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This study was carried out to determine the effect of 2-aminoethoxydiphenyl borate (2-APB), a common activator of transient receptor potential vanilloid (TRPV) type 1, 2, and 3 channels, on cardiorespiratory reflexes, pulmonary C fiber afferents, and isolated pulmonary capsaicin-sensitive neurons. In anesthetized, spontaneously breathing rats, intravenous bolus injection of 2-APB elicited the pulmonary chemoreflex responses, characterized by apnea, bradycardia, and hypotension. After perineural treatment of both cervical vagi with capsaicin to block the conduction of C fibers, 2-APB no longer evoked any of these reflex responses. In open-chest and artificially ventilated rats, 2-APB evoked an abrupt and intense discharge in vagal pulmonary C fibers in a dose-dependent manner. The stimulation of C fibers by 2-APB was attenuated but not abolished by capsazepine, a selective antagonist of the TRPV1, which completely blocked the response to capsaicin in these C fiber afferents. In isolated pulmonary capsaicin-sensitive neurons, 2-APB concentration dependently evoked an inward current that was partially inhibited by capsazepine but almost completely abolished by ruthenium red, an effective blocker of all TRPV channels. In conclusion, 2-APB evokes a consistent and distinct stimulatory effect on pulmonary C fibers in vivo and on isolated pulmonary capsaicin-sensitive neurons in vitro. These results establish the functional evidence demonstrating that TRPV1, V2, and V3 channels are expressed on these sensory neurons and their terminals.
- pulmonary chemoreflex
- vagal C fiber
- pulmonary sensory neuron
- transient receptor potential channels
the transient receptor potential (TRP) superfamily is a novel and rapidly expanding group of ion channel proteins. Mammalian homologs of the TRP channel gene encode a family of >20 related ion channels that are further divided into TRPC (canonical), TRPV (vanilloid), and TRPM (melastatin) subfamilies (12, 32, 33). These channels are widely distributed in a variety of mammalian organisms, tissues, and cell types and sense local changes in stimuli ranging from light, olfaction, temperature, pH, and osmolarity to mechanical, chemical, and metabolic stress (31, 43). Currently, the TRPV subfamily has six members. Like members in other TRP subfamilies, they are all cation channels; however, they vary substantially in their selectivity and mode of activation (32, 33). Except temperature as the common stimulus of thermosensitive TRPV channels, namely TRPV1–4, most TRPV channels can be activated by nonthermal stimuli (11, 16, 20, 40). For example, TRPV1 can be activated by capsaicin, protons, or endocannabinoids (8, 10, 21, 22, 27). TRPV4 can be activated by 4α-phorbol 12,13-didecanoate and several arachidonic acid metabolites (11, 35, 44, 45). 2-Aminoethoxydiphenyl borate (2-APB), which has been used extensively to investigate the effects of inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release and Ca2+ influx in a variety of cell types (15, 30, 46), was recently found to be a common and potent activator of three TRPV channels: TRPV1, V2, and V3, but not TRPV4, V5, and V6 (20).
Nonmyelinated (C) fibers represent ∼75% of the afferent fibers in the vagal branches innervating the entire respiratory tract (2, 14). Cell bodies of these afferent fibers reside in two adjacent but distinct anatomic structures, the nodose and intracranial jugular ganglia. The afferent activity arising from these C fiber endings plays an important role in regulating the respiratory and cardiovascular functions under both normal and abnormal physiological conditions (14, 26). Capsaicin, a pungent active ingredient of hot pepper, is the chemical agent most commonly used in studies of physiological properties and functions of these afferents because of its specificity and potency in stimulating these afferents (18, 19). Bolus injection of capsaicin into the pulmonary circulation stimulates pulmonary C fiber afferents and elicits pulmonary chemoreflex responses (apnea, bradycardia, and hypotension), which are mediated through the TRPV1 activation (14, 26). Indeed, expression of the TRPV1 and other members in the TRPV family in the vagal sensory (nodose and jugular) ganglia has been recently demonstrated (10, 17, 48). However, whether they are expressed by the neurons innervating the lungs is not known. Furthermore, the physiological roles of these TRPV channels, except the TRPV1, in regulating the function of pulmonary afferent nervous system, has been hampered due to a lack of selective activator and blocker of these channels. In light of the ability of 2-APB in activating these TRPV channels (11, 20), this study was therefore carried out: 1) to characterize the cardiorespiratory reflex responses to intravenous (IV) injection of 2-APB in spontaneously breathing rats and to evaluate the role of vagal C fiber afferents in eliciting these responses; 2) to determine the contribution of TRPV1 to the response of single unit pulmonary C fibers to 2-APB in artificially ventilated rats; and 3) to investigate the response of isolated pulmonary capsaicin-sensitive neurons to 2-APB and to differentiate the relative roles of TRPV1 and other TRPV channels in these responses.
Animal preparation.
The procedures described below were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health and were approved by the University of Kentucky Institutional Animal Care and Use Committee.
Sprague-Dawley rats (355–440 g) were initially anesthetized with an intraperitoneal injection of α-chloralose (100 mg/kg; Sigma Chemical, St. Louis, MO) and urethane (500 mg/kg; Sigma) dissolved in a borax solution (2%, Sigma); supplemental doses of α-chloralose (∼10 mg·kg−1·h−1) and urethane (∼50 mg·kg−1·h−1) were IV injected to maintain abolition of pain reflexes elicited by paw pinch. One femoral artery was cannulated for recording the arterial blood pressure (ABP) with a pressure transducer (Statham P23AA). For IV administration of pharmacological agents, the left jugular vein was cannulated, and a catheter was advanced until its tip was positioned just above the right atrium. The volume of each bolus injection was 0.1 ml, which was first injected into the catheter (dead space, ∼0.2 ml) and then flushed into the circulation by an injection of 0.3 ml of saline. A short tracheal cannula was inserted after a tracheotomy, and tracheal pressure (Ptr) was measured (Validyne MP 45-28) via a side port of the trachea cannula. Body temperature was maintained at ∼36°C by means of a heating pad placed under the animal, which was lying in a supine position. At the end of the experiment, the animal was killed by an IV injection of KCl (200 mg/kg).
Measurements of respiratory and cardiovascular responses.
Rats breathed spontaneously via the tracheal cannula. Respiratory flow was measured with a heated pneumotachograph and a differential pressure transducer (Validyne MP45-14) and integrated to give tidal volume (Vt). Respiratory frequency (f), inspiratory and expiratory durations (Te), Vt, minute ventilation (V̇e), heart rate (HR), and ABP were analyzed (Biocybernetics TS-100) on a breath-by-breath basis by an online computer.
Recording of pulmonary C fiber activity.
Pulmonary C fiber activities were recorded in anesthetized, open-chest, artificially ventilated rats, as described in details previously (18, 27). Briefly, the expiratory outlet of the respirator was placed under 3-cmH2O pressure to maintain a near-normal functional residual capacity. Vt and f were set at 8–10 ml/kg and 50 breaths/min, respectively. Both cervical vagus nerves were separated from carotid arteries and then sectioned to eliminate any possible influence of vagal-mediated reflex bronchoconstriction on afferent responses. The vagus nerve was ligated just above the diaphragm to eliminate afferent signals arising from lower visceral organs. The caudal end of the cut right vagus nerve was placed on a small dissecting platform and immersed in a pool of mineral oil. A thin filament was teased away from the desheathed nerve trunk and placed on a platinum-iridium hook electrode. Action potentials were amplified (Grass P511K), monitored by an audio monitor (Grass AM8RS), and displayed on an oscilloscope (Tektronix 2211). The thin filament was further split until the afferent activity arising from a single unit was electrically isolated. Our criteria for identifying pulmonary C fibers were as follows: 1) an abrupt and intense response to right atrial injection of capsaicin (1 μg/kg) within 2 s after the injection; 2) a weak response to lung inflation (Ptr = 30 cmH2O); and 3) the general locations of the receptors identified by their responses to gentle probing of the lungs with a blunt-ended glass rod. The signals of the fiber activity (FA), Ptr, and ABP were recorded on a video cassette format data recorder (Vetter 4000A) and were analyzed by an online data acquisition system (Biocybernetics TS-100) in 0.5-s intervals. Increase in FA (ΔFA) was calculated as the difference between peak FA (2-s average) and baseline FA (10-s average). A C fiber was considered to be activated when ΔFA exceeded 1 impulse/s.
Labeling pulmonary vagal sensory neurons with DiI.
Sensory neurons innervating the lungs and airways were identified by retrograde labeling from the lungs by using the fluorescent tracer 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI). Young adult Sprague-Dawley rats (150–200 g) were anesthetized with an intraperitoneal injection of pentobarbital (50 mg/kg) and intubated with a polyethylene catheter (PE-150) with its tip positioned in the trachea above the thoracic inlet. With the head tilted up at ∼30°, DiI was initially dissolved and sonicated in ethanol, diluted in saline (1% ethanol vol/vol), and then instilled into the lungs (0.15 mg/ml; 0.2 ml × 2). After 7–11 days, an interval previously determined to be sufficient for the dye to diffuse to the cell body, the nodose and jugular ganglia were extracted.
Isolation and culture of nodose and jugular ganglion neurons.
The animals were anesthetized with halothane inhalation and decapitated. The head was immediately immersed in ice-cold Hanks' balanced salt solution. Nodose and jugular ganglia were extracted under a dissecting microscope and placed in ice-cold DMEM/F-12 solution. Each ganglion was desheathed, cut into ∼10 pieces, placed in 0.125% type IV collagenase, and incubated for 1 h in 5% CO2 in air at 37°C. The ganglion suspension was centrifuged (150 g, 5 min) and supernatant aspirated. The cell pellet was resuspended in 0.05% trypsin and 0.53 mM EDTA in Hanks' balanced salt solution for 5 min and centrifuged (150 g, 5 min). The pellet was then resuspended in a modified DMEM/F-12 solution [DMEM/F-12 supplemented with 10% (vol/vol) heat-inactivated fetal bovine serum, 100 U/ml penicillin, 100 μg/ml streptomycin, and 100 μM MEM nonessential amino acids] and gently triturated with a small bore fire-polished Pasteur pipette. The dispersed cell suspension was centrifuged (500 g, 8 min) through a layer of 15% bovine serum albumin to separate the cells from the myelin debris. The pellets were resuspended in the modified DMEM/F-12 solution supplemented with 50 ng/ml of 2.5S nerve growth factor, plated onto poly-l-lysine-coated glass coverslips, and then incubated overnight (5% CO2 in air at 37°C).
Whole cell perforated patch-clamp recording.
The methods were described previously (20). Briefly, the coverslip containing the attached cells was placed in the center of a small (0.2 ml) recording chamber that was perfused by gravity feed (VC-6 perfusion valve controller; Warner Instruments, Hamden, CT) with extracellular solution (ECS) and ECS containing capsazepine or ruthenium red at 2 ml/min, whereas the chemical stimulants (2-APB and capsaicin) were applied by a pressure-driven drug delivery system (ALA-VM8; ALA Scientific Instruments, Westbury, NY), with its tip positioned to ensure that the cell was fully within the stream of the injectate. The ECS consisted of (in mM) 136 NaCl, 5.4 KCl, 1.8 CaCl2, 1 MgCl2, 0.33 NaH2PO4, 10 glucose, and 10 HEPES, pH 7.4. The intracellular solution contained (in mM) 92 potassium gluconate, 40 KCl, 8 NaCl, 1 CaCl2, 0.5 MgCl2, 10 EGTA, and 10 HEPES, pH 7.2. Recordings were made in the whole cell perforated patch configuration (50 μg/ml of gramicidin) using Axopatch 200B/pCLAMP 9.0 (Axon Instruments, Union City, CA). The experiments were performed at room temperature (22°C). The data were acquired at 5 kHz and filtered at 2 kHz. Series resistance was compensated at ∼80%. The resting membrane potential was held at −70 mV.
Experimental design and protocol.
Six series of experiments were carried out. Study series 1: the ventilatory and cardiovascular responses elicited by injections of increasing doses of 2-APB (1, 2, and 3 mg/kg) and its vehicle (for the 3 mg/kg dose) were determined. To avoid any accumulated effect, at least 10 min elapsed between two injections in this and subsequent protocols. Study series 2: the role of vagal C fiber afferents in 2-APB-induced cardiorespiratory responses was evaluated. The responses to injections of capsaicin (1 μg/kg) and 2-APB (3 mg/kg) were repeated at 2 and 15 min, respectively, after a bilateral perineural capsaicin treatment (PNCT), which produces a selective and reversible blockade of the C fiber conduction in the vagus nerves (27). Briefly, cotton strips soaked in capsaicin solution (250 μg/ml) were wrapped around a 2- to 3-mm segment of the isolated cervical vagi for 20 min and then removed. The responses to capsaicin and 2-APB were again tested at 60 and 75 min, respectively, after PNCT. Study series 3: single unit pulmonary C fiber responses to increasing doses of 2-APB (1, 2, and 3 mg/kg) and its vehicle (for the 3 mg/kg dose) were determined in 26 C fibers from 15 rats. Study series 4: this series was carried out to determine the role of the TRPV1 receptor in the 2-APB-induced stimulation of pulmonary C fibers. The 2-APB (3 mg/kg)- and capsaicin (1 μg/kg)-induced afferent responses were studied and compared before and after a constant IV infusion of capsazepine (0.3 mg·kg−1·min−1; 5 min), a selective TRPV1 receptor antagonist (4, 41), or its vehicle. When responses to 2-APB and capsaicin were studied in the same fibers (n = 8), the sequence of the injections of these two chemicals was alternated to achieve a balanced design. Study series 5: the responses to increasing concentrations of 2-APB (30, 100, and 300 μM) or its vehicle (for the 300 μM concentration) were determined in isolated pulmonary capsaicin-sensitive neurons. Study series 6: this series was carried out to differentiate the relative roles of TRPV1 and other TRPV channels in 2-APB-induced inward current in pulmonary capsaicin-sensitive neurons. Responses to 2-APB (300 μM) and capsaicin (0.3 or 1 μM) were studied before and after a 5-min pretreatment with capsazepine (10 μM) or ruthenium red (5 μM); the latter is an inorganic dye and a nonspecific blocker of Ca2+ channels and is also known for its nonselective but effective blocking effect on all the TRPV channels (13, 16). The sequence of applications of 2-APB and capsaicin was alternated when they were studied in the same neurons (n = 10).
A stock solution of 2-APB (100 mM; Tocris, Ellisville, MO) was prepared in DMSO (Sigma) and that of capsaicin (1 mM; Sigma) in 1% Tween 80, 1% ethanol, and 98% saline (study series 1–4) or ECS (study series 5 and 6). Stock solutions of capsazepine (Sigma) and ruthenium red (Sigma) were both prepared in DMSO at a concentration of 30 mM. Solutions of these chemical agents at desired concentrations were then prepared daily by dilution with saline on the basis of the animal's body weight in study series 1–4 or diluted with ECS in study series 5 and 6.
Statistical analysis.
Data were analyzed with a one- or two-way ANOVA. When the ANOVA showed a significant interaction, pairwise comparisons were made with a post hoc analysis (Fisher's least significant differences). A P value < 0.05 was considered significant. Data are means ± SE.
2-APB-induced pulmonary chemoreflex responses.
Bolus injections of 2-APB at the doses of 1 and 2 mg/kg only produced very mild ventilatory and cardiovascular inhibitions. A higher dose (3 mg/kg) of 2-APB consistently elicited apnea, bradycardia, and hypotension (Fig. 1). Both respiratory and cardiovascular responses returned to baseline within 10 s. The reproducibility of the cardiorespiratory responses to this high dose of 2-APB was established in four rats, and no tachyphylaxis was observed when at least 10 min elapsed between two injections. The apneic response induced by 2-APB at the dose of 3 mg/kg was clearly shown by a prolonged Te, reaching 545 ± 73% of the baseline Te (Fig. 1E). In contrast, the injection of vehicle did not cause any significant change in respiration.
Effect of PNCT on capsaicin- and 2-APB-induced pulmonary chemoreflex responses.
In control condition, IV injection of 2-APB (3 mg/kg) induced ventilatory and cardiovascular inhibition that was comparable to the degree and pattern of that caused by 1 μg/kg of capsaicin (e.g., Fig. 2, A and B). PNCT of both cervical vagi caused only slight but not significant increases in baseline f, Vt, HR, and ABP. However, it completely abolished the chemoreflexes (apnea, bradycardia, and hypotension) induced by capsaicin (1 μg/kg), verifying its effectiveness in blocking the conduction of vagal C fiber afferents (Figs. 2 and 3). In the same animals, the 2-APB (3 mg/kg)-induced respiratory and cardiovascular inhibitions were also abolished after the treatment (Figs. 2 and 3). The responses to both capsaicin and 2-APB returned toward the control in ∼60 min; however, the recovery of chemoreflex response to 2-APB was consistently slower and less complete compared with that of capsaicin (e.g., Fig. 2, E and F; Fig. 3, C and D).
Dose dependence of the stimulating effect of 2-APB on pulmonary C fibers.
2-APB stimulated pulmonary C fiber afferents in a dose-dependent manner (Fig. 4). Injections of 2-APB at the dose of 2 mg/kg activated 13 out of 26 C fibers tested, but the average response (ΔFA, 1.13 ± 0.38 impulses/s; n = 26) was not significantly different from that of either 1 mg/kg (0.10 ± 0.08 impulses/s; n = 26) or vehicle (0.09 ± 0.07 impulses/s; n = 10). A higher dose of 2-APB (3 mg/kg) activated all the C fibers tested (ΔFA, 10.82 ± 2.12 impulses/s; n = 26); most of the fibers started to discharge within 1 s, and the activity reached a peak in ∼2 s and returned to baseline within 4 s after the injection. In the majority of the animals, this high dose of 2-APB (3 mg/kg) also elicited a cardiovascular depression; the magnitudes of these responses were comparable to that of 1 μg/kg of capsaicin (e.g., Fig. 5, A and B).
Effect of capsazepine on capsaicin- and 2-APB-induced pulmonary C fiber activation and cardiovascular responses.
After pretreatment with capsazepine, there was no change in the baseline FA of pulmonary C fibers (before capsazepine, 0.01 ± 0.01 impulses/s, after capsazepine, 0.01 ± 0.01 impulses/s; P > 0.05; n = 20). However, the C fiber discharges induced by injection of 1 μg/kg of capsaicin were almost completely abolished by the treatment (ΔFA: before capsazepine, 12.4 ± 2.12 impulses/s; after capsazepine, 0.35 ± 0.13 impulses/s; P < 0.05; n = 11); so were the capsaicin-induced cardiovascular depressor responses (Figs. 5, 6, and 7); the response to the same dose of capsaicin returned to the control level ∼20 min after capsazepine treatment (10.2 ± 2.25 impulses/s). In sharp contrast, capsazepine treatment only blocked ∼74% of the ΔFA induced by 2-APB (before capsazepine, 13.4 ± 1.7 impulses/s, after capsazepine, 3.5 ± 0.83 impulses/s; P < 0.05, n = 17), whereas its blocking effect on 2-APB-induced cardiovascular depressor responses was substantially less (Figs. 5, 6, and 7). In a separate group of 16 C fibers, treatment with capsazepine vehicle did not have any detectable effect on the responses induced by either capsaicin (not shown) or 2-APB (Fig. 7A).
2-APB-induced whole cell inward currents in isolated rat pulmonary capsaicin-sensitive neurons.
Because of the potency and selectivity of capsaicin in activating the pulmonary C fibers (18), we consider "capsaicin-sensitive neurons" as "C neurons" in this study. To identify the sensory neurons that give rise to pulmonary C fibers for whole cell perforated patch-clamp recording, neurons isolated from nodose and jugular ganglia were selected based on the following criteria: 1) labeled with DiI as indicated by fluorescence intensity; 2) smooth surface and spherical shape without visible processes; 3) whole cell capacitance <30 pF; and 4) responding to capsaicin (1 μM). Application of 2-APB in the range of 30–300 μM (4–8 s) evoked incremental whole cell inward currents in a concentration-dependent manner (Fig. 8, A and B). 2-APB (300 μM) stimulated all the capsaicin-sensitive pulmonary nodose and jugular ganglion neurons held at −70 mV; the inward currents evoked by this high concentration of 2-APB and 0.3–1 μM capsaicin followed a very similar pattern and reached a comparable amplitude in 13 out of 24 pulmonary sensory neurons tested, and a clear disparity was displayed in the remaining neurons.
Effect of capsazepine and ruthenium red on capsaicin- and 2-APB-induced whole cell inward currents in isolated rat pulmonary capsaicin-sensitive neurons.
Pretreatment with capsazepine (10 μM, 5 min) completely abolished capsaicin (0.3–1 μM, 4–8 s)-induced inward current (Fig. 8, C and D; before capsazepine, 289.5 ± 44.7 pA; after capsazepine, 0.8 ± 0.4 pA; P < 0.05; n = 8) but only inhibited ∼60% of the currents induced by 2-APB (300 μM, 4–8 s) (Fig. 8, E and F; before capsazepine, 403.1 ± 74.2 pA; after capsazepine, 186.6 ± 49.8 pA; P < 0.05; n = 9); both capsaicin- and 2-APB-induced inward currents returned to the control level after ∼60 min of washout. In contrast, pretreatment with ruthenium red (5 μM, 5 min) almost completely abolished the inward currents induced by both capsaicin (before ruthenium red, 241.7 ± 34.9 pA; after ruthenium red, 0.7 ± 0.3 pA; P < 0.05; n = 6) and 2-APB (before ruthenium red, 293.1 ± 62.3 pA; after ruthenium red, 16.1 ± 4.9 pA; P < 0.05; n = 7); the antagonizing effects of ruthenium red were also reversed after ∼60 min of recovery (Fig. 9). Pretreatment with the vehicles of capsazepine and ruthenium red did not have any detectable effect on the inward currents induced by either capsaicin or 2-APB (n = 4).
In the present study, we have demonstrated that right atrium injection of 2-APB evoked the classic "pulmonary chemoreflex" responses, characterized by apnea, bradycardia, and hypotension. These reflex responses were completely abolished by PNCT of both cervical vagi, suggesting the involvement of vagal C fibers. The single-fiber recording experiments have confirmed that 2-APB (1, 2, and 3 mg/kg) stimulated the individual pulmonary C fibers in a dose-dependent manner. Results obtained from the capsazepine experiment indicated that the stimulatory effect of 2-APB resulted, in part, from the activation of TRPV1. Our patch-clamp studies in isolated pulmonary capsaicin-sensitive neurons have further demonstrated that 2-APB caused a stimulatory effect on these neurons. This stimulating effect was probably mediated through the activation of TRPV1, V2, and V3 channels because it was attenuated but not totally abolished by capsazepine, a selective TRPV1 antagonist (4, 41). In contrast, it was completely abrogated by ruthenium red, a nonselective TRPV channel blocker (13, 16).
2-APB was originally reported as a membrane-permeable antagonist of IP3 receptors (30) and has been used extensively as an inhibitor of store-operated Ca2+ influx and IP3-medicated Ca2+ release (5, 15). Recent studies have revealed a novel effect of 2-APB on TRPV channels (11, 20). In HEK-293 cells transfected with mouse TRPVs, Chung and colleagues (11) reported that 2-APB, at the concentration of 100 μM, generated a robust stimulatory effect on TRPV3, little effect on TRPV1, and no activation of TRPV2. In contrast, Hu and coworkers (20) demonstrated that 2-APB at a higher concentration (500 μM) is a common and potent activator of three TRPV channels, TRPV1–3. Using the fluo 4-based Ca2+ assay, they further determined that the EC50 values of 2-APB were 114 ± 8, 129 ± 13, and 34 ± 12 μM for TRPV1, V2, and V3, respectively, in HEK-293 cells expressing these TRPVs. As the first cloned member of the TRPV subfamily, TRPV1 is a Ca2+-permeable cation channel activated not only by vanilloids, such as capsaicin, but also by endogenous lipids (endocannabinoids, eicosanoids), protons (pH < ∼5.9), and temperature (>43°C) (8, 10, 21, 22, 27). The expression of TRPV1 was found exclusively in small- to medium-diameter neurons within dorsal root, trigeminal, and nodose sensory ganglia (8, 10, 25, 41). Both TRPV2 and TRPV3 are insensitive to capsaicin and show a steep dependence of temperature (43). TRPV2 seems to be expressed preferentially in medium- to large-diameter sensory neurons and is activated by hypoosmolarity (34), growth factor (23), and noxious heat (>52°C) (9). Expression of TRPV3 has been found not only in sensory neurons (e.g., dorsal root, trigeminal, and superior cervical ganglia) but also in skin, tongue, and other tissues (47). TRPV3 is activated by innocuous temperatures (>34–38°C) (36, 38, 47) and by the only known chemical stimulus, 2-APB (11, 20). In a recent study using RT-PCR, Zhang and colleagues (48) have demonstrated the presence of temperature-sensitive TRP channel transcripts (TRPVs, TRPN1, and TRPM8) in nodose ganglia gastrointestinal neurons. The expression of TRPV1 and TRPV2 in nodose ganglia was further confirmed by their immunohistochemical staining studies. Whether these TRPV channels are also expressed in the cell bodies of isolated pulmonary neurons and the pulmonary C fiber sensory endings is not known. Based on the results obtained in the present study and the literature described above, we suggest that activation of TRPV1, V2, and V3 is probably involved in the stimulation of these sensory neurons by 2-APB. Our results cannot completely rule out other potential excitatory effects of 2-APB on these neurons. For example, in addition to its inhibitory effect, 2-APB has been shown to activate or potentiate store-operated Ca2+ channels and a nonselective cation channel of unknown function (6, 29, 37). However, this possible involvement is less likely in our study because the 2-APB effect was completely abolished by ruthenium red.
Immunohistochemical studies have illustrated the presence of C fiber sensory endings in the mucosa of all sizes of airways in various species, including humans (1, 3, 24). These nerve endings display extensive axon arborization that either extends into the space between epithelial cells or forms network-like plexus immediately beneath the basement membrane of epithelium (1, 3, 24). The superficial locations of these nerve endings suggest an important role of these afferents in regulating the airway responses to inhaled irritants such as sulfur dioxide, ammonia, cigarette smoke, and acid aerosol, etc. Furthermore, pulmonary C fiber afferents are generally known to possess polymodel sensitivity; in addition to chemical irritants (e.g., acid, nicotine, capsaicin), these afferents can also be activated by certain endogenously released autacoids (e.g., prostaglandin, bradykinin, anandamide, etc.) as well as mechanical stimuli such as hyperinflation of the lungs (14, 18, 26, 27, 42). The overall electrophysiological properties and signal transduction processes of pulmonary sensory neurons are regulated by the functional expression of various receptor proteins. Indeed, a number of ligand (e.g., TRPV1, P2X3 purinoceptor, etc.) and voltage-gated ion channels (e.g., tetrodotoxin-resistant Na+ channel, Ca2+-dependent K+ channels, etc.) have been identified on the sensory terminals of C fibers as well as in the isolated C neurons innervating airways and lungs (7, 25). Using 2-APB as a chemical tool and based on the comparison of the antagonistic effects between capsazepine and ruthenium red, we have now for the first time demonstrated the functional expressions of TRPV2 and/or TRPV3 channels in pulmonary C fiber terminals as well as in their cells bodies. Considering the fact that the TRPV channels are the primary sensors of a diverse range of external physical (e.g., heat, cold, mechanical stress) and chemical (e.g., pH, pheromones, osmolarity) stimuli (12, 43), a better understanding of the roles of these channels in regulating the function of airway sensory nerves is certainly very important.
Our present study has provided direct evidence of a distinct stimulatory effect of 2-APB on pulmonary C fiber afferents. Stimulation of these sensory afferents is known to elicit other important defense reflex responses, in addition to the pulmonary chemoreflexes. These reflex responses, such as bronchoconstriction, mucus hypersecretion, airway irritation, and coughing, are mediated through the central nervous system and/or autonomic nervous system (14, 26). Moreover, sensory neuropeptides such as tachykinins (e.g., substance P, neurokinin A) and calcitonin gene-related peptide, synthesized in the cell bodies of pulmonary C fibers in various species, including humans, are released locally from the sensory terminals upon stimulation (28, 39). These peptides are known to act on a number of effector cells (e.g., airway smooth muscles, cholinergic ganglia, inflammatory cells, mucous glands) and produce potent local effects such as bronchoconstriction, plasma extravasation, and edema of airway mucosa (39). Although these reflexes and local responses resulting from the C fiber activation were not measured in this study, 2-APB can, presumably, evoke these airway responses to varying degrees of intensity, depending on the dose administered.
In the present study, we intended to compare the responses induced by 2-APB and capsaicin in the same pulmonary C fibers. Despite the large difference in the doses applied between these two chemicals (3 mg/kg vs. 1 μg/kg), more than half of the C fibers (16 out of 26 fibers tested) displayed an interesting resemblance between the afferent responses to 2-APB and capsaicin. However, certain disparity is evident in the remaining fibers; for example, a greater stimulatory effect of 2-APB than capsaicin was found in six fibers, whereas the opposite was found in others. This observation also holds true in the responses of isolated pulmonary sensory neurons to these two chemicals. Although the exact underlying mechanism is not known, we suspect that different expressions and distributions of various TRPV channel proteins among pulmonary C fiber terminals should, at least in part, account for their different sensitivities to capsaicin and 2-APB. This explanation is supported by the fact that the difference in the chemoreflex responses to these two chemicals at the same doses was much less (Fig. 3, C and D) because these reflex responses reflect integrated activities of the entire population of pulmonary C fibers. In addition, we have demonstrated that PNCT completely abolished the cardiorespiratory responses to both capsaicin and 2-APB (Figs. 2 and 3), indicating that these responses were indeed mediated through pulmonary C fibers. In sharp contrast to the responses to capsaicin, the cardiovascular depressor responses (bradycardia and hypotension) induced by 2-APB persisted even after the pretreatment with capsazepine (e.g., Fig. 6B). This observation lends additional support to our conclusion that the pulmonary chemoreflex responses elicited by 2-APB did not result exclusively from activation of the TRPV1 channel.
In summary, this study using 2-APB as a chemical tool to activate TRPV1, V2, and V3 channels has suggested the functional expression of these channels in pulmonary C neurons. This conclusion is further supported by our observation that the 2-APB-evoked response is only partially blocked by capsazepine but completely abrogated by ruthenium red. The sensitivities to specific stimuli and physiological functions of these neurons are likely influenced by the relative degree of expression of these TRPV channels in each individual neuron.
This study was supported by National Institutes of Health Grants HL-67379 (to L.-Y. Lee) and NS-42183 (to M. X. Zhu) and Kentucky Lung Cancer Research grant (to L.-Y. Lee).
The authors thank Robert F. Morton and Wen-Bin Yang for technical assistance.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2005 the American Physiological Society


text:
WEDGWOOD-L ArchivesArchiver > WEDGWOOD > 2005-10 > 1128683874
From: "John Wedgwood Pound" <>
Subject: RE: ANTHONY WEDGWOOD BENN
Date: Fri, 7 Oct 2005 12:17:54 +0100
In-Reply-To: <firstname.lastname@example.com>
Dear Julie,
You wrote to the list last year didn't you?
I am afraid that I have no further information on the reputed connection
between the Benn/Wedgwood Family - I had always assumed that the footnote in
the Wedgwood Pedigrees was correct.
I am copying in a lady who wrote last year about the Sparrow family, to whom
it is likely you are related.
Many years ago I wrote to Tony Benn to ask for his opinion - he denied any
connection with the Wedgwood Family - but this may have been for political
Can anyone on the list help with this problem? Are we related to
Wedgie-Benn? He does actually have a striking resemblance to my own
great-great grandfather, Thomas Wedgwood Hill b. 1866....
John Wedgwood Pound
-----Original Message-----
From: Julie Cottee [mailto:]
Sent: 06 October 2005 15:26
Subject: ANTHONY WEDGWOOD BENN
Dear John,
I am distantly related to Anthony Wedgwood Benn. His g.grandmother
Elizabeth Pickstone married John Williams Benn. Elizabeth's mother was
Eliza Sparrow who married John Pickstone.
My g.g.grandfather was Stephen Sparrow brother to Eliza. Their parents being
John Sparrow and Elizabeth Barker of Hanley, Staffordshire.
My question is do you have any proof that Anthony Wedgwood Benn was related
to the Wedgwood family? We (my cousin in England and I), have been trying
to establish a proven link to the Wedgwoods but cannot find anything which
is absolutely accurate.
There is a Thomas Sparrow, attorney at law of Newcastle under Lyme who is
supposedly the grandfather of Elizabeth Pickstone, mentioned in the Wedgwood
Pedigrees. This is inaccurate as John Sparrow was Eliza's father. Any
Best regards,
Julie Cottee.
This thread:
|RE: ANTHONY WEDGWOOD BENN by "John Wedgwood Pound" <>

subset: commoncrawl


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Pop Culture
Hollywood Now: Chris Pine, Rachel Weisz & Ari Graynor, Plus So Many Babies!By Gerri Miller
New flicks with celebs in interfaith relationships and from interfaith backgrounds, plus their baby news!Go To Pop Culture
March 11, 2009
The haggadah is the prayerbook that structures the Passover seder, the traditional ritual meal of the first night(s) of the holiday. The main part of the haggadah is a retelling of the story of the exodus from Egypt. The themes of the service are liberation and family connection to a shared history. You can make your own haggadah that fits your family--in this article, I'll tell you how.
Do-it-yourself projects are an American tradition. Computers have extended our ability to publish our work and now you can provide a Passover seder for your family and friends with a personalized haggadah. I've provided resources on my website and I'd love to have readers from InterfaithFamily.com share their work there.
|This illuminated haggadah is from the Jewish Museum in Budapest. The page shown has the Four Questions in Hebrew. Photo: Flickr/Paul Seligman.
When you create your own haggadah, you make a souvenir that seder participants can take home with them to remember family traditions. You can create just what you need for the one or two nights you celebrate, especially if every seder you host has different participants who have different backgrounds, skills and interests. Creating a haggadah together as a family also presents an inter-generational learning opportunity. You can include parents and children, grandparents and grandchildren, in the process of making something beautiful and meaningful to your family.
On my website, Jewishfreeware.org, I have provided several versions of the traditional haggadah. All of the versions on my site include Hebrew, English and transliterated Hebrew to maximally engage your seder participants, depending upon their familiarity with the seder, with Hebrew reading, or just visiting. These editions can be printed, copied and shared without limit as long as you are not using them commercially or making a profit.
You can use the traditional texts that I've provided to edit your own haggadah by printing the pages from .pdf format and using the hard copy to make your haggadah, editing in your own English texts and illustrations. Bind it with a three-hole-punch loose leaf binder or make a booklet with another binding. You can easily transfer cover art to heavier weight paper or cardboard at your local copy shop and make your own cover. Edit the text by removing pages you don't intend to recite at your seder and by adding readings or seder songs.
You can make the haggadah personal by creating your own contemporary readings, illustrations, cartoons and discussion questions and adding them to the booklet where you want them.
I strongly recommend adding a family genealogy for your concluding pages. You can include digital photos and a family tree.
You can also download the traditional haggadot I've provided in the software we used to create it, Davkawriter Platinum 6 Hebrew-English word processor. If you have this software, this option will enable you to edit the Hebrew side of the page electronically, including making the fonts larger.
Though I provided the text of the traditional haggadah for free, you might have found a published version of the service that you like better. You can still personalize this by downloading pages from other haggadot like the ones I've provided, or from my Seder Songbook. You can create personalized inserts for published books with supplementary readings that are meaningful for you.
Even if you don't feel up to making your own haggadah, you can soup up your seder with additional texts. Every year my family purchases new haggadot to put on the table for people to look at during the service according to their own interests. Then, using the shared, common Haggadah I've prepared, knowing that we are on the same page, we can have everyone adding to the discussion, comments, questions or songs in addition to whatever we've planned to share in advance.
I'm proud of the Seder Song Book I'm offering on my site. It's the world's largest book of parodies, traditional hymns and songs. You can print it up and bind it separately unless you want to select the songs and insert them into your personal haggadah. If you feel moved to write a new Passover song or parody, please send it to me! With your permission, I'll include it in my next collection.
Indeed, I'm interested in your whole creative haggadah. Nothing beats collecting books in my opinion. We have been collecting haggadot for decades and have literally hundreds--from the famous supermarket or coffee manufacturers to reprints of illuminated medieval manuscripts! Your creativity adds to the world of haggadot and collectors like me would LOVE to receive a PDF of your haggadah.
I love getting new creative haggadot so much that I am sponsoring a contest to find the best one. The contest closes March 26. I'm offering prizes including laptops, Jewish software and books. If you, or one of your children, would like to enter Hag HaHaggadah: A Creative Festival 5769, check out the rules on my site.
Happy Pesach!
Editor's Note: For more resources to add that special something to your interfaith family's seder, check out our Passover and Easter Resource Page. We have readings and tips for making the evening inclusive.


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The Dale® Post-Surgical Bra features a stretch knit fabric that lets the surgical site breathe and has a smooth, seamless design which stretches vertically and horizontally to provide the proper compression and support. Suitable for use following a wide range of procedures, the soft, breathable fabric stretches to accommodate edema without irritating sensitive tissue and has a Velcro®-type front closure to facilitate dressing changes. Providing maximum comfort throughout recovery, the Dale® Post-Surgical Bra was developed to replace elasticized bandages, tee-shirts, and traditional sports bras.
Related Reads


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A pair of teams coming off heavy defeats in the CONCACAF Champions League meet at BMO Field when Toronto FC entertain the Colorado Rapids. TFC defeated Columbus for the first time ever in league play last weekend, but lost to Mexican side Pumas 4-0 at midweek. The Rapids also lost to a Mexican side, a 4-1 defeat by Santos Laguna, and saw their MLS losing streak stretched to three games in their last league match.
REFEREE: Mark Kadlecik. SAR (bench): Claudio Badea; JAR (opposite): Brian Poeschel; 4th: Mark Geiger
MLS Career: 14 games; FC/gm: 23.1; Y/gm: 3.3; R: 5; pens: 5
INJURY REPORT: TORONTO FC – TORONTO FC -- OUT: MF Elbekay Bouchiba (R knee surgery recovery); DF Adrian Cann (R knee surgery recovery); DF Dicoy Williams (R knee surgery recovery); MF Joao Plata (L hamstring strain); DOUBTFUL: DF Demitrius Omphroy (R knee swelling); QUESTIONABLE: DF Dasan Robinson (L adductor tightness); GK Stefan Frei (quadriceps contusion); MF Matt Stinson (R metacarpal fracture) …
COLORADO RAPIDS – OUT: FW Conor Casey (L achilles tear); DF Anthony Wallace (R knee arthroscopic surgery); QUESTIONABLE: MF Jamie Smith (R hamstring strain / R calf strain); PROBABLE: GK Matt Pickens (R groin strain)
INTERNATIONAL ABSENCES: none
SUSPENDED: none
SUSPENDED NEXT YELLOW CARD: TOR: Danleigh Borman … COL:Conor Casey, Brian Mullan
SUSPENDED AFTER TWO YELLOW CARDS: TOR: Terry Dunfield, Ty Harden, Ryan Johnson, Javier Martina, Mikael Yourassowsky … COL: Ross LaBauex, Caleb Folan, Jeff Larentowicz, Pablo Mastroeni, Tyrone Marshall, Sanna Nyassi, Wells Thompson, Anthony Wallace
ALL-TIME (9 meetings): Toronto FC 5 wins, 11 goals … Rapids 3 wins, 9 goals … Ties 1
AT TORONTO (4 meetings): Toronto FC 4 wins, 9 goals …Rapids 0 wins, 4 goals … Ties 0
• The teams played to a scoreless draw in their first meeting this season, May 22 at Dick's Sporting Goods Park.
• TFC has a perfect record against Colorado at BMO Field, winning all four previous meetings.
• In nine all-time meetings between the clubs, the visiting side has won just once – a 1-0 win by Toronto FC at Dick's Sporting Goods Park in 2008.
• Coaches record: Aron Winter v COL: P1 W0 L0 D1 … Gary Smith vs. TOR: P5 W2 L2 D1
• Rapids goalkeeper Matt Pickens was the busier of the two on the night, making three saves, including one on a close-range effort from Nick Soolsma just before halftime. Mikael Yourassowsky also blasted a shot off the crossbar in the 62nd minute.
• TFC goalkeeper Stefan Frei made two saves for his third shutout, his second this season in a scoreless draw.
• COLORADO RAPIDS (4-4-2): Matt Pickens - Marvell Wynne, Drew Moor, Tyrone Marshall, Anthony Wallace - Kosuke Kimura, Pablo Mastroeni, Jeff Larentowicz, Jamie Smith (Sanna Nyassi 46) - Quincy Amarikwa (Wells Thompson 67), Conor Casey (Andre Akpan 61).
• TORONTO FC (4-3-3): Stefan Frei - Richard Eckersley, Dicoy Williams, Adrian Cann (Ty Harden 76), Dan Gargan - Alen Stevanovic, Nathan Sturgis (Nana Attakora 84), Mikael Yourassowsky - Nick Soolsma, Javier Martina, Joao Plata (Maicon Santos 60).
Toronto FC won the Trillium Cup for the first time, defeating the Columbus Crew for the first time ever, a 4-2 victory Saturday evening at Crew Stadium. TFC has 27 points from 29 games on the season, sitting in a three-way tie for seventh place in the Eastern Conference.
• Toronto FC took the lead in the 21st minute when a corner kick was headed out of the area by Crew defender Josh Gardner, but only as far as Torsten Frings, who cracked a 25-yard shot into the center of the box. The ball found Nick Soolsma in the mixer and he turned and quickly fired home.
• TFC then doubled their lead just before the break, when Joao Plata sent in a looping ball from the left flank than Ryan Johnson headed back across goal inside the left post.
• The Crew drew a goal back in the 67th minute after substitute Tommy Heinemann finished a quality combination play, turning home a low centering pass from Robbie Rogers past substitute 'keeper Milos Kocic. But Julian de Guzman restored the advantage in the 83rd minute, latching onto a loose ball and sending a low shot to the back of the net from outside the area.
• Columbus again cut down the lead when Andrés Mendoza hammered a rising shot into the goal from the top of the area, but TFC sealed the win in stoppage time when Danny Koevermans rounded goalkeeper William Hesmer well out of his area and curled the ball into an empty net.
• TFC head coach Aron Winter made two changes to the team that gained a 1-1 draw with the San Jose Earthquakes at BMO Field. Stefan Frei returned between the posts in place of Milos Kocic, and Nick Soolsma took the spot of Peri Marosevic in attack.
• TORONTO FC (4-2-1-3): Stefan Frei (Milos Kocic 66) - Richard Eckersley, Andy Iro, Ty Harden, Ashtone Morgan - Julian de Guzman, Torsten Frings - Eric Avila - Nick Soolsma (Matt Stinson 80), Ryan Johnson (Danny Koevermans 87), Joao Plata.
• The 4-2 win in Columbus was not only the first-ever against the Crew for TFC, it was also the first league road victory of the season for the Reds, leaving just Houston and Vancouver still searching for a road win in 2011. Three teams in MLS history have gone through a season without winning on the road.
• "I think if you're playing against a team like Columbus, away, and you're making four goals, it's a great compliment because it's not easy," said TFC head coach Aron Winter. "We were good with our opportunities but we also won in the pass as well. It's good, we are making improvements."
• TFC Designated Player Julian de Guzman scored for the second time in five games and recorded a goal and an assist in the same game for the first time in his MLS career in Columbus.
• "All the goals, the movement, how we played in the final entry, I think we did well," Winter said. "Most of the games we have created a lot of opportunities but we were not sharp enough with finishing, but today we were sharp with our opportunities even though they weren't that good."
• Joao Plata contributed his team-leading fifth assist. In the last six games – all starts – Plata has a goal and three assists.
• "If you watched the whole game, the goals we scored were great. After Stefan [Frei] got hurt there was about five minutes that we weren't very organized, but then they scored and the team reacted well," Winter said.
• TFC was forced into a crucial change at the three-quarter mark, when goalkeeper Stefan Frei and Crew forward Emilio Rentería had to leave the game after a robust collision as both went for the ball near the Crew goal in the 66th minute.
• Frei suffered a bruised thigh, and his availability is still to be determined. He was making his first start since Aug. 6; he suffered a bruised knee in training a few days following and gave way to Milos Kocic for three consecutive league starts.
• Joao Plata is also in doubt for the weekend after suffering a hamstring strain last weekend. "It should be three weeks and maybe he can play," Winter said.
• On Wednesday, Toronto FC crashed to a second successive defeat in the CONCACAF Champions League, falling 4-0 to Pumas UNAM in Mexico City. Martín Bravo completed a hat trick before the halftime whistle, and defender Efraín Velarde added the fourth.
• Here's the TFC team: Milos Kocic - Ty Harden, Andy Iro (Eddy Viator 39), Doneil Henry, Ashtone Morgan, Torsten Frings, Julian de Guzmán, Danleigh Borman, Danny Koevermans (Terry Dunfield 56), Ryan Johnson (Peri Marosevic 49), Nick Soolsma
The Colorado Rapids went down to a third consecutive defeat, falling 1-0 to the LA Galaxy on Friday evening at The Home Depot Center. The Rapids have 41 points from 29 games, sitting in fifth place in the Western Conference.
• The game's lone goal came in the 36th minute at the end of a flowing move. Chad Barrett received the ball in the center of the park after just staying onside. He slipped a ball forward to Sean Franklin, who then found Landon Donovan unmarked on the left side of the box. Donovan hammered the ball inside the far post, leaving Colorado 'keeper Matt Pickens no chance.
• Rapids head coach Gary Smith made two changes to the team that lost 2-0 to the Chicago Fire at Toyota Park. Danny Earls started in place of the suspended Drew Moor, and Macoumba Kandji replaced Sanna Nyassi in attack.
• COLORADO RAPIDS (4-4-2): Matt Pickens - Kosuke Kimura (Omar Cummings 69), Tyrone Marshall, Marvell Wynne, Danny Earls - Brian Mullan, Pablo Mastroeni, Jeff Larentowicz, Wells Thompson - Caleb Folan, Macoumba Kandji (Sanna Nyassi 39).
• The Rapids have been shut out in back-to-back games for the first time since going three games without scoring, in losses to FC Dallas, Real Salt Lake and Seattle Sounders FC from April 8-22.
• "We created a few chances. It's definitely a game that we need to reflect upon and continue work toward the type of form to make a run toward the playoffs," said Pablo Mastroeni.
• Macoumba Kandji made his first league start of the season, following three substitute appearances, missing the first 25 games of the year after undergoing knee surgery in the offseason.
• But Kandji lasted just 39 minutes before coming off for Sanna Nyassi, who had started the previous two matches. "Sanna's inclusion, I hoped, would give us a slightly better shape and a better opportunity to retain the ball. We saw more of that in the second half because he didn't get on until the dying moments of the first," said Rapids boss Gary Smith.
• Smith also made a tactical shift for the final 20 minutes, going into a 3-4-3 scheme as Omar Cummings came on as a substitute. It was the fourth consecutive substitute appearance in league play for Cummings.
• "Omar coming on to give us an added injection of pace as well. I think it unsettles defenders," said Smith. "The difficulty tonight was that Omar had played two games for Jamaica in a short space of time. He did a lot of travel, same with Sanna. He went through an absolute grind coming back from Nairobi. It's difficult."
• Goalkeeper Matt Pickens made a season-high eight saves in holding the Galaxy to the 1-0 result.
• "The home team is going to attack a lot, I didn't know it was going to be that much, but you have to try and be ready for anything," Pickens said. "You just try to keep your team in the game and hopefully we can nick one at the end and we can get a point. Unfortunately that didn't happen."
• On Tuesday, the Rapids fell 4-1 to Mexico's Club Santos Laguna in the third match of play in Group B in the CONCACAF Champions League. Daniel Ludueña (14) and Oribe Peralta (27) put Santos ahead by 2-0 at halftime, then Carlos Quintero (64) and Cristian Suárez (71) completed the rout. Brian Mullan pulled a goal back 13 minutes from full time.
• Here's the Rapids team: Steward Ceus - Drew Moor, Marvell Wynne, Scott Palguta, Danny Earls (Miguel Comminges 46), Pablo Mastroeni (Joseph Nane 69), Jeff Larentowicz, Wells Thompson (Brian Mullan 56), Sanna Nyassi, Omar Cummings, Macoumba Kandji


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Welcome to the Yellowstone Valley Animal Shelter
We are the provider for animal care services for the City of Billings. The City of Billings Police Department provides animal control services. Our organization is founded on the principle of community engagement with the goal of building partnerships to save lives. We cannot overemphasize the important role animals play in the lives of humans and we'd like to return the favor.
» Lost Your Pet
We want to see you reunited as soon as possible, so please don't wait.
Call the shelter at (406) 294-7387 and report that your pet is missing.
read more >
» Our Wish List
- Wet cat food
- Dry kitten food
- Wet dog food
- Raw hides/bones
- Washable cat toys
- Squeaky, durable dog toys
- Blankets (no stuffing or down)
- "Jolly Ball" Toys (Outside play/active toys for dogs)


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Tea or coffee, what would you prefer? This is not a metaphorical question that is asked socially. It could actually affect your health. We all know about the health benefits of tea. Whether it is black or green tea, each has its own set of benefits for the body. But coffee is generally not included in the list of healthy beverages.
Caffeine present in coffee is actually the reason for its exclusion from the the list of healthy beverages. Caffeine is a stimulant in mild proportions but when it is taken excessively, there are many side effects of it.
Let us examine this myth about tea being healthier than coffee to if it is true. Then we will be in a better decide which is a healthier choice, tea or coffee.
Both tea and coffee have antioxidants. However, these antioxidants are of different types. Tea contains flavinoids that are basically photochemicals. Coffee on the other hand contains quinines and chlorogenic acid. They serve almost the same purpose of getting rid of free radicals from the body.
Coffee has more caffeine. It is a well known fact that coffee has higher caffeine content than tea. The caffeine content of coffee is actually double the caffeine content of tea.
Tea is strained and coffee is mixed. Both tea and coffee have a certain amount of caffeine content. In fact, tea also has traces of nicotine. But the difference is that tea leaves are strained out of the liquor and coffee powder is mixed into the coffee liquor. So more of these harmful components enter your body when you drink coffee.
Tea is healthy for digestion. When it comes to your stomach, there is absolutely no choice of tea and coffee, tea is is the healthier option. Tea is good for digestion and light on the stomach if it is prepared without milk and sugar.
Both tea and coffee fight cancer. Tea drinkers have better protection against ovarian and breast cancer. Coffee drinkers have some amount of immunity against liver cancer.
Caffeine poisoning? Too much of anything is bad. Drinking too much coffee can lead to caffeine poisoning. It affects the central nervous system and causes insomnia, restlessness and headaches. Caffeine poisoning is also associated with miscarriages. Even if you drink too many cups of tea, it will not poison your body like caffeine.
Thus, there is no doubt that tea is healthy, atleast more so than coffee. So what do you prefer after reading this article; tea or coffee?


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Bella Quiz: Makeup Name or Adult Movie?
Bella Quiz: Makeup Name or Adult Movie?
BellaSugar writes, "We've come a long way from the days of Revlon Red. These days, makeup names are more likely to make you chortle at their cheekiness. The names are getting more and more raunchy—so raunchy, in fact, that some seem downright X-rated.
Think you can guess which ones are makeup colors, and which ones are titles of 'adult' movies? The quiz is 100% safe to take if you're at work—no naughty pictures or words involved!—so click away!"


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Rex Grossman had a 103-degree fever and London Fletcher was throwing up on the sideline. The Redskins 33-20 loss to the 1-5 Carolina Panthers was pretty difficult to stomach from the couch, as well.
John Beck, making his first start since 2007, overshadowed the Panthers all week, but unfortunately he forgot to show up until the Redskins trailed 16-6 in the third quarter.
Beck pulled it together after a poor start -- most notably leading a seven-play, 82-yard drive in which he completed all four of his passes and ran for a touchdown to make it 16-13. But before and after that, he struggled, fumbling on his first possession and failing to convert a key fourth down in the third quarter.
Working with a short field after sacking Beck on fourth down, Cam Newton completed a 37-yarder to Brandon LaFell and then dashed into the end zone to give Carolina a 16-6 lead.
The touchdown sparked Carolina and Beck couldn't do enough to overcome its 24-point second-half outburst against the Redskins defense.
Newton was magnificent, hitting receivers in stride, squeezing the ball into the tiniest of windows and victimizing what once looked like a respectable defensive unit.
Mike Shanahan must have taken a quick look across the sideline and wondered what could have been had the Redskins been a factor in the Newton sweepstakes. He's that once-in-a-lifetime find -- one of those elite quarterbacks in the making Shanahan so desperately covets.
Instead the head coach is dealing with Beck and an offense that looked remarkably similar to the same one we've seen for years. It was another stagnant effort from a unit Shanahan has expressed so much confidence in since his arrival.
Which begs the question: Why does he believe in them to such an extent? We're not coaches, but even the casual observer can point out the lack of coherency on offense.
The Redskins didn't need to overthink their final first half possession. They were getting the ball to start the second half tied 6-6, but Beck threw short over the middle to Jabar Gaffney, who fumbled, allowing the Panthers to score before halftime.
When an offense is on the right page, that doesn't happen. The coaching staff once again grossly overestimated its capabilities and it made a difficult game nearly unwinnable.
In fairness, it was Beck's first start of the year, but it doesn't alter the fact the offense's inefficiency has run rampant under Shanahan. He was supposed to turn things around, but through a year and a half it'd be optimistic to say there's even been progress.
And it wouldn't be nearly as maddening if he would cease singing the praises of two bad quarterbacks. Week after week, he's been emphatic in defending them when they've done little to back him up.
It becomes even more concerning when you consider Carolina's success offensively. Newton is a special player, but the rest of the Panthers have elevated their respective games to give Ron Rivera a team on the rise.
On Sunday, they thoroughly outplayed the Redskins on both sides of the ball, serving as another reminder this team is still stuck in neutral.
"I got to do a better job getting these guys ready to play," Shanahan said. "We should have played better than we did."
Come to think of it, Shanahan sounded sick to his stomach, too.


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Vets' team raises £400 for animals
8:00am Wednesday 20th November 2013
8:00am Wednesday 20th November 2013
A TEAM of four from Martin and Carr Vets in Pershore raised hundreds of pounds for animals around the world when they took part in the Vet Charity Challenge.
The event saw 55 teams from veterinary surgeries around the country descend on Pershore Horticultural College and Bredon Hill, where the orienteering challenge took place.
The groups were then sent off on the course, which saw them run or walk, mountain bike and kayak more than 40km.
Amy Blackwell, a vet at the surgery, nominated her four colleagues, Tom Carr, Alison Carr, Eliza Collins and Emma Faizey, to take part.
She said: "I entered them for it. The challenge was six-and-a-half hours of orienteering around Bredon Hill. There were checkpoints where they had to register electronically.
"The team came 9th out of 55 teams. They were chuffed with that. They enjoyed it but they were pretty tired by the end."
The team raised £400 for the three animal charities they were supporting: SPANA, a charity which tackles the suffering of working animals, Animals Asia and Hearing Dogs for Deaf People.
© Copyright 2001-2017 Newsquest Media Group


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On Monday the 17th, I changed internet service from Charter Cable to Hughes net satellite service.
After getting back on line, I got the ZA update notice and updated to ZA free 7.0.408.000.
Upon going to Gibson Research and doing a ShieldsUp port check, I found that my computer is wide open (almost no ports blocked).
Previous to all these changes, Gibson always showed my computer in complete stealth mode; nothing got in or out.
Anyone have any idea what might be wrong?I have a linksys 100 ethernet adapter and Hughes satellite modem.
Operating System:Windows XP Pro
Software Version:7.0
Product Name:ZoneAlarm (Free)


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HEARTS star Andrew Driver could be given the green light to play for Scotland under a new gentlemen's agreement among the Home Nations.
Scotland want to rewrite the rules on qualifying for an international cap to allow youngsters who have been at school in this country for over four years to become eligible for selection.
Under the current regulations players are only eligible through a parent or grandparent's bloodline, however Scotland, Wales and Northern Ireland met in Holland last month and agreed that it would be mutually beneficial to adjust the rules.
England will be asked to rubber stamp the gentlemen's agreement tomorrow when all four Home Nations get together at the annual meeting of the International Football Association Board and SFA President George Peat said: "We were thinking of the case perhaps of an asylum seeker who has been to primary school here. We are looking at it to apply to those who have been in Scottish education for four or five years before the school leaving age – which would be 16 – and then became a British passport holder.
"Essentially these people regard themselves as Scottish."


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Whether you have queries relating to property auctions or you're finding lease contracts difficult to understand, our Frequently Asked Questions section is designed to shed more light on common questions.
This website uses cookies to improve your experience when using the site. To find out more about how we use cookies and how you can control them please read our privacy policy. Use of this website means you have accepted the policy.


text:
Sextant by N.V. Observator Rotterdam HOLLAND w/ CASE NR
Sold for:
Start Free Trial
or Sign In to see what it's worth.
- Sold Date:
- Source: eBay
No Reserve Auction!Sextant by N.V. Observator Rotterdam HOLLAND DATED 1954 SETANT # 3275 EXCELLENT CONDITION , I SEE NO DAMAGES OR REPAIRS DONE. THE WOODEN CASE MEASURES APPROX. 6" X 10" X 12 Business hours are Monday - Friday from 9 am - 4 pm (EST). We will combine shipping for multiple transactions, Please request an invoice once you have completed bidding. Please do not assume anything, if it isn't written in the description or if it is not shown in the photos then it is not included with this auction. YOUR COMPLETE SATISFACTION IS OUR MAIN GOAL. SO PLEASE REMEMBER IF THERE ARE ANY PROBLEMS, OR YOUR UNHAPPY WITH YOUR ITEM PLEASE EMAIL US AND WE WILL DO OUR BEST TO HANDLE THE ISSUE PROMPTLY. CHECK OUT OUR POSITIVE FEEDBACK FROM OVER TWENTY THOUSAND SATISFIED CUSTOMERS. . 04.04.004


text:
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Thanks Toony :))
Oh my God, what have I done???
LOL! Thanks punkin!!It can have this effect pg :))I'll tell him to avoid Texas tex!!! Thanks.Oh you vain Hopper you :))) Thanks Dave!!Probably very little Shirley!! Thanks!
I wonder what's on his mind?
Wait, let me make sure eveything is in place before you push the button!
He better think twice before he gets into my plants! I've got a big bucket of sevin dust!! Thanks, RR. Good one.
I knew I overdid the nectar last night.
Thinking must be painful with such a wee brain.
Looks like it lyndee!!
Poor thing has a headache!


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Does it seem that some routes you take while running seem shorter than other routes even though they are the same distance?
The other morning, Shane and I ran a few miles out, turned around and ran the same route back. It wasn't too far from home, basically half a horse shoe from our house.
If I completed the same distance but ran zig-zag around the college, up one road, down another then came back in a straight line, it would seem longer.
Do you think it's a comfort zone thing? Being closer to home seems that we don't go as far?
My running this week was burdensome to say the least. I've been trying to crank up the miles and it finally wore me down. Sleep has been hard to come by. Because of the lack of sleep, I skipped out on my eleven miler Tuesday. Managed to eke out an extra mile on Wednesday for 7 miles. Thursday, woke up well before my alarm and got on the treadmill at… hold your breath…3:30AM! AAHHH! then ran my long run for the week of 17 miles. For about an hour, I kept telling myself it was just crazy being on that "hamster wheel" at 3:30AM. After giving up on the crazy thoughts and accepting that I was deeply disturbed, I started urging myself on and turned the thoughts to just finishing my run.
Friday my body dictates how far I run. I don't set the alarm and if I get up early, I'll go a little farther. BUT I WON'T GET UP AT 3:30AM! (unless it's a weekend that Ted has an out of town Triathlon or I have a marathon – those events are justifiably pre-dawn awakenings). This Friday morning my body only wanted 3.6 miles.
Saturday is the Newport Beer -n- Chili run. Ted wants to do the run, but will most likely stick to a 5K or take it really slow for the 10K. I'm not in a "race pace" kind of mood, especially since the course offers one big hill. It's a great race, friendly runners, good chili (even Vegetarian chili) and the 26.2 Mini Loaves will be given out to about 72 runners. Sorry I couldn't make more.
It should be a good weekend. Mild weather, good friends and, on Sunday, a Super bowl party! YAY!
Healthy Foods and Drinks This Week:
Massive bowl of fruit sprinkled with a few nuts and raisins:
Delicious Arbonne Shakes:
The following was copied from my friend Gaetan Tremblay's post "Amino Acids In Arbonne Essentials Shakes." Please see his post for the complete Arbonne Shake Amino Acid Profile.
Amino acids are the building blocks of the proteins that are found in our bodies. The human body can produce 12 of its 20 amino acids, but the other 8, which are called Essential Amino Acids can only be obtained by eating the right foods or using a proper Vitamin/Mineral Shake like the Arbonne Essentials Vitamin/Mineral Shake. When we eat food such as meat, fish, and cereals or indulge in a delicious Arbonne shake, the proteins contained in it are first degraded to the 20 kinds of amino acids, and then reassembled into proteins in the body.
When the body doesn't get enough of these essential compounds, it will begin to break down its proteins in search of the nutrients it needs. Since the body stores fat and starch, but not amino acids, it is necessary for individuals to consume all the required essential nutrients daily.
Below are the Amino Acid Content per serving of the Arbonne Essentials Vitamin/Mineral Shakes (And what each Amino Acid is used for in your body).
1. Alanine – 880 mg – protects the cells from damage by preventing the buildup of toxic substances that are released into the muscle cells when protein is broken down quickly to meet energy needs.
2. Arginine – 1,820 mg – Arginine helps strengthen the immune system by increasing the production of T-cells from the thymus gland.
3. Asparagine – Asparagine is needed to maintain balance of the central nervous system, as it is an essential component of proteins that are involved with equilibrium, signaling, neuron development and electrical transmission across nerve endings.
4. Aspartic Acid – 2,500 mg – Aspartic Acid is known for its treatment of chronic fatigue syndrome due to the role it plays in generating cellular energy. It helps keep the mind sharp and focused by increasing concentrations of NADH in the brain (an active coenzyme form of Vitamin B3 called Nicotinamide Adenine Dinucleotide) which boosts the production of neurotransmitters and chemicals needed for normal mental functioning).
5. Cysteine – 220 mg – Cysteine functions as a powerful antioxidant. It has been used to treat rheumatoid arthritis and hardening of the arteries.
6. Glutamic Acid – 4,006 mg – Glutamic Acid is important in the metabolism of both sugars and fats, and helps in the transportation of potassium into the spinal fluid and across blood-brain barrier.
7. Glutamine– Known as a superb brain fuel. Glutamine is also an important source of energy for the nervous system. If the brain is not receiving enough glucose, it increases Glutamine metabolism for energy. Glutamine users often report more energy, and less tiredness.
8. Glycine – 820 mg– Glycine helps prevent the breakdown of muscle by increasing the levels of Creatine in the body (a compound that helps build muscle mass). Without Glycine, the body would not be able to repair damaged tissue, and the skin would sag from exposure to UV rays, oxidation, and free radical damage. Wounds would also not heal.
9. Histidine – 540 mg– Histidine is needed for growth and for the repair of tissue, as well as the maintenance of the myelin sheaths that act as protector for nerve cells.
10. Isoleucine – 940 mg – C an be found in many foods but there are high contents in fish, meats and cheeses, as well as nuts and wheat germ. It helps in energy production.
11. Leucine – 1,740 mg – These essential amino acids can be metabolized to produce energy.
12. Lysine – 1,540 mg – Helps absorb calcium in the intestinal tract, promotes bone growth and the formation of collagen.
13. Methionine – 240 mg – Can't be found in proteins like legumes and peanuts, but it can be found in higher amounts in eggs and fish. Foods contain less amounts of methionine than any of the other essential amino acids.
14. Phenylalanine – 1,120 mg– Can be found in meats and milk products. It is one of the essential amino acids because it affects brain chemistry.
15. Proline – 880 mg– Proline promotes the formation of bone, skin and cartilage and it is extremely important for the proper functioning of joints and tendons, also helps maintain and strengthen heart muscles and is helpful in tissue repair after injury, or for any type of wound healing. Proline is also involved in energy production.
16. Serine – 1,120 mg– Serine is required for the metabolism of fat, tissue growth and the immune system as it assists in the production of immunoglobulins and antibodies.
17. Threonine – 780 mg – Of the essential amino acids, its role is to help in the formation of tooth enamel protein, elastin and collagen.
18. Tryptophan – 200 mg – Is one of the lower essential amino acids and it is found in corn, cereal grains and legumes. It can also be found in flesh foods, dairy products and nuts. It helps induce normal sleep; helps reduce anxiety, depression, and artery spasm risk; and helps produce a stronger immune system. It is a precursor for serotonin, which influences mood and sleep. This explains why turkey, which contains tryptophan, makes everyone sleepy after Thanksgiving dinner.
19. Tyrosine – 780 mg– The action of this amino acid in brain functions is clear with its link to dopamine as well as norepinephrine, but it is also helpful in suppressing the appetite and reducing body fat, production of skin and hair pigment, the proper functioning of the thyroid as well as the pituitary and adrenal gland. It is used for stress reduction and may be beneficial in narcolepsy, fatigue, anxiety, depression, allergies, headaches as well as drug withdrawal. In a study, using soldiers, tyrosine proved effective in alleviating stress and keeping them more alert.
20. Valine – 1,004 mg– Can be found in most foods and is a vital part of proteins. It can be metabolized to produce energy and it is a branched-chain amino acid.
Do you have a favorite nutritional shake? Brand? Flavor?


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Description & Details
Fancy stitches engraved in bright gold make up an earnest query for your closest, best, and truest friend. Not that you'll need to wait long for an answer, of course she'll say yes! From New Orleans based artist Alexa Pulitzer.
- Packaged with envelope
- Handmade Italian paper
- Hand engraved in USA
- Exclusive to BHLDN


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Man Who Killed Lover Commits Suicide In Police Custody
April 26, 2012 – Man Who Killed Lover Commits Suicide In Police Custody
An Ibadan man, Asimiyu Ayantayo, who allegedly beheaded his lover last Thursday, has committed suicide in police custody. www.naijagists.com
He was paraded with his alleged accomplice, Isiaka Akanbi, on Tuesday, in respect of beheading of a middle- aged woman in Ibadan.
After allegedly killing his mistress, Sakirat Emiola, he was accused of beheading her and cut off her two hands.
He was said to have hanged himself with his shirt which was tied to the iron bar of the cell where he was detained. After his parade, he was taken to the police station at Iyaganku.
The murder suspect was said to have killed himself yesterday morning at Iyaganku, Ibadan.
Confirming the incident, the Commissioner of Police Mr. Mohammed Tambari, said all the policemen on duty at the time would be queried.


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Edit Article
wikiHow to Be a Good Medicwhore in Battlefield 2
These instructions will teach you how to "medicwhore" in a game called Battlefield 2. The link for the game is provided below.
1Get the Medic kit. And get the G36E unlock as soon as Possible. It's the best medic gun for the game.
2Always go into alleys that have a lot of enemies and team members in, it's an easy source of reviving people.
3Follow people around that have a lot of deaths and die a lot. You can check their deaths by pressing the TAB button near Caps lock on your keyboard.
4Always throw medic bags in advance at places where you and your friendlies walk through the most. That way, when you or your friendlies are low on health they will know where to get a medic bag.
5When reviving friendlies, sprint to a downed friendly and when he is at your feet immediately prone. Once in the prone position, revive him with the shock paddles. Once he is revived, immediately get up and sprint away to cover. This method will make you fast and hard to hit while reviving friendlies. If the friendly you just revived gets killed again, repeat the procedure.
Community Q&A
Ask a Question
200 characters leftSubmit
- You have to remember, "whore" in games are slang. They're not talking about women, or men. Statwhoring is getting a lot of stats and not caring about your team, as Medicwhore is nearly the same. You revive, revive, and revive. Even if artillery is bombing down around them and they have the chance to die again, You revive them for the points.
- Play normal BF2, it's the easiest to medwhore in.
- Play on servers you don't have 130+ ping over.
- Play on the map "Strike At Karkand" or, "Sharqi Peninsula" Because those two maps are VERY easy to medwhore in. Karkand has many alleys that people Grenade/Claymore spam. Easy Revives. Peninsula is just all over chaos, people don't live for more than 3~ minutes.
- Join a Squad.
- Play on a high resolution. 1024x768 at least.
- Don't go after a person who's body is half in the ground, because you won't be able to revive him.
- Like the above, don't try to revive anyone on a hill or incline. You have to be at exactly their level to hit them with the shock paddles.
Things You'll Need
- Battlefield 2
- A Laser Mouse (Trust me. It's really bad with a trackball.)
- A Computer
Sources and Citations
Article Info
Categories: Battlefield
Thanks to all authors for creating a page that has been read 13,680 times.
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This enchanting escapade is the most important quest of Tarl Cabot's career. He must retrieve a potent shield ring from a strange explorer. It is imperative that the omnipotent Priest Kings obtain this ring so that the Goreans do not challenge their enormous power. Throughout his expedition, Cabot learns of uncharted territories on Earth's cosmic counterpart. In the dense forests he discovers, Cabot must use his skills to endure the perils that await his arrival. Cabot will encounter Gor's barbarism in full force through enchantingly dangerous beasts, bloodthirsty men, and exotic kingdoms.
©1979 John Norman (P)2013 Audible, Inc.
It's the same repetitive narrative over and over. The same discussion between Tarl and the slaves, same nauseating use of adjectives.
"Endless boring dialogue"
Listening to these in order they become less and less entertaining. This book is the worst thus far. I'm struggling to finish.
"Too wordy"
way way too much time wastep on repetition of female slaves. we get it. move on.
"Unexpectedly good"
Yes, it's a long series of long books but doesn't feel long it draws you in and is very entertaining.
The expanding of the world of Gor
He is the Voice of this series and does a great job.
Report Inappropriate Content
If you find this review inappropriate and think it should be removed from our site, let us know. This report will be reviewed by Audible and we will take appropriate action.


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Algae latest in string of problems at Milton's Clear Lake
Now, there�s a new problem further mucking up the spring-fed lake north of Milton: blue-green algae.
Rock County Environmental Health Director Tim Banwell said Rock County Health Department officials observed blue-green algae earlier this week on surface waters at Clear Lake near Blackhawk Beach, a public campground along the lake.
Banwell said it�s the first time officials have found blue-green algae in Clear Lake. He described it as a turquoise sheen on top of the water.
�It looks like pea soup,� he said.
Blue-green algae, technically a form of bacteria, can make people and animals ill. The sighting at Clear Lake prompted the health department to put out an advisory earlier this week, urging people who come in contact with the algae to wash off afterwards.
According to Banwell and information from the Wisconsin Department of Natural Resources, blue-green algae grows in warm water containing phosphorous and nitrogen, nutrients which can come from:
-- Fertilizers and manure from agricultural runoff.
-- Aquatic birds releasing waste into water.
-- Leaky septic systems.
Floods in 2008 raised the water table at Clear Lake, resulting in an 8-foot surge in lake levels. Officials don�t know why the water won�t recede, but the flooding has left lakefront properties swamped, putting a handful of residences and septic systems under shallow, standing water for the last two years.
Officials believe the flooded areas along the shore, which warm quickly on hot, sunny days, have created a breeding ground for blue-green algae, Banwell said.
Banwell said it�s hard to pinpoint what�s feeding the algae at Clear Lake, but the most likely culprit is agricultural runoff.
It�s not clear whether the algae and submerged septic systems along the lake�s shore are linked, although Banwell said officials know the systems have �contributed nutrients at the lake.�
Banwell said the health department takes weekly surface water samples at Clear Lake and other local bodies of water. He said the Wisconsin State Laboratory of Hygiene analyzes the samples, checking for E. coli, a type of fecal coliform bacteria often associated with animal and human waste.
Readings taken as recently as May show surface water at Clear Lake had 147 E. coli bacteria units per 100 milliliters of water, according to county records.
�That�s one where you�re going to have to start looking at the level,� Banwell said, noting that E. coli readings of 1,000 bacteria units per 100 milliliters of water or higher result in mandated shutdowns of beaches and public swim areas.
Clear Lake is the first body of water in Rock County where officials have spotted blue-green algae this year, Banwell said.
�It�s something we normally see along the quieter rivers and in (Lake) Koshkonong,� he said.
Unlike Lake Koshkonong, which is an impoundment of the Rock River, Clear Lake is a spring fed kettle lake. It has no natural outlets.
Banwell said that means once materials that can spur blue-green algae growth enter the lake, they�re slow to disperse. He pointed to heavy annual weed growth in Clear Lake�s lakebed as evidence of nutrient-rich soil deposits.
�Whatever goes into Clear Lake doesn�t leave Clear Lake,� he said.
Raze orders pending
For months, Clear Lake Improvement Association, a property owners group at Clear Lake, has tried to get Town of Milton and Rock County officials to force property owners to remove three flooded homes along the lake.
The town board in June approved raze orders for the buildings, which have been swamped since 2008, when floods caused the lake levels to surge several feet. The lake has not receded.
This week, the board announced raze orders for the swamped houses are pending but have not been delivered to property owners, said Clear Lake Improvement Association president Joyce Szymberski.
Szymberski said the property owners group hopes to see the flooded homes removed by the end of the year.
Meanwhile, Szymberski said an owner has allowed volunteers to start removing appliances, household items and chemical containers from one of the flooded homes.
Last updated: 2:21 pm Thursday, December 13, 2012


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The Best Big YouTubers.
Pages PREV 1 2 3 4 NEXT
Oh yeah... while I've never watched My Drunk Kitchen, it reminds me of... Drunk History! It got a TV spot so I think it counts as big!
And yes again to DBZ Abridged. I wonder if they need any other VAs for the future... probably not :(
I wish the Nerd actually had some new stuff, though. Maybe all the bad games are finally getting to him.
I like TeamFourStar, EpicMealTime and TheAmazingAtheist. Two of three appeared at least twice on the worst list though, go figure.
Gaming related:
Not Gaming related:
Those are the big ones.
honorable mention to Chad Neidt, having only recently discovered him.
Oh god, you just reminded me, how could I forget Yu-Gi-Oh: The Abridged Series? I swear that is actually more popular than what it was ripping off. Attention Duelists! My hair is assaulting you!
Two Best Friends Play
Their full Let's Play of Resident Evil 2 is one of the best things I ever saw on Youtube outside of RedLetterMedia's Star Wars prequel reviews.
Does no-one else watch the Angry Joe Show? Really just me? Fine.
Out of those already mentioned I do enjoy Total Biscuit, ERB and Yogscast.
Yogscast: Just something nice and not very serious to put on in the background while I'm doing something else.
-ChaoticMunki aka Cry. Dude is just so... I dunno, real.
Yogscast gets my vote. They've just got the exact kind of humour that tickles me, plus it's nice to see them use their fame to raise money for charities.
As far as being known from Youtube is concerned, I'd say Egoraptor and Game Grumps, TotalBiscuit, and TomSka.
As far as being hosted on Youtube as well is concerned, I'd say JonTron, Retsupurae, Chip & Ironicus, and Continue?.
As for why:
JonTron - Does extremely silly, over-the-top reviews of silly, over-the-top (or bad) media.
Game Grumps - Egoraptor and JonTron play games, make jokes, and talk about game philosophy. While they often say things I might disagree with, it's still generally interesting to hear their points of view and take into account their side of the discussion.
TotalBiscuit - I typically only watch his "WTF Is..." series, because he's rather informative about games I otherwise wouldn't have known anything about, and he can be quite funny and self-deprecating at times (such as any time he needs to play a puzzle-platformer).
TomSka - The guy is full of random, front-loaded humor and is a great voice actor. His sketches usually have rather high production values too, for being a Youtube channel.
Continue? - They're from Normalboots.com, the same place JonTron is hosted. It's three guys making jokes while playing older games and basically seeing whether they hold up today or not after playing the first half hour or so, and then giving a verdict on whether they would 'continue' to play the game or not.
Retsupurae - They do a few different things, with a similar motif: They riff over media.
And then they've got bad Let's Plays from Youtube, where they take the creme de la creme of poor quality videos - Camcorder LPs, Unregistered Hypercam LPs, LPs with little or awful commentary, LPs where the player just sucks at the game, etc. - and absolutely demolish them. This is when they're at their best, in my opinion, because they can play off of the poor recording, the bad commentary, the bad playing, technical difficulties, or any number of other things.
Chip & Ironicus - Chip Cheezum does a bunch of Let's Plays for SomethingAwful, hosted on blip.tv, and Ironicus is his primary co-commentator. Aside from their first two games they ever did, they've got really good quality on their videos and their commentary is top-notch. I've watched their 50 Cent: Blood on the Sand LP probably three times through. They also retsupurae bad Youtube videos, both on Chip's own channel and occasionally guesting in Retsupurae videos.
Jesse Cox and Totalbuiscuit are the two ones I like the most, I watch all thier stuff.
I'm subscribed to other people but they either aren't big or are big but I only like some of their stuff (Gamme Groomps)
A few of The Game Station guys (mainly TB, Jesse and Dodger, but also Ro's Nerdy Nummies stuff as well)
I would consider LittleKuriboh big considering he basically created an entire genre of YouTube videos, so him too
TomSka as well, but that's mainly for his asdfmovies.
Oh, and the Escapist CommuniCast one. It's the biggest and best of the lot, obviously =P
Well the biggest ones I watch all the time are Probably Ashens , Nerdcubed and Retsupurae. Ashens is just great in that he can turn a fricking poundland instant cupcake into an entertaining spectacle. Nerd cubed is probably my favourite letsplayer since he actually gives a damn how his content turns out and is consistently funny and Retsupurae ( and by extension ChipCheezum who do the same thing ) are just funny to watch rip into bad games , bad players of games and bad flash games. They also have a generally good podcast on itunes too which is nice to listen to.
I watch Totalbiscuit. Not as famous, but no less awesome, I subscribe to BigCatRescue. You should too.
TotalBiscuit is the only one I subscribe to. He's a reasonably intelligent guy, has good content and covers a lot of things I'm interested in.
Contrary to many people here, I actually very much enjoy Pewdiepie. Besides that, I don't watch any "big" Youtubers, except possibly TBFP.
Possibly the best walkthrough-er on Youtube.
Only channels I really visit nowadays.
To name but a few...
I watch the rad brad for all of my lets plays
Totalbiscuit: His in-depth look of the PC versions of games are a big draw for me, as well as the rest of the video being nothing but gameplay as well.
Do Team Four Star count?
That and Matt and Woolie playing Donkey Kong Country are my two video series where I'm like "Okay, I'm bored watching every video I know of on youtube, including the RE2 and DKC playthroughs... let's watch RE2 and DKC again."
TheSw1tcher (my favorite
and recently Jesse Cox.
By far Two Best Friends is the funniest channel I've seen on YouTube.
Angry Joe is good reviewer, he's a little-fanboyish but ultimately fair and isn't part of the whole "Okay = 9/10" trend that every other reviewer is used too.
TotalBiscuit is always entertaining whenever I watch him, and he's in that circle with Yoggscast, Jesse Cox and Angry Joe.
I am disappoint that nobody has mentioned the Vlogbrothers or any of their other endeavors. Those guys are amusing and enlightening, a rare combination on the internet.
Also the AVGN might be the first youtuber I really ever followed. He left me in stitches every times I watched him.
And YES TO THE GUY WHO SAID RETSUPURAE! Those guys are satire at its finest, MST3k style.
Lindsey Stirling is an amazing violinist, TheFineBros make fantastic content, Barley Political are super funny and TheYoungTurks are where I go for American news.
Came here to post this. Will add 666theheartless666 to the list as his LPs are such a refreshing antidote to the legions of shouty, hyperactive, swearing-and-rape-jokes LPs out there.
The Yogscast because they make me laugh. Northernlion because I'm addicted to his Binding of Isaac series (400+ episodes and going strong) and he does Let's Look Ats very professionally. JamesNintendoNerd because I was a nintendo kid and feel his pain regarding a lot of crappy games back in the day. OMFGcata (Jessie Cox) because he makes me laugh, the guy is hilarious. Simonscat because he's an excellent cartoonist. And Necroscope86 for getting me interested in watching videos on youtube about video games with his LP of X-com Enemy Unknown (the old version) and Breath of Fire 3.
There are others I watch and enjoy, but none like those above.
Toby/Tobuscus/TobyGames channels can be funny, I especially like his animated series and whacky hyperactive personality, his Amnesia the dark descent series introduced me to the game, as well as his Fallout New Vegas videos, both of which were 'less intense' with his whacky side, but it was still there. Lately though, I don't frequent his channels as much, I'm not sure why, he's a good youtuber.
Anyway those are the channels that I know of. I know of a couple others but they aren't 'big'.
Oh, this is gonna be good! So, in no particular order... (and with proper punctuation/capitalization/spacing/alternates/etc.)
Peanut Butter Gamer
The Completionist
Did you know Gaming?
Some Call me "Johnny"
Errant Signal
Rabbid Luigi
Yuri of Wind
Emcee Prof. It
Nintendo Capri Sun
Brutal Moose
Blind Zeo Power Kick
First-Person Trolling
Total Biscuit
The Bro Team
Chub Z. Doomer
Vengeful B.K.M.
Ego Raptor
Thumbs-Up Master
The Spoony Experiment
The Angry Joe Show
The Angry Videogame Nerd
The Great Clement
Josh Jepson
Chugga Conroy
The Game Grumps
Brain-Scratch Commentaries
Blake Robinson
Oliver Sirois
Daniel Alvarez
Tee Lopes
Sander Otten
Gold Jinjo
B.K. Pianist
Astroth Sounds
Clanky the Gorn
Freddie W.
Team Four Star
Shadow 759
Stoopid Monkey
Rooster Teeth
Sonic Paradox
Glad to see so much Grump love. Listening to the Banjo-Kascary episode as I type this.
I know one.
He's entertaining, humble and harmless. A very down to earth guy. No problems.
Also, Cyriak (TALENT), AVGN (unfunny, to me, but goddamned entertaining, adn bloody talented, can;t wait for the movie!).
Reviews Angry Joe http://www.youtube.com/user/AngryJoeShow and Jeremy jahns http://www.youtube.com/user/JeremyJahns
Funny stuff Cup of team http://www.youtube.com/user/CupOfTeamOfficial?feature=watch and Tobuscus and jacksfilms
I was the OP on the Worst YouTubers thread, and by God I was not expecting that amount of correspondence! I know people have to vent at that sort of unwarranted popularity on YouTube, which is why I made the thread in the first place, but I'll still name some of my favourites as well, to spread some of the more unknown ones around, but also so that I'm not just seen as a cynical, jealous bastard.
Jacksfilms: I'm really glad so many people on here love this guy. Your Grammar Sucks is such a simple idea I don't believe no-one capitalized on earlier, yet he "nails it" so well. His other videos (especially his Super Bowl one) deserve a shout out aswell
JonTron: Whilst I feel Game Grumps may outstay its welcome, his personal videos are some of the most hilarious, re-watchable and quotable on the site.
Caddicarus: This guy definitely deserves more attention. Whilst it's really obvious JonTron is a massive inspiration, that's not a bad thing, as he's genuinely funny in his own right. Also Jon himself subscribed to him, so he must be doing something right
Flula: This guy..... This is just surreal. Anyone who says Germans aren't funny haven't seen this guy
Wheezy Waiter: The only near-daily video maker who I haven't got sick of yet
ClementJ642: Okay I'm just a big Sonic fan. He LP's a lot of Sonic. His LP's are legitimately interesting to me. Sue me.
SomeCallMeJohnny: Again, quite a bit of Sonic. Good reviews in general though
JoshScorcher: Best gaming countdowns on the website, and also pretty good My Little Pony reviews. I don't even particularly like that show.
Matthew Patrick: Game Theory is an awesome, intelligent show. That is all
331ERock: I don't normally like metal, but his arrangements are just fucking brilliant.
MysteryGuitarMan: Some of the most brilliant editing online I've ever seen
Todd In The Shadows: Yeah, he's technically on ThatGuyWithTheGlasses, but I wasn't going to be able to mention him elsewhere. Quite possibly the best online pop music reviewer, and One Hit Wonderland is an awesome show as well.
Tobuscus: When he's not selling out or doing that stupid CuteWinFail series, I honestly like some of the other videos he puts out. He can actually be genuinely funny at times. I always get a kick out of the animated "Adventure" videos
Okay, lemme see:
GradualReport (His Unicorn Video is amazing)
I don't know about FAVORITE but I will agree to that. There's a lot of different character and comedic dynamics at play with game grumps and it makes great audio fodder. Every other commentary I've seen makes me feel like I'm 6 and I'm over at the house of that friend who doesn't ever let you have a turn on the nintendo. That said I prefer both Arin and Jon's content on their own respective channels much more.
Though anyone who does original cartoons has a lot of respect from me. Harrypartridge, psychicpebbles, Oney, StamperTV etc. Oh and I need to throw Ninjasexparty in there for being tragically underrated though they aren't really "big"
You practically stole my post. Egoraptor was the first thing to come to mind when seeing the title. I also fucking love Jabo0ody Dubs too. Retsupurae (how do you even pronounce that?) has some great stuff too. I can watch all three of those guys all day.
There's also this boyfriend/girlfriend combo that are always playing mean pranks on each other. I can't remember what they call their channel. Prank vs prank?
|Pages PREV 1 2 3 4 NEXT


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Imagine your car was involved in an accident and you claim for total loss under your motor insurance. You claim Rs 1 lakh but your general insurance company says you are eligible only to get Rs 75,000 due to some deductibles.
Instead of wasting time over arguing over the amount, you decide to accept Rs 50,000 and sign the 'discharge voucher' or 'settlement intimation voucher' hoping to later lodge a complaint or go to court if required.
But when the matter reaches court, the company says that because you have signed the voucher, the claim has been settled in full and you have agreed to it, thereby giving up your right to contest the claim.
But now this may change. In a recent guideline, the Insurance Regulatory Authority of India (Irdai) said, "…execution of such vouchers does not foreclose the rights of policy holder to seek higher compensation before any judicial fora or any other fora established by law".
This is good for policyholders, says Arvind Laddha CEO, Vantage Insurance brokers.


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Question: I am someone who has drunk the Kool-Aid on saving as much for retirement as possible and maxing out contributions each year if you can since you can never "get that year to contribute" back. However...
I'm a 40 year old single female who is I think in good shape in terms of savings. I make a little south of $200k/year and have about $300k in savings ($150k in an IRA, Roth IRA, and my 401k; $120k in mostly index funds, and $30k liquid) and own my own home in a gentrifying area with a low fixed rate mortgage. I have some school debt at very low interest so I'm comfortable with that, and no other debt. I chose not to convert my IRA to a Roth IRA this year because I believe I'll be in a lower tax bracket in my 60s than I am now, by "retiring" early (eg: going from being an executive to working part time somewhere fun).
I max out my annual 401k contribution and had been contributing to my traditional IRA each year as well -- but my accountant has been somewhat discouraging me from putting more money into my Traditional IRA, suggesting I put the money into funds with fewer restrictions. So when is maxing out your IRA each year no longer a sound investment? Karen, Los Angeles, CA
Answer: I am with your accountant on this one. You're a good saver. It will add to your financial flexibility to put money into taxable accounts.
Here's the thing: Over the past three decades with the rise of the 401(K) savings has become synonymous with setting money aside for retirement. I think it's time to break the grip that retirement has on our approach to savings. Now, don't get me wrong. It's important that you fund your retirement savings. It's the financially prudent thing to do.
But savings also should be geared toward funding transitions over a lifetime. Retirement is only one of those shifts in activity, although it's a major one. Saving isn't about old age. Saving should be about funding career and lifestyle shifts throughout our lifetimes.
You mentioned that you'll want to retire early and work part-time--a so-called job-tirement. Well, in that case having savings in taxable accounts will ease the cost of transition.
Yes, you'll pay taxes on dividends, realized capital gains, and interest payments along the way with your taxable accounts (depending on the investment). But if you pull money out of your 401(k) you would pay a 10% penalty plus your ordinary income tax rate on the withdrawal. You could borrow from the plan, but that maneuver reduces the long-term return on retirement savings.
With a taxable account you can tap the money at any time without penalty. You'll pay Uncle Sam a long-term capital gains tax rate when you cash it in--assuming you've owned the investment for more than a year--but it's still at a lower rate than ordinary income tax rates.
Financial flexibility is valuable.


text:
Call: N6KI Operator(s): Station: N6KI Added: 30/Jan/2011 Contest: CQ 160-METER CONTEST, CW Class: SINGLE OP ASSISTED HP QTH: ca Operating time: 18.5 Summary: Total: QSOs = 500 State/Prov = 54 Countries = 15
Total Score = 83,076 Club: Soapbox: Never heard ND, MS or ND and missed
6 tough and rare Canadian Provinces
! Best DX was Portugal for a new Band
Country. Really need some Beverages to
be able to hear the week ones as still
had S5 noise on 6 ft loop with preamp.
Gonna have to work something out with
neighbor and getting use of some
nearby vacant land he owns !


text: RED/Facebook [ RED with theObvious and Ultralink in Concert at the Lucky Mule By Frank Pain July 10, 2013 Red are coming back to Abilene for another round on the Rock 108 Summer Concert Series. This time around, they'll be sharing the stage with two of Abilene's best live bands, theObvious and Ultralink. Read More Category: Concerts, The Afternoon Binge Tags: lucky mule saloon, red, theobvious, ultralink Send to a friend! Share on Facebook Share on Twitter Pin it! Reddit This! Share on Tumblr!