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Journal of the Association for Research in Otolaryngology
© Association for Research in Otolaryngology 201010.1007/s10162-009-0204-9
Protection against Noise-Induced Hearing Loss in Young CBA/J Mice by Low-Dose Kanamycin
Program in Audiology and Communication Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
Fay and Carl Simons Center for Biology of Hearing and Deafness, Department of Otolaryngology, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, USA
Kevin K. Ohlemiller
Email: email@example.com
Received: 23 July 2009Accepted: 9 December 2009Published online: 22 January 2010
Animal studies indicate that a combination of kanamycin (KM) and noise produces a synergistic effect, whereby the threshold shift from the combination is greater than the sum of the shifts caused by either agent alone. Most such studies have focused on adult animals, and it has remained unclear whether younger, presumably more susceptible, animals show an even greater synergistic effect. The present study tested the hypothesis that young CBA/J mice receiving a low dose of KM (300 mg/kg, 2×/day, s.c.) from 20 to 30 days post-gestational age followed by brief noise exposure (110 dB SPL; 4–45 kHz, 30 s) would show greater noise-induced permanent threshold shifts (NIPTS) than mice receiving either treatment alone. Noise exposure produced 30–40 dB of NIPTS and moderate hair cell loss in young saline-treated mice. KM alone at this dose had no effect on thresholds. Surprisingly, mice receiving KM plus noise were protected from NIPTS, showing ABR thresholds not significantly different from unexposed controls. Mice receiving KM prior to noise exposure also showed significantly less outer hair cell loss than saline-treated mice. Additional experiments indicated protection by KM when the noise was applied either 24 or 48 h after the last KM injection. Our results demonstrate a powerful protective effect of sub-chronic low-dose kanamycin against NIPTS in young CBA/J mice. Repeated kanamycin exposure may establish a preconditioned protective state, the molecular bases of which remain to be determined.
Keywordsototoxicity preconditioning aminoglycosides cochlea hair cells development
The estimated incidence of clinically significant bilateral hearing loss in infants has been estimated at one per 500 live births (Mehl and Thomson 1998). Events that occur in the early days of life, including exposure to ototoxic antibiotics and/or noise, may result in an acquired hearing loss that is labeled congenital. Medically fragile neonates often receive antibiotics and may experience noise peaks of up to 125 dB SPL during emergency transport via aircraft (Skeoch et al. 2005; Shenai 1977; Buckland et al. 2003). This practice has remained, even though human neonates may be particularly susceptible to noise, ototoxins, and their combination (Henley and Rybak 1995; Bernard 1981; Li and Steyger 2009). Presently, the risk of noise-induced permanent threshold shifts (NIPTS) to human infants is largely uncharacterized.
An early window of heightened vulnerability to both noise and a wide variety of ototoxicants is well supported by animal studies (e.g., Pujol 1992; Bombard et al. 2005; Bernard 1981; Lataye et al. 2004; Rybak et al. 1991; Henley and Rybak 1995; Pryor et al. 1984). Cochlear targets most affected during this window include hair cells, neurons, and stria vascularis. Thus, no special susceptibility of any single structure or cell type can provide a complete explanation. Animal studies also support synergistic interaction between noise and ototoxins, at least in adults (e.g., Dayal et al. 1971; Dayal and Barek 1975; Marques et al. 1975; Hawkins et al. 1975; Ryan and Bone 1978; Brown et al. 1980; Brummett et al. 1992). Most of these applied high levels of noise and ototoxins. However, Brummett et al. (1992) identified a synergistic effect between subclinical doses of white noise (as low as 75 dBA) and kanamycin (300 mg/kg) on hair cell loss in adult guinea pigs. It has remained unclear to date whether such synergy extends to neonates or is perhaps even more pronounced in neonates (Humes 1984; Henley and Rybak 1995; Li and Steyger 2009).
Here, we explore the interaction of sub-chronic, low-dose kanamycin (KM) and damaging noise using young (post-wean) CBA/J inbred mice as a model. The laboratory mouse is a well-established model for human auditory conditions, as it possesses similar cochlear anatomy and physiology and similar patterns of age-related, noise-induced, and ototoxicity-related hearing loss (Ohlemiller 2006; Wang and Steyger 2009; Wu et al. 2001; Henry and McGinn 1992). Among inbred strains, CBA/J mice are frequently used as a "good hearing" strain that is resistant to age-associated pathology. Like other animals and humans, young mice are especially susceptible to NIPTS (Henry 1983; Ohlemiller et al. 2000). Noise vulnerability in mice appears greatest during the first month then gradually decreases up to about 4 months of age (Henry 1983). Young mice also show greater susceptibility to ototoxins (Henry et al. 1981; Chen and Aberdeen 1980; Chen and Saunders 1983). Similar to the pattern for noise, vulnerability to aminoglycosides in mice appears maximal during the first month. After 1 month, it can be difficult to elicit ototoxic injury in mice without co-administration of ethacrynic acid or furosemide (Wu et al. 2001; Taylor et al. 2008). In keeping with the literature, we hypothesized that young mice would show stronger KM plus noise synergistic effects on hearing than have been reported in adult animals. As we show, the nature of the interaction was surprisingly one of prevention of NIPTS, not potentiation.
Our study population included a total of 59 post-weanling CBA/J mice. All experimental groups included both genders. Most mice were bred from in-house breeding pairs, while a few of the animals were obtained directly from The Jackson Laboratory. Mice were assigned to one of seven primary experimental groups (Table 1) that included: No treatment, Noise alone, KM alone, KM plus noise, and Saline plus noise. An additional control group including mice that received the standard KM regimen but underwent ABR testing at the time noise exposure would have occurred. These mice served to detect any threshold elevation due to KM at the time of noise exposure. Another control group tested the effects of single dose of KM (300 mg/kg) administered 1 h prior to noise. These were intended to differentiate between the effects of a repeated KM dosing regimen versus a single dose. Finally, two smaller experimental groups tested the effects of KM on NIPTS when noise exposure was delayed by 24 or 48 h (N = 4 each) after the last KM dose. All procedures were approved by the Animal Studies Committee at Washington University School of Medicine.
Average ABR thresholds by experimental group at each test frequency
5 kHz
10 kHz
20 kHz
28.3 kHz
40 kHz
No treatment
41.44 (4.64)
23.56 (4.64)
31.67 (7.91)
32.11 (6.51)
38.33 (8.29)
Noise alone
68.11 (18.67)
58.56 (20.07)
64.44 (24.30)
73.78 (27.05)
90.00 (22.91)
KM alone ABR 10 days post noise
39.22 (3.63)
22.44 (1.67)
25.56 (3.00)
31.00 (5.00)
36.25 (9.71)
KM alone ABR same day
40.13 (5.30)
24.88 (2.59)
31.63 (6.78)
32.50 (4.63)
40.63 (4.17)
KM + Noise
42.63 (6.23)
22.38 (4.17)
30.63 (4.96)
34.13 (4.58)
53.13 (19.45)
Saline + Noise
67.00 (15.28)
63.71 (17.42)
66.00 (18.25)
75.71 (7.32)
82.86 (6.36)
1 dose KM + Noise
68.11 (17.81)
57.44 (21.28)
69.00 (15.90)
80.89 (6.62)
93.33 (8.29)
Kanamycin injections
Mice receiving kanamycin sub-chronically were injected subcutaneously twice daily at 300 mg/kg for 11 days (63.93 mg/ml KM in 0.9% saline). Injections began at 20 days post-gestational age (PGA) and ended at 30 days PGA. Mice were weighed prior to each injection. Injections occurred at 12-h intervals. The drug regimen was well-tolerated, and no mice were lost during the course of treatment. Mice in the saline treatment group received an equivalent volume of saline using the same injection regimen.
Noise exposure
At 30 days PGA, mice were exposed to 30 s of broadband noise (4 to 45 kHz) at 110 dB SPL. Noise was produced and filtered with General Radio 1310 generators and Krohn-Hite 3550 filters, respectively. Groups of two or three animals were placed in a wired cage suspended between four speakers at 0°, 90°, 180°, and 270° azimuth in a single-walled soundproof booth with foam treatment (Industrial Acoustics, Bronx, NY). The cage was rotated at approximately 0.013 Hz during the exposure to achieve a homogeneous sound field. For all noise groups except the group receiving a single KM dose, the noise exposure was initiated 15 min following the final dose of kanamycin or saline. This interval was based on previous pharmacokinetic analyses of subcutaneous kanamycin injections in mice showing peak serum levels at approximately 15 min post-injection and an elimination half-life of 1 h (Wu et al. 2001).
ABR recording
Because of the fragility of post-weaning mice at the time of initial treatment, our study design called for a single ABR recording in each animal following all other procedures. Thus, ABR thresholds, not threshold shifts, were compared by treatment group. For most groups, ABR recording was carried out 9–11 days post-treatment (39–41 days PGA) using Tucker–Davis Technologies (TDT) System II hardware and software. Animals were anesthetized with a solution of ketamine and xylazine (80/15 mg/kg, i.p.) and positioned dorsally in a custom headholder. Subdermal platinum needle electrodes (Grass) were placed in the mid-back (ground), behind the right pinna (active), and at the vertex (reference). Body temperature was monitored throughout testing using a rectal probe and maintained at 37.5 ± 1.0°C using a DC current-based isothermal pad (FHC). The right ear of each mouse was stimulated in freefield using a TDT ES-1 speaker placed placed at 7 cm distance along the interaural axis. Stimuli were 5 ms tonebursts (1,000 repetitions, 20/s, 1.0 ms rise/fall time) at frequencies of 5, 10, 20, 28.3, and 40 kHz. To eliminate contributions to the ABR by the unstimulated ear, the left external meatus was compressed using a spring-loaded clip. Responses were amplified ×100,000 and filtered at 100–10,000 Hz. Wave I of the ABR is considered to be generated by auditory nerve activity and is the most robust wave of the mouse ABR (Zheng et al. 1999). Thresholds were taken to be the lowest sound level for which Wave I could be identified, using a 5-dB minimum step size. Threshold differences by group were analyzed by two-way ANOVA (threshold by treatment, frequency) followed by Bonferroni multiple comparisons tests.
Tissue preparation and analysis
Cochleas of mice from two experimental groups, KM + Noise and Saline + Noise (N = 7 each), were prepared for histological analysis after recording. Animals were overdosed using Pentobarbital and perfused transcardially with cold 2.0% paraformaldehyde/2.0% glutaraldehyde in 0.1 M phosphate buffer (pH 7.4). Each cochlea was rapidly isolated and immersed in the same fixative, and the stapes was removed. Complete infiltration of the cochlea by fixative was facilitated by drilling a small hole at the apex of the cochlear capsule and gently circulating the fixative over the cochlea using a transfer pipet. After decalcification in sodium EDTA for 72 h, cochleas were post-fixed in buffered 1% osmium tetroxide, dehydrated in an ascending acetone series, and embedded in Epon.
Qualitative light microscopy
Left cochleas were sectioned in the mid-modiolar plane at 4.0 µm then stained with toluidine blue for bright field viewing with a Nikon Optiphot™ light microscope using a ×100 oil objective and a calibrated grid ocular. Typically 50 sections were obtained from each cochlea, spanning 200 µm centered on the modiolar "core."
Hair cell counts
Right cochleas were dissected using fine blades into half-turn segments, immersed in mineral oil in a depression slide, and examined as surface preparations by Nomarski optics using a ×20 oil objective and a calibrated grid ocular. The percent outer hair cells (OHCs) and inner hair cells (IHCs) missing (as judged by the absence of nuclei) was estimated in contiguous 200 µm segments, and data were recorded separately by cell type as a function of distance from the basal tip. For each hair cell type, distance versus percent present was plotted as a function of frequency based on Muller et al. (2005). Hair cell survival differences by group were analyzed by two-way ANOVA (cell loss by treatment, cochlear place), followed by Bonferroni multiple comparison tests.
ABR thresholds
Figure 1 shows ABR thresholds for the primary comparison groups. Nine to 11 days after noise exposure, mice receiving noise alone or saline plus noise showed nearly identical threshold shift profiles versus untreated controls, namely a 30–40-dB NIPTS at most test frequencies. By contrast, mice receiving KM plus noise exhibited thresholds that were statistically indistinguishable from untreated controls. There is some indication (not significant) of threshold elevation at 40 kHz in the KM-treated mice.
Mean (±SD) ABR thresholds for mice receiving either No Treatment, Noise Alone, KM + Noise, or Saline + Noise. Mice receiving Saline + Noise showed significantly elevated ABR thresholds versus unexposed controls (two-way ANOVA). Thresholds in saline-treated mice were not significantly different from the Noise Alone group. Mice receiving KM + Noise showed ABR thresholds not significantly different from the unexposed controls.
Administration of KM produced no threshold elevation, either at the time of noise exposure or 10 days after the final KM dose (Fig. 2). This suggests that (1) KM alone at the dose used was not toxic (see below) and (2) the apparent protective effects of KM were not linked to acute threshold elevation that could have reduced sensitivity to the noise exposure. A single dose of KM administered 1 h prior to noise was not protective, as NIPTS in these mice was similar to the effect of noise alone (Fig. 3). This indicated that an endogenous response to KM, not merely its acute presence, was required for protection.
Mean (±SD) ABR thresholds for mice receiving Kanamycin followed by ABR testing either at the time noise would normally have occurred, or 10 days post-treatment. ABR thresholds for either group were not significantly different from untreated controls.
Mean (±SD) thresholds for mice receiving a single kanamycin injection 1 h prior to noise exposure. These mice had ABR thresholds that were not significantly different from those receiving Noise Alone, indicating that a single KM injection was not effective.
We did not explicitly test for the minimal KM dosing regimen that produces protection. However, two smaller groups examined the protection afforded by KM when noise was applied either 24 (N = 4) or 48 h (N = 4) after the last dose. As Figure 4 shows, the additional delay showed no diminishing effect on the protection. These data argue that KM produces a "protected state" lasting at least up to 2 days after final application.
Mean (±SD) ABR thresholds for mice receiving KM followed by noise either 24 or 48 h later. Thresholds for these animals were indistinguishable from those in the original KM + Noise group. The window for full protection against NIPTS thus extends to at least 48 h following the final kanamycin injection.
Histologic findings
The pronounced threshold differences by treatment across all test frequencies led us to seek the histologic correlates of injury and protection. Comparison by light microscopy of mid-modular sections from KM + Noise and Saline + Noise animals yielded no obvious differences in the composition of the lateral wall, neuronal survival, or the condition of the organ of Corti, either in cochlear upper basal turn (Fig. 5) or more apically. In the lower base, however, profiles of the organ of Corti were often devoid of hair cells in saline-treated mice, but not in KM-treated mice (Fig. 6). Hair cell counts confirmed significant preservation of OHCs in the basal half of the cochlea of KM-treated mice (Fig. 7). Outer hair cell loss in saline-treated controls extended approximately 2.6 mm from the basal tip. According to the place map published for CBA/J (Muller et al. 2005), this would correspond to frequencies above 14 kHz, so that hearing losses at 20, 28.3, and 40 kHz in the saline controls (Fig. 1) appeared explained by OHC loss. KM-treated mice also showed OHC loss, yet only extending about 1.2 mm from the base. This appears consistent with the suggested trend toward hearing loss at 40 kHz in these mice (Fig. 1). Both treatment groups showed similar modest IHC loss within the cochlear hook region.
Light photomicrograph of the cochlear upper base (~18 kHz region) in two example mice receiving Saline + Noise (A–C) or KM + Noise (D–F). No features clearly and consistently distinguished mice by treatment group; Organ of Corti (A, D), spiral ganglion cells (SpG in B, E), and lateral wall (C, F) appeared similar in each group. Raised particles in C, F are processing artifacts. StV Stria vascularis; SpL spiral ligament; C capillaries; Bn bone.
Light photomicrograph of the cochlear lower base (~40 kHz region) in the same example mice depicted in Figure 5, receiving Saline + Noise (A, B) or KM + Noise (C, D). The sole clear distinguishing feature is the absence of outer hair cells in the saline-treated animal (arrows in B, D). StV Stria vascularis; RM Reissners membrane; SpLim spiral limbus; OC organ of Corti.
Mean (−SD) cochleograms for KM + Noise and Saline + Noise groups (N = 7 each). Outer hair cell losses differed significantly by treatment, extending on average ∼2.6 mm from the base in controls, but only ∼1.2 mm from the base in KM-treated mice. Losses of inner hair cells were modest and did not clearly vary by treatment. Horizontal bar indicates specific locations where OHC counts differed significantly (p < .032) by treatment, as indicated by Bonferroni multiple comparisons tests.
The finding of normal thresholds in mice receiving KM alone (Fig. 2) indicated that the KM dose applied was sub-toxic. Nevertheless, since the cochlear base is most vulnerable to ototoxins, we considered whether the modest hair cell loss in the cochlear hook region of KM-treated mice might be due to KM, and not noise. Examination of three cochleas from mice receiving KM without noise (not shown) revealed partial loss of OHCs spanning much of the hook region in one animal. Such loss is atypical of young CBA/J mice. Notably, however, two of seven mice receiving both KM and noise showed no hair cell loss. Combined with threshold data (Figs. 1 and 2), the evidence suggests that hair cell loss in the basal tip of some KM + Noise animals may have been caused by KM itself, but more often probably represented residual noise injury.
Summary of findings
No synergistic effect increasing NIPTS was found for mice treated with both kanamycin and noise. Instead, mice treated with a sub-chronic, low dose of kanamycin prior to noise exposure were paradoxically protected from NIPTS, showing ABR thresholds not significantly different from unexposed controls. The protected mice correspondingly showed significant preservation of OHCs in the basal half of the cochlea compared to saline controls. Kanamycin alone had no effect on ABR thresholds immediately following treatment (that is, at the time noise exposure occurred) or at the termination of experiments (Fig. 2). These findings argue against an acute hearing loss at the time of noise exposure, which could have potentially provided a degree protection against NIPTS. They also argue against any permanent effect of the KM treatment on thresholds, although we could not rule out that some hair cell loss in the extreme base was KM-related. A single dose of KM prior to noise was not protective; thus, the mere presence of kanamycin at the time of noise exposure was not sufficient to provide protection (Fig. 3). This result argues against any protective mechanisms that require only the presence of KM, such as plugging of transducer channels (Marcotti et al. 2005), thereby reducing active force generation by OHCs. Animals in the Saline + Noise group were not protected from NIPTS (Fig. 4). Therefore, protection afforded by the stress of handling and injection, potentially mediated by glucocorticoids (Wang and Liberman- did not appear to be a significant factor. Additional experiments in which the interval between the final KM dose and noise exposure was extended further indicated that KM's protective effects continue at least 48 h from the end of the dosing regimen. A corollary of the latter observation is that less rigorous dosing paradigms than the one we tested may be equally effective against similar exposures.
Noise vulnerability in CBA/J
Our original hypothesis called for an experimental paradigm involving subclinical levels of both noise and KM. While the chosen KM regimen appeared subclinical in most cases, exposure to 30 s of noise produced moderate NIPTS and hair cell loss in the young CBA/J mice. This was not an anticipated outcome, although it produced the benefit of a large NIPTS that uncovered KM-related protection. Previous research comparing the noise susceptibility of mice (CBA/CaJ, C57BL/6J, BALB/cJ) aged 1–2 and 5–7 months (Ohlemiller et al. 2000) determined NIPTS "threshold" for exposure duration of 3.4 min for young CBA/CaJ mice using the same noise applied here. Based on this result, it was presumed that young CBA/Js would show a noise dose-response pattern similar to the CBA/CaJ and that 30 s of noise would produce no NIPTS. CBA/CaJ and CBA/J mice are often treated as interchangeable for purposes of hearing studies. The present noise work, along with a recent comparison of aging CBA/J and CBA/CaJ (Ohlemiller 2009), suggests this is not the case. The surprising noise vulnerability of young CBA/J, which we describe elsewhere (Rybak Rice et al. 2009), contrasts with a lack of any notable susceptibility to kanamycin (Wu et al. 2001). The extent of NIPTS and hair cell loss in the young CBA/Js strongly suggest our KM results are not limited to an "unchallenging" noise or to noise that only causes a temporary threshold shift. In fact, the extent of both NIPTS and hair cell loss in these mice exceeded those produced by 2 h of similar noise in older CBA/J mice (Ohlemiller and Gagnon 2007). It is possible that the present results are closely tied to some unusual characteristic of young CBA/Js.
Cells impacted by noise and protected by KM
The only clear anatomic difference that distinguished the KM-protected mice from saline controls was the extent of OHC loss (Fig. 7). Both groups of mice showed inner and outer hair cell loss in the cochlear hook, a region not monitored by our highest ABR stimulus frequency (40 kHz). OHC loss in KM-treated mice also extended into the lower base so that essentially all NIPTS in these mice could be accounted for in terms of hair cell loss. Within saline controls, OHC loss extended apically to regions serving the three highest ABR test frequencies (20, 28.3, 40 kHz). The most parsimonious explanation for NIPTS in these mice was, therefore, OHC loss in the lower base and subtle OHC injury more apically. Within the cochlea, aminoglycosides preferentially injure the stria vascularis and outer hair cells (Taylor et al. 2008; Rizzi and Hirose 2007; Forge and Schacht 2000). Although noise can also injure the stria, the injury appears largely reversible under all but the most extreme conditions (Ohlemiller and Gagnon 2007; Hirose and Liberman 2003), and it is not clear that lateral wall events can ultimately impact the extent of NIPTS (Ohlemiller 2008). Since OHC function and survival represent the most salient common target of both noise and KM, we suggest that preservation of OHC function and survival constitutes the most likely locus of KM-related protective mechanisms and that KM engages protective cascades within OHCs. Recent studies in young mice (Wu et al. 2001; Wang and Steyger 2009) indicate that significant levels of KM would have been present in both cochlear fluids and hair cells at the time of our noise exposure. Aminoglycosides may enter hair cells from either endolymph or perilymph and may require 24 h to be cleared (Wang and Steyger 2009; Li and Steyger 2009). Thus, significant levels of KM were likely maintained and probably increased over the course of treatment. Even a single KM dose, which we found not to be protective (Fig. 3), should have yielded "therapeutic" levels within the organ of Corti 1 h later. The lack of efficacy in this case argues for an innate protective response to KM that activates with some delay. Whether any single dose paradigm may be protective is under study.
Sub-chronic kanamycin as a form of preconditioning
Sub-chronic low-dose application of kanamycin likely engages innate protective mechanisms and thus may be added to the ranks of preconditiong stressors. Preconditioning refers to a mildly injurious event that confers protection against a later, more injurious, event (Gidday 2006; Dirnagl et al. 2003; Eisen et al. 2004; Ran et al. 2005). Demonstrated preconditioning inducers against NIPTS in mice include mild noise, heat stress, restraint, and hypoxia (Yoshida et al. 1999; Wang and Liberman 2002; Yoshida and Liberman 2000; Niu and Canlon 2002; Gagnon et al. 2007). Two studies have reported partial protection in guinea pigs by amikacin or gentamicin against later, high-dose, application of the same ototoxins (De Oliveira et al. 2004; Maudonnet et al. 2008). Many pathways and processes have been implicated in preconditioning, including improved blood flow, increased glucocorticoid levels, enhanced antioxidant protections, and increased production of heat shock proteins. Those that participate in the protection demonstrated here remain to be determined. KM affects multiple organs (Henley and Rybak 1995; Rizzi and Hirose 2007; Forge and Schacht 2000), where it may also elicit protective cascades, so that systemically mediated preconditioning influences cannot presently be ruled out.
The principles of preconditioning link a sub-injurious event to protection against a later injurious event. Very likely, there exists a tradeoff between the severity of the initial event and the extent of later protection. Our effective KM dose may have caused some OHC loss and thus may not have been sub-toxic in every case. While we have not yet probed the limits of the protection against NIPTS afforded by KM, it is possible that KM-related injury and protection are causally related. It may, for example, be possible to find circumstances and models in which increasing protection against NIPTS at mid and low frequencies is positively linked to elevated thresholds and hair cell loss in the deep cochlear base.
Kanamycin in the early vulnerability window
An early window of heightened vulnerability has been found in animals to apply to noise injury as well as a variety of ototoxins. The targets of this early magnified injury show only partial overlap: Ototoxins primarily impact hair cells and stria (Bernard 1981; Lataye et al. 2004; Pryor et al. 1984; Rybak et al. 1991; Henley and Rybak 1995), while noise preferentially targets hair cells and neurons (Henley and Rybak 1995; Falk et al. 1974; Ohlemiller et al. 2000; Kujawa and Liberman 2006). The window of vulnerability also need not be the same for noise versus aminoglycosides (Henry et al. 1981; Henry 1983) or even for all ototoxicants (e.g., Lataye et al. 2004). The existence of somewhat different targets and timeframes for noise and ototoxic injury suggests that these operate at least partially independently. We know of no other study demonstrating a protective effect of kanamycin or any other ototoxin against NIPTS. Instead, many studies have shown exacerbation of NIPTS by aminoglycosides in animals (e.g., Bombard et al. 2005; Dayal et al. 1971; Dayal and Barek 1975; Marques et al. 1975; Hawkins et al. 1975; Ryan and Bone 1978; Brown et al. 1980; Brummett et al. 1992). This effect has, therefore, been predicted for humans and anticipated to be enhanced in human infants (see Li and Steyger 2009). The prediction of amplified synergistic interactions early in life has found some support in animal studies (Dodson et al. 1982) but, to date, no direct support in humans (see citations in Li and Steyger 2009). The robustness of the protection we find in young CBA/J mice may mean that at least for low KM doses, the true nature of KM/noise interactions during the early window is just the opposite of predicted outcomes. A general protective effect might reflect distinct characteristics of protective cascades early in life and may even be causally related to the very factor(s) that underlie the early vulnerability window.
The present findings may hold implications for which treatments in medically fragile human neonates pose extra risks and which do not. Once uncovered, the protective pathways that kanamycin engages may offer new pharmacologic interventions, both during the early vulnerability window and later. Should our findings ultimately prove limited to particular mouse models, it should be possible using standard genetic approaches to identify critical genes and pathways. These genes may provide insights into the nature of injury and innate protection during the early window and could lead to genetic tests for individual risk.
Thanks to M. Rybak Rice and A. Rosen for technical assistance and to Dr. K. Hirose for critical comments; supported by P30 DC004665 (R. Chole), P30 NS057105 (D. Holtzman), R01 DC03454 (KKO), R01 DC08321 (KKO), WUSM Department of Otolaryngology.
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Sony's sold-off PC brand has released several devices in Japan, but this will be its first to hit North America.
The tablet that appeared early this year on Kickstarter for as low as $39 is now available on Amazon, but it costs a bit more than that.
Microsoft is making available firmware updates this month for its Surface Pro 3 and Surface Pro 2 tablets running Windows 8.1.
Microsoft's relatively affordable Atom x7-powered Surface 3 can 'work like a laptop when you need it', so long as you stick to mainstream workloads and remember that a keyboard is an extra-cost option.
Fast Clean Phone App is really a Ram Booster for Android among the finest mobile phone booster, ram tester & speed cleaner through...
This week in Android we heard about Android M, a new tablet branded by AT&T, and features we'll see in the next Samsung Gear smartwatch.
Business use of tablets is now a reality, says IDC, but it can't make up for the dip in consumer demand.
Dental Data Manager Forms is a tool for data collection and analysis. Dental schools/clinics can register at the website and create...
Taiwan-based chipmaker MediaTek has increased its Helio system-on-chip (SoC) lineup with a new deca-core Helio X20 aimed at smartphones and tablets. But do consumers need it?
Research shows UK users are spending twice as much time online as they did ten years ago.
Citrix updated its product line at its flagship conference with a focus on making enterprise apps more accessible on tablets and mobile devices.
The 8-inch device will run Android 5.0 Lollipop and be available either for $49.99 with a two-year contract or for $10 per month on an installment plan.
After using the iPad Air and then the iPad Air 2 for years as my primary work system, the recent purchase of an iPad mini 3 has replaced them handily.
Even Tim Cook is saying that the large iPhone 6 Plus is eating into sales of the iPads. But comparing the two iPads with the iPhone 6 Plus shows the larger displays offer a lot of utility.
The Australian Department of Agriculture is replacing its fleet of desktops with HP Minis running Windows 8, as the company also undertakes an HP tablet deployment.
IDC said that shipments for tablets and 2-in-1 devices fell 5.9 percent from a year ago in the first quarter to 47.1 million.
Tasmania Police will soon go to tender to replace its first fleet of Acer Iconia tablets issued to over 1,000 police officers across the state.
The tablet-electronic planning system deployed by American Airlines ran into a few glitches and delayed flights. Get used to another reason to delay flights.
The company looks to extend its gaming brand with a competitor to the Nvidia Shield that may launch in Q3 2015.
An increased interest in wearable devices, along with the release of the iPhone 6 and market saturation, hit tablet sales in Australia during 2014, according to a new study by Telsyte.
Businesses and consumers are increasingly moving away from laptops with dongles towards using larger-screen smartphones and tethering, according to Telstra.

subset: commoncrawl


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Bookie codenames for cricketers
The spot-fixing scandal in the recently conculded sixth edition of the Indian Premier League has cast a dark shadow on Indian cricket as shocking revelations come to light with each passing day. As part of their probe into the scandal, investigators have found that the bookies and their underworld contacts used code names to refer to each other as well as cricketers to avoid detection by security agencies who could be tapping their phones. The Mumbai Crime Branch has been able to decode some of the names with the help of arrested Bollywood actor Vindoo Dara Singh (Jack). The code names were found in the diaries and iPads recovered from bookies. [CYCSPL]
- NZ won by 199 runsvs. NZENG2nd TestFri, May 29, 2015Leeds, EnglandNew Zealand in England Tes...
- Match abandonedvs. ZIMPAK3rd ODISun, May 31, 2015Lahore, PakistanZimbabwe in Pakistan ODI S...
- PAK won by 6 wkts.vs. ZIMPAK2nd ODIFri, May 29, 2015Lahore, PakistanZimbabwe in Pakistan ODI S...
- live match AUS 55/2 (21.3 Overs)vs. AUSWI1st TestLIVEWI 148/10;Roseau, Dominica, West IndiesAustralia in West Indies T...
- vs. NZENG1st ODITue, Jun 09, 2015Tue, Jun 09, 2015Birmingham, EnglandNew Zealand in England ODI...
- vs. INDBANOne-off TestWed, Jun 10, 2015Wed, Jun 10, 2015Fatullah, BangladeshIndia in Bangladesh Test S...
- vs. AUSWI2nd TestThu, Jun 11, 2015Thu, Jun 11, 2015Kingston, Jamaica, West IndiesAustralia in West Indies T...
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Mumbai Indians completed one of the most remarkable turnarounds in the eight-year history of the Indian Premier league by transforming a terrible start to the tournament - they were at the bottom of the table for the first two weeks - into a title win.
More » Action photos: The Mumbai-Chennai IPL final
Royal Challengers Bangalore set up a clash with Chennai Super Kings for a place in the final as they sent Rajasthan Royals out of the tournament. More » IPL8: Rajasthan Royals vs Royal Challengers Bangalore
A timely half-century by opener Lendl Simmons and some quality bowling helped Mumbai Indians secure a place in the Indian Premier League (IPL) 2015 final with a 25-run victory over Chennai Super Kings (CSK) in … More » IPL8: Mumbai Indians vs Chennai Super Kings
JP Duminy, the Delhi Daredevils captain, elected to bat at the Wankhede Stadium against Mumbai Indians. Duminy felt the wicket wasn't going to change much, and said it might offer "a little bit of turn" in the latter half. His counterpart, Rohit Sharma, sounded pleased with his team's recent run, … More » IPL 8: Mumbai versus Delhi, the highlights in photos
MUMBAI: Ajinkya Rahane and Karun Nair displayed superb batting skills to help Rajasthan Royals post a challenging 189/2 against Delhi Daredevils in an Indian Premer League (IPL) match at the Brabourne Stadium here on Sunday.
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Opening batsmen Lendl Simmons (71 in 56 balls) and Parthiv Patel (59 in 36 balls) helped Mumbai Indians (MI) register their … More » IPL8: Mumbai Indians thrash Kings XI Punjab by 23 runs
If you thought that the cheerleaders earn a lot during the Indian Premier League games, think again. While the pay may vary from team to team, with franchises like Royal Challengers Bangalore, Mumbai Indians and Kolkata Knight Riders paying a bit more than the others, reports say that at an … More » IPL8: Cheerleaders and what they earn in a season
Mandeep Singh worked the magic for Royal Challengers Bangalore who defeated champions Kolkata Knight Riders by seven wickets with two balls to spare. More » IPL 8: Royal Challengers Bangalore beat Kolkata Knight Riders
Mumbai Indians won Match 32 by 8 runs against Rajasthan Royals. More » IPL 8: Mumbai Indians beat Rajasthan Royals
Delhi Daredevils beat Kings XI Punjab by 9 wickets. More » IPL 8: Delhi Daredevils beat Kings XI Punjab
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RCB bowled out the home team for a mere 95 runs in 18.2 overs and then cruised during the run chase in just 10.3 overs. More » IPL8: Delhi Daredevils vs Royal Challengers Bangalore
Royal Challengers Bangalore beat Rajasthan Royals by 9 wickets in their match at the Sardar Patel Stadium, Motera on April 24, 2015.
Full scorecard here More » IPL8: Rajasthan Royals vs Royal Challengers Bangalore


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Originally written on Red's Army | Last updated 11/25/12
Tip: 6 PM Court: Amway Center Watch it: CSN Hear it: WEEI Referees: Dick Bavetta, Michael Smith and Josh Tiven Get your tickets here: Boston Celtics Tickets The Matchup Record: 7-6 Record: 5-7 On road: 3-3 At home: 4-2 Streak: Won 1 Streak: Won 2 Leaders Leaders Buckets: Pierce (19.8 ppg) Buckets: Aaron Afflalo (15.8 ppg) Boards: Garnett (7.2 rpg) Boards: Glen Davis (8.9 rpg) Dimes: Rondo (13.5 apg) Dimes: Jameer Nelson (6.7 apg) For the Stat Geeks: For the Stat Geeks: Offensive Rating: 105.6 (11th NBA) Offensive Rating: 97.8 (29th NBA) Defensive Rating: 107.0 (24th NBA) Defensive Rating: 101.4 (4th NBA) Pace: 92.1 (17th NBA) Pace: 92.2 (15th NBA) Last time The Celtics have won 5 straight vs Orlando, including all three match-ups last season. One of the victories was a 31-point beat down and another included a comeback from a 27 point deficit. Rajon Rondo missed all three games last season due to injuries. This time Get it to: Paul Pierc...
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Cheap TXL to Evreux flights
Popular Flights from Berlin, Germany
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Route information for flights from Tegel to Fauville Air Base.
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Cheap ATK to Burlington flights
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BakerHostetler Partner Paul Karlsgodt Discusses Privacy Class Actions
The TCPA: Deep Dive: Details, Class Actions, Regulations, and Defense Strategies
Insights and Strategies on Class Action Litigation from General Counsel and Chief Legal Officers
Employment Law Issues for Health Care Employers
Polsinelli Podcasts - Class Action Lawsuits: What to do When the Claim Arrives
An Overview of the 2014 Class Action Survey
Class Action Trends – Interview with Stephen Gulotta, Managing Member, Mintz Levin's New York Office
Class Action Litigation Reform – Interview with Dan Pascucci, Member, Mintz Levin
Employer Issues: Trade Secrets & Class Action Lawsuits – Interview with David Barmak, Member, Mintz Levin
China's Export Policy Changes After U.S. Antitrust Case
Bill on Bankruptcy: Sigmund Freud, Marx Brothers, Bernie Madoff
$300 Million Dairy Settlement Will Bring Reform, Lawyer Says
Weekly Brief: Patent Jury Awards, Law Firm Hiring, Scalia's Hat
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We didn't stay this hotel but we took the dinner at the terrace. It was a nice terrace but the food was terrible. I must say it was really for the farmers. The prices were very reasonable but it was not for us.
Beside that we were served by none friendly waitress.
Location: The Netherlands > Limburg Province > Berg en Terblijt
Ranked #3 of 3 B&Bs / Inns in Berg en Terblijt
Price Range (Based on Average Rates): $
Hotel Class:2 star — Hostellerie Brakke Berg 2*
Number of rooms: 8
- Reservation Options:
- TripAdvisor is proud to partner with Booking.com, Expedia, Priceline, Travelocity, Odigeo and Hotels.com so you can book your Hostellerie Brakke Berg reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.


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In view of the Lok Sabha elections, the Pune police and the excise department have seized illicit liquor, fire arms and other weapons worth Rs 25 lakhs in the city, Pimpri and rural areas of the district.
District collector Saurabh Rao, who is also the district election officer, told media persons that non-bailable warrants have been issued to 1,111 people from the city limits and 1,500 from the rural areas as a precautionary measure. He said illegal weapons and illicit liquor worth 1.25 lakhs have been seized from the district rural areas. The liquor and weapons are worth Rs. 25 lakhs, he added. Meanwhile, cases have been filed against 2,500 people to avoid law and order problems during the elections. Bonds have been taken from another 300 people and preventive action taken against 2,500 others in this regard, said Rao. As per the rules, weapons from 2,750 licence holders have been deposited in the government custody.


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Ancient Weapon Lovers GroupHobbies & Interests group with 317 members, open to all members
This group is for everyone who likes all kinds of ancient, roman, medieval, renaissance, and other old weapons and units from the past.
I like to play RPG, RTS and shooter games. I am a big fan of Star Wars movies and games most of all. I am looking forward to many good mods from this site :D
This group is for everyone who likes all kinds of ancient, roman, medieval, renaissance, and other old weapons and units from the past.
We are the survivors of the Empire we will bring the empire to its former glory But we ally with the Jedi to ensure peace
This is for jedi to talk about important stuff. Only jedi are excepted to this group so sith cannot eavsdrop on us. The stuff that we will be talking...
This is a group that was created for anyone who loves Star Wars, may it be the books, games, films and modding. This is the place for you to enjoy star...
modding for star wars games and editing them and that sort of thing ya know
The Jedi are characters in the fictional Star Wars universe and the series' main protagonists. They use a quasi-telekinetic power, known as the Force...
so yeah you're my prisoner now. in a holding cell with force-proof shields, (see the force unleashed for uses of these) you are guarded by magnaguards and you will be electrocuted by the cell if you try to use the force.
Pretty solid plan except that you forgot my X-Wing that was magnetically attached to the hull of your ship where I came in and my R-2 unit sitting in the X-Wing. It's all posted right there there in the battle if you don't believe me ;)
New avatar? :P Just to state the obvious xD
Lol! yeah, I changed it to a pic I took when I was on my trip and when I got back I couldn't find the old pic online :P I like this one anyway because I just finished reading one of the Rogue Squadron books, lol.
hello grand master i was once sith now i wish to become a jedi knight fight for the side of good
will you train me to become a jedi so one day i will be as great as you
Jedi scum! Your attacks will not go un punished
felow jedi please join with us
You are wise jedi. I would be honored if you accept me as a friend...
And I would be a fool to not accept the offered friendship of even a Sith, lol.
I am honored to be your friend ^^ Even though you are a jedi scum... :P


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"She's here!"
The announcement came with a brisk knock. His hands began to shake. Why was he so nervous? Maybe because it had been six months since the last time he'd seen her and it had taken every bit of his pull to get her here.
"She's here!"
The announcement came with a brisk knock. His hands began to shake. Why was he so nervous? Maybe because it had been six months since the last time he'd seen her and it had taken every bit of his pull to get her here.
Sharing My Wife Karen
I have always known my wife Karen's love for the male anatomy. She always comments when she sees "a nice package" in a pair of jeans. We got into swinging a few years ago and when we are at a party she really lets her h
A Sharing Vacation
My wife Karen and I were on vacation in Aruba standing at a beach bar and there was this guy across the bar who kept looking at Karen and smiling, smiles she was returning as he was a distinguished looking maybe Italian, d
I'm not sure when it started but I began having fantasies of being able to watch my wife Karen with other men. The more I thought of what it would be like the exciting it became.
One night when we were exchanging some fantasies, I tol
Chapter Nine
Angie reached the elevators and punched the number twelve. On her way up, the elevator stopped at the third floor, and a man stepped inside and pressed for the ninth floor. Silence reigned for a while until t
Chapter Eight
The next day was Angie's first day on the job. She eagerly jumped out of bed and started to get ready. Today was no ordinary first day at work—today was her first day to work with Michael Riles. Remember
Chapter Seven
Angie opened her eyes and found herself being stuffed into her own shirt. Michael was buttoning up her blouse, laying his lips on her chest each time he finished inserting a button into its proper hole. "D
The rain was really hammering down Scott drove home from his friends house that night. As he drove along he thought about the woman that had knocked on his friends door, he'd answered it expecting the pizza delivery guy and was stunned to find a pret
Monopoly 101
The best game I could ever play/ without my wife
It was with m good family friend when this happened I was 26 she was just 18. We were both away from home that year she was working at a lodge and I was a guide for the touri
When Laura first laid eyes on Shane, she wanted him immediately. He was tall and lanky with a shock of wheat colored hair and just enough growth of beard to proclaim MAN in capital letters. She also liked the way he fit into his jeans.
My God,
….as you got out of the car my eyes fixed to yours and I couldn't believe that what I was seeing was actually real. You looked about 234838 times fitter than what id thought about and suddenly you appeared 2301808 times fitter than you did on cam
We meet at the hotel as usual. I am so horny for you it seems like it has been forever since I had you in my arms. We undress each other as we kiss and fall into bed rubbing our naked bodies against each other. You feel so good in my arms and I love
Part Five
Alyssandria woke up to a book rather than a man. Needless to say she was disappointed, but intrigued nonetheless. She opened the book to find endless drawings of men and women fucking. Antony had left her a note, "Study."
He slouched, rather than sat in his seat in first class. His big floppy hat and oversized sunglasses blocked most of his face, which relieved him because the last thing he wanted was to be noticed. He just wanted to get back to Paris to his woman a
A DAY AT THE NURSERY…a true story, even though it sounds like a tale..!!
how well i remember that day….that day at the nursery.
it was a beautiful saturday and i left early to go to my local landscape center to purchase some more
My name is Mark and I am eighteen years old, and I am home for summer from University. I have for as long as I can remember I have had this special ability. I have the uncanny ability to get inside of peoples minds and make them do whatever I want
Juliet was on her way home from another long day. She had to get the kids and her husband out of bed since everyone seemed to forget to set the alarms again. Her husband was the first to leave without eating breakfast but that was something she was u
Her Mistress – Part One
Betsy is a professional woman, a few years older than me, and very unhappy in her marriage. She said her husband was not good in bed, calling him a "2 minute Charlie". We first met at a business function. She
I am 18 and just went off to college this year and tried out for the cheerleading squad as I have always liked it and have been told people love to see me cheer. I know they really mean, we love seeing your tits bouncing all over and your barely cov


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By Alanna Schubach
How a Home-Brew Hobby Launched Third Rail Beer
By Laura Shunk
By Zachary Feldman
There Goes the Neighborhood Pizzeria
By Zachary Feldman
By Zachary Feldman
By Scarlett Lindeman
Polo Dobkin's Meadowsweet Channels the Countryside and...
By Laura Shunk
Get Down with the Matriarchy at Claudette
By Zachary Feldman
A scant 60 miles from Syria in the far eastern Mediterranean, and far closer to Turkey than to Greece, Cyprus was riven by a 1974 conflict, so that now the top half is Turkish and the bottom half Greek-ish. Located in remote northern Astoria, Aliada revels in the food of the Greek half. Like most Astorian restaurants, the kitchen chugs along in the front window as a lure to passersby, and the dining room looks like any other modern dining room in town, with exposed brick and whitewashed walls, save for a niche toward the rear that holds a hookah, a ceramic olive-oil jar, and a gigantic flask of Metaxa, a brandy, with a brass spigot near the bottom of the bottle for quick access. Indeed, the Cypriot wines at Aliada are particularly impressive, including Keo Othello ($24), a dry, light, fruity red, and Commandaria, a sherry-style digestif named after an order of knight. Have a glass with the wonderful dessert of yogurt, nuts, and golden Greek honey ($3).
It will come as no surprise that a number of Middle Eastern specialties have crept into the Cypriot table of mezedes. At Aliada, you'll find a fascinating hummus ($4.95), looser and more chunky than the usual chickpea puree, and a version of tabbouleh too. More surprising, perhaps, is the falafel. Shaped like small footballs, and larger than average, these falafel have a rugged texture and a distinctively nutty and cinnamony taste. They clearly do not come from a box. You could easily make a complete meal of the vegetarian mezedes, and if you do, it should also include manitaria krasata (mushrooms cooked in wine), kolokithokeftedes (free-form zucchini croquettes), kopanisti (a Slavic-seeming mush of red pepper and feta), and especially, the charcoal-grilled haloumi cheese in all its charred and rubbery glory. Like Texans, the Cypriots will grill almost anything.
29-19 Broadway
Long Island City, NY 11103
Category: Restaurant > Greek
Region: Long Island City
Though the menu neglects seafood, there is a fine grilled-octopus appetizer ($11.95). But this cephalopod makes more of an impression in a salad named after the restaurant that matches the tentacles with potatoes and strips of roasted red pepper. All this is leading up to the best thing on the menu, charcoal-grilled lamb chops ($19.95). Five to a serving and accompanied by a fine plate of fries, these luscious chops have no equal in Astoriaperhaps in the entire city.
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This section contains 304 words
(approx. 2 pages at 300 words per page)
Critical Essay by Malcolm Bradbury
[More and more J. G. Ballard] looks like a leading figure in a very rich and developing field. His earlier work was usually cast as science fiction, but he has long since worked loose from that pocket. Like many excellent contemporary writers, from Italo Calvino to Thomas Pynchon, he draws on science-fiction methods to create a magical modern fantasy. A writer of enormous inventive powers, an explorer of the displacements produced in modern consciousness by the blank ecology of stark architecture, bare high-rises, dead superhighways and featureless technology, he has, like Calvino, a remarkable gift for filling the empty, deprived spaces of modern life with the invisible cities and the wonder worlds of the imagination.
"The Unlimited Dream Company" is a book of this kind, a remarkable piece of invention, a flight from the world of the familiar and the...
This section contains 304 words
(approx. 2 pages at 300 words per page)


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Johnny Rockets Releases Popular Hamburger Recipe in Time for Fourth of July.
LAKE FOREST, Calif., June 27 /PRNewswire/ -- The Johnny Rockets Group, Inc., the restaurant chain known for juicy hamburgers and table-top jukeboxes, is releasing its popular "Rocket Single" recipe for Americans to enjoy at home during the Fourth of July holiday and summer grilling season. In addition, the restaurant chain commissioned a national survey to uncover how Americans identify the classic American hamburger.
What's the secret to creating your own slice of cheeseburger heaven? Johnny Rockets chairman and chief executive officer, Mike Shumsky, reveals it is all in the technique.
"From my personal experience, the best way to create that mouthwatering balance of beef and cheese is to grill the meat with the cheese on top," says Shumsky. "A true cheeseburger connoisseur will wait until the meat is fully cooked, then add a slice of cheese and cover for 30 seconds so that the cheese melts perfectly."
According to the recent survey, conducted by the Caravan Opinion Research Corporation, Americans still prefer the classics. Despite the advent of gourmet hamburgers, 74 percent of Americans believe the cheeseburger best embodies the classic American hamburger. Eighty-six percent of Americans also prefer beef hamburgers over turkey or veggie patties. When it comes to toppings, most respondents agree simplicity is key, with 40 percent choosing raw onions over grilled.
For Americans craving classic hamburgers, their destination is clear: forty percent of people associate Johnny Rockets with the classic American hamburger.
Recipe: Rocket Single Ingredients: Hamburger bun Special sauce (mix Thousand Island dressing, Dijon mustard and hot sauce to taste) 1 slice of cheddar cheese 1/3 lb. fresh ground beef, seasoned, hand-pressed and grilled Fresh lettuce Ripe tomato Onion (sliced)
Instructions: Grill the hamburger until its internal temperature reaches at least 160 degrees Fahrenheit, according to preference. Place cheese on top and cover for another 30 seconds. Place in a bun. Mix dressing and spread it on the bun. Layer on tomato, lettuce and onion.
About Johnny Rockets
For 20 years, Johnny Rockets has offered the food, fun and friendliness reminiscent of feel-good Americana. Every Johnny Rockets restaurant offers its guests simple, great-tasting food from a menu of all-American favorites, including juicy hamburgers, hand-dipped shakes and malts and freshly-baked apple pie. Guests also enjoy an all-American diner look and feel, servers who know the secret behind getting ketchup out of the bottle, tabletop jukeboxes that belt out tunes for a nickel and authentic decor.
Johnny Rockets has received many accolades recognizing it as a top restaurant, including the highest rating from Zagat in association with Parenting Magazine for their 2007 U.S. Family Travel Guide, the Nation's Restaurant News 2006 "Hot Again!" award and numerous top 10 rankings from AOL City Guide and Citysearch in multiple categories in cities across the country. Headquartered in Lake Forest, Calif., Johnny Rockets boasts 194 corporate and franchise-owned restaurants in 29 states and ten countries. To learn more about Johnny Rockets, visit us at JohnnyRockets.com.
Media Contact: Katy Darnaby Johnny Rockets News Bureau (310) 633-9419 email@example.com
CONTACT: Katy Darnaby of Johnny Rockets News Bureau, +1-310-633-9419, firstname.lastname@example.com
Web site: http://www.johnnyrockets.com/
Reader Opinion
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|Jun 27, 2006
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KIA Interactive is a indie group of hobbyist game developers currently working on our ambitious zombie survival game, Not Dead Enough. This company is trying to bring people quality gaming for very low prices. Soon, we will start updating this site as well.
No downloads were found matching the criteria specified. We suggest you try the download list with no filter applied, to browse all available files. Join now to share files with the community.


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A frustrating aspect of arthritis is the fact that what might work and relieve pain for one sufferer may not do the same for another. There is no one remedy for this condition, especially the auto immune disease Rheumatoid Arthritis. But many with osteo-arthritis have found chondroitin to be helpful.
Chrondroitin, along with glucosamine, plays a part in normal, healthy cartilage. Also known as chondroitin sulfate (chondroitin with mineral salt), chondroitin sulfuric acid or chonsurical; it can be made from natural sources such as shark cartilage, pig or cow cartilage or it can synthetically be made in a laboratory.
Taken together with glucosamine can help restore the cartilage in the damaged joint, therefore possibly relieving pain for the sufferer. With fewer side effects than ibuprofen, this may be a good avenue to take for many arthritis patients.
Like glucosamine, chondroitin comes in tablet, capsule, liquid or powder and sometimes may be already combined as one form instead of taking them separately.
In the research that I have done on chondroitin there have been 2 sides, some sing it's praises and some say it's no better than a placebo.
Since I need to be on high amounts of blood thinners, I've been strongly advised not to take chondroitin because of possible interactions, but I would love to hear from someone who has experience with this supplement.
I'm very interested if anyone who has rheumatoid or osteo arthritis and has taken chondroitin and/or glucosamine and what they thought of it. Drop me a line!
Follow along my Aud Life of Living with Rheumatoid Arthritis (C)Copyright AnAudLife.com All Rights Reserved


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Meadowood Apartments1387 30th Ave, Kenosha, WI 53144 View On Map (262) 552-9080
For rates, availability, and other information fill out the availability request form and a representative from Meadowood Apartments will contact you shortly
Meadowood Apartments is located in the Kenosha Area in the 53144 zip code. View this apartment on a map.
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On September 25, the Pennsylvania Supreme Court held that Pennsylvania state courts have jurisdiction over foreclosure actions where the foreclosing party may have failed to fully comply with the Pennsylvania Emergency Mortgage Act (Act 91) in providing notice of foreclosure. Beneficial Consumer Discount Co. v. Vukman, No. 29-WAP-2012, 2013 WL 5354330 (Pa. Sept. 25, 2013). A state trial court and intermediate appellate court set aside a judgment in a foreclosure action and subsequent sheriff's sale, holding that the foreclosing party's failure to comply with the Act 91's foreclosure notice requirement stripped the state courts' of subject matter jurisdiction. The Supreme Court disagreed and held that the pre-foreclosure requirements do not implicate the jurisdiction of the court—the borrower's failure to pay the mortgage provided sufficient cause to pursue foreclosure. The court remanded the case to the trial court without addressing the foreclosing party's arguments that its notice was sufficient because it was drafted by the state housing authority.
DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.
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Sorry if this is in the wrong section. But i am really happy with my theme, but when i upload more than 5 photo's the 6th photo appears blank, does anyone know what i am doing wrong?
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News & Analysis
May 22 03:30pm EST
There are plenty of different ways to celebrate Pac-Man's big birthday.MORE >
May 22 02:22pm EST
The tech would turn toys into Internet-connected controllers of gadgets in the home.MORE >
May 22 01:25pm EST
iOS 9 is reportedly being developed to work with devices like the iPhone 4s.MORE >
May 22 12:51pm EST
A hacker leaked data from 3.9 million AdultFriendFinder members onto the Web.MORE >
May 25 03:55pm EST
Android M Codename: Macadamia Nut Cookie?
Android M is being referred to internally as Macadamia Nut Cookie, thanks to code with references to "mnc-dev.MORE >
May 25 08:00am EST
Has iPhone Growth Reached its Peak?
Apple will likely see serious iPhone growth through 2016.MORE >
May 24 03:02pm EST
Instagram Launching New 'Highlights' Email
Miss something super-interesting that a friend posted to Instagram? If you're getting the company's new "highlights" email, you might get a second chance to see it.MORE >
May 24 02:05pm EST
Amid Restructuring, Blackberry Calls for More Layoffs
Blackberry is laying off an undisclosed number of employees as it continues to consolidate its hardware, software, and applications businesses.MORE >
May 23 04:12pm EST
Microsoft Testing Cross-Platform Clipboard App, 'OneClip'
The app is in an internal beta right now, but the Windows and Windows Phone versions have already leaked out.MORE >
May 23 03:23pm EST
Uber Testing Self-Driving Car in Pittsburgh? Not Quite
Alas, Uber is just driving around a sensor-laden car, not testing one that can drive itself places.MORE >
May 23 02:33pm EST
Amazon Starts Teasing New 'Handmade' Marketplace
We're very curious to see what kind of fees might be associated with Amazon's to-be-launched "Etsy killer.MORE >
May 23 09:00am EST
55 Movies and TV Shows Leaving Netflix in June
Summer is movie seasonunless you're a fan of the flicks getting nixed by the 'flix next month. MORE >
May 23 07:00am EST
7 Cell Towers Having an Identity Crisis
They dot the landscape rather than mar it. Would they fool you?MORE >
May 22 05:21pm EST
Report: Don't Put Too Much Trust in an Android Factory Reset
According to new research, a typical Factory Reset for your Android device might not be as data-destroying as you think it is.MORE >
May 22 05:10pm EST
Uber Tries to Wriggle Out of ADA Lawsuits
Uber says the Americans With Disabilities Act doesn't apply, since it's not a transportation company.MORE >
May 22 03:30pm EST
Pac-Man Turns 35, Gets Updated iOS App
There are plenty of different ways to celebrate Pac-Man's big birthday today. Here are some of our favorites.MORE >
May 22 02:55pm EST
New Zealand Wanted New Flag Ideas: The Internet Did Not Disappoint
See, this is why we can't have anything nice on the Internet.MORE >
May 22 02:35pm EST
Tasty Spam: Affiliate Spammers Will Push Anything, Even Security Software
Affiliate spam doesn't always mean fake pharmaceutical ads and dodgy payday loan scams. Spammers will push legitimate products and collect commission for every sale.MORE >
May 22 02:30pm EST
Google Working on 'Brillo' OS for Low-Powered Devices
Is this the start of Google's big step into smarthomes?MORE >
May 22 02:22pm EST
Google Toy Patent Will Give You Nightmares
Google wants to patent technology that would turn toys into Internet-connected controllers of gadgets in the home.MORE >
May 22 01:45pm EST
Business Choice 2015: Internet Service Providers
When you're working, which ISP has the fastest, most reliable Internet service? PCMag readers weigh in.MORE >
May 22 01:25pm EST
Report: iOS 9 to Play Nice With Older iPhones, iPads
iOS 9 is being developed to work with devices like the iPhone 4s and original iPad mini, 9to5mac reports.MORE >
May 22 12:51pm EST
AdultFriendFinder Exposed in Data Hack
A hacker leaked data from 3.9 million AdultFriendFinder members onto a darknet forum.MORE >
May 22 11:50am EST
Save Big on 14-Inch ThinkPad X1 Carbon Ultrabook
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May 22 11:35am EST
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May 22 11:20am EST
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May 22 10:30am EST
Surprise: NSA Poking Around App Stores, Your Phone
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May 22 09:55am EST
Uber Self-Driving Car Spotted in Pittsburgh
The sedan has "Uber Advanced Technologies Center" written on the doors, so Uber isn't trying to hide.MORE >
May 22 08:00am EST
Google's Fully Autonomous Cars Are a Good Thing
While I love to drive, there are almost 33,000 reasons why I applaud Google for pushing the envelope.MORE >


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Uva Rossa
Though often noisy, Uva Rossa in Malverne is always a fine spot to catch a good Italian meal without the huge Italian portions. Small plates and an attractive brick and wood interior make this restaurant modern and enjoyable -- so long as you don't mind the chatter.
16 favorite outdoor dining spots on LI 22 must-eat lobster rolls on LI Restaurants with a water view Latest fine dining reviews Dinner and a movie: Deer Park National Burger Day: 36 to try on LI Lawson Pub 50 Cheap Eats to try on LI Pulcinella Neapolitan Restaurant Pizza of the Week: Specialty pie picks 10 great eats en route to Jones Beach Dinner and a movie: Levittown


text:
Films with fully developed elderly characters shouldn't be a rarity, but this charming sequel highlights how scarce, and welcome, they are. Continue reading
Tag Archives: romantic comedy
Cameron Diaz and Jason Segel try to fool us into thinking they're making a raunchy sex comedy, but really star in a half-baked remake of "Date Night." Continue reading
Words and Pictures
Clive Owen and Juliette Binoche star in this peculiar romantic comedy about life, art and literature. Continue reading
The Other Woman (2014)
"The Other Woman" is a mindless, predictable film with enough slapstick and physical humor to make it fairly enjoyable. Continue reading
Class of 1994: "Reality Bites"
Formless and fuzzy, "Reality Bites" is a film whose legacy as an encapsulation of an ethos and an era has little to do with the film itself. Continue reading
About Last Night
This reboot is both sitcom-y and superfluous but has some sweet spots. Continue reading
Don Jon
Joseph Gordon-Levitt's directorial debut about an Italian stallion with a secret is mostly middling but has a few pleasant surprises. Continue reading
The Romcom Chase
In a romantic comedy, the race against time to stop the hero's beloved from leaving their life forever. Continue reading
Much Ado About Nothing
Joss Whedon tackles iambic pentameter served under the guise of modern day aesthetics in "Much Ado About Nothing." Continue reading
The Judy Greer
The unheralded buddy character in romantic comedies who is infinitely more interesting than the star, but gets almost nothing to do in the movie. Continue reading


text: "Jingle Bells" is one of the best-known and commonly sung winter songs in the world. It was written by James Lord Pierpont (1822–1893) and published under the title "One Horse Open Sleigh" in 1857. Despite being widely regarded as a Christmas song, it is said to have been written about Thanksgiving.[1]


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The Dura-Ace name is so consistently synonymous with success, it needs no introduction. If you're thinking of upgrading to Dura-Ace there's no doubt that you know what you're shooting for—the absolute best. From the bike path to the pro peloton Dura-Ace sets the pace for the rest of the pack. With the introduction of Di2, Dura-Ace changed the face of performance cycling once again. The Shimano Dura-Ace Di2 RD-9070 Rear Derailleur utilizes state of the art Di2 electronic technology and takes Shimano's already stellar reputation to a new all-time high.
Take control with precise, lightning-fast shifts across an 11-speed cassette, whatever the conditions, with just a button click. The 9070 rear derailleur is now lighter and more compact, with E-tube connection to simplify installation and fine tune performance. Automatic crash protection moves the cage out of harm's way in the event of a spill and the sleek grey colorway goes well with any build. Smooth, effortless shifting. No compromise performance. Dura-Ace is the pinnacle of cycling performance.
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Folk Dance Friday
Learn simple traditional dances from around the world at 7 p.m. Friday at the Unitarian Universalist Congregation Hall. Attendees, from middle schools and older, are invited to join in the fun, fellowship, exercise and get introduction to the music and movement of diverse cultures. Elaine Gelbard will teach the dances. No experience necessary. There is no charge for the event, but donations will be gratefully accepted for the UUCO Building Fund. The UU Hall is at 31 CR 198. A map with directions is available at www.uuoxford.com. For more information, call Gelbard at 236-2545. (August 20, 2010)
Members of the Disabled American Veterans, Chapter 48, will meet at noon Saturday at the Veteran's Building, located at 125 Veterans Drive. (August 20, 2010)
C.A.R.E. Support, Exchange Group
The Caring for Aging Relatives Effectively, or C.A.R.E., support and exchange group will meet at noon Wednesday at Azalea Gardens Assisted Living Community. This is an informal luncheon that provides those in caring situations an opportunity to exchange ideas, resources and concerns with others. A light lunch is provided compliments of Azalea Gardens. All caregivers are welcome. For more information, contact Sandra Enfinger at 234-9600 or Jo Ann O'Quin at email@example.com. (August 20, 2010)
Getting to know hereditary hemochromatosis
This week, Dr. Keith Mansel writes about a topic unfamiliar to many – an illness first described in 1872 and in 1917 was linked to abnormal iron absorption by the body. For more information go to www.hemochromatosis.org (August 19, 2010, Page 5)
Thursday's obituaries
- Robert L. Barlow — 76, died Wednesday, Aug. 18, 2010. Services will be held at 2 p.m. Friday in the chapel of Waller Funeral Home. Burial will follow in Forrest Memorial Park in Batesville.
- Carole Lindsey Baughman — 68, died Wednesday, Aug. 18, 2010. Arrangements for a private family service are incomplete at this time. Coleman Funeral Home of Oxford is in charge of local arrangements.
- Lanny Eugene Phillips — 58, died Wednesday at his home in Lafayette County. Arrangements are incomplete with Coleman Funeral Home of Oxford.
Healthier chicken salad choices
Think twice when ordering a grilled chicken Caesar salad. These salads may sound healthy, but in fact they are high in calories and fat. In this weeks Eating Well column a new flavorful, grilled recipe is offered up to try instead of the usual high calorie stand-by. (August 18, 2010, Page 6)
Wednesday's obituaries
- Ruby O'Dell — 77, died Tuesday, Aug. 17, 2010. Services will be held at 11 a.m. Friday at New Prospect Baptist Church. Burial will follow in Kingdom Cemetery. Visitation will be held from 4 to 6 p.m. Thursday at Waller Funeral Home.
Cab driver apologizes to Rebels' Kennedy
Ole Miss basketball coach Andy Kennedy settled a defamation lawsuit Tuesday with a cab driver and a valet stemming from a dispute over a ride in the downtown district of Cincinnati in December, 2008.
Details of the settlement are confidential as attorneys told Judge Melba Marsh in Hamilton County Common Pleas Court that they had reached an agreement. According to a source, Kennedy did not pay cab driver Mohamed Jiddou, or valet Michael Strother a monetary settlement as some papers reported today. (August 18, 2010, Page 8)
Kennon Observatory Open House
The Kennon Observatory at Ole Miss will have an open house from 8 to 10 p.m. Friday. The Moon is strong and looks great in a telescope. Saturn, Venus and (tiny) Mars are all observable after sunset, but they all go down very early. The best time to view them is in the beginning of the session.
Uranus is up all night, Neptune is next to Jupiter. Jupiter comes up at 9, and is best visible an hour later. Afterwards will be observing star clusters, and colorful double stars. As the dome of Kennon Observatory is being repaired, the large telescope inside can't be used. However, some good quality scopes will be set up in the parking lot. Observations are possible only if the weather cooperates. In case the weather is cloudy, or rainy, there can be no observation. Families and children are welcome, the event is free. (August 18, 2010)
Girl Scouts Registration
Girls Scouts Heart of the South will have an informational meeting and registration event from 6 to 8 p.m. Thursday at the Oxford-University United Methodist Church. Those interested in joining Girl Scouts as a troop member or adult leader are encouraged to attend. For more information, call Dianna Wilson at 662-816-5190. (August 18, 2010)


text:
14 March 2013 12:27 [Source: ICIS news]
LONDON (ICIS)--Huntsman has acquired a 20% stake in Nippon Aqua, a spray polyurethane (PU) foam insulation company based in Yokohama, Japan, the US-based chemicals producer said on Thursday.
Huntsman has also entered into a 10-year supply agreement with the company, it added.
The US producer supplies various advanced methyl di-p-phenylene isocyanate (MDI)-based PU systems to Nippon Aqua.
The financial terms of the deal were not disclosed.
Nippon Aqua has business operations in over 30 locations across Japan, and is a subsidiary of residential home builder Hinokiya Holdings, Huntsman said.
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Arabinogalactan is a marvelously effective, water soluble fiber that is also an
immune enhancer
As safe as water, acceptable to finicky cats, and recommended for cats, dogs, and humans.
Mix into any wet food.
Put it into your morning coffee to reduce stomach acidity.
Supplements just do not get any better.
And, we sell it for less money than anyone on the web!
All arabinogalactan is the same. It is a patented product made by one manufacturer. We separate it into cat and dog for our records.
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Product Info
Arabinogalactans occur naturally in most plant cell walls.
The most commercially available Arabinogalactans occur in Larch trees, which are the nutritional source.
Arabinogalactan powder supports colon health. Arabinogalactans work in the colon by activating immune cells. Acting as a fermentable fiber, they promote growth of probiotic bacteria (such as PetFlora) in the colon and contribute to healthy microflora levels.
Arabinogalactan powder supports the immune system and colon health by moderating acidic buildup in the intestinal tract.
The fiber is non-allergenic and does not stimulate an insulin response.
Royal Society Of Medicine of Great Britain has written that
"90% of all chronic disease is caused by an unhealthy intestinal tract,"
Arabinogalactan powder enhances the immune system by increasing the number of immune cells present in the bloodstream, enhancing natural killer cell and macrophage activation, and limiting unhealthy cell replication.
It follows then that Arabinogalactan powder may limit the
progress of a disease by stimulating immune cell activation.
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How to Use
Cats: 0.5 tbl (1.5 gms.)
Dogs: Under 25 lbs. 1 tbl.
Dogs: 25-50 lbs. 1.5 tbl.
Dogs: 50-100 lbs. 2 tbl.
Arabinogalactan is so gentle that there is no upper limit on dosage. It supports the immune system, calms the stomach, and soothes GI function at the recommended dose but more is perfectly safe and may be necessary for some animals.
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Arabinogalactan powder is 100% Larch Tree extract, with 98% Arabinogalactans.
Arabinogalactan is the name for a patented fiber extract, which is a long chain polysaccharide extracted from larch trees.
We formulate our own products.
All our ingredients are purchased from United States sources. We maintain a C of A (Certificate of Authenticity) for all ingredients.
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We manufacture so that humans, including family and friends can confidently take any of our products. Family and friends as well as customers take
Pet Flora
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"Arabinogalactan has worked great on all my corgis and all problems of theirs are resolved."
Dona Straway
Ocala, FL
"First let me say that I have had great success with your products. I help run a small Cat rescue group in New Jersey. I have used Pet Flora, Luxolite, Arabinogalactan, Anti-Inflammatory & Soothing Solution on both my own cats and those of the rescue group. The rescued cats often have diarrhea problems and just a general state of declined health. I keep preaching to adopters the important of a good quality food (raw or at least something like the Wellness brand) and of course your products. We now have a kitten that has tested positive for Feline Leukemia but currently is otherwsie healthy. We have put the kitten on your supplements of Pet Flora, Arabinogalactan and also Vitamin C and will retest the kitten in a few months.
Thank you for great products that my cats easily take in their food."
Gilda McCauley Purrfect Feline Friends
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Scientific Studies
Arabinogalactan stimulates macrophage activity and therefore may be effective in preventing cancer
Arabinogalactan Research Update
Immunomodulating activity of arabinogalactan and fucoidan in vitro.
J Med Food. 2005 Winter;8(4):446-53. Department of Biotechnology & Bioproducts Research Center, Yonsei University, Seoul, South Korea.
Many polysaccharides obtained from natural sources are considered to be biological response modifiers and have been shown to enhance various immune responses. These data suggest that arabinogalactan and fucoidan are activators of lymphocytes and macrophages.
This property may contribute to their effectiveness in the immunoprevention of cancer.
Arabinogalatcan has no effect on blood sugar levels and is well accepted by consumers
J Am Diet Assoc. 2004 Apr;104(4):636-9. Marett R, Slavin JL.
Arabinogalactan proteins have a pronounced anti-microbial activity.
Antimicrobial activity of Andrographis paniculata and arabinogalactan proteins.
Fitoterapia. 2003 Dec;74(7-8):692-4.
Effect over time of in-vivo administration of the polysaccharide arabinogalactan on immune and hemopoietic cell lineages in murine spleen and bone marrow.
Phytomedicine. 2003 Mar;10(2-3):145-53.
Immunological activity of larch arabinogalactan and Echinacea: a preliminary, randomized, double-blind, placebo-controlled trial.
Altern Med Rev. 2002 Apr;7(2):138-49. Kim LS, Waters RF, Burkholder PM. Research Department, Southwest College, Arizona
Arabinogalactan improves bowel chemistry.
Effects of dietary larch arabinogalactan on gastrointestinal and blood parameters in healthy human subjects.
J Am Coll Nutr. 2001 Aug;20(4):279-85. Robinson RR, Feirtag J, Slavin JL. Department of Food Science and Nutrition, University of Minnesota
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California Supreme Court rejects appeal on Tempongko domestic violence murder
More News from INQUIRER.net US Bureau
SAN FRANCISCO, California – The California Supreme Court rejected an appeal March 19 the case of People v. Beltran, by a man convicted of murdering his former girlfriend, Filipino American single mother Claire Grace Tempongko.
Tar Ramirez Beltran was convicted of second-degree murder and sentenced to 26 years to life in prison for fatally stabbing Claire Tempongko, 28, in front of her two children in her Richmond District apartment in October 2000.
He testified that he had been thrown into a rage after she told him, in insulting language, that she had been pregnant by him and had gotten an abortion. The state's high court unanimously denied review of the case on March 19.
San Francisco District Attorney George Gascón applauded the court for upholding the murder conviction.
"The circumstances surrounding the tragic murder of Claire Joyce Tempongko dealt a heavy blow to all victims of domestic abuse, but it rallied the domestic violence community to push for a myriad of necessary changes that have enhanced our response to incidents of domestic violence," Gascon stated.
"It is essential that we maintain our focus, resolve and commitment to protecting victims of domestic violence, and ensuring perpetrators are held accountable for their crimes," he added.
Calif. Supreme Court mulls Tempongko domestic violence case – was it murder or manslaughter?
CA court reinstates murder conviction of Fil-Am woman's batterer
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text:
No Facebook for You!
by Alexandra DeFelice on printer friendly
By Alexandra DeFelice
"Access Denied."
This is the message I received when trying to log in to my Facebook account from an accounting firm's office.
Those words confirmed my suspicions that several firms ‒ and businesses in general ‒ are blocking their employees from using Facebook during working hours, at least from their work-assigned computers within the walls of their company office.
Although I'm not a CPA, I actively engage with CPAs on Facebook, and I've noticed that many of them answer me after hours. Part of me argued that because worlds are increasingly colliding, maybe they were choosing to use Facebook at night when they typically converse with their friends, share pictures, and perhaps catch up on their professional articles and blogs. Hey, why not?
Then reality kicked in. I bet that given the choice, most people would prefer to connect with accounting publications, such as AccountingWEB, during the day. And let's be honest, they'd rather connect with their friends during the day, too.
For decades, before all this social media hoopla came into the mainstream, people found ways to take care of their personal business during the workday. They'd go to the DMV on their "lunch break," which we all know took longer than an hour; they'd wait in long lines at the bank, pre-ATM days; and they'd even chat on their phone with their spouses or children.
Perhaps some companies had strict policies prohibiting such activities and monitored everyone's conversations and time away from the office. It's doubtful that was the norm.
Yet somehow, it got into the heads of a bunch of decision makers that they have to block Facebook because employees ‒ especially younger ones ‒ will "spend all day talking to their friends." My favorite ironic conversation took place just the other week with a CPA whose firm blocks Facebook for junior staff but allows partners to use it.
"So what do you use it for?" I inquired.
"To talk to my kids," he replied.
Let's face reality. If people want to talk to their friends during the day, they're going to do it. Unless you make them drop their phones at the door when they come into the office so they can't send text messages, you centralize all phone calls, and you block access to every e-mail site, employees can talk to their friends. I've known people who only had access to their work e-mails and used those just like personal accounts, even going so far as to apply for other jobs through those accounts, despite warnings in their employee contract that their firm monitors e-mails.
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There's always more at AccountingWEB. We're an active community of financial professionals and journalists who strive to bring you valuable content every day. If you'd like, let us know your interests and we'll send you a few articles every week either in taxation, practice excellence, or just our most popular stories from that week. It's free to sign up and to be a part of our community.
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text: http://www.unix.com – I want to implement an FTP server on RHEL 5.8 system where the users can upload files either from RHEL or Windows systems but am not able to copy files to it from a browser session. For eg. URL - ftp://10.101.17.80/incoming I want to copy files from to it from my Windows Google chrome browser session. I have done following steps to make FTP server writable on my RHEL 5.8 server:- Code: mkdir /var/ftp/incoming chgrp ftp /var/ftp/incoming chmod 730 /var/ftp/incoming semange fcontext a -t public_content_rw_t /var/ftp/incoming(/.)? setsebool P allow_ (HowTos)