100 mg/kg of P but not at 25 mg/kg (Fig.2C), which was selected for kindling development studies.
Fig. 2

Fig. 2

Effect of P on behavioral seizures (A), afterdischarge duration (B), and motor activity in fully-kindled WT mice

3.2. Effect of P on hippocampus kindling development in WT mice

The development of hippocampus-kindled seizures in control mice, and in mice that had received P (25 mg/kg) treatment from day 1 to 14 is shown in Fig.3. There was no significant group difference in initial AD threshold (control: 85 ± 10 µA; P-treatment: 84 ± 20 µA). In control WT mice, there was a progressive increase in behavioral seizure intensity with all animals achieving stage 5 after 13 stimulations (Fig.3A). The electrographic AD duration did not vary significantly during the initial stimulation sessions but continued stimulation was associated with an increase in AD duration in control animals (Fig.3B). In WT animals, P produced a marked retardation of development of kindling epileptogenesis, as evident by significant suppression of behavioral seizures in comparison to controls at the corresponding stimulation sessions (Fig.3A). However, P did not significantly affect the mean AD duration (Fig.3B). Table 1 presents the mean number of stimulations to achieve various seizure stages. The P-treatment group showed marked suppression of the development of partial (stage 2 and 3) and generalized (stage 4 and 5) seizures (Table 1). The rate of kindling, measured by the number of stimulations required to elicit stage 5 seizures, was significantly inhibited in mice treated with P compared to controls (Fig.4), indicating disease-modifying effect of P on the limbic epileptogenesis.
Fig. 3

Fig. 3

Inhibition of hippocampus kindling epileptogenesis in WT and PRKO mice by P
Table 1

Table 1

Mean number of stimulations to achieve kindling stages.

Rate of kindling epileptogenesis in control and P-treated WT and PRKO mice

3.3. Comparison of the rate of kindling progression during P treatment and discontinuation

To compare the progression of kindling in the P-treatment period (from day 1 to 14) with that in the subsequent P-free period (from day 14 to stage 5), the rate of kindling in the two phases was determined in WT mice (Fig.1, protocol #1). As shown in Fig.5A, there was no significant difference in the rate of kindling in two phases in control animals. However, there was a significant decrease in the rate of behavioral kindling progression during the P-treatment period (disease-modifying effect) and a significant increase in rate during drug-free stimulation sessions following abrupt discontinuation of P-treatment period (rebound or withdrawal effect) (Fig.5A). These results suggest that P inhibition of kindling development is associated with a substantial rebound or withdrawal in the apparent rate of kindling when the P is discontinued abruptly.

Comparison of the rate of kindling development during P-treatment and P-free periods in WT and PRKO mice

3.4. Comparison of rate of kindling progression during P treatment and washout period

To compare the progression of kindling in the P-treatment period (from day 1 to 14) with that in the subsequent period after a 1-week washout, the rate of kindling in the two phases was determined in WT mice (Fig.1, protocol #2). As shown in Fig.6, there was a significant decrease in the rate of kindling progression during the P treatment period. Following the washout period, the rate of kindling did not differ significantly between the P-treated and control groups. The washout period prevented the acceleration of the kindling rate that was observed in animals following the abrupt withdrawal of P (Fig.5A), indicating that P withdrawal may have counteracted the disease-modifying effect of P treatment.

Comparison of the rate of kindling development during P-treatment and following a one week washout period in WT mice

3.5. Effect of P on hippocampus kindling development in PRKO mice

To determine the role of PRs in P’s activity against kindling epileptogenesis, we utilized the PRKO mice that lack both the PR-A and PR-B subtypes in the brain. We first compared the progression of kindling in PRKO mice with WT mice (Table 1, Fig.3). PRKO mice showed slower kindling development as revealed by reduced behavioral seizure stages and shorter AD duration than WT controls at corresponding stimulation sessions (Fig.3CD). The rate of kindling for induction of stage 5 seizures was significantly (p<0.05) delayed in PRKO mice compared to WT mice (Fig.4), indicating a modulatory role of PRs in seizure susceptibility.
In PRKO mice, P (25 mg/kg, twice daily for 2 weeks) treatment did not affect the behavioral seizures (Fig.3C) and AD duration (Fig.3D) during early kindling progression, but there was significant retardation of behavioral seizure progression at the later period. The PRKO mice that received P showed marked suppression of the development of generalized (stage 4 and 5) seizures (Table 1). P significantly (~2-fold) inhibited the overall rate of kindling for induction of the fully kindled state (third stage 5 seizures) in PRKO mice (Fig.4), which was comparable to its effect in WT mice. No significant group differences in initial AD threshold were observed in PRKO mice (control: 90 ± 14 µA; P-treatment: 71 ± 12 µA). In contrast to WT mice, there was no evidence of rebound increase in kindling rate in PRKO mice following discontinuation of P treatment (Fig.5B). Thus, these results indicate that the disease-modifying effect of P may occur partly through PR-dependent and PR-independent mechanisms.

3.6. Plasma levels of P during chronic treatment

To determine the pharmacokinetic factors in P’s effects on the kindling development, we determined the plasma levels of P in control and 7-day chronically P treated mice. Plasma levels of P were determined 30 min after the administration of P (25 mg/kg, s.c.) in WT and PRKO mice. Plasma P levels were similar in control WT and PRKO mice (Fig.7). There were no significant differences in the mean P levels achieved between WT and PRKO mice during chronic P treatment (Fig.7). These results suggest that any lasting effects of P on kindling after chronic administration in WT mice were not due to its accumulation.

Plasma P levels in control mice and that had been chronically treated with P (25 mg/kg, s.c., twice daily) for 7 days

3.7. Effect of P on seizure expression in fully-kindled PRKO mice

In fully-kindled PRKO mice showing stage 5 seizures, P (50 and 100 mg/kg) produced a dose-dependent inhibition of behavioral seizures and electrographic AD durations (Fig.8B). The P-induced inhibition of behavioral seizure activity was greater in PRKO mice as compared to their WT controls (Fig.8A). In PRKO mice, finasteride (100 mg/kg, ip) treatment, given 1 h prior to P (100 mg/kg) injections, significantly reduced plasma allopregnanolone levels (P alone: 854 ± 47 ng/ml; P+finasteride: 386 ± 55 ng/ml), and reversed the P’s suppression of behavioral seizure stage (P alone: 0.5 ± 0.22; P+finasteride: 4.6 ± 0.4) and AD duration (P alone: 16 ± 1.4 s; P+finasteride: 26 ± 2.5 s). Thus, these results confirm that the acute anticonvulsant activity of P mainly occur through PR-independent mechanisms, most likely via P’s conversion to the neurosteroid allopregnanolone.
Fig. 8

Fig. 8

Inhibition of fully kindled seizures and afterdischarge duration by P in WT (A) and PRKO mice (B)

4. Discussion

The present study shows that P can retard or suppress kindling epileptogenesis in female mice. The key observations of this study are: (i) Treatment with P, at dosages that do not have anticonvulsant efficacy and that do not shorten the afterdischarge, significantly delays the development of hippocampus kindling epileptogenesis; (ii) Abrupt withdrawal of P accelerates the kindling rate that may counteract the disease-modifying effect of P treatment; (iii) PRKO mice show slower kindling development than WT mice; and (iv) The kindling-retarding effect of P is partially decreased in PRKO mice. Collectively, these studies suggest that P has disease-modifying effects that could delay or limit the severity of limbic epileptogenesis. However, there are certain caveats that must be considered in regards to the interpretation of these findings. First, the results apply only to the kindling model used in this study. Second, this study supports the disease-modifying potential of P to the extent that kindling development represents a model of limbic epileptogenesis. However, the relationship of this model to human epilepsy is not well validated. Third, the relevance of the dosages of P that were used in this study in relation to those required for prophylactic treatment is uncertain. Nevertheless, our findings are consistent with previous reports on the effect of P on epileptogenesis (Edwards et al., 2001) and kindled seizures (Mohammad et al., 1998; Lonsdale and Burnham, 2003).

P exerts disease-modifying effect on kindling

In the present study, we investigated the development of hippocampus kindling during P treatment and P-free period or 1-week after washout following the termination of P treatment (Fig.1). Treatment with P, at a dose that does not affect seizure expression and does not exert sedative/motor performance, significantly inhibited the development of hippocampus kindling epileptogenesis. P’s retardation of behavioral manifestations of kindled seizures without affecting electrographic AD duration is consistent with the possibility that P inhibits the generalization of the seizure discharge from the hippocampus focus, and thereby modulates progression of epileptogenesis. This data confirms previous observations of Holmes and Weber (1984) and Edwards et al. (2001) who have reported that P significantly delays amygdala kindling in rats. Although our results are consistent with these and other earlier reports (Edwards et al., 1999), there are major differences on several aspects of the study. We utilized the mouse hippocampus kindling paradigm and tested the low dose P that did not affect seizure expression and AD activity, whereas previous studies have utilized gonadectomized male rats (Edwards et al., 2001) or immature male rats (Holmes and Weber, 1984). Although limbic seizures may affect hormones (Edwards et al., 1999), the kindling attenuating effect of P is not entirely dependent on the endocrine milieu (Holmes et al., 1984). Moreover, plasma P levels are similar between genotypes during a chronic treatment period, demonstrating that pharmacokinetic factors such as drug accumulation cannot account for the P’s protective activity in WT mice. These findings may have translational relevance to interrupt epileptogenesis in patients at risk for developing epilepsy, especially in people with stroke, TBI, brain infection, status epilepticus and related injury-induced triggering factors (Pitkänen et al, 2009; Stein and Sayeed, 2010).
There are general limitations in our studies, especially issues on the relevance of the kindling model. Kindling and post-SE models are the most commonly used for studies of epileptogenesis and for testing antiepileptogenic and neuroprotective agents (Löscher, 2002, Pitkanen, 2002). Kindling is a widely used model to test the efficacy of drugs that suppress the development of epileptogenesis (McNamara et al., 1992). Several studies have suggested that drugs that inhibit the development of kindling may have disease-modifying properties in humans. However, there is no strong evidence on the validity of the kindling model for testing antiepileptogenic agents, because traditional kindling does not lead to epilepsy (only after >50–100 stimulations, ~50% of animals develop spontaneous seizures). The conventional AEDs do not exert a true disease-modifying effect, except valproate and levetiracetam that retard kindling during the treatment period and following drug withdrawal (Silver et al., 1991; Löscher et al., 1998). Despite promising effects in the kindling model, levetiracetam failed to exhibit antiepileptogenic action in post-SE model of epileptogenesis (Brandt et al., 2007). Although post-SE models with a latent period could possibly be more relevant to human epilepsy, they are more labor intensive and are not highly suitable for extensive screening of potential antiepileptogenic agents. Despite concerns on validity and generalization to other models, kindling is a very useful model for rapid identification of disease-modifying drugs.

Abrupt withdrawal of P accelerates kindling

Our results indicate that the stage of kindling achieved during P-treatment and after the termination of P treatment in WT mice is significantly below that of the control level obtained with a corresponding number of stimulations. Thus, there is strong retardation of kindling with P treatment. However, experimental agents that inhibit the development of kindling epileptogenesis may accelerate the rate of kindling development when the treatment was terminated abruptly (Rogawski et al., 2001). Kindling rebound may occur during drug-free period or drug effects on kindling development attenuate over time; this would imply that the irreversible processes of kindling development continue during the drug-treatment period, but that drug treatment prevents the behavioral manifestations. This is highly unlikely in case of P effects on epileptogenesis because of low doses that did not affect behavioral seizure expression. However, our results clearly demonstrate that following termination of treatment with P, there was a marked (~2-fold) increase in the rate of kindling development as monitored by the expression of kindled seizures in WT mice (Fig.5A). This is attributed to abrupt discontinuation of P or P-derived neurosteroids (withdrawal effect) because withdrawal from chronic treatment with P and neurosteroids has been shown to trigger increase in seizure susceptibility (Moran and Smith, 1998; Reddy et al., 2001). Following the washout period, the kindling rate is similar between both groups. Therefore, continuous P treatment or tapered P discontinuation is desirable for persistent inhibition of kindling epileptogenesis.

Potential mechanisms of the disease-modifying activity of P

The molecular mechanisms underlying P’s attenuating effect on kindling development remains unknown. There are several potential mechanisms by which P could inhibit epileptogenesis, including activation of PRs, synthesis of neurosteroids, modulation of oxidative cascades, and promoting neuroprotection. The effect of P on the early kindling progression is reduced in mice lacking PRs, which provide evidence that PRs may be partly involved in P’s disease-modifying effects. These findings are consistent with the role of PRs in P inhibition of epileptiform activity in the hippocampus (Edwards et al., 2000). The PRKO mice exhibited a marked delay in the rate of kindling, suggesting that PRs are not involved in the later part of the kindling progression. However, the extent to which PRs mediate the P’s disease-modifying effect remains unclear because we unexpectedly observed that PRKO mice exhibit delayed kindling, indicating that PRs may influence seizure susceptibility. Collectively, the disease-modifying effect of P may occur through a complex mechanism partly involving PR-dependent and PR-independent pathways.
P is rapidly metabolized into pregnanediol, allopregnanolone, and other hydroxylated derivatives. P is a major substrate for endogenous neurosteroids such as allopregnanolone, which could mediate P’s attenuating effects on kindling epileptogenesis. This possibility is supported by emerging evidence that neurosteroids can retard the development of spontaneous seizures in post-SE models of epileptogenesis (Biagini et al., 2006, 2009). In a rapid kindling model in adult mice, pre-treatment with finasteride (50 mg/kg) significantly blocked P’s inhibition of epileptogenesis (Reddy and Mohan, 2010), suggesting that neurosteroids may be involved in P’s antiepileptogenic effects. Neurosteroid increase in tonic inhibition in the hippocampus could inhibit the spread of the seizure discharge from the hippocampus focus and thereby suppress the rate of development of behavioral kindled seizure activity without affecting the focal electrographic discharges. Increased tonic inhibition by allopregnanolone is shown to impair the NMDA receptor-mediated excitability in the hippocampus (Shen et al., 2010). It is likely that such a mechanism may underlie the P’s disease-modifying effects in the kindling model.
In addition, P’s modulation of inflammation is suggested as an appealing mechanism because pro-inflammatory molecules and oxidative signaling has been found to be activated in animal models of epilepsy (Vezzani, 2005; Patel, 2004). P has pleiotropic effects on inflammation and cell growth/survival (He et al., 2004; Stein and Sayeed, 2010), that may contribute to its attenuating effects on epileptogenesis. P inhibits secreted phospholipase A2 enzyme, a very high level target in the inflammatory cascade that has been shown to induce neurodegeneration through glutamate release (Yagami et al., 2002; DeCoster et al., 2002). P has been shown in numerous preclinical models to be a neuroprotective after injury (Roof et al., 1994; Koenig et al., 1995; Jiang et al., 1996; Cutler et al., 2007). Recently, two clinical studies have evaluated P as a treatment for moderate to severe TBI (Wright et al., 2007; Xiao et al., 2008). The P was administered over a period of 3 or 5 days beginning within 8 or 11 hours of the injury. In both studies, the groups receiving P had significantly fewer deaths than those receiving placebo. In addition, there was evidence of improved functional outcomes in the P-treated groups, suggesting that P is highly efficacious in reducing morbidity and mortality in TBI, which is a leading cause of epilepsy in adults and military persons.
In summary, our results demonstrate that P, in addition to exerting anticonvulsant activity, has the potential to retard kindling-induced epileptogenesis. To the extent that hippocampus kindling development represents a model of limbic epileptogenesis, this study supports the potential of P as a prophylactic treatment in people at high risk for developing epilepsy or in early stages of the disease. The disease-modifying effect of P occurs through a complex mechanism partly involving PR-dependent and PR-independent pathways including P’s conversion to neurosteroids that have been recently demonstrated to retard epileptogenesis in a spontaneous model (Biagini et al., 2006) and exert neuroprotective effects in a TBI model (Meffre et al., 2007).

This work was supported by National Institutes of Health grant NS051398 (to D.S.R.).

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Publicamos en este Blog sobre acúfenos este articulo sobre el efecto inhibidor del fenomeno de kindling que tiene la progesterona sobre el hipocampo como fuente de epilepsia, ya que los pacientes con acúfenos presentan tambien efecto kindling, tal vez desencadenado en el area del circuito limbico del que el hipocampo forma parte.
Dr. Darío Roitman
Centro de acúfenos Buenos Aires.


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Posts by tag: Jason Wu

The Best from New York Fashion Week (NYFW) Spring/Summer 2015

September 18, 2015

I have a love/hate relationship with the Fall: I hate that I have to start dressing warmer and putting socks on grrr….

I LOVE it because its the start of Fashion Week and NYFW is by far one of my favourites. If I could choose out of the four cities (New York, London, Paris, Milan) I think I’d definitely pick New York.  I mean even the grand Puba Ricardo Tisci decided to bring his Givenchy show to NYC this year. That’s the power of the Big Apple.

Kerry Washington Scandalizes Saks Fifth Avenue

October 03, 2013

Kerry Washington appeared on The View this morning looking gorgeous as usual, to promote the highly anticipated third season of the hit show Scandal and to announce her collaboration with Saks Fifth Avenue in New York.


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Search results “Sea slug lettuce”
Lettuce Nudibranch (sea slug)
Caesar my Nudibranch got caught in the power head and was completely stripped of his lettuce but after 3 weeks he is almost fully recovered
Views: 2467 Nola Reefer
Hair Algae and Lettuce Nudibranchs
If your aquarium has hair algae, then the lettuce nudibranch may be the solution. In This Fincast we interview Kevin Gaines of the Coral Reef Foundation and learn how effictive this can be.
Views: 13883 UltimateAquariumsVa
'The Lettuce Slug'
'The Lettuce Slug' (Natural History Episode 18) Lettuce sea slugs (Elysia crispata) are a commonly found in protected nearshore Floridian waters where green macroalgae proliferates. They belong to a clan of sea slugs, the sarcoglossans, that are characterized by their 'sap-sucking' feeding habits of algae. These slugs slowly patrol mangrove roots and rocks searching for green algae upon which they feed. They store some of the chloroplasts from eaten algae in their tissue, giving it the green coloration. The chloroplasts continue to function, providing the slug with photosynthetic energy. The ruffles along the back of the lettuce sea slug are called parapodia, and help provide more surface area for the chloroplasts to inhabit. They also camouflage the slug amongst the leafy algae that they live amongst. It is very easy to swim past a lettuce nudibranch without ever noticing it. Video, Aquarium + Original Soundtrack: Coral Morphologic 2010 See http://bit.ly/bPe2OK for more details. Twitter: http://twitter.com/CoralMorph
Views: 11003 Coral Morphologic
Romaine, my green lettuce sea slug, rockin' to the waves
He was purchased 12/08/2016 and placed in my 75 gallon mixed reef tank.
Views: 846 segooey
Salt Water 14Biocube Lettuce Sea Slug, Eats Hair Algae ?
Hopefully will keep this one long enough to consume some of the long hair algae, he is very cool, his diet may be a concern. For the more serious, see how things go.
Views: 3125 wnppmy
Lettuce Leaf Sea Slug
Views: 48 DanaT
Elysia Chlorotica: A Sap-Sucking, Solar-Powered Sea Slug
Complete video at: http://fora.tv/2010/05/05/Sneaky_Sea_Slugs_Three_Tales_of_Tidepool_Thievery Dr. Rebecca Johnson, invertebrate zoologist at the California Academy of Sciences, introduces Elysia chlorotica, a sea slug with interesting eating habits. The sap-sucking sea slug has evolved to undergo photosynthesis using chloroplasts obtained from the algae it eats. ----- Academy invertebrate zoologist Dr. Rebecca Johnson, discusses her research on the astounding biology and diversity of nudibranchs (sea slugs). Learn how these beautiful and colorful mollusks use their food to defend themselves from predators! This talk is part of an intertidal excursion sponsored by the Academy and the Gulf of the Farallones National Marine Sanctuary. - California Academy of Sciences Dr. Rebecca F. Johnson is an invertebrate zoologist at the California Academy of Sciences.
Views: 62579 FORA.tv
Lettuce Sea Slug
Shot during a night dive in Roatan, Honduras, with OLYMPUS OMD EM-1 MARK II. On assignment for PADI & Aqualung, scubadiving with http://sundiversroatan.com Music by https://www.bensound.com
Views: 134 Manu Bustelo
Slow and Steady - Lettuce Leaf Sea Slug on Grand Cayman's reefs
Not your garden variety slug these beautiful creatures are a favorite find on most shallow sites in Grand Cayman. Ranging in color from greyish white to electric blue, Lettuce Leaf Sea Slugs are very photogenic. For more information go to : http://www.ehow.com/info_8299675_lettuce-sea-slug-characteristics.html
Sea Slug
One of my sea slugs swimming in my 55 gallon saltwater aquarium. It swims around then grabs the back glass and flattens out. No copyright violation intended.
Views: 414 B-Rad
Amazing Sea Slugs! HD
Song: Eklipse - Cry me a river
Views: 9297 terrabithian2
The Solar Powered Sea Slug
The Wildlife Trusts: Protecting Wildlife for the Future We are working for an environment rich in wildlife for everyone. With more than 800,000 members, we are the largest UK voluntary organisation dedicated to conserving the full range of the UK’s habitats and species, whether they be in the countryside, in cities or at sea. More than 150,000 of our members belong to our junior branch, Wildlife Watch. There are 47 local Wildlife Trusts across the whole of the UK, the Isle of Man and Alderney. We manage around 2,300 nature reserves covering more than 90,000 hectares; we stand up for wildlife; we inspire people about the natural world and we foster sustainable living. Find out more: http://www.wildlifetrusts.org/
Views: 1921 The Wildlife Trusts
Sea Slugs of the Red Sea - 30 colorful species Nudibranchs & Sea Slugs
30 bunte Nacktkiemer und Meeresnacktschnecken, Rotes Meer. Nudibranchia: Aeolids (Facelinidae, Flabellinidae, Tergipedidae), Dorids (Chromodorididae, Discodorididae, Gymnodorididae, Hexabranchididae, Phyllidiidae, Polyceridae) Headshield slugs / Cephalaspidea: Aglajidae Sap-sucking slugs / Sacoglossa: Plakobranchidae Sea Hares / Anaspidea: Aplysidae Nacktschnecken - Meeresschnecken ohne Gehäuse – kann man überall, zu jeder Jahreszeit und in allen Meerestemperaturen antreffen. Sie leben in flachen Meerestümpeln in Korallenriffen und einige haben sich sogar in der Tiefsee angesiedelt. Ihre Artenanzahl und Varietät erscheinen unendlich. Die meisten der farbenprächtigen Tiere sind tagaktiv und ein Lieblingsmotiv für Fotografen. Nacktkiemer gehören zu den farbenprächtigsten Tieren. Sea slugs are among the most colorful animals. Sea Slugs are incredibly amazing and diverse. From practising photosynthesis to baffling reproductive practises. Music: Schiller....Swan Lake
Views: 3601 Frank Ude
Lettuce Sea Slug, Pinel Islet, Saint Martin
A lettuce sea slug (Elysia crispata) found while Extreme Shallow Snorkeling off the Islet of Pinel in Saint Martin, French West Indies.
Views: 1402 lesfruitsdemer
Lettuce sea slug
Views: 125 dirkje84
Bullock's Sea Slug ( Hypselodoris bullock )
Bullock's Sea Slug ( Hypselodoris bullock ) in HD
Views: 8540 alonnano
Lettuce sea slug Bonaire
Lettuce sea slug Bonaire
Views: 266 ron solodiver
Lettuce Sea Slug Cayman Brac
Lettuce sea slug in Cayman Brac. Notice size...
Views: 129 ecorl001
Spanish dancer nudibranch sea slug aquarium
A strange type of sea slug the spanish dancer they're able to swim to avoid predators. Instagram: @cowturtle9427
Views: 285 Cow Turtle
Surprising Sea Slug Dance | Video
The predatory sea slug Pleurobranchaea californica approaches & tries to eat a stinging Spanish shawl (Flabellina iodinea). The Spanish shawl stings the predator & begins a frenetic dance of escape, but Pleurobranchaea quickly learned to get away.
Views: 12242 LiveScience
CURIOUS lettuce leaf sea slug
A macro shot of a lettuce leaf sea slug, Elysia crispata, trying to find its next destination. Filmed in Exumas, Bahamas
Views: 130 Save Our Plankton
All about nudibranch in aquariums
By Paul Talbot http://paultalbot.com.au/ http://www.majesticaquariums.com.au
Views: 7312 Majestic AquariumsTV
Green Lettuce Sea Slug
Green Lettuce Sea Slug ( Elysia crispata) http://www.herraduradivers.com/
Views: 602 Herradura Divers
sea slug
lettuce sea slug
Views: 162 MrGreygoose101
A sea slug Costasiella kuroshimae - Actual creatures in the Pokemon & Picachu movie
Strange creatures lurking underwater "look is love" Many people had "stood the" extreme cuteness front of the sea slugs. Looking at the picture below, you said that this beautiful creature is a sheep or a cow sea sea? The answer will surprise you that many. The truth of this cute creature is a sea slugs have Costasiella kuroshimae scientific name, are found in Japan, Indonesia and the Philippines. This is one of the most unique species of marine snails in the world because they eat algae and is capable of photosynthesis. Sea slugs absorb genes from algae code and start producing chloroplasts (chloroplasts) to turn sunlight into energy. We just need to eat ... only once in a lifetime, then hovering in the sun is not to die of starvation. Slug next generation has inherited this genetic code from our parents (the phenomenon of horizontal gene transfer), causing them to remove the limit of evolution took place thousands of years. However, the sea slug Costasiella kuroshimae still need "eat" seaweed to keep this gene does not disappear. --------------------------- Loài sinh vật lạ ẩn mình dưới biển "nhìn là yêu" Không ít người đã "đứng hình" trước vẻ đáng yêu tột độ của loài sên biển này. Nhìn vào bức hình dưới đây, bạn cho rằng, loài sinh vật xinh đẹp này là một chú cừu biển hay một chú bò biển? Câu trả lời sẽ khiến không ít bạn bất ngờ. Sự thật loài sinh vật dễ thương này là một chú sên biển có tên khoa học là Costasiella kuroshimae, được tìm thấy nhiều ở Nhật Bản, Indonesia và Philippines. Đây là một trong những loài sên biển độc đáo nhất trên thế giới bởi chúng ăn tảo biển và có khả năng tự quang hợp. Sên biển hấp thu các mã gene từ tảo biển và bắt đầu sản xuất lục lạp (chloroplasts) để biến ánh nắng Mặt trời thành năng lượng. Chúng chỉ cần ăn… duy nhất một lần trong đời rồi lượn lờ dưới ánh nắng là không bị chết đói. Thế hệ sên kế tiếp vẫn được thừa hưởng mã gene này từ bố mẹ chúng (hiện tượng chuyển gene ngang) khiến chúng tháo bỏ giới hạn tiến hóa diễn ra hàng ngàn năm. Tuy nhiên, sên biển Costasiella kuroshimae vẫn cần “ăn” tảo biển để giữ cho gene này không bị biến mất. --------------- Fictional creatures Cartoon creature Animated creatures are real The creature has actually been adapted into anime
Views: 31603 MTC Channel
Lettuce sea slug
Close up of a lettuce sea slug on the glass. It's very active, crawling all over the aquarium. The algae it 'eats' turns white after it has passes over it.
Views: 1523 Josh S
Aplysia swimming sea slug
a sea slug swimming past in Oualidia, Morroco
Views: 13484 Kate Holder
Boanire - Blue Lettuce Sea Slug
A nice example
Views: 183 Bob Asher
Dottie - Lettuce Sea Slug
Dottie at LCBR impersonates a Lettuce Sea Slug
Views: 168 clcgen
Lettuce Sea Slug
Cute little sea slug! Produced by www.manuelbustelo.com Music by Bensound.com
Views: 12 Sun Divers Roatan
baby lettuce leaf sea slug
video of a cute little lettuce leaf sea slug I found on Pickles Reef that was the size of my pinky nail!
Views: 88 imafunkychild
Lettuce Leaf Sea Slug
Taken with RX100II, with Gobe 700W light and CMC +15 lens
Views: 36 Helen Walter
Lettuce sea slug
Views: 10 Kandace Mills
Cape San blas
Views: 34 russell pipes
Lettuce Sea Slug Dominica
Views: 4 Brian White
Cayman Sea Slugs and Nudibranchs
Cayman waters have many different species of Sea Slugs and Nudibranchs. Here are three of the most common ones ranging in size from about .5 inches to 2 inches in length. Lettuce Leaf Sea Slug, Painted Elysia's and Purple Crowned Sea Goddess's. Beautiful!!!!
My sea slug cruising the reef
Views: 1168 Joe
Lettuce Leaf Sea Slug
Mitchel Friedman Holmdel, NJ
Views: 34 Mitchel Friedman
Sea of Lettuce - Coastal
Views: 1273 Sea of Lettuce
Sea slug ????
Discovered strange live in my tank, ehich i did not introduced myself, so it must have grown spontaniously
Views: 247 Glenn Fong
The sea slug that eats the sun | Sidney Pierce | TEDxTampaBay
Dr. Sidney Pierce is currently a professor at the University of South Florida's Department of Integrative Biology. His current research involves photosynthetic animals, especially the molecular biology behind the intracellular symbiosis between the digestive cells of a sea slug (Elysia chlorotica) and algal (Vaucheria litorea) chloroplasts, with applications in medicine—gene therapy. Dr. Pierce's work has been featured on radio, TV, newspapers, magazines, and even Weekly Reader, internationally as well as domestically. In fact, his research was recently featured in a French documentary, "The Power of Plants" on the France 5 network in France.
Views: 10114 TEDx Talks
snoring sea slug
Views: 256 gummybearcavity
Purple Sea Slug
New Purple Sea Slug added to the 30 Gallon.
Views: 254 TheBroHammy
Beautiful sea slug
December 2014 dive trip at Anilao, Philippines
Views: 378 harry Chan

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Posted by Jimmy on May 13, 2015

Meet Colin Allen, joining the crew from Brooklyn, New York. This isn’t Colin’s first time orienteering. He used to be a guide / troupe leader for the Boy Scouts! He is also responsible for our new website. Thank’s Colin.

Colin is at the bottom left.


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To receive full pricing details please contact CJ through the Inquire Page or through her email at cj@charlie-juliet.com. Her schedule does tend to book up 6-8 weeks in advance, however even though weekend sessions are the most popular, she still has a variety of weekday dates available and CJ will take last minute sessions based on her availability. Keep in mind most newborn sessions are captured within the first 7-15 days of your little ones arrival. Collections include 1-2 hours at the location of your choice and a digital suite of all the edited images.

Yearly Collections
Yearly collections are available so that every family has a chance to capture each special milestone of your growing family. Whether it’s your baby’s first year, or your children are surpassed the age of one and you just want to capture their adorable little personalities, you can choose from either a 2 Session Collection or a 3 Session Collection. Maternity, Newborn, 6 Months, 1 Year and Seasonal Sessions are always popular with the Yearly Collections. You will not only receive all of the digital files but you will also receive priority booking during the peak seasons and discounted a la carte products. Please contact CJ for the full pricing.


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Next Hopeful!

Well the last house we want to look at was recently rented because it was not sold.  So this is the next one on our list!  We hope to see it this week.  My issue with this house is that it does not have a basement and has small square footage.  I guess we will see as the week goes on!


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01932 732600

01932 780581

Charlton Grange, Charlton Lane,

Upper Halliford, Middx,

TW17 8QN

We have an ‘Open House’ policy on visiting. We encourage relatives, friends and voluntary organisations to visit the Home during the day or evening. Visitors should be able to go into residents’ rooms, if acceptable to the individual. We also have a guest bedroom with en-suite facility for a relative or a friend, who wish to stay over, subject to availability and there’s also a room available for more private meetings.

All visitors must confirm who they are and whom they are visiting. The visitors’ book must be signed so that if there is a fire, there is a record of who is in the Home.

We are opposite the Sunbury golf course on the A244 and next to the very popular Goat pub in the village of Upper Halliford.

By Train:

Nearest Station:

Upper Halliford StationUpper Halliford station is situated under half a mile away from us, near the bridge on Upper Halliford Road to Sunbury or Walton over the M3.

When you exit the Upper Halliford train station, turn right and walk along Upper Halliford Road. You will then reach a roundabout, here you will see a sign for Upper Halliford Village to your left, turn left here. Follow the road down until you pass a group of shops on your right, then turn right down Charlton Lane. Follow Charlton Lane to the end of the road, and you will see Charlton Grange care home on your left.

If you are planning to visit us, please give us call, we may be able to help you further to plan your journey.

By Car:

In your navigation device, you can use the post code – TW17 8QN, to reach us.

Alternately, you can get the directions via Google maps using the link below.

Google map directions to home

By Bus:

Depending on which direction you are travelling from either Sunbury,Walton-on-Thames or Kingston, the following buses cover our village; 216, 235, 290, 555, 557 and 571.

Please check your own connections before starting your journey to Upper Halliford

Send us a message

Employment Opportunities

Do you want to make a difference to the lives of elderly people?

If so You may enjoy working with us. We strive to help our employees in their professional development.

We offer a variety of exciting positions for dedicated people. Along with attractive pay packages we strive to help our employees in their professional development.

So if you are interested in working with a company that cares about its residents and staff please contact us.

Current Vacancies

© Copyright - Charlton Grange


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Our Mission is to inspire and prepare all students to realize their potential and enhance our global community.

Administrative offices for the West Hartford Public Schools are located in the Town Hall building at 50 South Main Street.

Software decisions about access and use are made by building administrators and their staff so not all of the programs listed below are used at every school. Talk with your school principal if you have questions about your school's access and login options. For more information about Public Act 16-189 compliance, click here. Below, you will find general descriptions of commonly used technology-based programs, info on how to log in, and privacy policy information for many of the software programs that are used in some of our schools.

AIMSWeb is used for universal screening, progress monitoring, and data management for Grades K-12.

AIMSWeb Privacy Policy

Blackboard Connect

Blackboard Connect assists with mass notification services.

Blackboard Connect Privacy Policy

This is an online literacy resource that pairs classic video storybooks with related non-fiction eBooks from Scholastic to build a love of reading and learning. This is funded through library budget and may not be available at every school.

BookFlix Privacy Policy

This educational program provides content in the following subject areas: Science, Math, English, Social Studies, Health, Arts & Music and Technology. The district subscribes to BrainPOP, BrainPOP Jr. (K-3), BrainPOP ESL and BrainPOP Spanish.

Brain Pop Privacy Policy

Britannica Online School Edition

This online encyclopedia provides four levels of access:

  • PreK-2 –Britannica Learning Zone
    (accessible from the Elementary page)

  • Elementary School

  • Middle School

  • High School

Britannica Online School Edition

This online library catalog is available 24/7. Create reading lists and access eBooks with your personal login.

Use the WHPS Edublog to create teacher blogs. Features include the ability to customize the site and embed videos, images and more.  Edublogs can be linked to FinalSite webpage. Your other option for website/blog creation would be creating a Google Site or building your page with FinalSite. If you would like to discuss the benefits of either one, please contact helpdesk@whps.org.

EduBlog Privacy Policy

Enchanted Learning

This resource for teachers includes lesson plans, activities, outline printouts, preschool activities, picture dictionaries in several languages, graphic organizers and information on a variety of topics.

FinalSite hosts the West Hartford Public School webpages.

FinalSite Privacy Policy

Glogster EDU

Use this site to create Glogs, online multimedia posters, with text, photos, videos, graphics, sounds, drawings, data attachments and more. This resource is paid for use at primarily the middle schools. It is not available in every school.

Glogster Privacy Policy

G Suite for Education (Google for Education)

Image Quest

This is a database of copyright free images for student and staff use.

Image Quest

Keyboarding without Tears

This paid subscription is for keyboarding instruction for grades 2-5 in the district. This subscription works on any device.

Khan Academy

Khan Academy is a learning resource that offers practice exercises, instructional videos, and a personalized learning dashboard that empower learners to study at their own pace in and outside of the classroom.

Khan Academy Privacy Policy

Kimono is a cloud-based interoperability platform that provides control of information infrastructure.

Kimono Privacy Policy

Naviance is a college and career readiness software provider that partners with high schools and other K–12 institutions to provide students with college planning and career assessment tools.

Naviance Privacy Policy

Use this site to create and edit bibliographies or works cited lists in MLA, APA or Chicago format and digital note cards.

Google Login

Login to your WHPS Google Account, open the waffle (grid) menu and select More.

Click on NoodleTools. If your account has been set up then NoodleTools automatically opens.

The NWEA assessments are: Measures of Academic Progress® (MAP®) – These computerized tests are adaptive and offered in Reading, Language Usage, and Mathematics. When taking a MAP® test, the difficulty of each question is based on how well a student answers all the previous questions.

NWEA Privacy Policy

One More Story

This site is an online library of children’s classic and contemporary literature. Children can point and click to choose a book, see the illustrations and have the book read to them.

NOTE: Not available for access outside of school.

One More Story Privacy Policy

PebbleGo and PebbleGo Next

PebbleGo and PebbleGo Next are visual research databases designed for emergent readers. Databases include: Animals, Earth and Space, Biographies and Social Studies. Information is enhanced with spoken-word audio, text highlighting and audio and video clips.

PerformancePLUS is a product suite comprised of Performance Tracker, Assessment Builder, and Curriculum Connector. These three modules interact to assist districts in managing and organizing vital and timely student data, creating local assessments and mapping curriculum.

PerformancePLUS Privacy Policy

Poll Everywhere is a web-based system that can be used both in and outside of the classroom to create polls.

Polleverywhere Privacy Policy

PowerSchool is a Web-based software application that allows teachers, parents and school administrators to track and share information about students. Teachers can use PowerSchools to keep a record of students' grades and attendance, which parents can then view at home by logging into a PowerSchools account.

PowerSchool Privacy Policy

Protraxx is an online professional development registration system.

Protraxx Privacy Policy

Quia Web

This teacher resource provides a variety of tools including: templates for creating online activities (e.g. flashcards, word search, cloze exercises) and online testing which enables teachers to create quizzes and score them with computer assistance and receive detailed reports

Schoology houses the curriculum for each grade level’s ELA, Writing and Math Curricula. Updated units of study are posted two weeks before expected delivery date and are available for downloading. Teachers are encouraged to upload student work and post questions or comments about how the implementation of the units of study are going. This site is intended as a sharing site for teachers to access the curriculum, post questions and student work for their colleagues.

Elementary staff - contact helpdesk@whps.org for join codes for your grade level’s curriculum. Create a free account on schoology.com and enter in your grade level’s join code.

SchoolDude is an education platform of cloud solutions for schools to manage facilities, maintenance, and technology.

SchoolDude Privacy Policy

Click here to visit the Seesaw Help Center, which includes getting started tips, tutorial videos, activity ideas, FAQs, and more.

SeeSaw Privacy Statement

Smarter Balanced Assessment Consortium (SBAC)

The Smarter Balanced Assessment Consortium (SBAC) is a standardized test consortium. It creates Common Core State Standards-aligned, adaptive, online exams.

Smarter Balanced Assessment Consortium Privacy Policy

Soundzabound is royalty free music library for student and staff use.

Soundzabound Privacy Policy

Sumdog is a way for kids to practice math skills while playing fun, math-related games against friends, classmates, or students from around the world. Games are individualized for each kid's ability level, so users can play against opponents who have the same skills.

SumDog Privacy Policy

TalentEd is a performance management application that provides easy access to data and evaluations.

TalentEd Privacy Policy

TenMarks is a comprehensive, standards-based math curriculum with scaffolded lessons, guided practice, assignments, assessments, and interventions designed for state and Common Core standards.

TenMarks Privacy Policy

Trueflix is an online resource for accessing informational texts on varied subject, common core aligned grade level topics to support inquiry and independence. This resource may not be available in every school.

Tumblebooks Library

Tumblebooks Library is an online collection of electronic children’s picture books with animation, sound, music and narration. The collection includes both fiction and nonfiction books.

Voicethread is a web-based tool that allows you to place collections of media (e.g. images, videos, documents, presentations) at the center of an asynchronous conversation. A VoiceThread allows people to have conversations and make comments using any combination of text, microphone, webcam, telephone or uploaded audio file.

Access Voicethread through an app on your google apps launchpad under more apps.

West Hartford Public Schools

50 South Main St, West Hartford, CT  06107

T: 860-561-6600

F: 860-561-6910

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The Sexuality Snare, Balancing Hormonal Agents and the Noggin

As I had my morning coffee, the "Dear Abby" column captured my eye. A reader wrote in with a dating dilemma and ended her letter with that often-heard stereotype that "Women use sex to obtain love, and males use love to get sex." This is a excellent summation of the "Sex Trap."

The Sex Trap resembles the Love Trap, where singles analyze great sex as love. However those who fall into the Sex Trap go even farther since for these singles, having sex carries immense meaning and consequences.

Singles fall under the Sex Trap in one (or both) of two ways:

A.they believe sex is a necessary test of compatibility, (if the sex is excellent then the relationship will be good as well).

B.more typically, all consciousness goes out the window, and one or both formerly level-headed singles consider themselves a dedicated couple as quickly as they have sex.
Rather than looking at whether this other person might be a match on levels other than physical tourist attraction-- such as long-term requirements, requirements, and wants-- they are blind-sided by the chemistry under the covers.

No doubt, it can be challenging to correspond with truth when all those hormonal agents are cutting loose. Our body responds to somebody we are drawn in to by producing hormones such as PEA or phenylethylamine (natural amphetamine), dopamine and norepinephrine (natural mood enhancers), and testosterone (increases sexual desire), which makes the opportunity to make love with somebody we are drawn in to exceptionally difficult to resist. After orgasm, we produce oxytocin (which acts on the hypothalamus to produce emotions), which makes us feel really close to and bonded with our sex partner.

These chain reactions are strong and involuntary , leading to effective sensations of tourist attraction, excitement, love, wellness, and try this closeness .

When problems emerge, those who fall into the Sex Trap frequently rationalize by believing, "Well, we've got problems, however the sex is fantastic!" They more than likely wouldn't confess, but they prioritize physical intimacy and concern the rest as optional. Their primary searching tools are sexual attraction and physical compatibility.

Barry North, an RCI coach who works mostly with gay males, says that much of his clients have actually fallen under the Sex Trap.

" For gay men especially in cities, sex is readily available, and that in itself is a trap," North says. "In addition, the culture, with its focus on read review physical look, encourages sexual activity. If a prospective partner is going to be sexually suitable, lots of gay males want to find out from the starting. Why waste your time if the sex isn't going to be good?".

North adds, "I believe this is a ' person' thing rather than a 'gay' thing.".
I do want to point out that chemistry special info is essential. Yet, chemistry is a provided that we cannot manage in a relationship; it is either there or not there, and it should be there for the collaboration to work. If not there, we cannot "make" chemistry take place, though sometimes it can grow in time.

Singles who pursue a relationship based upon sexual chemistry risk relationship failure when the hormone-induced intoxication wears away and truth hits.

To prevent the Sex Trap, you must stabilize your heart (and hormonal agents) with your head. This indicates combining chemistry with common sense. While excellent sex is necessary for a sustainable relationship, you require to make your partner choices by paying full attention to your vision, requirements, worths, and objectives -- while feeling all those amazing triggers!

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