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Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-β (Aβ) 1–42, and the adjuvant, QS–21. To avoid this toxicity, we have been using Aβ derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Aβ burden, Aβ levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Aβ deposit burden by 31% and Aβ levels by 30–37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Aβ burden or improve cognition. Significantly, the immunotherapy in the 11–24 months treatment group, that reduced Aβ burden, did not increase cerebral bleeding or vascular Aβ deposits in contrast to several Aβ antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Aβ burden when used with an adjuvant suitable for humans, without increasing vascular Aβ deposits or microhemorrhages.
Extensive evidence suggests that amyloid β (Aβ) accumulation in the brain is central to the pathogenesis of Alzheimer's disease (AD). Immunotherapy for AD targeting Aβ remains a promising approach although the initial clinical trial was halted because of encephalitis in a subset of patients. Following the first mouse studies on vaccination with Aβ1–42 (Schenk et al., 1999), several laboratories have confirmed and extended these findings, showing that this approach can prevent Aβ deposition and improves cognition in mouse models (Lemere et al., 2003; Gelinas et al., 2004; Weksler et al., 2005; Sigurdsson, 2006). More limited data from the aborted trial suggest that some patients may have benefited cognitively (Hock et al., 2003; Gilman et al., 2005) and autopsies on participants indicate that parenchymal Aβ deposits were reduced (Nicoll et al., 2003; Ferrer et al., 2004; Masliah et al., 2005). The meningoencephalitis seen in 6% of the patients was likely caused by the immunogen (Aβ1–42) and excessive cell-mediated immunity. We have proposed to prevent this reaction by using nonfibrillogenic, nontoxic Aβ homologous peptides (Sigurdsson et al., 2001; Sigurdsson et al., 2004). Adjuvants also influence the immune response and most of the prior animal studies used Freund's adjuvant, which promotes a cytotoxic Th1 response. The adjuvant QS–21, which also promotes Th1 response was used in the Alzheimer's trial and may have contributed to the encephalitis. Prior to these adverse effects we advocated the use of adjuvants that promote a humoral response such as alum, which is approved for human use (Sigurdsson et al., 2001; Scholtzova et al., 2002). One important aim of our current study was to establish if alum could be used as an effective adjuvant in conjunction with our Aβ derivative immunogen.
Another potential side effect of immunotherapy targeting Aβ is cerebral bleeding, which may be related to rapid clearance of parenchymal Aβ, leading to increased vascular Aβ deposition and vessel friability. Three studies in AD mouse models have observed increased brain microhemorrhages following passive immunization with different Aβ antibodies (Pfeifer et al., 2002; Wilcock et al., 2004; Racke et al., 2005). In the three autopsy cases from the clinical trial, extensive vascular Aβ remained despite parenchymal Aβ clearance, and one of these individuals had numerous brain microhemorrhages (Nicoll et al., 2003; Ferrer et al., 2004; Masliah et al., 2005). These observations suggest that increased vascular Aβ and hemorrhage may also be an issue with active immunization in humans. In the present study, we determined if our active immunization approach would be associated with this form of toxicity. Furthermore, to determine the prophylactic vs. the therapeutic effect of Aβ derivatives, we immunized Tg2576 mice (Hsiao et al., 1996) with K6Aβ1–30 in alum starting at 11 or 19 months of age with treatment continuing until 24 months. We previously observed an 81–89% reduction in brain amyloid burden in this model using this immunogen with Freund's adjuvant (Sigurdsson et al., 2001). Towards the end of the study, extensive behavioural testing was performed with subsequent brain analysis, which included assessment of parenchymal- and vascular-Aβ deposits, Aβ levels, as well as associated gliosis and microhemorrhages.
K6Aβ1-30-NH2 was synthesized at the Keck Foundation at Yale University, as described previously (Sigurdsson et al., 2001). This Aβ derivative maintains the two major immunogenic sites of the Aβ peptide, which are residues 1–11 and 22–28 of Aβ1–42 based on an antigenic index (Jameson & Wolf, 1988). The peptide is amidated on the C terminus to maintain the immunogenicity of that epitope. The six lysyl residues on the N terminus were added to enhance immunogenicity and further reduce β-sheet content. All other chemicals were from Sigma (St. Louis, MO) unless otherwise stated.
The vaccination was performed in the heterozygous Tg2576 amyloid precursor protein (APP) mouse model (Hsiao et al., 1996). These mice show rapid increases in Aβ levels at approximately 6 months of age with Aβ deposition developing in the following months although extensive amyloid burden is usually not observed until the animals are well into their second year (Kawarabayashi et al., 2001). The animals were maintained on a 12-h light : 12-h dark cycle, and animal care was in accordance with institutional guidelines in AAALAC approved facilities. The animal experiments were approved by the IACUC committee at NYU School of Medicine and were carried out in accordance with NIH Guidelines.
K6Aβ1-30-NH2 was administered as described previously (Sigurdsson et al., 2001). The peptide was mixed with Adju-Phos adjuvant (Brenntag Biosector, Denmark) at a concentration of 1 mg / mL and the solution was rotated overnight at 4 °C prior to administration to allow the peptide to adsorb onto the aluminium phosphate particles. The mice received a subcutaneous injection of 100 μL followed by a second injection 2 weeks later and monthly thereafter. Vaccination started at 11–12 months and 19–20 months of age and continued until the animals were 23–24 months of age at which time the animals were perfused and their organs collected for analysis. The mice went through a battery of behavioural tests in the two months prior to killing. In the younger treatment group, 19 mice received K6Aβ1–30 and 21 mice received the adjuvant alone. Fifteen wild-type littermates served as additional controls. At the end of the study, 12 and 16 Tg animals remained in the treatment and control groups, respectively. In the older treatment group, 13 mice were immunized with K6Aβ1–30 and 12 mice received adjuvant alone. At the end of the study, ten and eight mice remained in the treatment and control groups, respectively. For gender split and number of mice in the behavioural tests, see Table 1.
Prior to testing, the mice were adapted to the room with lights on for 15 min.
Spatial learning was evaluated using an eight-arm radial maze with a water well at the end of each arm. Clear Plexiglas guillotine doors, operated by a remote pulley system, controlled access to the arms from a central area from which the animals entered and exited the apparatus. After 3–4 days of adaptation, water-restricted mice (2 h daily access to water) were given one training session per day for ten consecutive days. For each session, all arms were baited with saccharine flavored water, and animals were permitted to enter all arms until the eight rewards had been consumed. The number of errors (entries to previously visited arms) and time to complete each session were recorded.
This apparatus is a rectangular field 30 cm square with 9 cm high walls divided into 36, 9.5 cm squares and covered by a clear Plexiglas top. Endboxes, each 11 × 16 × 9 cm, are situated at diagonal corners of the field. The symmetrical maze (Davenport et al., 1970) is a modification of the Hebb–Williams (Hebb & Williams, 1946) and Rabinovitch–Rosvold (Rabinovitch & Rosvold, 1951) type of tests. Briefly, the main difference is that each end-compartment functions as both a startbox and a goalbox, and the mice run in opposite direction on alternate trials, thereby eliminating intertrial handling. The barriers are placed in the field in symmetrical patterns, so that mice face the same turns going in either direction within a given problem. Prior to testing, the mice were adapted to a water restriction schedule (2 h daily access to water). The mice were given two adaptation sessions prior to the beginning of testing. In the first session, all animals were given saccharine flavored water in the goal box for 10 min. In session 2, they were placed in the start chamber and permitted to explore the field and enter the goal box where water reward (0.05 mL) was available. When the mice were running reliably from the start chamber to the goal box, they were given three practice sessions on simple problems where one or two barriers were placed in different positions in the field so as to obstruct direct access to the goal box. Formal testing consisted of the presentation of seven problems graded in difficulty. One problem was presented per day and the mice were given five trials on each problem with an intertrial interval of 2 min. Performance was scored manually by the same observer in terms of errors (i.e. entries and reentries into designated error zones) and time to complete each trial.
Prior to testing, the mice were adapted to the room with lights on for 15 min. The main objective of performing these sensorimotor tasks was to verify that any treatment related effects observed in the cognitive tasks could not be explained by differences in sensorimotor abilities.
A Hamilton–Kinder Smart-frame Photobeam System was used to make a computerized recording of animal activity over a designated period of time. Exploratory locomotor activity is recorded in a circular open field activity chamber measuring 70 × 70 cm. A video camera mounted above the chamber automatically recorded horizontal movements in the open field in each dimension (i.e. x, y, and two z planes). Total distance was measured in centimeters (cm) travelled and is defined as sequential movement interruptions of the animal measured relative to the background. The duration of the behaviour was timed for 15 min. Results are reported based on distance travelled (cm), mean resting time, and velocity (average and maximum) of the animal.
This task tests balance and general motor coordination and function integration. Mice were assessed by measuring their ability to traverse a graded narrow wooden beam to reach a goal box [modification of (Torres et al., 1994)] which specifically examines hindlimb function. The mice were placed on a 1.1-cm wide beam 50.8-cm long suspended 30 cm above a padded surface by two identical columns. Attached at each end of the beam was a shaded goal box. Mice were placed on the beam in a perpendicular orientation to habituate, and were then monitored for a maximum of 60 s. The number of foot slips each mouse has before falling or reaching the goal box was recorded for each of three successive trials. The average foot slips for all four trials was calculated and recorded. Errors are defined as footslips and recorded numerically. To prevent injury from falling, a soft foam cushion was always kept underneath the beam. Animals that fell off were placed back in their position prior to the fall.
The animal was placed onto the rod (diameter 3.6 cm) apparatus to measure forelimb and hindlimb motor coordination and balance (Rotarod 7650 accelerating model; Ugo Basile, Biological Research Apparatus, Varese, Italy; Carter et al., 1999; Hyde et al., 2001). This procedure was designed to assess motor behaviour without a practice confound. The animals were habituated to the apparatus by receiving training sessions of two trials, sufficient to reach a baseline level of performance. Then the mice were tested a further three times, with increasing speed of the rotating rod. During habituation, the rotor rod was set at 1.0 r.p.m., which was gradually raised every 30 s, and it was also wiped clean with 30% ethanol solution after each session. A soft foam cushion was placed beneath the apparatus to prevent potential injury from falling. Each animal was tested for three sessions, with each session separated by 15 min, and measures were taken for latency to fall or invert (by clinging) from the top of the rotating barrel.
Antibody levels were determined by 1 : 200 and 1 : 1000 dilutions of plasma using ELISA as described previously (Sigurdsson et al., 2001), in which Aβ or its derivative is coated onto microtiter wells. The antibodies were detected by a goat anti-mouse IgG linked to a horseradish peroxidase (Amersham Biosciences, Piscataway, NJ) or a goat anti-mouse IgM peroxidase conjugate (Sigma; A8786), and tetramethyl benzidine (TMB; Pierce, Rockford, IL) was the substrate.
Mice were anaesthetized with sodium pentobarbital (150 mg / kg, i.p.), perfused transaortically with phosphate buffer, and the brains processed as described previously (Sigurdsson et al., 1996). The right hemisphere was immersion-fixed in periodate-lysine-paraformaldehyde, whereas the left hemisphere was snap-frozen for measurements of Aβ levels. Serial coronal sections (40 μm) were cut, and every fifth section (30–40 sections in total) was stained with 6E10, a monoclonal antibody that recognizes Aβ and stains both preamyloid and Aβ plaques (Kim et al., 1990). Staining was performed as described previously (Sadowski et al., 2004; Sigurdsson et al., 2004). Every tenth section (15–20 sections in total) was stained with tomato lectin (Vector Laboratories, Burlingame, CA), polyclonal interleukin-1β antibody (Biosource International, Camarillo, CA), polyclonal anti-glial fibrillary acidic protein (GFAP; Dako, Glostrup, Denmark), or with Perl's iron stain. Tomato lectin binds to poly N-acetyl lactosamine residues and in neural tissue it has specific affinity for microglial cells (Acarin et al., 1994). Interleukin-1β is a cytokine that is primarily found in microglia. GFAP is a component of the glial intermediate filaments that form part of the cytoskeleton and is found predominantly in astrocytes. Both microglia and astrocytes are associated with Aβ deposits.
Immunostaining was performed as described previously (Sigurdsson et al., 2001; Sigurdsson, 2005). Briefly, sections were incubated in 6E10 at a 1 : 1000 dilution for 3 h. A mouse-on-mouse immunodetection kit (Vector Laboratories, Burlingame, CA) was used, with the biotinylated anti-mouse IgG secondary antibody reacted for 1 h at a 1 : 2000 dilution. The avidin-peroxidase complex was subsequently reacted for 30 min at the same dilution. GFAP- (1 : 500; 3 h) and interleukin-1β-staining (1 : 250, overnight) was performed as described (Sigurdsson et al., 1996) with the diluent for the primary antibody composed of 2.0% Triton X-100, 0.1% sodium azide, 0.01% bacitracin, 2% bovine serum albumin, and 10% normal goat serum in PBS, and the secondary biotinylated anti-rabbit antibody (Vectastain, ABC Elite kit, Vector) was reacted for 1 h at a 1 : 1300 dilution followed by avidin-peroxidase reaction for 30 min at the same dilution. Tomato lectin staining was performed as described (Sigurdsson et al., 2001) with a 2 h incubation (biotinylated tomato lectin, 10 μg / mL PBS; Vector) followed by 1 h reaction in avidin-horseradish peroxidase (Vector). The sections were reacted in 3,3-diaminobenzidine tetrahydrochloride with nickel ammonium sulphate (Ni; Mallinckrodt, Paris, KY) intensification.
Perl's iron stain was performed to detect cerebral bleeding by placing defatted and hydrated sections in a solution containing 5% potassium ferrocyanide and 10% hydrochloric acid for 30 min. The slides were then rinsed in distilled water, and the sections were dehydrated, cleared in Hemo-De, and coverslipped. This same method was used in the three previous reports that showed that passive immunization against Aβ increased the frequency of microhemorrhages in AD model mice (Pfeifer et al., 2002; Wilcock et al., 2004; Racke et al., 2005). Diamino benzidine intensification of the iron staining, which is useful for detecting low levels of iron in Aβ plaques, did not appear to improve sensitivity for detecting the microhemorrhages and was therefore not employed. To verify that our methodology would allow us to detect increases in hemorrhages, positive controls were used. These mice had brain hemorrhages that were caused by intracerebral cannula placement. These hemorrhages were more extensive than the microhemorrhages observed in the Tg mice.
Immunohistochemistry of tissue sections was quantified with a Bioquant image analysis system (BIOQUANT Image Analysis Corporation, Nashville, TN), and unbiased sampling was used (West, 1999). All procedures were performed by an individual blinded to the experimental condition of the study. The cortical area analysed was dorsomedial from the cingulate cortex and extended ventrolaterally to the rhinal fissure within the right hemisphere. The area of the grid was 800 μm2 ×800 μm2, and Aβ deposit load was measured in 20 cortical frames per mouse (640 ×480 μm2 each) chosen randomly. For the initial Aβ burden measurements, no distinction was made between vascular and parenchymal Aβ deposits. Subsequently, vascular Aβ deposits were specifically measured in the 11–24 months old group in an additional 20 randomly selected cortical frames per mouse. The Aβ burden is defined as the percentage of area in the measurement field occupied by reaction product.
The assessment of the tomato lectin (microglia) stained sections was based on a semiquantitative analysis of the extent of microgliosis associated with the Aβ deposits (0, a few resting microglia; +, a few ramified and / or phagocytic microglia; ++, moderate number of ramified / phagocytic microglia; +++, numerous ramified / phagocytic microglia)
Extraction of Aβ from brain tissue was performed as described in detail (Schmidt et al., 2005a; Schmidt et al., 2005b) with the following modification. Instead of adding three protease inhibitors (leupeptin, antipain, and pepstatin A; 1 / 1000 volume of 5 mg / mL stock solution) to the homogenization buffer, a protease inhibitor cocktail (Complete, Roche Diagnostics, Indianapolis, IN) was used according to the manufacturer's description as well as pepstatin A at the concentration listed above. Brains were weighed and homogenized (10% w / v) in homogenization buffer [(20 mμ Tris base, 250 mμ sucrose, 1 mμ EDTA, 1 mμ EGTA) with 100 mμ phenylmethylsulphonyl fluoride in ethanol and the protease inhibitors added immediately before homogenization].
Homogenate (200 μL) was added to 440 μL cold formic acid and sonicated for one minute on ice. Subsequently, 400 μL of this solution was spun down at 100 000 × g for one hour at 4 °C. Then, 210 μL of the supernatant was diluted into 4 mL of formic acid neutralization solution (1 μ Tris base, 0.5 μ Na2HPO4, 0.05% NaN3), aliquotted, flash frozen on dry ice and stored at −80 °C until used for Aβ measurements with ELISA. For measurements of Aβ1–40 vs. Aβ1–42, the aliquots were diluted 1000–2500-fold vs. 100–500-fold, respectively, prior to loading onto ELISA plates. The ELISA procedure was performed as described by the ELISA kit manufacturer (Biosource International).
Homogenate (200 μL) was mixed with equal volume of cold 0.4% diethylamine containing 100 mμ NaCl, and subsequently centrifuged at 100 000 ×g for 1 h at 4 °C. Then, the supernatant was neutralized with 1 / 10 volume of 0.5 μ Tris pH 6.8, aliquotted, flash frozen on dry ice and stored at −80 °C until used for Aβ measurement. For measurements of Aβ1–40 vs. Aβ1–42, the aliquots were diluted 100–1000-fold vs. 20–50-fold, respectively, prior to loading onto ELISA plates (Biosource International).
Aβ deposit burden and the levels of total and soluble Aβ within the brain were analysed by a Student's t-test, one-tailed (Graph Pad Prism 4.0). The data from the radial arm maze, traverse beam and rotarod were analysed by two-way ANOVA repeated measures and the Neuman–Keuls posthoc test (Statistica 6.1). The data from the closed field symmetrical maze was analysed by regular two-way ANOVA with the Neuman–Keuls posthoc test (Statistica 6.1). The data from the locomotor activity and brain microhemorrhage analysis was analysed by one-way ANOVA followed by the Neuman–Keuls posthoc test (11–24 months) or a t-test (19–24 months). When the data analysed with one-way ANOVA failed the Bartlett's test for equal variance, the Kruskal–Wallis test was performed with the Dunn's multiple comparison posthoc test. Correlation was determined by calculating the Pearson r correlation coefficient.
In the Tg2576 mouse model, Aβ deposition is usually modest around one year of age with numerous parenchymal plaques and extensive vascular amyloid observed towards the end of their second year (Hsiao et al., 1996). To compare a prophylactic vs. a therapeutic effect of Aβ-targeting immunization in an adjuvant that is approved for human use (alum), mice were immunized from (i) 11 to 24 months and (ii) 19–24 months of age. Antibody response towards the vaccine was assessed periodically, and at the end of the study the animals went through extensive behavioural testing with subsequent brain analyses of levels of Aβ and its deposition, as well as associated gliosis and cerebral bleeding. The behavioural analyses consisted of both a cognitive assessment as well as measurements of sensorimotor performance. The latter tests were run primarily to verify that cognitive performance was not influenced by abnormalities in sensory and motor systems and to assess if the vaccine affected these regions. The brain analyses were designed to determine efficacy and possible toxicity of immunization with our Aβ derivative under these conditions.
The K6Aβ1–30 immunized mice developed IgG antibodies that recognized the immunogen and Aβ1–40 (Fig. 1A). As expected, the antibody levels subsided over time but remained overall higher than levels of autoantibodies in vehicle-treated control animals. Because the animals were bled two weeks following immunization, IgM levels were similar to baseline values.
In these older animals, the immunization did not elicit measurable antibody response (Fig. 1B).
Quantitative analysis of brain Aβ deposition (plaques and vascular Aβ) revealed that the volume of total cortical Aβ deposits was reduced by 31% (P < 0.05) in mice immunized with K6Aβ1–30 in alum adjuvant from 11 to 24 months of age, compared to vehicle-treated animals (Fig. 1C). The amount of vascular Aβ deposits was near identical in the two groups and was 22% and 32% of total Aβ burden in Tg controls vs. Tg K6Aβ1–30-treated animals, respectively (Fig. 1C). Similar treatment effect was observed in total brain Aβ levels (Aβ1–40, 30% reduction, P = 0.03; Aβ1–42, 37% reduction, P = 0.02), but soluble Aβ levels were not significantly affected although there was a strong trend for lower levels of soluble Aβ1–42 in the vaccinated mice (32% reduction, P = 0.08). A comparison of the percentages of total Aβ burden (plaques and Aβ in vessels) and Aβ burden in the vasculature indicates that the vaccination preferentially removes parenchymal- rather than vascular-Aβ deposits.
Histological observation in the 11–24-month-old group indicated that immunized mice appeared to have fewer large plaques and fewer diffuse plaques of all sizes compared to control mice (Fig. 2A and B), which fits with the quantitative analysis. The measurements of total Aβ deposit burden and total Aβ levels correlated well and indicated a similar percentage reduction in the vaccinated mice. The total Aβ deposit burden correlated better with total Aβ levels (Aβ1–40, P < 0.0001; Aβ1–42, P < 0.01) than with soluble Aβ levels (Aβ1–40, NS; Aβ1–42, P < 0.05). Likewise, soluble Aβ1–40 levels did not correlate with total Aβ1–40 levels but there was a strong trend for a correlation between total and soluble Aβ1–42 levels (Aβ1–40, NS; Aβ1–42, P = 0.07). No significant gender differences were observed in plaque burden or Aβ1–40/ 42 levels but only a few males were in the study (see Table 1).
No significant difference was observed between the groups in cortical amyloid deposits or Aβ levels (Fig. 1D).
Immunization with K6Aβ1–30 in alum adjuvant did not increase the extent of brain microhemorrhages (Fig. 2C–E). However, Tg2576 mice had more iron-positive profiles per section than wild-type animals, which is likely related to vascular Aβ deposition in the transgenic mice (Kruskal–Wallis P < 0.01; Dunn's posthoc test Tg control vs. wild-type, P < 0.01; Tg K6Aβ1–30 vs. wild-type P < 0.05). To verify that our staining method would allow us to detect increases in cerebral bleeding we used positive controls. These mice had brain hemorrhages caused by intracerebral cannula placement. The bleeding in these animals was associated with the cannula track and was substantially more extensive than the microhemorrhages that we observed in the Tg mice (data not shown).
As in the other treatment group (11–24 months), immunization with K6Aβ1–30 in alum adjuvant did not increase the extent of brain microhemorrhages compared to control Tg mice (Fig. 2F).
Semiquantitative analysis of microglial staining with lectin indicated more microglial involvement with Aβ plaques in the immunized animals compared to their Tg controls but the differences were not robust (Mann–Whitney, P < 0.05; see Table 2 and Fig. 3). Subsequent staining for IL-1β that is primarily found in microglia and for GFAP, a marker of astrocytes, did not reveal obvious differences between the treatment groups.
No apparent differences were observed between the groups in microglial or astroglial activation.
The immunized mice and their vehicle controls were assessed on two cognitive tests in addition to various sensorimotor tasks. We and others have used these tests extensively in AD model mice except for the closed-field symmetrical maze, which consists of mazes of varying difficulties and was included to confirm the cognitive effect of the vaccine.
The Tg mice immunized with K6Aβ1–30 (n = 14) navigated the maze much better than the vehicle-treated Tg mice (n = 19), and their performance was similar to that of their wild-type littermates [(n = 15), Fig. 4A, ANOVA, repeated measures; group effect, P < 0.001; days effect, P = 0.198, interaction (days × treatment), P = 0.024]. Posthoc analysis revealed a treatment effect (Tg C vs. Tg K6Aβ1–30, Newman–Keuls P = 0.01). Also, wild-type mice differed from Tg controls (P = 0.001) but not from immunized Tg mice. Wild-type littermates were vaccinated with the peptide, received adjuvant alone or no injection. No difference was observed between these groups, which were then combined for subsequent analysis. The groups did not differ significantly in their time taken to run the maze (data not shown).
No difference was observed between the K6Aβ1–30 immunized mice (n = 11) and their transgenic controls (n = 8) in their performance in the radial arm maze (Fig. 4B).
The overall performance (number of errors) of the mice differed between groups (P < 0.0001) and mazes (P < 0.0001) as analysed by two-way ANOVA. There was also an interaction (P < 0.0001) between these two factors, which indicates that group performance depended on the maze that the animals were navigating. Posthoc analysis between the groups indicated that the Tg controls (n = 16) differed significantly from the Tg K6Aβ1–30 treated mice (n = 11, P < 0.001) and the wild-type mice (n = 15, P < 0.0001), whereas the TgK6Aβ1–30 mice did not differ significantly from the wild-type animals. Significant differences between individual groups were observed in Mazes 3 and 7 (Fig. 5C and G). In Maze 3, Tg controls performed worse than wild-type mice (P < 0.05), and in Maze 7, Tg controls had more errors than both wild-type mice and immunized Tg mice (P < 0.0001) but those latter two groups showed a more modest difference (P < 0.01). Of all the mazes, #7 had the most complex navigation pattern, followed by #3, as shown by the total number of errors committed. A strong trend for significance, with treated Tg mice performing similarly to wild-type littermates, was observed in #1 and 6 that are of medium difficulty (Fig. 5A and F). In the three simplest mazes (#2, 4 and 5), as judged by the number of errors committed, the three groups performed at a similar level (Fig. 5B, D and E). A similar pattern was observed when maze and group differences in the time taken to run the maze were analysed instead of the number of errors (data not shown).
Group differences were not observed in any of the seven mazes (data not shown).
The transgenic mice were more active than their wild-type littermates (n = 15) but significant differences were not observed between the K6Aβ1–30 treated (n = 12) and control Tg mice (n = 16) in any of the parameters measured (Fig. 6A). Group differences were observed in: (i) distance travelled (ANOVA, P < 0.01); (ii) average speed (ANOVA, P < 0.01) and (iii) rest time (ANOVA, P < 0.001). Maximum speed obtained did not differ between the groups. Posthoc analysis revealed that the wild-type mice travelled less distance than Tg controls (P < 0.01) or immunized Tg mice (P < 0.05). They also moved at a slower speed than both Tg groups (P < 0.01–0.05), and rested longer as well (P < 0.001–0.05).
Group differences were observed in the animals' performance on the traverse beam (Fig. 7A; ANOVA repeated measures, P < 0.05). Although the vaccinated Tg mice had more foot slips than wild-type mice (P = 0.03), they did not differ from their Tg controls. This indicates that the slips are probably related to the increased locomotor activity observed in both groups of Tg mice, compared to wild-type controls. The animals performed better on subsequent trials as expected (ANOVA, P < 0.0001) and the improvement in performance was group dependent (ANOVA, treatment × trials, P = 0.0003). On the rotarod, the groups performed equally well and the animals did better on subsequent trials as expected (Fig. 7B; ANOVA repeated measures, P = 0.0003).
No statistical difference was observed between the groups in their performance on the traverse beam, and there was a strong overall trend for fewer foot slips with more trials (Fig. 7C; ANOVA repeated measures, P = 0.06). On the rotarod, the immunized and control Tg mice performed equally well and the mice performed better on subsequent trials as expected (Fig. 7D; ANOVA repeated measures, P = 0.0023).
Whether immunotherapy for AD will go into clinical practice depends on minimizing potential side-effects. In the aborted clinical trial, toxicity was linked to excessive cell-mediated immunity while a therapeutic response was thought to be associated with humoral immunity (Bennett & Holtzman, 2005; Gilman et al., 2005; Sigurdsson, 2006). Hence, passive immunization appears feasible. However, as AD is a chronic disease, multiple injections of monotypic antibodies or Fv fragments would likely be needed, which could result in an anti-idiotypic response with subsequent complications. Furthermore, passive immunization can lead to increased cerebral hemorrhages in animal models (Pfeifer et al., 2002; Wilcock et al., 2004; Racke et al., 2005) and has been associated with encephalitis (Lee et al., 2005). Therefore, if toxicity can be reduced, active immunization may prove simpler and more effective.
Prior to the encephalitis in the clinical trial of AD vaccination, we promoted the use of an immunogen and adjuvant that favours a Th2 instead of a Th1 response (Sigurdsson et al., 2001). We have shown previously that our nontoxic, nonfibrillogenic Aβ derivatives with altered sequences to minimize Th1 response, reduce the Aβ deposit burden when used with strong adjuvants such as Freund's (Sigurdsson et al., 2001; Sigurdsson et al., 2004). In the present study we extend those observations by demonstrating that one of our homologs reduces the Aβ burden when used in conjunction with alum adjuvant, which is commonly used in humans and primarily induces a Th2 response (Gupta, 1998). This contrasts to Freund's adjuvant, which was used in most prior AD model vaccination protocols and QS-21, which was employed in the clinical trial. Alum has not been previously tested in AD mouse models. Our use of it is supported by our preliminary findings (Scholtzova et al., 2002), and a recent study, in which wild-type mice were immunized with truncated Aβ peptides (Agadjanyan et al., 2005). In that study, high titres of Aβ antibodies were generated but splenocytes were not reactive with Aβ.
We show a robust reduction of 31% in Aβ deposit burden (parenchymal and vascular) in the group treated from 11 to 24 months but vascular Aβ specifically was not altered. These findings indicate that our approach, in contrast to prior passive immunization studies does not increase vascular Aβ deposition (Wilcock et al., 2004). The reduction in deposited Aβ and total Aβ levels (30–37% reduction) correlated very well, which strengthens the findings. Soluble Aβ levels measured approximately 200- and 800-fold less than total Aβ1–40 and Aβ1–42, respectively. These substantially lower levels were not altered by the therapy, which can be explained by their small percentage of total Aβ.
While our results show a group correlation between cognitive improvements and Aβ burden, no relationship was observed when an individual animal's Aβ deposition or Aβ levels were correlated with its performance on the two cognitive tests (radial arm maze and symmetrical maze). This fits with prior reports by us and others, and it may be that behaviour will correlate more with levels of oligomeric Aβ (Janus et al., 2000; Morgan et al., 2000; Dodart et al., 2002; Kotilinek et al., 2002; Sigurdsson et al., 2004; Jensen et al., 2005). However, although plaque deposition and subsequent encapsulation by glial cells is likely to be an attempt to isolate excess Aβ that cannot be cleared, this pathological process can eventually affect neuronal connectivity, and chemicals released by reactive glial cells can be neurotoxic. Hence, any immunotherapy should at least slow the progression of plaque deposition.
Cognitive improvements were observed in the radial arm maze and the symmetrical maze. The radial arm maze has consistently allowed us to detect improvements in spatial / working memory in vaccinated mice (Sigurdsson et al., 2004). We have now confirmed these findings in another cognitive measure, the closed-field symmetrical maze, which has not been previously used for AD model mice. This test consists of several mazes of varying difficulties, that have permitted comparisons of spatial learning across species (Shore et al., 2001), and its virtual form can easily be applied to humans. Hence in future studies, the potential cognitive effects of therapy for AD could be compared using the same test in mouse models and AD patients.
To verify that the apparent enhanced cognitive abilities of the vaccinated mice were not due to unrelated behavioural effects, the mice went through a battery of sensorimotor tests. Although the transgenic mice were more active than wild-type littermates in a locomotor activity test, no differences were observed between the treated and control transgenic groups. The rotarod test did not reveal any differences between the groups and although the vaccinated transgenic mice had more foot slips than wild-type mice on the traverse beam, they did not differ from their transgenic controls, indicating that this effect is probably related to their increased locomotor activity. Also, the impaired motor balance while crossing a beam cannot explain why the vaccinated mice performed better on the cognitive tests. Overall, the results from the sensorimotor tests strengthen the findings of cognitive improvements in the radial arm maze and the closed field symmetrical maze.
We did not observe changes in Aβ burden or cognition in mice immunized from 19 to 24 months. This can likely be explained by the lack of an antibody response in these older mice, which in turn may be due to immunosenescence observed with aging and the relatively mild adjuvant employed. These findings are in agreement with a prior study showing that Aβ1–42 immunization in Freund's adjuvant at different ages reduced Aβ levels and / or Aβ deposition more effectively when treatment was initiated prior to extensive plaque development (Das et al., 2001). This has also been found to be the case with passive immunization approaches using a variety of Aβ antibodies and mouse AD models (Levites et al., 2006). However, because cognitive improvements have often been observed following immunotherapy in different AD model mice without an obvious relationship to various Aβ measurements (Janus et al., 2000; Morgan et al., 2000; Dodart et al., 2002; Kotilinek et al., 2002; Sigurdsson et al., 2004; Jensen et al., 2005), it remained to be determined if immunotherapy at a late stage of Aβ deposition could improve cognition even though plaques were not cleared.
Besides an excessive Th1 response, another potential side-effect of Aβ immunotherapy is cerebral bleeding. Several reports have shown an increase in microhemorrhages in different AD mouse models following passive intraperitoneal immunization with different monoclonal antibodies with high affinity for Aβ plaques and congophilic angiopathy (Pfeifer et al., 2002; Wilcock et al., 2004; Racke et al., 2005). This effect was not observed with yet another Aβ antibody following a single intracerebroventricular injection in the Tg2576 model (Chauhan & Siegel, 2003), or with a monoclonal Aβ antibody which binds soluble Aβ and does not recognize amyloid deposits (Racke et al., 2005). Also, in a recent study using several different Aβ antibodies, microhemorrhages were not observed even in control animals (Levites et al., 2006). However, those AD model mice were much younger than the mice in the current study or those used in the previous reports discussed above. There are no prior reports of microhemorrhage assessment following active immunization in animal models; however, the clinical trial data from the few autopsies suggest that vascular Aβ deposits were not being cleared and hemorrhage may have been increased (Nicoll et al., 2003; Ferrer et al., 2004; Masliah et al., 2005). In the present study we did not observe increased cerebral bleeding in the vaccinated mice, indicating that active immunization with an immunogen and adjuvant favouring a Th2 response, may be a safer approach than passive immunization. Our findings need to be interpreted with caution because we did not include a group that received passive immunization, but the extent of microhemorrhages in our Tg2576 control mice is similar to a previous report in the same model at a similar age (Wilcock et al., 2004). Also, our positive control sections indicated that our staining method was of a sufficient sensitivity to detect increases in vascular bleeding. The microhemorrhages are likely caused by rapid clearance of parenchymal Aβ deposits and subsequent vascular deposition by high doses of high affinity antibodies, as well as a direct immune response to Aβ laden vessels. In active immunization paradigms, a polyclonal response with antibodies of different affinities and against various epitopes is likely to have a less acute effect on Aβ clearance, which may provide for compensatory changes to minimize the detrimental effects related to rapid removal of Aβ. Because the vaccine was not immunogenic in the old treatment group (19–24 months), the present data does not clarify if active immunization such as ours would result in microhemorrhages if animals generate Aβ antibodies once extensive vascular amyloid is in place. The passive immunization studies resulting in microhemorrhages were conducted in old mice that very likely had severe congophilic amyloid angiopathy (CAA) at the onset of the treatment whereas CAA in our 11-month-old group was presumably modest.
Our results extend our previous findings showing that our Aβ derivatives can reduce Aβ burden, and lead to cognitive improvement, when used with an adjuvant suitable for humans, without any associated increase in vascular Aβ burden or microhemorrhages. As in other studies, we also found that immunization has to be initiated early in the course of pathology to be effective. This highlights the need to develop methods to detect Aβ deposits prior to the development of clinical symptoms of dementia, at which point the Aβ burden may be quite high (Wisniewski & Frangione, 2005). It can be envisioned that because a self-antigen is being targeted and individual immune responses vary, that future immunotherapy may have to be individually tailored. The aim would be to modestly shift the balance between brain Aβ accumulation and clearance. For example, an Aβ-derived immunogen may be selected based on haplotype screening to provide first a T cell-independent IgM response, which will generate antibodies that recognize different epitopes and conformations of Aβ, which may be more efficacious than targeting a single entity. If this relatively modest immune response would prove ineffective, vaccination could proceed with other Aβ derivatives predicted to elicit a slightly stronger immune response. This process could be continued until cognitive measures would improve and / or Aβ burden would be reduced as assessed by imaging techniques that are currently under development (Wadghiri et al., 2003; Klunk et al., 2004; Sigurdsson et al., 2006).
Supported by NIH grants AG020197, AG020245 and AG005891, and the Alzheimer's Association. We thank Julie Eng and Ashlyn Lines for technical assistance.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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(A scream of pure, hellish agony rips from the TV. Daphne jerks around
to stare, Niles and Martin rear back in horror)
Harvest: (enraptured) Oh, look at Cindy glow!
Cindy: (on TV) Mother of God, just kill me! (scream)
Daphne: (nervously) She seems like she's in a little pain. (scream)
Harvest: Oh, pain is just fear leaving the body.
Martin: (staring at the TV) That's a boatload of fear. (scream)
Cindy: STOP THAT DAMN DRUM BEFORE I PUT YOUR HEAD THROUGH IT! (scream)
Harvest: She laughed at that afterwards. (scream)
Daphne: I've seen enough.
(She stops the tape, cutting off the latest scream)
Harvest: Wait, wait! You'll see how Cindy pushes through the pain.
Daphne: I'm not pushing through anything. I'm having my baby the way God intended – in a hospital, numb from the waist down.
(As she escorts Harvest to the door, Martin nods in approval and reaches
for his goldfish crackers)
Daphne: Now, take your incense and your woo-woo stick and get out.
(She shuts the door on Harvest, then turns. Niles is rubbing his
nipples again)
Daphne: And you, stop acting pregnant – you're a man, for God's sakes.
(Niles drops his hands)
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User Score: 150
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subset: commoncrawl


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Foxy Brown is currently single.
Inga DeCarlo Fung Marchand (born September 6, 1978), better known by her stage name Foxy Brown, is an American rapper, model, and actress. She is best known for her solo work, as well as numerous collaborations with other artists and her brief stint ...as part of hip hop group The Firm. Raised in Brooklyn, New York, her father Keith Stahler abandoned the family at a young age to pursue his career at ERAC records. Her albums include Ill Na Na in 1996, followed by Chyna Doll in 1999, and Broken Silence in 2001. She also performed on the 1997 self-titled album by the Firm, the only album to be released by that group to date. Throughout her career, Brown has held an extensive arrest record and served some time in jail.
Connect any celebrity with Foxy Brown to see how closely they are linked... romantically!
ew she has bad taste who is she
What a waste of space! Someone needs to do the world a favor and put this low rent Ghetto B**ch out of her misery!!!!!!!
foxy is dammmm prety! i love her.
how are u doing
she was also in woo as ms. foxy woo`s sisnlaw 2 be
she is hot. i love her but icant have her
damn foxy brown
I heard Foxy suppose to be going out with Rick Ross now...
Foxy Brown: reading: Lisa Lavie: Free Your Mind: Just For You: do it right: A-L-I-N-A: Nur Für Dich/Nur Fuer Dich: Big Bad Mamma: is not clear: do what you like but do it right: all tracks like: wishing you the best to the grammy awards: you got only one life: girl you know it´s true: Van Helsing !
I am so damn happy that foxy brown got her slef out of jail
she`s with baby cham for a long time, no?


text:
A Welcome to Washington Day for newcomers held this past Saturday at the Presbyterian Church attracted a small, but interested crowd, said Paula Obermark, one of the organizers.
The event featured displays, brochures and information from a variety of groups and organizations.
You must login to view the full content on this page.
Or, use your linked account:


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A word or two --- or, I guess, about 1,000 -- about predictions. Some fans with way too much time on their hands who insist on littering my inbox with snarky to downright obnoxious hate mail seem to believe that by simple virtue of making a prediction on a game or series,
a) you take the whole exercise seriously
b) you are "not giving the other team proper respect," or
c) you're saying the other team "has no chance"
Now, I typically cut more slack to lobotomy survivors, but yeesh ... I'm simply aghast at the number of yahoos who heard our "Baseball Today" crew choose the Padres, pick the Yankees, and equate that with our claiming that the Cardinals and Tigers were a bunch of sick nuns. (Uh-oh, do sick nuns have iPods, too?) Yes, 16 of 17 ESPN analysts, including me, picked San Diego, and 17 of 17 took the Yankees. But this did not mean that we collectively thought the Cardinals had a 1 in 17 shot, and the Tigers none at all. We did, to varying degrees, discuss how the Cardinals and Tigers could win, even if the scales appeared to tilt against them.
(It goes like this -- if I tell you a coin appears to come up heads 60 percent of the time, would you pick tails just for variety's sake or to appease the Tail Lobby? Seems pretty silly. You go with what you think is more likely, no matter how slight you might consider the advantage. This is how Las Vegas pays for all the flashing lights.)
Like the Division Series themselves, our shows saw some errors, some solid at-bats, and overall, some (at least we thought) harmless fun. Below is the week that was, the rights and wrongs, the best and worst. Seriously, send us your predictions on any game or series, complete with analysis, and we'll get the best comments on the air. Just don't forget to include your e-mail address, huh?
Quotes Of The Week
Cardinals dispatch Padres
Right: "The construction of [the Padres'] roster, which now basically includes no usable bench, is a huge negative. Bases loaded, and basically no pinch hitter. Bruce Bochy has gone with veterans across the board instead of using the guys who played in Portland this season -- the problem is, the guys in Portland are better hitters than the guys he has on his roster. That's exactly the kind of bench that Tony La Russa must be salivating over." (Rob Neyer, before Game 2)
Wrong: "I think La Russa is very, very good at getting his teams into the postseason. I also think that sometimes in the postseason he's been outmanaged, and other times, the fact that his teams aren't really that strong, like the Cardinals in 2004, comes to the fore when he faces a really good team. This year, of course, he's got the weakest team he's ever brought to the postseason. ... If they advance past the Padres, it'll be pretty shocking." (Gary Gillette)
Tigers stun Yankees
Right: "I'm taking Justin Verlander. I think he's gonna throw five or six pretty good innings, come out with it 3-2 or something, and Joel Zumaya's gonna be able to come in for two innings, because he is rested. I think Joel Zumaya's gonna be a real force today. I think he might end up being the story." (Alan Schwarz, before Game 2)
Wrong: "[Verlander] has 14 innings since Sept. 7, right? It's funny, people have talked about how tired he is. It might be more the fact that he hasn't had enough work. ... I really don't particularly like his odds against that Yankee lineup. The Yankees faced him earlier this season and basically clocked him, and that was around the time when he was pitching great. (Jerry Crasnick, before Game 2)
Mets sweep Dodgers
Right: "I'd start John Maine. John Maine's ERA in 15 starts this season is actually better than Derek Lowe's, who's gonna start for the Dodgers. Is he as good a pitcher as Derek Lowe? No, he's not. But you have to roll the dice a little bit." (Rob Neyer, before Game 1)
Wrong: "I think the Dodgers are gonna give the Mets a heck of a run. ... This is before the Orlando Hernandez injury. I think the Mets are ripe for a fall, and I think the Dodgers are considerably more dangerous than people are giving them credit for." (Alan Schwarz)
A's rock Twins
Right: "Dan Haren can run that fastball up there very, very well. I'm going Oakland to finish this series off in a sweep today. I think going back home, power arm on the mound, Brad Radke's a great story ... but he has the type of stuff that gets knocked around in the postseason." (Steve Phillips, before Game 3)
Wrong: "The Twins -- they can win without Santana. If they couldn't, they wouldn't have done as well as they did in the second half. ... I'll take the Twins [today] with Joe Mauer having a big day." (Rob Neyer, before Game 2)
Listener Mail
"I applaud the Dodgers for their aggressive play. Everyone is coming down on them for the two outs at home, and saying that losing that game by one run may cost them this series, but I think that kind of play is what will win them this series."
--Alan (Long Beach, Calif.)
"I actually like the Cardinals in a short series, especially against the Padres. The first round is the singular round Tony La Russa's clubs are proficient at winning. They can do the short ones."
--Gavin Morgan (Portland, Ore.)
"I've heard a lot about how it's better to have hard throwers in the postseason than finesse pitchers. ... Personally, I'd love to have an experienced Greg Maddux over a young flamethrower any day."
--Steve (Oklahoma City, Okla.)
Crystal Ball Standings
As if trading Jason Isringhausen for Billy Taylor weren't enough, this could have been the week when immortality found Steve Phillips. Our favorite GM-turned-analyst picked all three of his games correctly on Friday to pull ahead in the Crystal Ball standings, with former leader Rob Neyer taking his second straight 0-for-3. Will Steve meet the same fate as Rob over the last three weeks? Will Jerry Crasnick continue his stealthy pursuit of the top? Stay tuned ...
Alan Schwarz is the host of ESPN.com's Baseball Today and the senior writer of Baseball America. His book, "The Numbers Game: Baseball's Lifelong Fascination With Statistics," can be ordered on Alan's Web site.


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→EyGordini← 👉"Soñemos con un mundo perfecto en donde no exista la discriminación"👈 #LaGordaNaii #Smiler #Cosplay #LGBT #Vegetariana #SakuraHarunoCosplay 👭😝😛😜⚽🍕🔫🎷🎧💅 #ArgentinaCosplay #Argentina #HinataCosplay
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For some, there's only a thin line between cosplay and Reenactment. But believe me...these two things are totally different ;-)
Hi. Im Sen ! Cosplayer from Jakarta, Indonesia. Vocalist. Fate Series lovers. Thank you for follow and support me ! find and follow me on : soundcloud : sen0v0 instagram : sen.plurinne Hope y'all enjoy my Cosplay works~ Let's be friend and enjoy cosplaying~
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Hi, I'm Yu, I'm a stalker, isn't coser =)))) I want to cosplay but I don't ave monney :'( I hope I can cosplay in the future <3
A photographer, and my hobby is cosplay photography, thou im not always doin cosplay photography. I started as a cosplay photographer in 2012, but recently i just made my World Cosplay account. Currently reside in Indonesia. Hope i can bring a memorable yet amazing photo for you guys! :D ah, kindly visit our facebook page : https://www.facebook.com/OkutabiPhotography Thanks for visiting my page here! XD
Hi my name is Ginanjar :o I've known a cosplay since 2004 ^o^ I live in Surabaya East Java Indonesia ;) i will following all of you ... ^^; heheheheheh.... nice to meet you cosplayers :p WOW new fitures!!! chatting!! :v let's chatting everyone!! XD~~ sorry if my english is bad :'(
コスプレ/ファション/描く。 Cosplayer/Japanese Fashion/Drawing stuff. FB [PROFILE] facebook.com/vivienneprofile FB [PAGE] facebook.com/viviennecorner TWITTER twitter.com/viviennecorner D.ART viviennecorner.deviantart.com INSTA. instagram.com/viviennecorner
Yoroshiku minna :) Facebook★https://www.facebook.com/felicialiang94


text:
Why is it that some make a Shehechiyanu at a Bris and some don't? And an identification of those who do and do not would be appreciated.
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Sefardim make a Shecheyanu at a bris. This is also the prevailing custom among Ashkenazim (and everyone else) in Israel.
Also see this article on the topic, as well as the footnotes here.


text:
The water-based colorants of Outlast Lipstain give lips a beautiful, lightweight flush of color that won't come off, lasting for hours without the heavy look or feel of an ordinary lipstick. Its pen-like precision applicator makes it easy to define your lips – just draw on the lip stain color without any hassle!
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New York
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Skin Tone:
Great lip lining & staying power! Wonderful in summer! Won't melt in my purse or even in the car. Feels like nothing on your lips when out for a run!
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Skin Tone:
I LOVE this lip stain. I like to call it a lip enhancer because I still feel natural and clean wearing this, and it stays put!


text:
Menopause Health Center
When Will You Reach Menopause?
It's a question many women wonder about, especially if you're thinking about planning a family and your 20s are but a distant memory.
How many more years of fertility might you have, and how much longer will it be before you start experiencing "the change?"
Recommended Related to Menopause
Hormone Therapy for Menopause and Perimenopause
By Francesca ColtreraYour need-to-know guide to today's hormone therapy -- what's safe, what's new, what's right for you Not long ago, a friend told me about a coffee date she'd had with a 50-something former office mate, Susan. As the two women were sipping their lattes and catching up on each other's lives, Susan nervously glanced around the coffee shop, then leaned across the table and confided in a low voice, "I'm taking estrogen." So it's come to this. Whereas women once chatted openly about...
Read the Hormone Therapy for Menopause and Perimenopause article > >
Here's what does -- and does not influence the age at when a woman reaches menopause.
The Top Factor
There are a number of factors that affect a woman's age at menopause, but one is more important than any other: the age her mother experienced menopause.
"Menopause is strongly genetically linked, so you're very likely to fall within a few years either way of the age your mother was at menopause," says Nanette Santoro, MD, director of the division of reproductive endocrinology and infertility at the University of Colorado-Denver School of Medicine and a member of the board of directors of the American Society for Reproductive Medicine.
This isn't always true, of course. Some women reach menopause at an unusually early age -- before 45 or so -- with no known cause, which could be the result of an inherited issue or a one-time genetic mutation. "These can be random events, but can also be passed on," says Howard Zacur, MD, PhD, who directs the reproductive endocrinology and infertility division at Johns Hopkins School of Medicine.
So if your mother reached menopause at 40, but her sisters and your grandmother were all around the average age of 50, it's unclear whether you'll follow her path or theirs.
But if most of the women in your family, your mother included, reach menopause early, late, or somewhere in the middle, you can eye your calendar with some degree of confidence.
Menopause Age: 4 More Influences
Your mother's age at menopause is a key factor, but not the only one. Here are four others to consider:
- Smoking . No other lifestyle factor does more damage to your ovaries than smoking. So if you smoke and your mother didn't, you'll probably reach menopause earlier than she did. If she smoked and you don't, you probably reach menopause later than she did.
- Chemotherapy . Most forms of chemotherapy used in younger women are at least mildly toxic to the ovaries. Many women go through temporary menopause while undergoing chemotherapy; if cycles do return (they don't always), you can still expect to reach regular menopause a couple of years earlier than you otherwise would have.
- Ovarian surgery. "The more you operate on the ovaries, the more healthy tissue gets damaged," says Marcelle Cedars, MD, director of the division of reproductive endocrinology at the University of California, San Francisco, School of Medicine. So if you've had diagnostic surgery for endometriosis, for example, Cedars recommends using medical options (such as hormonal suppression) to treat the condition in order to avoid repetitive surgeries.
- Ethnicity. "Certain ethnic groups may have menopause at slightly different ages," says Santoro. "Hispanic and African-American women reach menopause a little earlier, and Chinese and Japanese women a little later, than the average Caucasian woman, who reaches menopause at about age 51.5." Those are averages; every woman is different.


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On Second Thought is a one-hour, daily news talk show that airs at 9 a.m. ET weekdays.
Discover hidden treasures including an 18th-century Chinese cinnabar lacquer box and a shadow box that may have been made by Joseph Cornell. Thursday, July 28 at 7 PM
National Signing Day is over and the reigning AAAAAA Champions, the Colquitt County Packers, had 25 players sign letters of intent on National Signing Day. I had a chance to go one-on-one with Head... MORE
Make your secure online donation at GPB.org.
Sat., August 24, 2013 7:00am
Fulton County Limits Travel And Training
— The Fulton County Board of Commissioners has approved a resolution imposing a temporary moratorium on some employee travel and training expenses and calling for a review of county policies.
Full Story


text:
Meet the CHEW CREW
|Barbara Gwinn Schubert, MHS, MCHES is the Associate Director for the Center for Health Education & Wellness. She holds a Bachelors Degree in Social Work/Sociology from UMBC and a Masters of Health Science with a concentration in Community Health from Towson University. She advises Stressbusters but also works closely with CHEW's other student groups as well as numerous campus departments to create a healthier JHU community. Prior to Hopkins, her career in health education included community outreach for the Epilepsy Association of Maryland and managing Cancer Control initiatives for the Mid-Atlantic Division of the American Cancer Society. She has also taught as an Adjunct Professor in the Health Science Department at Towson University. She is a member of the American College Health Association and the Society for Public Health Education. Barbara can be reached at email@example.com
|Alyse Campbell, MSW,LGSW is the Sexual Violence Prevention, Education & Response Coordinator for the Center for Health and Wellness. She holds a Bachelors Degree in Womens Studies from Goucher College, a Masters Degree in Social Work from University of Maryland, Baltimore, and is a licensed Social Worker. At JHU, she advises the Bystander Intervention Training (BIT) program and SARU, the Sexual Assault Resource Unit (SARU). Formerly, she worked as the Connector for the Susan G. Komen Breast Link program at Saint Agnes hospital. There she assisted underserved women in Baltimore City in obtaining mammograms, created awareness raising groups, and acted as a patient advocate. She also teaches Womens Studies at the Community College of Baltimore County. Alyse can be reached at email@example.com
Student Groups
- Bystander Intervention Training (BIT) program
- BIT is an interactive, student-facilitated training that aims to engage everyone in preventing gender violence on the JHU Homewood campus. Bystander Intervention Training helps students identify situations of concern, and provides knowledge and tools to encourage safe and successful interventions. Adapted from a curriculum developed at the University of New Hampshire and Duke Univeristy, the goal of the program is to reduce the incidence of sexual and relationship violence on campus by training particpants to intervene in safe and creative ways, rather than standing aside as a passive bystander.If you would like to schedule a BIT program for your student group, please contact firstname.lastname@example.com
- Hopkins Kicks Butts (HKB) [homepage] Student-led coalition which works to support and advocate national, state, local, and university anti-tobacco related policies and activities. Committee members are needed to serve on the coalition.
- PEEPs [homepage]
- PEEPs (Preventative Education & Empowerment for Peers) are part of a peer health education program designed to provide a setting in which students can discuss and explore health issues. PEEPS are trained to present health information for their peers on a variety of topics such as healthy living, sexual health, nutrition, stress management, and alcohol, drugs, and tobacco.
- Stressbusters [homepage]
- Stressbusters provide FREE five minute back-rubs to other students and staff at events or meetings to promote relaxation. You can become a stressbuster: the requirements are stress free & the training is for life!


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- Bacterial Infections 101 Pictures Slideshow
- Take the Tummy Trouble Quiz
- Hepatitis C Pictures Slideshow
- Meningococcemia facts
- What is meningococcemia?
- What causes meningococcemia?
- What are risk factors for meningococcemia?
- What are symptoms and signs of meningococcemia?
- How is meningococcemia diagnosed?
- What is the treatment for meningococcemia?
- What is the prognosis of meningococcemia?
- Is it possible to prevent meningococcemia?
- Where can people find more information on meningococcemia?
What is meningococcemia?
Meningococcemia is a bacterial infection of the blood due to Neisseria meningitidis. This bacterium is most famous for causing meningococcal meningitis which may also be present in meningococcemia. Many bacteria can cause bloodstream infections (septicemia), including staphylococci, Streptococcus B, or Streptococcus A. In addition, other bacteria can cause meningitis, including Streptococcus pneumoniae or leptospirosis. However, N. meningitidis is concerning because it is more contagious than these other bacteria and causes very serious disease. Rates of infection are typically highest in older children and adolescents, although meningococcemia has been reported in all age groups.
What causes meningococcemia?
As mentioned, the bacterium that causes meningococcemia is called N. meningitidis, also known as "meningococcus." Meningococcemia may also be called meningococcal bacteremia. Under the microscope, the bacteria usually appear in pairs, looking like two small kidney beans side by side. N. meningitidis is surrounded by a capsule made of complex carbohydrates called polysaccharides. These polysaccharides stimulate the immune system, which helps the body fight the infection. There are several different types (serogroups) of N. meningitidis. Most human disease is caused by serogroups A, B, C, Y, and W135.
Transmission of N. meningitidis is from person to person through respiratory secretions. Some people can harbor the bacteria in their throats and not get sick, which is called a "carrier" state. In others, the bacteria rapidly invade the tissues and bloodstream and cause disease.


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50+: Live Better, Longer
News Related to Healthy Seniors
Recessions May Contribute to Mental Decline Years Later: Study
By Robert Preidt HealthDay Reporter THURSDAY, Nov. 21, 2013 (HealthDay News) -- Recessions can have long-lasting effects, and they may not be just financial. A new study has found that people affected by an economic downturn in middle age may be at risk for mental decline later in life. ResearchersRead Full Article
Cells Show Signs of Faster Aging After Depression
By Brenda Goodman HealthDay Reporter TUESDAY, Nov. 12 (HealthDay News) -- The cells of people who have had depression may age more quickly, a new study suggests. Dutch researchers compared cell structures called telomeres in more than 2,400 people with and without depression. Like the plastic tips aRead Full Article
Jury Still Out on Routine Mental Tests for Seniors, Panel Says
By Randy Dotinga HealthDay Reporter MONDAY, Nov. 4 (HealthDay News) -- Physicians give screening tests to older adults who show signs of mental decline, and some experts have theorized that all seniors might benefit from routine memory testing. But proposed guidelines from a U.S. government-appointeRead Full Article
Mediterranean Diet May Help Women Live Longer, Healthier Lives
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The top 10 songs and albums on the iTunes Store
iTunes' Official Music Charts for the week ending Nov. 26, 2015:
Top Songs
1. Hello, Adele
2. Sorry, Justin Bieber
3. Love Yourself, Justin Bieber
4. When We Were Young, Adele
5. Hotline Bling, Drake
6. Like I'm Gonna Lose You (feat. John Legend), Meghan Trainor
7. Same Old Love, Selena Gomez
8. What Do You Mean?, Justin Bieber
9. Ex's & Oh's, Elle King
10. Stitches, Shawn Mendes
Top Albums
1. 25, Adele
2. Purpose (Deluxe), Justin Bieber
3. Top 5 Dead or Alive, Jadakiss
4. That's Christmas To Me, Pentatonix
5. Traveller, Chris Stapleton
6. Made In The A.M., One Direction
7. 21, Adele
8. Beauty Behind the Madness, The Weeknd
9. Dark Sky Island (Deluxe), Enya
10. A Head Full of Dreams, Coldplay
(copyright) 2015 Apple Inc.
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End of Millennium: The Information Age: Economy, Society, and Culture Volume III / Edition 2by Manuel Castells
Pub. Date: 04/12/2010
Publisher: Wiley
This final volume in Manuel Castells' trilogy, with a substantial new preface, is devoted to processes of global social change induced by the transition from the old industrial society to the emerging global network society.
- Explains why China, rather than Japan, is the economic and political actor that is revolutionizing the global system /li>
This final volume in Manuel Castells' trilogy, with a substantial new preface, is devoted to processes of global social change induced by the transition from the old industrial society to the emerging global network society.
- Explains why China, rather than Japan, is the economic and political actor that is revolutionizing the global system
- Reflects on the contradictions of European unification, proposing the concept of the network state
- Substantial new preface assesses the validity of the theoretical construction presented in the conclusion of the trilogy, proposing some conceptual modifications in light of the observed experience
Product Details
- 9781405196888
- Publisher:
- Wiley
- Publication date:
- 04/12/2010
- Series:
- Information Age Series, #10
- Edition description:
- 2nd Edition with a New Preface
- Pages:
- 488
- Sales rank:
- 647,542
- Product dimensions:
- 5.90(w) x 8.90(h) x 1.20(d)
Table of Contents
List of Tables xi
List of Figures xii
List of Charts xiii
Preface to the 2010 Edition of End of Millennium xiv
Acknowledgments 1997 xxvii
A Time of Change 1
1 The Crisis of Industrial Statism and the Collapse of the Soviet Union 5
The Extensive Model of Economic Growth and the Limits of Hyperindustrialism 10
The Technology Question 26
The Abduction of Identity and the Crisis of Soviet Federalism 37
The Last Perestroika 46
Nationalism, Democracy, and the Disintegration of the Soviet State 56
The Scars of History, the Lessons for Theory, the Legacy for Society 62
2 The Rise of the Fourth World: Informational Capitalism, Poverty, and Social Exclusion 69
Toward a Polarized World? A Global Overview 74
The De-humanization of Africa 85
Marginalization and selective integration of Sub-Saharan Africa in the informational-global economy 85
Africa's technological apartheid at the dawn of the Information Age 93
The predatory State 97
Zaïre: the personal appropriation of the state 100
Nigeria: oil, ethnicity, and military predation 103
Ethnic Identity, economic globalization, and state formation in Africa 106
Africa's plight 116
Africa's hope? The South African connection 123
Out of Africa or back to Africa? The politics and economics of self-reliance 128
The New American Dilemma: Inequality, Urban Poverty, and Social Exclusion in the Information Age 130
Dual America 131
The inner-city ghetto as a system of social exclusion 142
When the underclass goes to hell 150
Globalization, Over-exploitation, and Social Exclusion: the View from the Children 154
The sexual exploitation of children 159
The killing of children: war massacres and child soldiers 162
Why children are wasted 164
Conclusion: the Black Holes of Informational Capitalism 166
3 The Perverse Connection: the Global Criminal Economy 171
Organizational Globalization of Crime, Cultural Identification of Criminals 173
The Pillage of Russia 185
The structural perspective 189
Identifying the actors 190
Mechanisms of Accumulation 193
Narcotrafico, Development, and Dependency in Latin America 198
What are the economic consequences of the drugs industry for Latin America? 202
Why Colombia? 204
The Impact of Global Crime on Economy, Politics, and Culture 209
4 Development and Crisis in the Asian Pacific: Globalization and the State 215
The Changing Fortunes of the Asian Pacific 215
Heisei's Japan: Developmental State versus Information Society 223
A social model of the Japanese developmental process 225
Declining sun: the crisis of the Japanese model of development 236
The end of "Nagatacho politics" 248
Hatten Hokka and Johoka Shakai: a contradictory relationship 251
Japan and the Pacific 258
Beheading the Dragon? Four Asian Tigers with a Dragon Head, and their Civil Societies 259
Understanding Asian development 261
Singapore: state nation-building via multinational corporations 262
South Korea: the state production of oligopolistic capitalism 266
Taiwan: flexible capitalism under the guidance of an inflexible state 270
Hong Kong model versus Hong Kong reality: small business in a world economy, and the colonial version of the welfare state 274
The breeding of the tigers: commonalities and dissimilarities in their process of economic development 279
The developmental state in East Asian industrialization: on the concept of the developmental state 286
The rise of the developmental state: from the politics of survival to the process of nation-building 288
The state and civil society in the restructuring of East Asia: how the developmental state succeeded in the development process 293
Divergent paths: Asian "tigers" in the economic crisis 297
Democracy, identity, and development in East Asia in the 1990s 303
Chinese Developmental Nationalism with Socialist Characteristics 311
The new Chinese revolution 312
Guanxi capitalism? China in the global economy 317
China's regional developmental states and the bureaucratic (capitalist) entrepreneurs 321
Weathering the storm? China in the Asian economic crisis 325
Democracy, development, and nationalism in the new China 328
Conclusion: Globalization and the State 337
5 The Unification of Europe: Globalization, Identity, and the Network State 342
European Unification as a Sequence of Defensive Reactions: a Half-century Perspective 344
Globalization and European Integration 352
Cultural Identity and European Unification 361
The Institutionalization of Europe: the Network State 365
European Identity or European Project? 368
Conclusion: Making Sense of Our World 371
Genesis of a New World 372
A New Society 376
The New Avenues of Social Change 387
Beyond this Millennium 389
What is to be Done? 394
Finale 395
Summary of Contents of Volumes I and II 397
References 399
Index 433
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Posted 30 June 2011 - 11:32 PM
It took 2 years for Queen Anne's Revenge to sail round the LEGO Caribbean and sink every ship in her midst. The Barracuda, Schooner, Rum Runner, Bounty; all were overrun by the ferocity of her cannons and crew. Likewise, every port she settled in was ravaged beyond recognition, the victims strung up from masts for all to see.
It fell on us redcoats to stem the tide of flesh-toned hate, and send Blackbeard plus crew to meet the Devil. Our Flagship, the true power of these waters, sailed for months following the trail of bodies and bricks she left behind, like a shark seeking blood from a corpse.
Nightfall. We came upon her by surprise, and only by this means did we gain any advantage. Despite our four guns launching numerous volleys, the ship fought like a lion, as if desperate to take us to the ocean's grave along with her. We had to muster the courage of King and country to board her vile deck. The cursed crew and zombie officers were both horrific and brutal. And least should we forget Blackbeard himself, who took his own daughter hostage and threw her against us with a gift in her bosom: a stick of dynamite. And yet, despite all this, we survived the night and saw the enemy sink in a fiery collection of brick and sail.
However so much had been lost, that our victory was hollow. And just when we prepared to leave we were blindsided. The Black Pearl rose up from the sea and opened fire. We knew that this was the end for us all. Some took their lives, while others, like the Admiral, simply stood and watched the horror overtake him. Me? I finished this letter and prepared to meet death with cutlass in hand.
Posted 01 July 2011 - 12:48 AM
I am again impressed by the variety of entries in this contest. Here, a letter or journal entry depicting the final days of the classic redcoats and I assume, the LEGO Pirates as well. What I love about this is how it reminds me of a journal recovered from a naval officer. I love history, so in this sense it speaks to me.
Also, I like the tone with which you took this; it is dark and disturbing in some instances (particularly the part with Blackbeard and his daughter, which I think is spot on, considering that in the movie he was very much not above using his daughter to achieve his own means). It also works for me because you took out the typical elements of Jack, Barbossa, etc and instead gave the reader a tooth and nail slugfest between the QAR and the Imperial Flagship, which I believe up until now, has yet to be mentioned in the contest.
Can't say enough about the ending as well; I love that eerie last sentence, and kudos to the sailor who wrote the letter for going down fighting :) The inclusion of the Pearl was also a nice touch, playing on everyone's anticipation (or disappointment) with the upcoming ship.
There are a couple of things to point out; a few minor and another one that I think should be looked into. For starters, the first line should have a 'the' before Queen Anne's Revenge.
Next is the first line of the third paragraph which should have 'these means' instead of 'this means'. Again, just minor stuff that you don't want to cost you points. Like I told one of the other writers, you don't want to have grammar be the difference between your story and someone else's entry.
This sentence is a bit tricky:
"while others, like the Admiral, simply stood and watched the horror overtake him"
I think you meant to say that other people, such as the Admiral, stood and let themselves die. Keyword here is the plural at the end. If you take out the part of the Admiral:
"while others simply stood and watched the horror overtake him."
It should be obvious here how it makes more sense if 'him' is them'.
Finally, there is one thing that concerns me about this entry. While there is mention of the yellow head Pirates here, namely from Pirates II, does that qualify for Classic LEGO Pirates? I think the contest rules called for the classic LEGO pirates to encounter Pirates of the Caribbean:
"To write a short story (300 words or less) about the classic LEGO Pirates encountering the characters/vessels/locations from the Pirates of the Caribbean franchise."
While I understand that classic pirates have the 6271 Imperial Flagship, I believe you are referring to the new Imperial Flagship no? What adds some controversy to this as well is that you do mention some classic Pirate ships (BSB, SES) that the QAR sank in the beginning of the letter. Is this enough to warrant a meeting/encounter between POTC and classic LEGO Pirates? If it becomes a problem, I would suggest changing the redcoats to bluecoats and that the ship in question be the Caribbean Clipper instead of the IF. That would keep your story intact! Unless of course Pirates II is considered part of classic Pirates; at which point my concern is unwarranted.
Sorry for the long post, just wanted to lend a hand, particularly with the last part in case it violates the rules.
Good Luck!
Posted 01 July 2011 - 05:41 AM
Edited by Cap'n Crunch, 01 July 2011 - 05:42 AM.
Fan of sugarythirsty pirates
Posted 01 July 2011 - 07:51 AM
I'd just add here I'd finish the last sentence like this ... prepared to meet death with a cutlass in my hand. I didn't count the words, so I don't know how you're doing.
As for the content part, I think there's too many real fans of POTC movies rather than only LEGO fans (including me) and therefor are disturbed by facts that were not in the movies instead of imagining that in LEGO world anything is possible. Therefor I too would change the Black Pearl with the Flying Dutchman. It's one of the ships everyone is eagerly waiting for, but noone survived to discribe how it looks like.
I have no other problems with the content. Even if you leave the Black Pearl in it could easily sink the Imperial flagship, since I presume after a big fight with QAR it was heavily damaged! And about the classic pirates, I do think the 2009 line should also go into that group, but let the moderator answer you this one or ask in the competition rules to be sure.
Posted 01 July 2011 - 08:25 PM
You've already gotten a lot of specific comments, some of which I agree with and some that I don't.
I agree with Bricks4Fun, that this line should be changed from "him" to "them":
"while others, like the Admiral, simply stood and watched the horror overtake him"
I understand that you've left out words here and there, probably to make it under 300, but I actually like this styling as it fits with the dialect of the time, if this were a real historical period.
I don't mean to pick on Bricks4Fun, but I disagree with this suggestion: "Next is the first line of the third paragraph which should have 'these means' instead of 'this means'."
It actually should remain this because the word "means" can be used for singular or plural identification. The word itself contains the s, but it does not make it plural. Consider this phrase: "The means justifies the end." Means is a way of doing something. It could be a single thing or many. So your sentence should remain as you wrote.
Like everyone else, it doesn't fit with the movies to have the Black Pearl to rise out the water. If you want to keep the Black Pearl, I'd suggest having it sail in. Otherwise, change it to Flying Dutchman to rise up out of the water.
I personally think any pirates that is not POTC would classify as Classic. But you can always ask on the main contest thread for clarification.
Check out my profile & blog entries at The Brick Blogger
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Posted 02 July 2011 - 03:39 AM
Bricks4fun thank you in particular for your insightful and supportive commentary, I will now ask the mods if my story counts for the contest because of the characters. I would've never picked up such an oversight and it would've been pretty bad for me if I would've been disqualified for not including the proper characters. Also, thanks for giving me a quick fix by including the bluecoats if I have to change it, very clever! Just to be safe, I think I will change the ending to accommodate a more LEGO type encounter based on cannons and size. One thing to remember though is that the Black Pearl did rise up out of the water in the 3rd movie when it crossed over from the world of the dead. But I agree its better if its the Flying Dutchman.
Posted 03 July 2011 - 12:14 AM
Julie - Thanks, I'm glad you found my comments useful! I'll be around to read the revision and best of luck in the contest!
Edited by Bricks4Fun, 03 July 2011 - 12:19 AM.
Posted 07 July 2011 - 08:01 PM
Want to throw out a few opinions before the end. Typically, in a literary work you will spell out numbers like "two" instead of writing them in their numeric form.
Also, it's true that the Black Pearl rose out of the water, but from my recollection no one was prepared for fighting unlike the Dutchman. And since there currently is no LEGO version of the Dutchman, I'd recommend that the Black Pearl simply flanked the ship. As it is, it's at night so this is very likely since no one would be on the watch with a battle raging on one side of their decks.
If you want something that sounds more poetic, you could say that "it seemed" like the Black Pearl rose from the depths.
Hope this helps.
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