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The neurological effects of organophosphate pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here we characterized the effects of the broadly-used insecticide chlorpyrifos on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. Chlorpyrifos potentiated PKA-dependent phosphorylation of the striatal protein DARPP-32 and the GluR1 subunit of AMPA receptors in mouse brain slices. It also increased GluR1 phosphorylation by PKA when administered systemically. This correlated with enhanced glutamate release from cortical projections in rat striatum. Similar effects were induced by the sarin congener, diisopropyl fluorophosphate, alone or in combination with the putative neuroprotectant, pyridostigmine bromide and the pesticide DEET. This combination, meant to mimic the neurotoxicant exposure encountered by veterans of the 1991 Persian Gulf War, also induced hyperphosphorylation of the neurofibrillary tangle-associated protein tau. Diisopropyl fluorophosphate and pyrodostigmine bromide, alone or in combination, also increased the aberrant activity of the protein kinase, Cdk5, as indicated by conversion of its activating cofactor p35 to p25. Thus consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration.
A wide variety of pesticides are known to have neurotoxic properties. For example, prenatal exposure to a class of compounds known as organophosphates (OP) reduces child IQ (Bouchard et al. 2011), impairs mental development (Engel et al. 2011), and causes cognitive deficits (Eaton et al. 2008; Bouchard et al. 2010; Rauh et al. 2011). Furthermore, exposure to cholinesterase-inhibiting compounds including OP, pesticides, pyridostigmine bromide (PB, an anti-nerve agent medication), and low-level sarin nerve gas is linked epidemiologically with a chronic multi-symptom illness in veterans from the Persian Gulf War (Staines 2005; Thomas et al. 2006; Haley et al. 2009). Symptoms include cognitive disturbances, muscle fatigue, fever, diarrhea, and insomnia.
OP nerve agents and insecticides disrupt cholinergic neurotransmission by inhibiting acetylcholinesterase (AChE) (Wiener and Hoffman 2004). Acetylcholine (ACh) is the major excitatory neurotransmitter at neuromuscular junctions of the peripheral nervous system and a widely distributed first messenger throughout the central nervous system. Termination of cholinergic transmission is completely dependent upon active AChE. Inactivation of AChE by OP increases nervous system levels of ACh, overstimulating both nicotinic (nAChR) and muscarinic (mAChR) receptors (Felder et al. 2000). Acute high level exposure to OP induces seizures, respiratory failure, coma, and death (Wiener and Hoffman 2004). Low level exposures to chlorpyrifos (CPF), the most well-known OP insecticide in agriculture and domestic use, alters the expression of genes involved in cell growth and differentiation, cAMP-related signaling, neurotransmitter synthesis and release, and receptors that target the actions of many neurotransmitters including ACh and dopamine (Auman et al. 2000; Slotkin and Seidler 2007; Eells and Brown 2009).
Dopaminergic pathways within the mesocorticolimbic circuitry mediate reward learning, motivation, and motor control (Philibin et al. 2011). At the hub of this circuitry, striatal medium spiny neurons (MSNs) receive cholinergic input via α4β2 nAChRs and α7 mAChRs at dopaminergic and glutamatergic terminals, respectively (Nomikos et al. 2000; Wonnacott et al. 2000). Furthermore, nicotine exhibits differential dose-dependent actions on pre-synaptic nAChRs, stimulating dopamine release and activation of D1- and D2-dependent signaling pathways in the neostriatum (Hamada et al. 2004). Interestingly, organophosphate exposure is linked to ADHD epidemiology, a disorder that targets corticostriatal circuitry (Bouchard et al. 2010; Drerup et al. 2010). Furthermore, single photon emission computed tomography (SPECT) revealed abnormal brain responses to cholinergic challenges in the basal ganglia of Gulf War veterans (Haley et al. 2009).
These findings suggest that the harmful effects of OP exposure are due, at least in part, to dysregulation of dopamine neurotransmission and neurotoxic effects on striatal neurons. Therefore, we assessed the effects of AChE-inhibiting agents on neostriatal dopamine signal transmission. The results revealed dysregulation of the D1 receptor/cAMP/PKA signaling pathway, potentiation of corticostriatal glutamatergic transmission, hyperphosphorylation of tau, and induction of aberrant activity of the neuronal protein kinase Cdk5. These data define novel molecular targets that may mediate OP neurotoxicity and provide an avenue for the development of therapeutic treatments following nerve agent exposure.
Adenosine deaminase, anti-phospho-tau (P-T205), CPF, diisopropyl fluorophosphate (DFP), N,N-Diethyl-meta-toluamide (DEET), N-Methyl-D-Aspartic Acid (NMDA), pyridostigmine bromide (PB), and R(+)-SCH-23390 hydrochloride were purchased from Sigma-Aldrich (St. Louis, MO, USA). Phospho-DARPP-32 (P-T34), phospho-DARPP-32 (P-T75), and DARPP-32 antibodies were from Cell Signaling Technology, Inc. (Beverly, Massachusetts, USA). Chlorpyrifos oxon (CPO) was from Chem Service Inc. (West Chester, PA, USA), glutamate receptor 1 (GluR1) subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antibody from Abcam (Cambrigde, MA, USA), anti-phospho-GluR1 (P-S845) from PhosphoSolutions (Aurora, CO, USA), mouse (monoclonal) anti-tau from Biosource (Camarillo, CA, USA), and P35 (C-19) sc-820 antibody from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA). Goat anti-mouse IgG and goat anti-rabbit IgG peroxidase conjugated secondary antibodies were from Thermo Fisher Scientific (Rockford, IL). All other chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA).
All animal experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the US National Institutes of Health. All protocols were approved by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center or the CDC-NIOSH. For experiments involving systemic injections with nerve agents, drugs were administered via subcutaneous (s.c.) or intraperitoneal (i.p.) route to adult male FVB or adult male or female C57BL/6 mice at the indicated dose levels. For studies of the systemic effects of CPF, female C57BL/6 mice were dosed daily for 7 d (30 mg/kg, s.c.). On the seventh day, the mice were sacrificed 2 h following CPF treatment and striatal tissue was rapidly dissected for immunoblotting. Vehicle (Veh) treated mice received corn oil alone. Chlorpyrifos was dissolved in dimethylsulfoxide (DMSO) (for slice pharmacology experiments), and corn oil or peanut oil (for systemic injections). All experiments involving the use of DEET and DFP were performed at the CDC-NIOSH. In those experiments, for evaluation of phospho-Ser845 GluR1 and phospho-Thr205 tau, male FVB mice were dosed daily for 15 d with PB (2.5 mg/kg, s.c.) and DEET (5 mg/kg, s.c.). On the fifteenth day, a challenge dose of DFP (4 mg/kg, i.p.) was given and the mice were sacrificed 2 h following DFP for immunoblot analysis. The mice were sacrificed by focused microwave fixation. For evaluation of p25 levels, the dose of DEET was increased to 30 mg/kg (s.c.). Control mice received vehicle only. Mice that received DFP injections exhibited seizure-like behaviors and mortality was approximately 10% among all DFP treatment groups. For studies of the systemic effect of PB following a delay period from the time of exposure, male C57BL6 mice were dosed daily for 10 d (1 mg/kg, s.c.) and sacrificed 4 weeks after the last treatment for immunoblotting. Pyridostigmine bromide, diisopropyl fluorophosphates, and N,N-Diethyl-meta-toluamide were dissolved in 0.9% saline.
Brains from male C57BL/6 mice (6-10 weeks old) were rapidly dissected and placed in ice-cold oxygenated Krebs buffer (124 mM NaCl, 4 mM KCl, 26 mM NaHCO3, 10 mM d-Glucose, 1.5 mM CaCl2, 1.5 mM MgSO4, 1.25 mM KH2PO4). Using a vibratome, coronal slices (350 μm) were prepared, and the striatum was microdissected and incubated at 30°C under 95% O2/5% CO2 for the indicated periods. Slices were separately treated with pharmacological reagents following a preincubation and recovery period in Kreb's buffer containing adenosine deaminase (10 μg/mL) to allow homeostasis to be achieved. For experiments involving the D1 antagonist SCH-23390, a 10 min preincubation with the compound was performed before treatments with CPO as specified in the experiment. Following drug treatment, slices were snap frozen in dry ice and stored at −80°C.
Protein phosphorylation levels were evaluated by quantitative immunoblotting with phosphorylation state-specific antibodies. Samples were transferred to dry ice, then removed, immediately sonicated in boiling lysis buffer (10 mM NaF in 1% SDS), and boiled for 5 min. Protein concentrations were determined by bicinchoninic acid (BCA) protein assay (Thermo Fisher Scientific, Rockford, IL). Equal amounts of total protein (100 μg) were subjected to SDS-PAGE, followed by overnight transfer to nitrocellulose membranes. Membranes were blocked in 5% powdered skim milk dissolved in Tris-buffered saline-Tween, then probed with primary antibodies for P-T34 DARPP-32 (1:500), P-T75 DARPP-32 (1:1000), DARPP-32 (1:1000), P-S845 GluR1 (1:1000), GluR1 (1:1000), P-T205 tau (1:1000), tau (1:1000), and P35 (C-19) (1:500). Blots were washed several times and incubated with HRP-conjugated secondary antibodies (1:10,000). For detection of phosphorylation, blots were stripped and reprobed for total protein. Antibody was detected using enhanced chemiluminescence (GE Healthcare, Piscataway, NJ). Multiple exposure times were evaluated for each blot to ensure linearity.
Following anesthetization of male or female p14-p18 Sprague-Dawley rats, brains were removed and immediately immersed in ice-cold, oxygenated, modified artificial cerebral spinal fluid (aCSF) containing the following (in mM): sucrose, 194; NaCl, 30; KCl, 4.5; MgCl2, 1; NaHCO3, 26; NaH2PO4, 1.2; D-glucose, 10. 300 μm slices were generated using a vibratome (Leica Microsystems, GmbH, Wetzlar, Germany) and subsequently placed in continuously oxygenated aCSF containing the following (in mM): NaCl, 124, KCl, 4.5; MgCl2, 1; CaCl, 2; NaHCO3, 26; NaH2PO4, 1.2; D-glucose, 10. The aCSF osmolarity was 320 mOsm and the pH was 7.3. Slices were equilibrated at 33°C for 1 h and subsequently incubated at room temperature until hemisected slices were transferred to the recording chamber.
Whole-cell electrophysiological recordings of dorsolateral striatal MSN miniature excitatory postsynaptic currents (mEPSCs) were performed in 29-31°C aCSF containing picrotoxin (50 μM), tetrodotoxin (TTX) (1 μM), and 0.1% DMSO. Intracellular glass recording electrodes were pulled from borosilicate glass on a Flaming/Brown micropipette puller (Sutter Instrument Co., Novato, CA) to a resistance of 2-5 mΩ. Recording electrodes were filled with a CsMeSO3–based solution of 295-300 mOsm containing (in mM); 120 CsMeSO3, 5 NaCl, 10 TEA-Cl, 10 HEPES, 5 QX-314, 1.1 EGTA, 0.3 Na-GTP, and 4 Mg-ATP. MSNs were voltage clamped at - 60 mV using a Multiclamp 700A amplifier (Axon Instruments) following rupture of the cell membrane and achievement of the whole-cell recording configuration. After a 3 min equilibration period, baseline mEPSC recordings were taken for 5 min, followed by a 10 min bath-application of CPO (100 μM, dissolved in DMSO) for a total of a 15 min recording session. The concentration of DMSO remained at 0.1% throughout the experiment. Recordings were filtered at 2 kHz and digitized at 10 kHz and were discarded if series resistance exceeded 25 MΩ or changed by more than 15%.
For quantitative immunoblotting analysis, immunoreactivity signals were captured by autoradiography and quantified with ImageJ software (NIH). The quantified effects were derived by normalization of the signals to total protein levels. Data are presented as mean ± standard error of the mean (SEM). Student's t-test or analysis of variance (ANOVA) was performed to compare data sets using GraphPad Prism (GraphPad Software).
For electrophysiological analysis, baseline (0-5 min) and CPO (10-15 min) mEPSC data were analyzed using the Mini Analysis program version 6.0.7 (Synaptosoft, Decatur, GA, USA). Amplitude and area thresholds were manually set, and the accuracy of mEPSC detection was manually verified for all data sets. A paired t-test was used to compare data sets using GraphPad Prism (GraphPad Software). Data are expressed as mean ± SEM.
To explore the effect of nerve agents on dopamine neurotransmission we evaluated the influence of the organophosphate, CPF, on the PKA-dependent phosphorylation state of two important downstream effectors of striatal dopamine neurotransmission, DARPP-32 and the GluR1 subunit of the AMPA receptor. Treatment of acutely prepared mouse striatal slices with the CPF active metabolite, CPO caused a 1.9 ± 0.1-fold increase in phospho-Thr34 DARPP-32 (Fig. 1a). When PKA phosphorylates DARPP-32 at Thr34, it is converted into a potent inhibitor of protein phosphate 1 (PP1), thereby allowing dopamine to control the phosphorylation state of numerous phosphoproteins that regulate striatal neuron function (Greengard et al. 1999). CPO did not alter the phosphorylation state of DARPP-32 at Thr75, a Cdk5 site that converts it into a PKA inhibitor (Bibb et al. 1999) (Fig. 1b). GluR1 is another important downstream effector of the D1 receptor/cAMP/PKA cascade. Phosphorylation at Ser845 GluR1 is increased by D1 dopamine receptor agonists, and the phosphorylation of this site controls GluR1 trafficking, stability, and striatal neuron excitability (Song and Huganir 2002). Treatment of striatal slices with CPO enhanced PKA-dependent phosphorylation of Ser845 GluR1 by 2.1 ± 0.4-fold (Fig. 1c). Furthermore, treatment of striatal slices with the anti-nerve agent cholinesterase inhibitor PB revealed a 2.7 ± 0.5-fold enhancement in phospho-Ser845 GluR1 (Fig. 1d). Thus, CPO and PB regulate important downstream effectors of striatal dopamine neurotransmission.
To determine if OP exposure in vivo could activate striatal PKA, the effect of systemic administration CPO on PKA-dependent phosphorylation of GluR1 was assessed. Mice were treated with 8 daily injections of 1 mg/kg or 2.5 mg/kg of CPO. These doses were empirically determined to cause minimal lethality. However, no significant effect on phospho-Ser845 GluR1 was detected under these conditions. As an alternative, mice were injected subcutaneously with 30 mg/kg of the less lethal CPO parent compound, CPF, for 7 d while control mice received only vehicle. Striatal tissue was acutely dissected 2 h after the last dose of nerve agent. Interestingly, repeated treatment with CPF resulted in a 1.36 ± 0.04-fold increase in striatal phospho-Ser845 GluR1 levels (Fig. 1e). These in vivo data were consistent with the effects observed in striatal slices indicating that OP exposure activated striatal D1 receptor/cAMP/PKA effectors.
To understand the mechanism by which nerve agents could dysregulate dopamine neurotransmission we evaluated the effects of CPO on phospho-Ser845 GluR1 levels in mouse striatal slices in the absence or presence of the D1 receptor antagonist, SCH 23390. SCH 23390 caused a reduction in the basal levels of phospho-Ser845 GluR1 to 50% (0.6 ± 0.1-fold) of control levels in untreated slices (1.2 ± 0.1-fold) (Fig. 1f). Furthermore, the increase in phospho-Ser845 GluR1 induced in the presence of the D1 receptor antagonist was 57.1% (1.2 ± 0.1-fold) of that induced by CPO treatment alone (2.1 ± 0.2-fold) (Fig. 1f). These findings suggest that at least a portion of the effect of the OP in phospho-Ser845 GluR1 was mediated by a pathway other than the activation of D1 receptors. These data also suggest that antagonists of D1 receptors may serve to counter some of the effects of nerve agents on dopamine signaling.
To further define the pathophysiological effects of OP on striatal neuron function, the effects of CPO on corticostriatal glutamatergic neurotransmission was assessed by whole-cell patch clamp recording. For these neurophysiological analyses, TTX-insensitive mEPSCs from dorsolateral striatal MSNs were evaluated. Compared to baseline values, a 10 min bath-application of CPO did not affect mEPSC amplitude (baseline, 29.16 ± 1.32 pA vs. CPO, 28.81 ± 2.65 pA), but caused a significant decrease the inter-event interval (increase in frequency) of mEPSC events (baseline, 0.68 ± 0.16 s vs. CPO, 0.51 ± 0.15 s) (Fig. 2a-d). CPO application did not change the holding current (Fig. 2e). These results suggest that CPO alters striatal neurotransmission by enhancing glutamate release from corticostriatal terminals in an action potential-independent manner.
Studies using CPO and CPF revealed effects of this OP on striatal dopamine signaling and excitability. During the 1991 Gulf War, exposure to CPF used as an insecticide likely occurred in combination with use of the insect repellant, DEET, and, potentially, exposure to low levels of sarin gas (Golomb 2008). In addition, the reversible OP cholinesterase inhibitor, PB, was used prophylactically as a neuroprotectant in the event of nerve agent exposure. To mimic these conditions, mice were treated with different combinations of agents of potential relevance to Gulf War Illnesses. One cohort of subjects received a single subcutaneous injection of 4 mg/kg of DFP, a sarin surrogate compound. Another group was given 2.5 mg/kg PB and 5 mg/kg of DEET daily for 15 d. For still another group, to this regimen, a challenge dose of DFP was added on the final day. Quantitative immunoblot analysis was conducted on lysates from acutely dissected regions of the mesolimbic circuitry including striatum and hippocampus 2 h following the final treatment. Mice treated with DFP alone exhibited a trend toward enhanced phosphorylation of GluR1 at the Ser845 site (p=0.0586). However, PB/DEET treatment with or without the DFP challenge had no detectible effect at this phosphorylation site in the striatum (Fig. 3a).
While the vast majority of dopamine neurotransmission occurs in the striatum, dopamine neurons also innervate the hippocampus. Nerve agents have been suggested to cause deficits in hippocampal-dependent tasks designed to measure cognition. Therefore, we also assessed the effects of systemic administration of PB, DEET, and DFP on phospho-Ser845 GluR1 levels in the hippocampus (Fig. 3b). Immunoblot analysis from hippocampal lysates of mice treated with the same dose described above showed a 1.5 ± 0.1-fold increase in phospho-Ser845 GluR1 following DFP treatment. Exposure to PB and DEET alone did not induce changes in phosho-Ser845 GluR1 compared to vehicle-treated mice. However, a 1.7 ± 0.1-fold increase in PKA-dependent phosphorylation was induced by the combination of these agents with DFP. Together, these data suggest that PKA signaling is enhanced in vivo by DFP alone or in combined exposure to other neurotoxicant acetylcholinesterase inhibitors.
It addition to the dysregulation of PKA-dependent phosphorylation of downstream effectors of dopamine neurotransmission, the effects of OP on neurological function suggest more severe neuronal injury may occur. The hyperphosphorylation of the neurofilament binding protein, tau, has been strongly implicated in an array of neurological and neurodegenerative diseases (Baumann et al. 1993; Lopes and Agostinho 2011). Moreover, phosphorylation of tau at Thr205 by the protein kinase Cdk5 has been associated with loss of neuronal function and death (Baumann et al. 1993; Lopes and Agostinho 2011). Interestingly, immunoblot analysis from mice exposed to PB, DEET, and DFP revealed a dramatic 17.0 ± 1.9-fold increase in the levels of phosphorylation of the aberrant Cdk5 substrate Thr205 tau in striatal lysates. DFP exposure alone caused a 15.5 ± 2.0-fold increase at that site. Furthermore, hippocampal lysates from mice exposed to all three neurotoxicants showed a 21.5 ± 1.3-fold increase in phospho-Thr205 tau levels, while DFP-treated mice exhibited a 17.1 ± 1.1-fold enhancement compared to mice that received vehicle treatment alone. These marked effects suggest that toxicity induced upon DFP exposure, alone or in the presence of PB and DEET, induces neuropathological effects in striatum and hippocampus.
Cdk5 regulates dopamine neurotransmission (Bibb et al. 1999) and contributes to many other neuronal functions (Cheung et al. 2006). However, neuronal injury and loss of homeostasis can cause activation of the Ca2+-dependent protease, calpain (Kusakawa et al. 2000; Lee et al. 2000). Cleavage of the Cdk5-activating neuronal cofactor p35 to p25 by calpain, results in hyper-activation and redirection of the kinase towards aberrant substrates including Thr205 tau. Cdk5 bound to p25 exhibits aberrant activity, contributes to neuronal death, and has been implicated in neurotoxicity and neurodegenerative diseases (Cruz et al. 2003; Lopes and Agostinho 2011). Furthermore, animal models of p25 overexpression exhibit behavioral deficits that correlate with dysregulation of dopamine signaling (Meyer et al. 2008).
To investigate the ability of nerve agents to induce aberrant Cdk5 activity, we examined p25 generation in different paradigms of AChE inhibitors exposure. While CPO alone as a systemic (1.0 or 2.5 mg/kg, s.c. 7 days) didn't induce appreciable p25 generation, the effects of DFP alone or in combination with other OPs on tau hyperphosphorylation, suggested these, possibly more severe, treatments might have an effect on p25 generation. To investigate this possibility, mice were treated with the same dose regimen of PB, DEET, and DFP described above (i.e., Figs. Figs.33 and and4)4) and lysates from acutely dissected regions of the striatum and hippocampus were analyzed 2 h following DFP exposure. Surprisingly, these conditions did not result in a detectable increase in p25 production. However, striatal lysates from a cohort of mice that received a higher dose regimen of the insecticide DEET (30 mg/kg, vs. 5 mg/kg in the earlier experiments) in combined exposure with PB and DFP reveal a 13.4 ± 3.3-fold increase in p25 generation 2 h following the last exposure (Fig. 5a). These mice displayed no changes in phosphorylation at Thr75 DARPP-32 (Fig. 5a). Interestingly, 6 h after the last exposure, mice exhibited a 10.0 ± 1.5-fold increase in p25 generation that was accompanied by a reduction in phospho-Thr75 DARPP-32 to 60% (0.6 ± 0.1) of control levels in vehicle-treated mice (1.0 ± 0.1) (Fig. 5b). Similar effects were also observed in hippocampus with 12.8 ± 3.9 and 17.4 ± 1.1-fold increases at 2 and 6 h, respectively, after the final treatment (Fig. 5c and d). These data indicate that nerve agents induce aberrant Cdk5 activity and shift its specificity away from physiological substrates, most likely, toward aberrant substrates such as tau.
While neurotoxic exposure could be limited to self-administration of PB, the data indicated that PB in the presence of DEET had little initial neurotoxic effect. However, it has been suggested that the pathological effects to subclinical doses of OP such as PB may only manifest after a delay period of the last exposure (Kamel and Hoppin 2004). Therefore, we examined the effect of systemic administration of PB following a 4-week delay period after the last exposure. Mice were treated with 10 daily injections of 1 mg/kg PB and immunoblot analysis was conducted on lysates from acutely dissected regions following the delay period. Mice treated with PB exhibited a 1.6 ± 0.3-fold increase in p25 generation accompanied by a decrease in phospho-Thr75 DARPP-32 levels to 69% (0.69 ± 0.05) of control levels in vehicle-treated mice (1.0 ± 0.1) (Fig. 6a). Comparable effects were detected in hippocampus with 1.8 ± 0.2-fold increase following the delay treatment. The detection of high levels of p25 in these two brain regions and redirection of Cdk5 specificity support the hypothesis that this compound which was administered to Gulf War veterans during combat has the capacity to induce neuronal injury, even after considerable delay from the time of exposure to subclinical doses.
Nerve agents are thought to induce brain damage through hyperstimulation of cholinergic receptors (McDonough and Shih 1997). However, both glutamatergic and dopaminergic neurotransmitter systems mediate the biological and pathological effects of AChE inhibitors (McDonough and Shih 1997; Wonnacott 1997; Wonnacott et al. 2000). Furthermore, the neostriatum has been implicated as a target of the long-term neurotoxic effects of organophosphates in clinical studies (Haley et al. 2000; Haley et al. 2009). To better understand the deleterious and pathogenic effects of these compounds, we examined the consequences of nerve agent exposure on dopamine signaling pathways, glutamate neurotransmission, and neuronal injury mechanisms in the neostriatum in rodent brain slices and whole animals in vivo.
We found that CPF and PB increased PKA-dependent phosphorylation of downstream effectors of striatal dopamine neurotransmission including the GluR1 subunit of the AMPA receptor and/or DARPP-32 in slices and in vivo. A previous study found that, high concentrations of nicotine induced a D1 receptor-dependent activation of PKA, and increased phosphorylation of Thr34 DARPP-32 through activation of the striatonigral pathway (Hamada et al. 2004). However, given that a potent D1 receptor antagonist did not block the activation of striatal PKA, it is possible that at least a portion of the effects of CPF are mediated by pathways, such as those modulated by mAChR, which do not directly involve D1 receptor activation. Accordingly, acetylcholine released from striatal cholinergic interneurons interacts in a dynamic manner with dopamine signaling at multiple levels including presynaptic regulation of neurotransmitter release and postsynaptic effects (Threlfell and Cragg 2011). The degree to which CPF activates PKA through non-dopamine mediated mechanisms may warrant further study. Moreover, the deleterious effects of these agents may occur across a spectrum of biological and pathological mechanisms. At relatively low levels of exposure, effects may be occur via AChR activation and subsequent dopamine release, while higher doses may induce dysregulation of Cdk5, removal of tonic inhibition of PKA, or direct covalent modifications due to organophosphate reactivity.
The effects of CPF on the phosphorylation state of downstream effectors of the D1 receptor/cAMP/PKA pathway suggest that nerve agents may exert some of their pathological effects via alterations in dopamine neurotransmission. CPF has been shown to increase dopamine turnover and to alter dopamine and other monoamine metabolite levels (Moreno et al. 2008; Eells and Brown 2009). Furthermore, CPF exposure during the gestational days of developing rats evoked long-term increases in serotonin and dopamine turnover (Aldridge et al. 2005). Some of the positive effects of CPF on PKA activity in slices and whole animal subjects (see Fig. 1) were not replicated when combined organophosphate regimens, including higher DEET concentrations, were used (see Figs 3a, for example). However, these more toxic exposures may have invoke mechanisms of neuronal injury associated with Cdk5/p25 that possibly occluded effects observed at lower doses.
Excessive glutamate release may constitute a principle cause of neuronal injury and death. ACh can modulate glutamate release through presynaptic α7 nACh receptors in striatal synaptosomes (Marchi et al. 2002). Furthermore, nicotine has been shown to enhance hippocampal synaptic transmission on presynaptic terminals containing α7 nAChRs (Gray et al. 1996). Consistent with these observations, CPF attenuated the inter-interval period between excitatory mini-EPSC events, presumably as a result of enhanced striatal glutamate release. Surprisingly, there are few other reports of the potentiation of striatal glutamate neurotransmission by AChE inhibitors. On the other hand, a study on the effects of nerve agent soman-induced seizures has shown that the levels of excitatory amino acids are attenuated following intoxication (Shih and McDonough 1997). AChE inhibitors such as donepezil, rivastigmine, and galantamine are used as clinical treatments to delay or slow the onset of cognitive deficiencies accompanying Alzheimer's disease pathology, and these compounds have been suggested to attenuate excitotoxicity in the hippocampus and cortex (Standridge 2004; Hansen et al. 2006). Furthermore, it has been suggested that the elicited neuroprotective effects of donepezil may involve down-regulation of NMDA receptors, thereby attenuating glutamate-induced Ca2+ increase following α7 nAChRs activation (Shen et al. 2010).
Nerve agents induce seizure-related brain damage through hyper-stimulation of cholinergic receptors. Subsequent excessive stimulation of the glutamatergic system triggers a prolonged intracellular increase in Ca2+, causing the activation of secondary pathways responsible for neuronal injury (McDonough and Shih 1997). NDMA receptor antagonists such as memantine, a drug used clinically to treat Alzheimer's (Thomas and Grossberg 2009), have been recognized for their ability to reduce Ca2+ overload. However, controversy exists regarding their efficacy and resulting neurotoxic effects (Filbert et al. 2005). Current studies are focused on identifying secondary intracellular signaling pathways that could be targeted for the development of therapeutics that prevent or alleviate the symptoms following nerve agent exposure.
DFP alone or as part of a combination of neurotoxicants meant to mimic the exposure encountered by veterans of the 1991 Persian Gulf War caused hyper-phosphorylation of Thr205 tau. Tau functions to stabilize the cytoskeleton, and its hyper-phosphorylation can result in the formation of neurofibrillary tangles and neurodegeneration (Hanger et al. 2009). Phosphorylation at this site is Cdk5-dependent and it has been implicated as a biomarker for Alzheimer's pathology (Cruz et al. 2003; Cruz and Tsai 2004). Cdk5 plays a critical role in corticogenesis, synaptic plasticity, drug addiction, and cognition (Bibb 2003; Angelo et al. 2006; Cheung et al. 2006). Dysregulation of its activity may depend on prolonged NMDA receptor activation. The resulting intracellular Ca2+ influx could then cause calpain-dependent conversion of p35 to p25 (Lee et al. 2000). Unnecessary NMDA receptor activation due to excessive cholinergic stimulation is one of the most prominent effects of nerve agent exposure that ultimately leads to neuropathology (McDonough and Shih 1997).
PB/DEET/DFP exposure also resulted in p25 generation and induction of aberrant Cdk5 activity in both striatum and hippocampus. Interestingly, the high levels of p25 in striatum correlated with a decrease in phospho-Thr75 DARPP-32, possibly disinhibiting PKA activity. Similar effects were induced by PB after an extensive delay from the time of exposure. High levels of nicotine also reduce Cdk5-dependent phosphorylation of DARPP-32 at Thr75, possibly through a dopamine-release dependent pathway (Hamada et al. 2005). Moreover, induction of transgenic p25 overexpression reduced Thr75 DARPP-32, altered dopamine signaling, and shifted Cdk5 specificity with regard to physiological and aberrant substrates (Meyer et al. 2008). Nonetheless, striatal signaling may be differentially dysregulated depending on the profile of exposure.
Our data indicate that dysregulation of Cdk5 is a component of the long-term effects that arise from exposure and is consistent with at least two reports suggesting organophosphates neurotoxicants dysregulate Cdk5 (Wang et al. 2006; Zhu et al. 2010). Thus, nerve agent-induced dysregulation of Cdk5 may dramatically affect striatal-dependent brain function, and may be relevant to subclinical neurotoxicity and disorders involving dopamine neurotransmission. For example, pregnant women exposed to pesticides such as chlorpyrifos and DEET have a higher risk to manifest deficits in fetal neurodevelopment and altered birth outcomes (Berkowitz et al. 2004; Barr et al. 2010). Prenatal insecticide exposure reduces IQ and delays mental and psychomotor development (Rauh et al. 2006; Bouchard et al. 2011; Engel et al. 2011; Rauh et al. 2011), and children with elevated urinary levels of OP metabolites had a higher ADHD prevalence (Bouchard et al. 2010). Furthermore, a recent study has shown that chlorpyrifos oxon alters the firing activity of the locus coeruleus noradrenergic neurons, a brain region associated with anxiety and stress (Cao et al. 2011). Taken together, the present study is among the first to examine the mechanisms by which organophosphates may alter brain function and cause long-term pathological effects. The secondary signaling targets identified here may contribute to the development of treatments to prevent or counter these neurotoxic effects.
We thank Suzanne Saldanha, Brenda Billig and Christopher Felton for technical assistance. This work was supported by U.S. National Institutes of Health Grants to J.A.B (MH79710, MH083711, and DA016672), Intramural funds from Centers for Disease Control and Prevention-NIOSH, and the Division of Intramural Clinical and Biological Research of NIAAA. Portions of this research were supported by IDIQ contract VA549-P-0027 (Robert W. Haley, M.D., PI), awarded and administered by the Department of Veterans Affairs Medical Center, Dallas, TX. The content does not necessarily reflect the position or the policy of the Federal government or the sponsoring agency, and no official endorsement should be inferred.
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Aviation Festival 2015 will accentuate on the on-going equilibrium of the industry. The show will bring together eminent personalities, professionals and companies under one roof. Focussing on latest developments, demands and notions, the event aims to respond for various aspects of the aviation and other related fields. Over 500 airline executives will grave the event to generate leads and increase business. Gain insights of the industry and source out the best information to benchmark strategies for business. If coming from distant regions or other countries, one can book a stay with hotels around Business Design Centre (BDC). Browse through Exhibitioncentrehotels to find best deals on premium lodgings around the event's venue.
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Odd Molly
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text: Finance Quiz Welcome to our finance Quiz. You will be answering 10 not so easy questions about currencies, financial markets and investment. Press Start to get to the questions immediately. Start the quiz! 0% Where is the world-famous Wallstreet? New York Dallas Washington D.C. San Francisco Correct!Wrong!- Continue >>Which banks do not accept deposits? Commercial Banks Post Offices Retail Banks Investment Banks Correct!Wrong!- Continue >>What does ATM stand for? Augmented Teller Money Automated Teller Machine Automatic Takeout Money Automatic Tap Money Correct!Wrong!- Continue >>What is online banking? Teller banking Computer or Mobile Banking Mail Banking Phone Banking Correct!Wrong!- Continue >>What is not a credit card? American Express Visa Maestro Card Master Card Correct!Wrong!- Continue >>What is the currency of the European Union? Francs Ruble Euro Deutsche Mark Correct!Wrong!- Continue >>Who is featured on the $100 bill? Benjamin Franklin Abraham Lincoln Franklin the Turtle George Washington Correct!Wrong!- Continue >>How much does the 400-troy-ounce gold ingot weigh? 438.9 ounces 398.9 ounces 400.1 ounces 400 ounces Correct!Wrong!- Continue >>What is the second-largest exchange in the world by market capitalization, behind the New York Stock Exchange? NESCAFÉ NASCAR NASDAQ NESTLÉ Correct!Wrong!- Continue >>What other country uses the US-Dollar? France Tibet Brazil Ecuador Correct!Wrong!- Continue >> Share the quiz to show your results ! Facebook Facebook Just tell us who you are to view your results ! Show my results >> Finance Quizz I got %%score%% of %%total%% right Share your results Facebook Facebook Twitter Google+ ↺ PLAY AGAIN ! Change of heart? Click here to reset your answer!


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UFC 196 Weigh-in Results: Conor McGregor, Nate Diaz Official for Main Event
People follow the crowd, and the crowd follows Ultimate Fighting Championship featherweight titleholder and resident cash cow Conor McGregor.
McGregor clocked in at 168 pounds, as he moves up two divisions to face Nate Diaz (169) in the UFC 196 main event on Saturday at the MGM Grand Garden Arena in Las Vegas. Women's bantamweight champion Holly Holm (134.5) and challenger Miesha Tate (135) also met the contracted weight requirements for their assignment in the co-headliner at Friday's official weigh-in.
UFC 196 "McGregor vs. Diaz" -- which airs live on pay-per-view at 10 p.m. ET/7 p.m. PT -- will also feature a women's bantamweight clash pitting MMA Masters rep Amanda Nunes (136) against Valentina Shevchenko (134) and a pair of light heavyweight battles, as former Ring of Combat champion Gian Villante (205) meets Ilir Latifi (205) and "The Ultimate Fighter 19" winner Corey Anderson (204) confronts Tom Lawlor (204.5).
Two hours prior, Fox Sports 1 will carry four preliminary bouts: Brandon Thatch (170) vs. Siyar Bahadurzada (170), Erick Silva (170) vs. Nordine Taleb (170), Vitor Miranda (185.5) vs. Marcelo Guimaraes (185.5) and Chas Skelly (145.5) vs. Darren Elkins (145.5). The three remaining undercard matchups will stream to UFC Fight Pass at 6:30 p.m. ET/3:30 p.m. PT: Jim Miller (155.5) vs. Diego Sanchez (156), Justin Salas (156) vs. Jason Saggo (155.5) and Julian Erosa (156) vs. Teruto Ishihara (146).
UFC 196 Weigh-in Results:
Conor McGregor (168) vs. Nate Diaz (169)
Holly Holm (134.5) vs. Miesha Tate (135)
Gian Villante (205) vs. Ilir Latifi (205)
Corey Anderson (204) vs. Tom Lawlor (204.5)
Amanda Nunes (136) vs. Valentina Shevchenko (134)
Brandon Thatch (170) vs. Siyar Bahadurzada (170)
Erick Silva (170) vs. Nordine Taleb (170)
Vitor Miranda (185.5) vs. Marcelo Guimaraes (185.5)
Chas Skelly (145.5) vs. Darren Elkins (145.5)
Jim Miller (155.5) vs. Diego Sanchez (156)
Justin Salas (155.5) vs. Jason Saggo (156)
Julian Erosa (144.5) vs. Teruto Ishihara (146)


text:
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text:
|Publication number
|Publication type
|Application number
|Publication date
|May 13, 2008
|Filing date
|May 5, 2005
|Priority date
|May 5, 2005
|Fee status
|Also published as
|Publication number
|Scott Stubbs, Conrad L. Sowder, William J. Linder, Lynn S. Elliott, Kenneth P. Hoyme, Hiten J. Doshi
|Original Assignee
|Cardiac Pacemakers, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (14), Referenced by (22), Classifications (8), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is related to the following co-pending applications both of which were filed on May 5, 2005, and are hereby incorporated by reference in their entirety: "SYSTEM AND METHOD FOR PROVIDING BRADYCARDIA THERAPY BY IMPLANTABLE DEVICE IN PRESENCE OF SYSTEM FAULTS", Ser. No. 11/122,982, and "SYSTEM AND METHOD FOR RECOVERING FROM TRANSIENT FAULTS IN AN IMPLANTABLE MEDICAL DEVICE", Ser. No. 11/123,246.
This invention pertains to systems and methods for operating implantable medical devices.
Cardiac rhythm management devices (CRMDs) are implantable devices that provide electrical stimulation to selected chambers of the heart in order to treat disorders of cardiac rhythm. A pacemaker, for example, is a cardiac rhythm management device that paces the heart with timed pacing pulses. The most common condition for which pacemakers are used is in the treatment of bradycardia, where the ventricular rate is too slow. Atrio-ventricular conduction defects (i.e., AV block) that are permanent or intermittent and sick sinus syndrome represent the most common causes of bradycardia for which permanent pacing may be indicated. If functioning properly, the pacemaker makes up for the heart's inability to pace itself at an appropriate rhythm in order to meet metabolic demand by enforcing a minimum heart rate and/or artificially restoring AV conduction. Pacing therapy may also be delivered for the purpose of restoring synchronous ventricular contractions in patients with inter-ventricular or intra-ventricular conduction disorders, termed cardiac resynchronization therapy. Other cardiac rhythm management devices are designed to detect atrial and/or ventricular tachyarrhythmias and deliver electrical stimulation in order to terminate the tachyarrhythmia in the form of a cardioversion/defibrillation shock or anti-tachycardia pacing. Certain combination devices may incorporate any or all of the above functionalities.
CRMD's are complex electronic devices which are subject to failures of various kinds after implantation. It is desirable for such devices to be able to detect when these failures occur and then take action which minimizes harm to the patient.
A system and method is disclosed by which an implantable cardiac device may deliver tachyarrhythmia therapy in the event of a system fault. A hardware-based safety core provides the logic circuitry for detecting tachyarrhythmias and delivering shock therapy in the event of a fault which disables operation of the device's primary control circuitry. The safety core defibrillator eliminates common mode failure of the primary control circuits used in the primary defibrillator system. Failures in the primary controller memory or execution will activate the safety core defibrillator.
Implantable cardiac rhythm management devices are usually microprocessor-based devices whose normal operation can be disrupted by fault events, either arising from a hardware failure or a software problem. The disruption in normal operation, if left unchecked, could cause the device to behave in way which is unsafe for the patient. It is common for CRMD's to incorporate fault detection circuitry which, upon detecting a fault, causes the device to enter a state which is expected to be safe for the patient. For example, a watchdog timer is a hardware timer which runs continuously and is reset periodically by the main control software of the CRMD during normal operation. If a fault disrupts normal operation of the main control software (e.g., a software crash), however, the watchdog timer is allowed to time out and generate a reset signal which re-initializes the system or causes the device to revert to specified operating state. Reset and recovery mechanisms in low-power medical devices historically have been ad hoc designs, attempting to provide limited recovery mechanisms in response to specific fault conditions. These mechanisms can be complex to get to work correctly, and do not effectively respond to unanticipated fault conditions.
In contradistinction to previous systems which employ ad hoc fault recovery mechanisms, the system and method described herein employs a global fault response which enables a CRMD to consistently recover from transient faults while maintaining a history of the reason for the device fault. System resets are generated within the device by either software or hardware as the global fault response. Upon detection of a fault, the primary controller signals the reset controller which then issues a reset command. All sub-systems of the primary device controller are then reset together rather than resetting individual sub-systems independently to ensure deterministic behavior. In an exemplary embodiment, described in greater detail below, a primary device controller providing full-capability diagnostics and therapy in the device is interfaced to a reset controller which manages the reset process. A fail-safe sub-system, referred to below as a safety core, is an optional secondary system that can provide limited therapy as backup while the reset process proceeds. Prior to issuing the reset command, the reset controller causes primary device operation to halt, enables a back-up therapy subsystem, causes the primary controller to log the failure condition prior to initiation of the reset process. However, if the fault interferes with the ability of the device to perform logging, the reset process will occur unconditionally. The activation of the back-up therapy subsystem also occurs unconditionally, independent of the success or failure of the logging process. During the reset process, the primary therapy system executes a complete self-test and re-initialization, to ensure that the primary system is functioning correctly, before returning control to that component. If the self-test fails, the device remains on the back-up therapy subsystem.
1. Exemplary Implantable Device Description
Implantable cardiac rhythm management devices such as pacemakers and cardioverter/defibrillators are battery-powered devices which are usually implanted subcutaneously on the patient's chest and connected to electrodes by leads threaded through the vessels of the upper venous system into the heart.
The components of electronic circuitry 135 are illustrated in
The primary controller 200 controls the overall operation of the device in accordance with programmed instructions stored in memory, including controlling the delivery of paces via the pacing channels, interpreting sense signals received from the sensing channels, and implementing timers for defining escape intervals and sensory refractory periods. The pulse generator circuit of each pacing channel is interfaced to the controller 200 so that the output of pacing pulses is under program control. The sensing circuit of each sensing channel is interfaced to the controller and includes a sense amplifier connected to an electrode and a threshold comparator. In
The primary controller 200 constitutes the primary control system of the device for providing diagnostics and therapy. Also provided as part of the electronic circuitry 135 are components for enabling fault detection and recovery. A fault monitoring circuit 270 detects various kinds of faults and may include, for example, a watchdog timer, a clock deviation monitor, and circuitry for detecting memory errors. The primary controller 200 may also detect faults related to either the hardware or program execution. When a fault is detected by either the primary controller or the fault monitoring circuit, an input signifying the fault event is provided to reset controller 275. As described below, the reset controller manages the reset process in response to the fault and enables operation of safety core 150. The safety core 150 is a hardware-based fail-safe sub-system for controlling the operation of the device in delivering certain types of therapies when the primary controller is halted due to a system fault. For example, the safety core 150 may provide basic pacing therapy, tachyarrhythmia detection, and shock delivery using hardware-based logic which operates independently from the primary controller.
2. System Reset Process
The reset sequence, as illustrated by
The operation of the reset controller may be optionally modified to provide improved tolerance to system faults by incorporating a system-reset monitor which detects system resets caused by non-recoverable and persistent faults. The system-reset monitor provides a mechanism to bound repeated system resets that may occur as a result of faults that are not corrected by system resets and helps to prevent denial of therapy due to non-recoverable and persistent faults. As described above, either software or hardware within the device may generate internal resets which are used to reset the system in an attempt to recover from a transient fault. Telemetry from external equipment may generate resets, referred to as external resets. In this embodiment, a reset count maintained by the system-reset monitor is incremented when an internal reset occurs and is cleared by an external reset. The reset count is decremented by one count every 48 hours (or other specified time period), where the 48 hour time period starts from the first reset and stops when the reset count is zero. Since many system tests are executed daily, this allows faults that occur daily to eventually trip the monitor. The 48 hour time period also provides some margin for delay of daily tests.
A non-recoverable or persistent fault is detected when a specified number (e.g., three) of internal resets occur within a 48-hour period. When a non-recoverable or persistent fault is detected, the system-reset monitor inhibits further attempts to restart the primary system and allows the fail-safe backup system to maintain therapy indefinitely without interruption. The system-reset monitor logs the three most recent resets in a FIFO buffer. As the reset count is decremented, the oldest logged event is deleted, and external resets clear the entire buffer. The logged resets may be interrogated with telemetry. The system-reset monitor is disabled once it has tripped to prevent subsequent internal resets from overwriting data and is re-enabled with an external reset.
3. Backup Defibrillation Therapy
As aforesaid, a fail-safe subsystem may be provided as part of the fault recovery system in order to allow limited device operation in providing therapy when the primary controller is halted during the reset process or if the primary controller is unable to recover from the fault. The safety core 150 may be configured to provide treatment of cardiac tachyarrhythmia events in the presence of system faults which prevent tachyarrhythmia therapy from being delivered by the primary controller 200. Common circuitry is used to both independently monitor therapy delivery from the primary system as well as provide therapy when the primary system has failed. The safety core defibrillator is implemented in hardware logic rather than firmware logic executed by a processor. This reduces the dependency on the correct functioning of all of the components needed to make firmware operate, increasing the reliability of this safety function. During the system reset or when the primary controller is disabled, the safety core defibrillator is configured to use sense signals generated by the right ventricular sensing circuit in order to detect tachyarrhythmias.
Safety core defibrillator operation is initiated with each system reset. When the primary controller 200 successfully completes its reset sequence, it is responsible for disabling the safety core defibrillator. If non-recoverable or repeated transient system faults occur during the operation of the primary system, control is transferred to the safety core defibrillator. A number of mechanisms may be provided to enable or disable the safety core defibrillator. For example, telemetry may be used to allow a clinician to enable or disable therapy by the safety core defibrillator after the device is implanted. A keyed control register may be provided to allow the primary controller to disable the safety core defibrillator in order to prevent therapy competition. The primary would use this mechanism, for example, after it has successfully completed its initialization. The safety core defibrillator may also be automatically disabled in the event of charge faults during operation to prevent therapy retries when the shock pulse output circuits has been damaged or in the event that the battery capacity is insufficient to delivery therapy. A non-volatile register may be used to provide a priority disable for the safety core defibrillator which may be used, for example, to allow the primary controller to be tested during manufacture. This provides a safe guard preventing dangerous voltages on the output leads during manufacture. In another embodiment, when a magnet is detected by actuation of magnetic switch 225, therapy delivery by the safety core defibrillator is immediately inhibited. After the magnet has been applied for a period of time (e.g. 1 second), the therapy may be diverted and further detection of tachyarrhythmias inhibited until the magnet is removed. In one embodiment, the magnet must then be removed for a period of time (e.g., 2 seconds) in order to allow detection to continue.
Although the invention has been described in conjunction with the foregoing specific embodiment, many alternatives, variations, and modifications will be apparent to those of ordinary skill in the art. Such alternatives, variations, and modifications are intended to fall within the scope of the following appended claims.
|Cited Patent
|Filing date
|Publication date
|May 27, 1977
|Aug 21, 1979
|Mieczyslaw Mirowski
|Fault detection circuit for permanently implanted cardioverter
|Sep 30, 1994
|Nov 5, 1996
|Intermedics, Inc.
|Device and method for cardiac arrhythmia therapy with failure detection and backup
|Nov 25, 1996
|Apr 7, 1998
|Sulzer Intermedics Inc.
|Cardiac stimulator with backup-mode self-recovery
|Mar 18, 1999
|Oct 3, 2000
|Medtronics, Inc.
|Error code calculations for data stored in an implantable medical device
|Nov 18, 1998
|Oct 3, 2000
|Agilent Technologies, Inc.
|Fail-safe defibrillator
|Jun 15, 1999
|Mar 6, 2001
|Intermedics Inc.
|Implantable cardiac stimulator with safe noise mode
|Apr 10, 2001
|Jun 24, 2003
|Cardiac Pacemakers, Inc.
|System and method for measuring battery current
|Apr 28, 2000
|Oct 21, 2003
|Medtronic, Inc.
|Implantable medical pump with multi-layer back-up memory
|Oct 26, 1999
|Mar 14, 2002
|Kurt R. Linberg
|Apparatus and method for remote troubleshooting, maintenance and upgrade of implantable device systems
|Aug 2, 2001
|Feb 20, 2003
|Foster Thomas H.
|MRI-compatible implantable device
|Jan 17, 2002
|Jul 17, 2003
|Cardiac Pacemakers, Inc.
|Method and apparatus for recording fault history information
|Dec 9, 2002
|Sep 18, 2003
|Cardiac Pacemakers, Inc.
|Site reversion in cardiac rhythm management
|Oct 29, 2003
|Jul 15, 2004
|Sieracki Jeffrey M.
|Failsafe programming of implantable medical devices
|Jul 9, 1996
|Jan 15, 1997
|Pacesetter Inc.
|Safety optimization in microprocessor-controlled implantable devices
|Citing Patent
|Filing date
|Publication date
|May 5, 2005
|Jan 27, 2009
|Cardiac Pacemakers, Inc.
|System and method for recovering from transient faults in an implantable medical device
|May 9, 2008
|Jul 12, 2011
|Cardiac Pacemakers, Inc.
|Medical data transport over wireless life critical network
|Jan 26, 2009
|May 1, 2012
|Cardiac Pacemakers, Inc.
|System and method for recovering from transient faults in an implantable medical device
|Jan 27, 2010
|Nov 27, 2012
|Cardiac Pacemakers, Inc.
|Modular patient portable communicator for use in life critical network
|Jul 12, 2011
|Feb 12, 2013
|Cardiac Pacemakers, Inc.
|Medical data transport over wireless life critical network
|May 9, 2008
|Mar 12, 2013
|Cardiac Pacemakers, Inc.
|Wireless patient communicator employing security information management
|May 9, 2008
|Aug 20, 2013
|Cardiac Pacemakers, Inc.
|Wireless patient communicator for use in a life critical network
|Dec 22, 2010
|Sep 17, 2013
|Cardiac Pacemakers, Inc.
|Implantable device failsafe mode for MRI
|Apr 30, 2013
|Oct 29, 2013
|Boston Scientific Neuromodulation Corporation
|Method for controlled shutdown of an implantable medical device
|Feb 4, 2013
|Nov 19, 2013
|Cardiac Pacemakers, Inc.
|Medical data transport over wireless life critical network
|Nov 26, 2012
|Jan 28, 2014
|Cardiac Pacemakers, Inc.
|Modular patient communicator for use in life critical network
|Jan 27, 2010
|Aug 19, 2014
|Cardiac Pacemakers, Inc.
|Communications hub for use in life critical network
|Jul 31, 2013
|Aug 26, 2014
|Cardiac Pacemakers, Inc.
|Wireless patient communicator for use in a life critical network
|Nov 5, 2013
|Mar 3, 2015
|Cardiac Pacemakers, Inc.
|Medical data transport over wireless life critical network
|Dec 19, 2014
|Feb 23, 2016
|Cardiac Pacemakers, Inc.
|Medical data transport over wireless life critical network
|Jul 28, 2014
|Apr 12, 2016
|Cardiac Pacemakers, Inc.
|Communications hub for use in life critical network
|Dec 23, 2013
|Jan 24, 2017
|Cardiac Pacemakers, Inc.
|Modular communicator for use in life critical network
|Nov 1, 2010
|Mar 28, 2017
|Cardiac Pacemakers, Inc.
|Implantable device with post-MRI cardiac signal sensing adjustment
|Jan 30, 2014
|Aug 8, 2017
|Medtronic, Inc.
|Methods, implantable medical devices, and systems to continue implementing a special mode of operation after experiencing a device reset
|Jan 26, 2009
|May 21, 2009
|Cardiac Pacemakers, Inc.
|System and method for recovering from transient faults in an implantable medical device
|Nov 1, 2010
|Jun 30, 2011
|Stubbs Scott R
|Implantable device with post-mri cardiac signal sensing adjustment
|Dec 22, 2010
|Jun 30, 2011
|Stubbs Scott R
|Implantable device failsafe mode for mri
|U.S. Classification
|607/5, 607/27, 607/63
|International Classification
|Cooperative Classification
|European Classification
|Aug 8, 2005
Owner name: CARDIAC PACEMAKERS, INC., MINNESOTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:STUBBS, SCOTT;SOWDER, CONRAD L.;LINDER, WILLIAM J.;AND OTHERS;REEL/FRAME:016617/0432;SIGNING DATES FROM 20050628 TO 20050629
|Sep 19, 2011
|Fee payment
Year of fee payment: 4
|Oct 28, 2015
|Fee payment
Year of fee payment: 8


text:
Logo design: Exclamation marks, question marks ; Quadrilaterals with lines ; Blue
The European Union Trademark for iTis (Figurative) was filed on 12.04.2001 for goods and services in class(es) 9 and 41 at the European Union Intellectual Property Office (EUIPO). The current status of the trademark No. 002194025 iTis is 'registration expired'.


text:
Scissor Lifts
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CL Computers Group is a Pan-Asia information technology company, founded in 1979. Emerged from the engineering team of the Group, CL Technical Services Ltd is now the largest subsidiary of the Group. The Company provides service outsourcing, one-stop IT services, warranty and maintenance service, call centre and helpdesk service, installation and rollout service as well as recruitment & secondment service to many major corporations of diversified business natures. We aim to assist her clients the IT support functions which enabling them to increase their service capabilities and focus on developing the core business.
Please visit our company web-site via www.clts.com to explore more on our business and job opportunities.
IT Operator (Data Centre)
|Job level
|Work exp
|Minimum 1 Year
|Diploma / Certificate
|Hong Kong
|Employment type
|Full Time
|Information Technology
|Job function
Information Technology > Others
Information Technology > Engineering - Network
Information Technology > Help Desk / IT Support
|Published On
Job Duties:
- Assist in the operation and maintenance of the data centre systems
- Provide first line help service to terminal network users and perform associated help desk activities
- Fulfill logging and administrative reporting requirements
- Update and maintain inventory records of computer hardware, perform physical checks and maintain procedure manuals and documentation
- Monitor the availability of data centre systems, including network appliances, server equipments and environmental control systems
- Diploma or above in Computer Science or related subjects
- Minimum 1 year experience in IT
- Solid experience in operation of computer systems in Windows server and Networking support
- Willing to learn and good interpersonal skill
- 7 x 24 shift duty is required
If interested for the above position, please send detailed resume with current and expected salary as well as date of availability via firstname.lastname@example.com.
For more job opportunity, please visit our website: www.clts.com
Personal information is collected strictly for recruitment purpose only.
cpjobs.com - IT Operator (Data Centre) - is a part of Information Technology, Information Technology, in Hong Kong, placed by CL TECHNICAL SERVICES LIMITED


text:
By Frederick N. Dyer, Ph.D.
On November 7, 1855, Dr. David Humphreys Storer gave the Introductory Lecture that commenced the term of Harvard's Massachusetts Medical College where Storer was the Professor of Obstetrics and Medical Jurisprudence. The lecture was titled, 'Duties, Trials and Rewards of the Student of Midwifery,' but the last portion of the lecture also dealt with the sharp increase in induced abortion and with what David Humphreys Storer argued was a direct result, the increase in women's diseases. David Humphreys Storer's son, Dr. Horatio Robinson Storer, is credited as the founder of the 'physicians' crusade against abortion,' and Horatio repeatedly credited this lecture of his father as the stimulus for his crusade.
The Introductory Lecture was traditionally published as a pamphlet, and this was true for David Humphreys Storer's Lecture, as well. However, at the request of Dr. Henry J. Bigelow, Professor of Surgery at the Medical College, the abortion portion of the lecture was omitted from the pamphlet. Unnecessary abortion was a taboo and controversial topic in 1855, and one reason for suppression was that publication would lead to the condemnation of New England because induced abortion was prevalent. It also was believed that publication would reflect badly on the Medical College and cause fewer students to enroll, reducing the fees students paid directly to their professors.
Although the Boston Medical and Surgical Journal was typically controlled by the Medical College, its editors, William W. Morland and Francis Minot, bravely criticized the medical school faculty for suppressing the anti-abortion segment of the Introductory Address. One passage from their December 1855 editorial on the Introductory Lecture read:
'We referred to the fact that the fair proportions of this Address have been essentially diminished by an omission of certain portions. While we confess the truth of the adage that 'half a loaf is better than no bread,' we particularly dislike all processes which abstract the leaven from any compound. Deferring to the judgment of others, whose opinions we all delight to honor, Professor Storer has omitted the very paragraphs, which, in our judgment, should have been allowed to go forth as freely as they were spoken. To whom shall the community look for a verdict upon practices which disgrace our land and prevail to an extent that would hardly be credited, if not to physicians-and, chiefest among them, to medical teachers? For ourselves, we have no fear that the truth, as told by the writer of this Address, in reference to the crime of procuring abortion and the scarcely less heinous offence of preventing impregnation, would do aught but good in this, or in any, city. It would appear that sheer ignorance, in many honest people, is the spring of much of the horrible intra-uterine murder which exists among us; why not, then, enlighten this ignorance? It would be far more effectually done by some bold and manly appeal like that to which we allude, than by the private and scattered influence of honorable practitioners alone. In this case we will guarantee that vice would be all the more 'hated' the more it was revealed, and would be neither 'pitied' nor 'embraced.' The alarming extent of these evil practices is admitted; why attempt to conceal them any longer? Will not the mischief bye and bye be all the more deadly for delaying exposure and attempting relief?'
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The suppressed portion of the Lecture was finally published seventeen years later in the sixth volume of the first medical journal devoted to gynecology. This was the Journal of the Gynecological Society of Boston which was started and edited by Horatio Robinson Storer. Horatio not only was responsible for the publication of the abortion portion of his father's Introductory Lecture, he probably made input to it when it was being composed in 1855. A year earlier, Horatio was providing a great deal of material to David Humphreys Storer to assist him in his new Professorship which began in November 1854. At that time, Horatio was in Edinburgh, Scotland studying with Great Britain's most famous obstetrician and gynecologist, Dr. (later Sir) James Young Simpson. Horatio was sending his father notes and copies of diagrams from Simpson's lectures at Edinburgh University. Horatio returned to Boston in June 1855 and it is probable that Horatio's assistance to his father continued, including input to the upcoming major Introductory Lecture. It is even possible that the anti-abortion portion was Horatio's idea, even his composition. If Horatio were primarily responsible for the anti-abortion portion of his father's lecture, it could account for why David Humphreys Storer allowed it to be suppressed when it was published a few weeks after delivery. Horatio later referred to this as one of the few times that his pugnacious father was to 'show the white feather.' It also could account for why David Humphreys Storer did not persist in anti-abortion efforts after the Introductory Lecture. Horatio was to actively commence his campaign against abortion in early 1857, a little more than one year following David Humphreys Storer's Introductory Lecture.
Whether original with David Humphreys Storer and the inspiration for Horatio's 'physicians' crusade' (as Horatio repeatedly claimed in later writing), or whether more-or-less authored by Horatio, the anti-abortion segment of this Introductory Lecture is a landmark event in the successful 'physicians' campaign against abortion.' Within a few decades this campaign against abortion led to passage of laws in almost every state and territory protecting the unborn from conception. The effect was to reduce abortion among married Protestant women (abortion was rare among Catholic women). Given the exponential increase in subsequent generations of descendents of the additional 'Storer survivors of pregnancy,' it is probable that a majority of Protestant Americans can thank the 'physicians' campaign,' and its Father-and-Son founders, for one or more of their ancestors.
The following is the abortion portion of David Humphreys' Introductory Lecture printed as, 'Two Frequent Causes of Uterine Disease,' in the March 1872 issue of Horatio's Journal of the Gynecological Society of Boston:
'I should feel that I had been guilty of an unpardonable neglect were I to omit to glance at a subject the importance of which, each succeeding year, has been more forcibly impressed upon my mind. I had hoped that, long ere this, some one of the strong men of the profession,-strong in the affections of the community, strong in the confidence of his brethren,-would have spoken, trumpet-tongued, against an existing, and universally acknowledged evil. I have waited in vain. The lecturer is silent, the press is silent, and the enormity, unrebuked, stalks at midday throughout the length and breadth of the land. It is time that this silence should be broken. It is time that men should speak. It is no presumption in the humblest individual to point out a much-needed reformation, however others may doubt the expediency of his course, if he thinks by thus doing he shall awaken in any mind the slightest attention to the subject; particularly if he sincerely believes that anything which can be found to be wrong can be rectified, that anything which ought to be done can be done sooner or later, whether it affects an individual, a community, or a race.
'Within the past few years one of the most striking changes which has been observed in the phases of disease has occurred in the affections peculiar to the female. All physicians are familiar with the fact, not only that the different seasons produce peculiar derangements, but also that those derangements differ in a greater or less degree as the natural causes vary, and that the further removed from a state of health any individual may be, the more liable that individual is to suffer from periodical influences; that at these different periods one set of organs suffers disproportionately to others; that in winter and spring the thoracic organs are most frequently deranged; that in summer and autumn the digestive apparatus is the seat of disease; and that each organ of the body is most affected when any of its important functions are unnaturally excited, either by being called into action too frequently or by that action being too long continued. These are well-established laws, intelligible to all; but when the diseases of an important organ are rapidly becoming more and more frequently observed, pervading every class of society, noticeable among those surrounded by the luxuries of wealth as well as in the beggar at our door, affecting those who have heretofore enjoyed the most perfect health as well as those whose constitutions had ever been infirm,-and no apparent cause exists for these sudden and alarming inroads,-the question naturally arises, how can this be explained? Why is it that the females of the present day suffer so much more from uterine diseases than those of the previous generations? If an answer to this inquiry does not instantaneously rise to the lips of every medical man, however limited may be his experience, his powers of observation must be exceedingly defective. The same natural laws exist which have ever existed; by them the same derangements are produced,-these are unavoidable; and that the same amount of disease should be observed in a given number of individuals, as was formerly noticed, ought to be expected-no more. Assuming this proposition to be self-evident, unnatural causes are exerting a fearful influence. An immense amount of disease exists which is unnecessary, which might be prevented. Various reasons have been assigned by different authorities for this alarming increase, each of which, while it explains a few isolated cases, leaves by far the larger number unaccounted for; from which it would appear that there is a great unwillingness, on the part of the profession, to dwell upon, or even to refer to, one of the principal causes of this class of derangements. But why should this be? Why should we shrink from the performance of any duty, however unpleasant or ungrateful to our feelings it may be, if we think that it is demanded of us? If we know it is clearly a duty, it should be performed. We may, it is too true, be misunderstood; we may be misinterpreted. But this should not prevent us from the full, free expression of our convictions. A true man fears, can fear, nothing.
'The most inattentive observer must be surprised when he remarks the comparative smallness of the families of the present day. Formerly, it was by no means an uncommon circumstance for parents to estimate their wealth by the number of their children; to be willing to suffer any privation, to endure any hardship, in order to rear and educate a numerous progeny. Now, a large family of children is a rare spectacle, and if any can be pointed at consisting of what was once a not unfrequent number, the principals are considered by many as proper subjects to occupy apartments in an insane hospital. Fashion, which controls everything, is the regulator here. The absurd, the preposterous desire so universally cherished among the different circles of society, each to appear as nearly equal in externals to the others as is possible to be done; the extravagance necessary to be indulged by an inferior grade in order to imitate the modes of living of a higher one, are the great remote causes of existing opinions, of existing acts.
'The fashionable young bride, accustomed to adulation, is reluctant to forego at once the excitement of society; she is too often unwilling to feel that she 'has taken the veil'-that she has consecrated her affections to one being-and that his approval and his devotion should keep her heart ever full to overflowing; but wishing still to enjoy the immunities of unmarried life-to be as free, as unshackled as ever-she will not endure the seclusion and deprivations necessarily connected with the pregnant condition, but resorts to means, readily procurable, to destroy the life within her, apparently unconscious that she is not only committing a crime in the sight of the law, but also a sin in the sight of her Maker.
'The mother, too, while she acknowledges the happiness she enjoys in the possession of her children, and looks upon them as the most valuable blessings she can possess, not unfrequently is willing, anxious, to pursue a similar course to produce a similar result. Unfortunate, perhaps pecuniarily unable to have her family provided for in the manner in which they have been accustomed to live, her pride will not allow her to see those already dependent upon her, appearing less 'respectable,' to use a word thus applied in common parlance, as she thinks must be a necessary consequence upon the introduction of every addition to the circle; or learning from others that woman was born for higher and nobler purposes than the propagation of her species, that it is unreasonable that so large a portion of her life should be yielded to its drudgery, or, imagining, from some misinterpreted remark her physician may have carelessly made, that it would really be dangerous for her again to be called upon to give birth to a mature child, and even that it would certainly cause her death, she persuades herself into the belief that it is not morally wrong, that it is really her duty, to destroy her unborn child.
'I do not presume to stand here as a moralist. I would attempt only to point out a few of the duties obligatory upon the physician, as such. I should, however, be faithless to the noble profession which occupies my every thought; I should be unworthy the confidence or esteem of my brethren did I refrain, while referring to this subject, to enter my solemn protest against the existing vice; to express, emphatically, the universal sentiment of horror and indignation entertained among the upright men of the profession in this community. Of horror, that the female can so completely unsex herself, that her sensibilities can be so entirely blunted, that any conceivable circumstances can compel her to welcome such degradation! Of indignation, that men can be found so regardless of their own characters, so perfectly indifferent respecting those of their cotemporaries [sic], as to lend their services in such unholy transactions.
'To save the life of the mother we may be called upon to destroy the foetus in utero, but here alone can it be justifiable. The generally prevailing opinion that although it may be wrong to procure an abortion after the child has presented unmistakable signs of life, it is excusable previous to that period, is unintelligible to the conscientious physician. The moment an embryo enters the uterus a microscopic speck, it is the germ of a human being, and it is as morally wrong to endeavor to destroy that germ as to be guilty of the crime of infanticide. But there are many who will pretend not to be convinced on this point, whatever arguments may be adduced; they choose to think for themselves, and of the morality of the subject they feel they can judge for themselves. Upon such, should be urged the unavoidable injury to their physical condition, the serious inroads upon their health which inevitably follow, if they do not always accompany, these forbidden procedures; they should be entreated to hesitate in their career before their systems are undermined; they should be made to comprehend that their well-being depends upon a proper observance of certain natural laws, which are readily understood, and which are as exacting as they are intelligible; that each organ has a law of its own, if I may be allowed thus to speak, controlling the performance of its functions,-a law which cannot be broken with impunity. The Lawgiver is inexorable.
'A law of the organ of which we have been speaking, requires that a certain specified time shall be occupied in perfecting its most important work; this period is fixed, uniform, universal. In a state of perfect health deviation may be said to be unknown. When any irregularity is noticed it may be traced almost invariably to some unnatural cause. When the entire limit is reached, when the foetus has become perfectly developed, the system of the mother, gradually being prepared for the approaching event, is able to bear the momentous change unimpaired. The unfortunate cases are exceedingly rare; they are the exceptions to the rule. When, however, from any accidental cause the organ is called upon to perform a duty for which it is unprepared, a greater or less degree of injury must be produced; and when any rude attempt is deliberately made to effect this object, infinitely greater is the probability of there being increased detriment and irretrievable harm; for in addition to the circumstance I have referred to, of the unpreparedness of the organ for the attempted change, are the unavoidable local lesions; and that cause, even more important than these (say what men may to the contrary), the deep, heart-felt depression which must weigh upon the spirit of the evil-doer. Hundreds of lives are unquestionably yearly lost by the innumerable methods which are resorted to to produce premature delivery, and thousands of females who escape the grave may date, from these operations, the origin of many exhausting, painful, incurable diseases. The laws of the land, with all their penalties annexed, can do but little to abolish the crime. Compulsory measures may meet individual cases, and cause a temporary respite in a limited circle, but in order to produce an effect co-extensive with the transgression, that course should be pursued, the lenity of which proves its sincerity. Reason should be dealt with; moral suasion should be used, and no one can exert a greater influence than the physician; for no one is compelled like him to witness the misery, to see the distress which is acknowledged by the sufferer to have been thus produced, to hear the disclosures as they reluctantly fall from the lips of the dying penitent. We can do much-we can do all. If our profession will feel and act as one man; if they cannot all regard the subject in the same light as I have, as respects its morality, but will look at it merely as a cause of physical suffering to the mother; if they will upon all proper occasions freely express their convictions of its injurious effects, of its present danger, of its detrimental consequences,-a triumphant result must follow. Years, a half century perhaps, may elapse before such a reaction shall have been produced, but, slow although it would be, it would be certain. Like all other crimes it might be occasionally perpetrated. To preserve a previously unsullied character, to prevent a deep and damning stain upon a family's reputation, it would be clandestinely resorted to, but the virtuous mother would no longer be found sacrificing her offspring.
'In this connection I would for a moment refer to a subject which seems entirely to have escaped the notice of the medical writer, and yet it is one which must often force itself upon the mind of the physician, not merely as a prominent ground for variations in tables relating to population, but also as being a no inconsiderable cause of uterine disease. I allude to the means so extensively employed to prevent impregnation. Although there exists a large number of individuals whose conscientious scruples would prevent them from deliberately producing an abortion, very many of these consider that it is perfectly right to use all practicable means to avoid conception. To such an extent is this feeling carried, that it is a very common occurrence for the physician to be told that children need not be conceived, and by such persons they are not conceived; frequently to these individuals no children are ever born. This procedure is continually gaining strength, and is to a great extent based upon the same causes as those which prompt others to free themselves of the product of conception. The question of its morality I leave for others to argue, and only cursorily look at it as a cause of disease. The physiologist well knows that the functions of no organ can be interfered with without suffering being induced; that as an organ may be destroyed by excessive action, so may it become atrophied by disuse; that it requires a natural incentive, a peculiar, an appropriate stimulus to preserve its healthful condition; that a function may lie dormant for years, for life, may never be called into action, and yet the integrity of the organ may not apparently be affected,-but should it once be excited; the application of any cause which shall interfere with its perfect performance must be detrimental; and that if, when the system is perfectly developed, and the union of the sexes exists, the uterus is not allowed to be excited by the stimulus provided for that purpose, and for that purpose only, it cannot but suffer. An unusual determination of blood to the organ uniformly takes place at the moment referred to; if the sexual desire is gratified, the function naturally performed, this local plethora is relieved, and the organ is left sound. If, however, the operations of nature are interrupted, different results must follow. The interior of the organ, debarred from its appropriate excitement, executes imperfectly its function, the congestion is not readily removed, and, increased by every repetition of the unnatural intercourse, gradually passes into a state of confirmed hypertrophy. Without sufficient data to warrant me in stating positively the fact, I would, nevertheless, venture the belief that numberless cases of induration, and finally of organic disease, must be the inevitable consequences.
'I need not state that I have been induced to touch upon these most ungrateful topics from a sense of their vast importance; from a feeling that they have not received the attention they deserve from the profession at large; from the hope that even my feeble voice might not be raised entirely in vain; conscious that should any of my brethren fail to entertain similar views, they will appreciate my motives, and at least respect the expression of my opinions.'
AFTERWORD: Recent research showing that premature termination of pregnancy increases women's risk of breast cancer, shows the perspicacity and wisdom of David Humphreys Storer and Horatio Robinson Storer in the middle of the nineteenth century when they emphasized the health risks of induced abortion, even when the abortion itself was survived without incident.
To respond to this article, contact the author: Frederick N. Dyer, Ph.D.


text:
I'm working on a few shorter projects while I make the rounds with my query letter. One is a short story that I'm getting closer and closer to happy with, it's not a direct prequel for the book as much as an earlier adventure featuring the same characters. I'm also poking at a story idea, one that will probably be closer to novella length, that gives a science fiction update to a historical subject I'm slightly obsessed with.
Part of me is a bit surprised I'm not just huddled up and obsessing over my queries, but it feels way better to keep working.
about Tunes for Tuesday
Tunes for Tuesday: Revolution Year Zero
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Tuesday, January 21, 2014
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libview is VMware's Incredibly Exciting Widgets, a useful collection of GTK+ widgets used within VMware products, free for everybody's use.
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