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Introducing one or more stimulating drugs to the brain and/or applying electrical stimulation to the brain is used to treat movement disorders. At least one implantable system control unit (SCU) produces electrical pulses delivered via electrodes implanted in the brain and/or drug infusion pulses delivered via a catheter implanted in the brain. The stimulation is delivered to targeted brain structures to adjust the activity of those structures. In some embodiments, one or more sensed conditions are used to adjust stimulation parameters.
1. A method of treating a patient with a movement disorder, comprising:
implanting at least one system control unit entirely within the brain of the patient, wherein the at least one unit controls the delivery of at least one stimulus to at least one area of the brain affecting a movement disorder;
applying the at least one stimulus to the at least one area of the brain in order to at least in part alleviate the movement disorder of the patient being treated; and
applying the at least one stimulus to increase neural activity of the relatively large diameter fibers of the nucleus tractus solitarius (NTS);
wherein the at least one system control unit is a microstimulator implanted entirely within the brain.
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8. A method of treating a patient with a movement disorder, comprising:
providing at least one system control unit that generates stimulating pulses in accordance with prescribed parameters, which stimulating pulses are at least one of infusion pulses and electrical stimulation pulses;
providing, connected to the at least one system control unit, at least one catheter with at least one discharge portion or at least one lead with at least one electrode;
implanting at least one of the at least one discharge portion and the at least one electrode adjacent to at least one brain structure affecting a movement disorder;
implanting at least one system control unit in the patient, wherein the at least one unit controls the delivery of the stimulating pulses applied to the at least one brain structure to be stimulated;
tunneling at least one of the at least one catheter and the at least one lead between the at least one brain structure and the system control unit location;
applying the stimulating pulses to increase activity of the at least one brain structure in order to at least in part alleviate the movement disorder of the patient being treated; and
wherein the at least one brain structure is at least one of the nucleus tractus solitarius (NTS), pallido-subthalamic tracts, and putamen to GPi fibers.
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14. A method of treating a patient with a movement disorder, comprising:
providing at least one system control unit that generates stimulating pulses in accordance with prescribed parameters, which stimulating pulses are at least one of infusion pulses and electrical stimulation pulses;
providing, connected to the at least one system control unit, at least one catheter with at least one discharge portion or at least one lead with at least one electrode;
implanting at least one of the at least one discharge portion and the at least one electrode adjacent to at least one brain structure affecting a movement disorder;
implanting at least one system control unit in the patient, wherein the at least one unit controls the delivery of the stimulating pulses applied to the at least one brain structure to be stimulated;
tunneling at least one of the at least one catheter and the at least one lead between the at least one brain structure and the system control unit location;
applying the stimulating pulses to decrease activity of the at least one brain structure in order to at least in part alleviate the movement disorder of the patient being treated; and
wherein the at least one brain structure is at least one of the pallido-thalamic axons, putamen to GPe fibers, and subthalamo-pallidal fibers.
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The present application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/383,316, filed May 24, 2002, which application is incorporated herein by reference in its entirety.
The present invention generally relates to implantable drug delivery and electrical stimulation systems and methods, and more particularly relates to utilizing one or more implantable devices to deliver electrical stimulation and/or one or more stimulating drugs to certain areas of the brain as a treatment for movement disorders.
Movement disorders are neurologic syndromes characterized by either an excess or a paucity of movement. These disorders affect approximately two million Americans, including over one million suffering from benign essential tremor, and half a million suffering from Parkinson's Disease. A substantial percentage of those afflicted with movement disorders experience a significant decrease in quality of life, suffering such problems as incapacitating tremor, limited mobility, bradykinesia (difficulty consciously initiating movement), dysarthria (difficulty with speech), and consequent social isolation. The etiology of many movement disorders, e.g., benign essential tremor, is poorly understood. For other movement disorders, e.g., Parkinson's disease, the mechanism of the disorder and brain cells affected have been identified, but even with optimal care the disease may not be reversed and may even continue to progress.
Parkinson's Disease is caused by a gradual loss of dopaminergic (i.e., dopamine-secreting) neurons in the substantia nigra. Consequently, levels of dopamine decrease in the striatum (i.e., the putamen and the caudate nucleus). Although dopamine has both excitatory and inhibitory effects on the striatum, the predominant effect of the loss of dopamine is decreased inhibition (by GABA) of the internal segment of the globus pallidus. This leads to increased GABA output from the internal segment of the globus pallidus, which inhibits the ventrolateral thalamus. This leads in turn to decreased inhibition of (and ultimately decreased control over) the motor cortex. The subthalamic nucleus appears to increase its activity in Parkinson's Disease as well, and this is believed to contribute to the symptoms of the disease.
Essential Tremor (ET), a.k.a., Benign Essential Tremor, is the most common movement disorder. It is a syndrome characterized by a slowly progressive postural and/or kinetic tremor, usually affecting both upper extremities. The prevalence of ET in the US is estimated at 0.3–5.6% of the general population. A 45-year study of ET in Rochester, Minn. reported an age- and gender-adjusted prevalence of 305.6 per 100,000 and an incidence of incidence of 23.7 per 100,000.
ET affects both sexes equally. The prevalence of ET increases with age. There are bimodal peaks of onset—one in late adolescence to early adulthood and a second peak in older adulthood. The mean age at presentation is 35–45 years. ET usually presents by 65 years of age and virtually always by 70 years. Tremor amplitude slowly increases over time. Tremor frequency decreases with increasing age. An 8–12 Hz tremor is seen in young adults and a 6–8 Hz tremor is seen in the elderly. Although ET is progressive, no association has been found between age of onset and severity of disability.
Mortality rates are not increased in ET. However, disability from ET is common. Significant changes in livelihood and socializing are reported by 85% of individuals with ET, and 15% report being seriously disabled due to ET. Decreased quality of life results from both loss of function and embarrassment. In a study of hereditary ET, 60% did not seek employment; 25% changed jobs or took early retirement; 65% did not dine out; 30% did not attend parties, shop alone, partake of a favorite hobby or sport, or use public transportation; and 20% stopped driving.
A number of US patents have addressed using electrical and/or drug stimulation to increase and/or decrease excitement of various brain structures to treat movement disorders. See, for instance, U.S. Pat. Nos. 6,094,598; 5,833,709; 5,716,377; 5,832,932; 5,711,316; 5,792,186; and 6,227,203. Portions of these seven patents are identical, and they teach both increasing excitement/activity (or decreasing inhibition) and decreasing excitement/activity (or increasing inhibition) of the ventrolateral (VL) thalamus, the globus pallidus interna (GPi), the substantia nigra reticulata (SNr), the subthalamic nucleus (STN), the globus pallidus externa (GPe), the neostriatum, and the striatum. Also taught is increasing excitement of the motor cortex, stiatopallidal fiber pathway, GPe to STN fiber pathway, pallido-thalamic axons, putamen to GPe fibers, and subthalamo-pallidal tracts. U.S. Pat. No. 6,356,784 teaches increasing the activity of the pendunolopontine nucleus (PPN) to treat movement disorders such as Parkinson's Disease, while decreasing PPN activity is used for treating other conditions such as schizophrenia.
While these various treatment locations, methods, and systems exist, the inventors believe that enhanced systems, alternative locations, and modified methods will lead to improved treatment of movement disorders.
The invention disclosed and claimed herein provides systems and methods for introducing one or more stimulating drugs and/or applying electrical stimulation to one or more areas of the brain for treating or preventing movement disorders, as well as the symptoms and pathological consequences thereof. Treatment locations include the nucleus tractus solitarius (NTS), pallidosubthalamic tracts, and putamen to GPi fibers. In addition, treatment by decreasing activity of pallido-thalamic axons, putamen to GPe fibers, and/or subthalamo-pallidal fibers is taught.
The treatment provided by the invention may be carried out by one or more system control units (SCUs) that apply electrical stimulation and/or one or more stimulating drugs to one or more predetermined stimulation sites in the brain. In some forms of an SCU, one or more electrodes are surgically implanted to provide electrical stimulation from an implantable signal/pulse generator (IPG) and/or one or more infusion outlets and/or catheters are surgically implanted to infuse drug(s) from an implantable pump. In other forms of an SCU, a miniature implantable neurostimulator (a.k.a., a microstimulator), such as a Bionic Neuron (also referred to as a BION� microstimulator), is implanted. The systems of the invention may also include one or more sensors for sensing symptoms or conditions that may indicate a needed treatment.
In some configurations, the SCU is implanted in a surgically-created shallow depression or opening in the skull, such as in the temporal, parietal, or frontal bone. In some such configurations, one or more electrode leads and/or catheters attached to the SCU run subcutaneously to an opening in the skull and pass through the opening into or onto the brain parenchyma and surrounding tissue. The SCUs programmed to produce electrical stimulation may provide either monopolar electrical stimulation, e.g., using the SCU case as an indifferent electrode, or bipolar electrical stimulation, e.g., using one of the electrodes of an electrode array as an indifferent electrode.
The SCU used with the present invention possesses one or more of the following properties, among other properties:
An SCU may operate independently, or in a coordinated manner with other implanted SCUs, other implanted devices, and/or with devices external to a patient's body. For instance, an SCU may incorporate means for sensing a patient's condition. Sensed information may be used to control the electrical and/or drug stimulation parameters of the SCU in a closed loop manner. The sensing and stimulating means may be incorporated into a single SCU, or a sensing means may communicate sensed information to at least one SCU with stimulating means.
The above and other aspects of the present invention will be more apparent from the following more particular description thereof, presented in conjunction with the following drawings wherein:
Corresponding reference characters indicate corresponding components throughout the several views of the drawings.
The following description is of the best mode presently contemplated for carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles of the invention. The scope of the invention should be determined with reference to the claims.
The pathophysiology of essential tremor (ET) is essentially unknown. There are no known pathological findings associated with ET. However, the following has been hypothesized: 1) ET is the result of an abnormally functioning central oscillator, which is located in Guillain Mollaret triangle near the brainstem, and involves the inferior olivary nucleus. 2) There is probable involvement of cerebellar-brainstem-thalamic-cortical circuits.
When harmaline, a Monoamine Oxidase (MAO) inhibitor, is administered to primates with lesions of ventromedial tegmental tract or lateral cerebellum, an ET-like tremor is produced. In these animals, inferior olivary nucleus neurons file synchronously at the tremor frequency. C-2-deoxyglucose PET studies demonstrate hypermetabolism in the inferior olivary nuclei of rats and cats with harmaline-induced tremor. Stimulation of the vagus nerve helped resolve tremor in rats with harmaline-induced tremor.
In patients with ET, [18F]-fluorodeoxyglucose PET studies identified increased glucose consumption in the medulla. [15O]-H2O PET studies demonstrate an increase in medullary regional cerebral blood flow (CBF) in subjects with ET, only after the administration of ethanol, and showed bilateral overactivity of cerebellar circuitry.
The nucleus tractus solitarius (NTS) sends fibers bilaterally to the reticular formation and hypothalamus that are important in the reflex control of cardiovascular, respiratory, and gastrointestinal functions. The NTS also provides input to the dorsal motor nucleus of the vagus that enables the parasympathetic fibers of the vagus nerve to control these reflex responses. The NTS runs the entire length of the medulla oblongata, and the NTS receives somatic sensory input from all cranial nerves, with much of its input coming from the vagus nerve. Since the NTS receives much of its input from the vagus nerve, and since electrical stimulation of the vagus nerve has been demonstrated to be effective in the treatment of an animal model of essential tremor (i.e., for harmaline-induced tremor), then electrical stimulation of the NTS may be effective in the treatment of movement disorders such as essential tremor.
Patients suffering from tremor and other symptoms may undergo surgery to lesion a part of the brain (e.g., the ventral intermediate (Vim) nucleus of the thalamus the internal segment of the globus pallidus (GPi), or the subthalamic nucleus (STN)), which may afford some relief. However, a lesion is irreversible, and may lead to side effects such as dysarthria or cognitive disturbances. Additionally, lesions generally yield effects on only one side of the body (the contra-lateral side), and bilateral lesions are significantly more likely to produce side effects. Other surgical procedures, such as fetal tissue transplants, are costly and unproven.
Other areas of the brain exhibit decreased neural activity in some patients with movement disorders. For instance, some Parkinson's disease patients demonstrate decreased neural activity in parts of the caudate and putamen, the external segment of the globus pallidus (GPe), substantia nigra, and/or parts of the thalamus.
An article published online by Gill, et al. describes delivery of glial cell line-derived neurotrophic factor (GDNF) directly into the putamen of five Parkinson patents in a phase 1 safety trial. [See Gill, et al. "Direct brain infusion of glial cell line-derived neurotrophic factor In Parkinson disease." Nature Medicine epub ahead of print: 2003 Mar. 31.] Baseline positron emission tomography (PET) scans indicated that the posterior segment of the putamen in all patients had low [18F]dopa uptake. After 18 months, PET scans showed a 28% increase in putamen dopamine storage, in contrast to the predicted decline of up to 20% over this period for Parkinson disease patients. The authors note, however, that the exact mechanism by which GDNF works has yet to be established.
Levy, et al., 2001, present data based on microelectrode recordings from the GPi and the STN during administration of apomorphine, a fast-acting non-selective D1-dopamine and D2-dopamine receptor agonist. [See Levy, et al. "Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease." Journal of Neurophysiology 2001 July;86(1):249–60.] Apomorphine has previously been demonstrated to ameliorate symptoms of Parkinson's disease. In the study, the authors administered doses of apomorphine sufficient to produce relief of Parkinson symptoms, but not sufficient to induce common side effects such as dyskinetic movements. Following baseline microelectrode recordings, apomorphine was administered. The spontaneous discharge of neurons encountered before, during, and after the effect of apomorphine had waned was also sampled.
A reduction in Parkinson symptoms (e.g., limb tremor) was observed in patients when apomorphine reached therapeutic levels. Apomorphine significantly decreased the overall firing rates of GPi neurons, but there was no change in the overall firing rate of neurons in the STN. Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (i.e., tremor cells) was found to be significantly reduced from 19% to 6% in the STN and from 14% to 0% in the GPi following apomorphine administration. Apomorphine also decreased the firing rate of STN tremor cells. As the effects of apomorphine waned, the overall firing rates of GPi neurons increased. In contrast to the findings above, Stefani, et al., 2002, found that administration of apomorphine did indeed reduce the firing rates of all STN cells in patients with Parkinson's disease, concurrent with a reduction in the clinical symptoms of Parkinson's disease. [See Sefani, et al., "Subdyskinetic apomorphine responses in globus pallidus and subthalamus of parkinsonian patients: lack of clear evidence for the 'indirect pathway'." Clinical Neurophysiology 2002 January;113(1):91–100.] These results suggest that the discharge frequency of the GPi and possibly of the STN is a measurable quantity that correlates with the clinical efficacy of medication.
While not previously observed, this GPi discharge frequency phenomenon may occur during deep brain stimulation (DBS) as well. The subthalamic nucleus (STN) is believed to demonstrate increased neurotransmitter release in Parkinson's disease, and it responds to deep brain stimulation. Thus, it may demonstrate a similar discharge frequency phenomenon as the GPi. Since the Vim nucleus of the thalamus also responds to deep brain stimulation, it may also demonstrate a similar discharge frequency phenomenon.
In addition, high frequency chronic electrical stimulation (i.e., frequencies above 100 Hz) of certain areas of the brain has been demonstrated to be as efficacious as producing a lesion in any one of those areas. In contrast to ablation surgery, chronic electrical stimulation is reversible. Additionally, stimulation parameters may be adjusted to minimize side effects while maintaining efficacy; such "fine tuning" is unavailable when producing a lesion.
An implantable chronic stimulation device for DBS is available and similar systems are under development. DBS has proven to be effective for treating some patients with movement disorders; however, the current procedure is highly invasive, and the initial surgery for placement of the available system requires essentially an entire day. These systems require the power source and stimulation electronics to be implanted far from the electrodes, generally in the chest or elsewhere in the trunk of the body. These bulky systems therefore require extensive invasive surgery for implantation, and breakage of the long leads is highly likely. In addition, current DBS systems for movement disorders use no feedback for regulation of stimulation.
For instance, the system manufactured by Medtronic, Inc. of Minneapolis, Minn. has several problems that make it an unacceptable option for some patients. It requires a significant surgical procedure for implantation, as the implantable pulse generator (IPG), a major component of the system containing the stimulation electronics and power source, is implanted in the thorax and connected via a subcutaneous tunnel to an electrode through the chest, neck and head into the brain. Additionally, the IPG is bulky, which may produce an unsightly bulge at the implant site (e.g., the chest), especially for thin patients.
The present invention provides electrical and/or drug stimulation to one or more of the above mentioned areas (and in particular, the NTS 100, pallidosubthalamic tracts 106, the pallido-thalamic axons 107, the putamen to GPe fibers 108), subthalamo-pallidal fibers (not shown), putamen to GPi fibers (not shown), and/or the cerebellum (not shown) as a treatment for movement disorders. Thus, via mechanisms described in more detail herein, the present invention provides electrical stimulation and/or stimulating drugs to these areas to adjust the level of neural activity in these areas, and thereby treat or prevent motor disorders.
For instance, for patients who demonstrate increased neural activity of Vim 104, pallido-thalamic axons 107, putamen to GPe fibers 108, GPi 110, STN 120, subthalamo-pallidal fibers, and/or the cerebellum, inhibitory stimulation may be applied to one or more of these areas. On the other hand, for patients who exhibit decreased neural activity of NTS 100, substantia nigra pars reticulata 102, pallido-subthalamic tracts 106, GPe 112, putamen 116, and/or putamen to GPi fibers, excitatory stimulation may be applied to one or more of these areas. As used herein, stimulate, stimulation, and stimulating refer to infusion of a stimulating drug(s) and/or supplying electrical current pulses. As such, infusion parameters and/or electrical current parameters are sometimes referred to herein as simply stimulation parameters, which parameters may include amplitude, volume, pulse width, infusion rate, and the like. Similarly, stimulation pulses may be pulses of electrical energy and/or pulses of drugs infused by various means and rates of infusion, such as intermittent infusion, infusion at a constant rate, and bolus infusion.
Herein, stimulating drugs comprise medications and other pharmaceutical compounds, anesthetic agents, synthetic or natural hormones, neurotransmitters, interleukins, cytokines, lymphokines, chemokines, growth factors (e.g., glial cell line-derived neurotrophic factor (GDNF), brain cell line-derived neurotrophic factor (BDNF)), and other intracellular and intercellular chemical signals and messengers, and the like. Certain neurotransmitters, hormones, and other drugs are excitatory for some tissues, yet are inhibitory to other tissues. Therefore, where, herein, a drug is referred to as an "excitatory" drug, this means that the drug is acting in an excitatory manner, although it may act in an inhibitory manner in other circumstances and/or locations. Similarly, where an "inhibitory" drug is mentioned, this drug is acting in an inhibitory manner, although in other circumstances and/or locations, it may be an "excitatory" drug. In addition, stimulation of an area herein may include stimulation of cell bodies and axons in the area.
A number of drugs have demonstrated efficacy in the treatment of Parkinson's disease. Primary among these is levodopa. Levodopa is effective for Parkinson's disease only in the brain; in the periphery it can cause side effects. Levodopa is typically administered with a dopa decarboxylase inhibitor in order to prevent systemic side effects.
Patent Cooperation Treaty publication WO 00/38669(A2) teaches administration of naloxone to the substantia nigra for the prevention of neural degeneration. (Naloxone is an opiate antagonist.) Since degeneration of the substantia nigra is the primary pathology of Parkinson's disease, chronic administration of naloxone to the substantia nigra may be therapeutic.
In some alternatives, stimulation is provided by at least one system control unit (SCU) that is an implantable signal generator connected to an electrode(s) and/or an implantable pump connected to a catheter(s). These systems deliver electrical stimulation and/or one or more stimulating drugs to specific areas in the brain. One or more electrodes are surgically implanted in the brain to provide electrical stimulation, and/or one or more catheters are implanted in the brain to infuse the stimulating drug(s).
In various alternatives, stimulation is provided by one or more SCUs that are small, implantable stimulators, referred to herein as microstimulators. The microstimulators of the present invention may be similar to or of the type referred to as BION� devices (see
As shown in
Certain configurations of implantable microstimulator SCU 160 are sufficiently small to permit placement in or adjacent to the structures to be stimulated. For instance, in these configurations, capsule 152 may have a diameter of about 4–5 mm, or only about 3 mm, or even less than about 3 mm. In these configurations, capsule length may be about 25–35 mm, or only about 20–25 mm, or even less than about 20 mm. The shape of the microstimulator may be determined by the structure of the desired target, the surrounding area, and the method of implantation. A thin, elongated cylinder with electrodes at the ends, as shown in
Microstimulator SCU 160, when certain configurations are used, may be implanted with a surgical tool such as a tool specially designed for the purpose, or with a hypodermic needle, or the like. Alternatively, microstimulator SCU 160 may be implanted via conventional surgical methods (e.g., via a small incision), or may be placed using endoscopic or laparoscopic techniques. A more complicated surgical procedure may be required for sufficient access to, for instance, the NTS 100, or for fixing the microstimulator in place.
Deep brain stimulation (DBS) electrodes are typically targeted and implanted with the guidance of a stereotactic frame. The diameter of the test or stimulation DBS electrodes is typically 1.5 mm or less. Microstimulator SCU 160 may be implanted with the aid of a stereotactic frame/tools via a minimal surgical procedure (e.g., through a small burr hole) adjacent to or in the sites mentioned above for the treatment of movement disorders, e.g., the NTS, among other locations. As mentioned earlier, microstimulator SCU 160 may have a diameter of about 3 mm or less, allowing it to fit through a conventional burr hole in the skull. Instead of or in addition to stereotactic techniques, microstimulator SCU 160 may be implanted with the aid of other techniques, e.g., CT or ultrasound image guidance. However, even with such techniques, microstimulator SCU 160 itself requires only a relatively small hole in the skull for implantation, i.e., a hole as large as the diameter of the implanted device.
The external surfaces of microstimulator SCU 160 may advantageously be composed of biocompatible materials. Capsule 152 may be made of, for instance, glass, ceramic, or other material that provides a hermetic package that will exclude water vapor but permit passage of electromagnetic fields used to transmit data and/or power. Electrodes 172 and 172′ may be made of a noble or refractory metal or compound, such as platinum, iridium, tantalum, titanium, titanium nitride, niobium or alloys of any of these, in order to avoid corrosion or electrolysis which could damage the surrounding tissues and the device.
In certain embodiments of the instant invention, microstimulator SCU 160 comprises two, leadless electrodes. However, either or both electrodes 172 and 172′ may alternatively be located at the ends of short, flexible leads as described in U.S. patent application Ser. No. 09/624,130, filed Jul. 24, 2000, which is incorporated herein by reference in its entirety. The use of such leads permits, among other things, electrical stimulation to be directed more locally to targeted tissue(s) a short distance from the surgical fixation of the bulk of microstimulator SCU 160, while allowing most elements of the microstimulator to be located in a more surgically convenient site. This minimizes the distance traversed and the surgical planes crossed by the device and any lead(s). In most uses of this invention, the leads are no longer than about 150 mm.
As mentioned earlier, stimulation is provided in accordance with the teachings of the present invention by electrical stimulation and/or one or more stimulating drugs delivered to the body by one or more system control units (SCUs). In the case of electrical stimulation only, SCUs include a microstimulator and/or an implantable pulse/signal generator (IPG), or the like. In the case of drug infusion only, an SCU comprises an implantable pump or the like. In cases requiring both electrical stimulation and drug infusion, more than one SCU may be used. Alternatively, when needed and/or desired, an SCU provides both electrical stimulation and one or more stimulating drugs.
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In embodiments such as in
In some alternatives, the electrical stimulation may be provided as described in International Patent Application Serial Number PCT/US01/04417 (the '417 application), filed Feb. 12, 2001, and published Aug. 23, 2001 as WO 01/60450, which application is incorporated herein by reference in its entirety. As such, the electrical stimulation of the present invention may be as provided in this PCT application, which is directed to a "Deep Brain Stimulation System for the Treatment of Parkinson's Disease or Other Disorders".
In the case of treatment alternatively or additionally constituting drug infusion, SCU 160 (which herein refers to IPGs, implantable pumps, IPG/pump combinations, microstimulators for drug and/or electrical stimulation, and/or other alternative devices described herein) may contain at least one pump 162 for storing and dispensing one or more drugs through outlet(s) 182/182′ and/or catheter(s) 180/180′ into a predetermined site(s) in the brain tissue. When a catheter is used, it includes at least one infusion outlet 182, usually positioned at least at a distal end, while a proximal end of the catheter is connected to SCU 160.
According to some embodiments of the invention, such as described in the previously referenced '417 application and as depicted in
Substantially cylindrical catheter(s) 180 and lead(s) 170 of certain embodiments of the present invention may be less than about 5 mm in diameter, or even less than about 1.5 mm in diameter. In embodiments using one or more paddle-shaped leads (e.g., cerebellum stimulation may use substantially cylindrical or paddle-shaped leads), lead(s) 170 may be less than 15 mm in width, and less than 1.5 mm in thickness. Electrodes 172, 172′ on leads 170, 170′ may be arranged as an array, for instance, as two or more collinear electrodes, or even as four or more collinear electrodes, or they may not be collinear. A tip electrode may also be supplied at the distal end of one or more leads.
In some embodiments, SCU 160 is programmable to produce either monopolar electrical stimulation, e.g., using the SCU case as an indifferent electrode, or bipolar electrical stimulation, e.g., using one of the electrodes of the electrode array as an indifferent electrode. Some embodiments of SCU 160 have at least four channels and drive up to sixteen electrodes or more.
SCU 160 contains, when necessary and/or desired, electronic circuitry 154 for receiving data and/or power from outside the body by inductive, radio frequency (RF), or other electromagnetic coupling. In some embodiments, electronic circuitry 154 includes an inductive coil for receiving and transmitting RF data and/or power, an integrated circuit (IC) chip for decoding and storing stimulation parameters and generating stimulation pulses (either intermittent or continuous), and additional discrete electronic components required to complete the electronic circuit functions, e.g. capacitor(s), resistor(s), coil(s), and the like.
SCU 160 also includes, when necessary and/or desired, a programmable memory 164 for storing a set(s) of data, stimulation, and control parameters. Among other things, memory 164 may allow electrical and/or drug stimulation to be adjusted to settings that are safe and efficacious with minimal discomfort for each individual. Specific parameters may provide therapeutic advantages for various types and severities of movement disorders. For instance, some patients may respond favorably to intermittent stimulation, while others may require continuous treatment for relief. In some embodiments, electrical and drug stimulation parameters are controlled independently, e.g., continuous electrical stimulation and no drug stimulation. However, in some instances, they may advantageously be coupled, e.g., electrical stimulation may be programmed to occur only during drug infusion.
In addition, different stimulation parameters may have different effects on neural tissue. Therefore, parameters may be chosen to target specific neural populations and/or to exclude others, or to increase neural activity in specific neural populations and/or to decrease neural activity in others. For example, relatively low levels of stimulation current (e.g., about 0.5 mA to about 5.0 mA, or even about 0.05 mA to about 2.0 mA) are likely to recruit only relatively large diameter fibers. According to certain embodiments of the invention, the stimulation can selectively increase neural activity of only the relatively large diameter fibers of NTS 100. Relatively low amplitude electrical current pulses are likely to produce such selective excitation.
As another example, relatively low frequency neurostimulation (i.e., less than about 100–150 Hz) typically has an excitatory effect on surrounding neural tissue, leading to increased neural activity, whereas relatively high frequency neurostimulation (i.e., greater than about 100–150 Hz) may have an inhibitory effect, leading to decreased neural activity. Similarly, excitatory neurotransmitters (e.g., glutamate, dopamine, norepinephrine, epinephrine, acetylcholine, serotonin), agonists thereof (e.g., glutamate receptor agonist(s), apomorphine), and agents that act to increase levels of an excitatory neurotransmitter(s) (e.g., edrophonium, Mestinon) generally have an excitatory effect on neural tissue, while inhibitory neurotransmitters (e.g., dopamine, glycine, and gamma-aminobutyric acid, a.k.a. GABA), agonists thereof (e.g., muscimol, apomorphine), and agents that act to increase levels of an inhibitory neurotransmitter(s) generally have an inhibitory effect. (Dopamine acts as an excitatory neurotransmitter in some locations and circumstances, and as an inhibitory neurotransmitter in other locations and circumstances.) However, antagonists of inhibitory neurotransmitters (e.g., bicuculline) and agents that act to decrease levels of an inhibitory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity. Similarly, excitatory neurotransmitter antagonists (e.g. prazosin, metoprolol, atropine, benztropine) and agents that decrease levels of excitatory neurotransmitter(s) (e.g., acetylcholinesterase, Group II metabotropic glutamate receptor (mGluR) agonists such as DCG-IV) may inhibit neural activity.
Some embodiments of SCU 160 also include a power source and/or power storage device 166. Possible power options for a stimulation device of the present invention, described in more detail below, include but are not limited to an external power source coupled to the stimulation device, e.g., via an RF link, a self-contained power source utilizing any suitable means of generation or storage of energy (e.g., a primary battery, a replenishable or rechargeable battery such as a lithium ion battery, an electrolytic capacitor, a super- or ultra-capacitor, or the like), and if the self-contained power source is replenishable or rechargeable, means of replenishing or recharging the power source (e.g., an RF link, an optical link, a thermal link, or other energy-coupling link).
In embodiments such as shown in
According to certain embodiments of the invention, an SCU operates independently. According to various embodiments of the invention, an SCU operates in a coordinated manner with other SCU(s), other implanted device(s), and/or other device(s) external to the patient's body. For instance, an SCU may control or operate under the control of another implanted SCU(s), other implanted device(s), and/or other device(s) external to the patient's body. An SCU may communicate with other implanted SCUs, other implanted devices, and/or devices external to a patient's body via, e.g., an RF link, an ultrasonic link, a thermal link, and/or an optical link. Specifically, an SCU may communicate with an external remote control (e.g., patient and/or physician programmer) that is capable of sending commands and/or data to an SCU and that may also be capable of receiving commands and/or data from an SCU.
For example, some embodiments of SCU 160 of the present invention may be activated and deactivated, programmed and tested through a hand held programmer (HHP) 200 (which may also be referred to as a patient programmer and may be, but is not necessarily, hand held), a clinician programming system (CPS) 202 (which may also be hand held), and/or a manufacturing and diagnostic system (MDS) 204 (which may also be hand held). HHP 200 may be coupled to SCU 160 via an RF link 195. Similarly, MDS 204 may be coupled to SCU 160 via another RF link 196. In a like manner, CPS 202 may be coupled to HHP 200 via an infra-red link 197; and MDS 204 may be coupled to HHP 200 via another infra-red link 198. Other types of telecommunicative links, other than RF or infra-red may also be used for this purpose. Through these links, CPS 202, for example, may be coupled through HHP 200 to SCU 160 for programming or diagnostic purposes. MDS 204 may also be coupled to SCU 160, either directly through RF link 196, or indirectly through IR link 198, HHP 200, and RF link 195.
In certain embodiments, using for example, a BION microstimulator(s) as described in the above referenced publications, and as illustrated in
External components for programming and/or providing power to various embodiments of SCU 160 are also illustrated in
Alternatively or additionally, external electronic appliance 230 is provided with an electronic interface means 246 for interacting with other computing means 248, such as by a serial interface cable or infrared link to a personal computer or to a telephone modem or the like. Such interface means 246 may permit a clinician to monitor the status of the implant and prescribe new stimulation parameters from a remote location.
The external appliance(s) may be embedded in a cushion, pillow, hat, or the like. Other possibilities exist, including a head band, patch, or other structure(s) that may be affixed to the patient's body or clothing. External appliances may include a package that can be, e.g., worn on the belt, may include an extension to a transmission coil affixed, e.g., with a Velcro� band or an adhesive, or may be combinations of these or other structures able to perform the functions described herein.
In order to help determine the strength and/or duration of electrical stimulation and/or the amount and/or type(s) of stimulating drug(s) required to produce the desired effect, in some embodiments, a patient's response to and/or need for treatment is sensed. For example, head acceleration, electrical activity of the brain (e.g., EEG or discharge frequency of a neural population), nerve activity (e.g., ENG), muscle activity (e.g., limb EMG), or other activity may be sensed.
For instance, one or more electrodes may be used for recording electrical signals from the brain. Recording of the neural activity of one or more areas being stimulated, e.g., NTS 100 or pallido-subthalamic tracts 106, may be performed in order to determine the discharge frequency of the neural population. This sensing may occur during stimulation or during a temporary suspension of stimulation. The amplitude of stimulation is increased if the discharge frequency is above a programmable threshold frequency, and the amplitude of stimulation is decreased if the discharge frequency is less than another programmable threshold frequency. The two programmable threshold frequencies may be the same or may be different in order to achieve hysteresis.
In another example, one or more accelerometers may be used for sensing acceleration of the head. Rhythmic acceleration of the head is seen in head tremor. Thus, the amplitude of rhythmic head acceleration is an indicator of the amplitude of head tremor. The amplitude of stimulation is increased if the amplitude of rhythmic head acceleration is above a programmable threshold amplitude, and the amplitude of stimulation is decreased if the amplitude of rhythmic head acceleration is below a programmable threshold amplitude. The two programmable threshold amplitudes may be the same or may be different in order to achieve hysteresis. This sensing may advantageously be used for patients with significant head tremor as a component of their movement disorder, such as certain patients with benign essential tremor.
Other measures of the state of the patient may additionally or alternatively be sensed. For instance, one or more neurotransmitter levels, their associated breakdown product levels, hormone levels, or other substances, such as dopamine levels, interleukins, cytokines, lymphokines, chemokines, growth factors, electrolytes, enzymes, medication, and/or other drug levels, or levels of any other bloodborne substance(s), and/or changes in one or more of these may be sensed, using, e.g., one or more Chemically Sensitive Field-Effect Transistors (CHEMFETs) such as Enzyme-Selective Field-Effect Transistors (ENFETs) or Ion-Sensitive Field-Effect Transistors (ISFETs, as are available from Sentron CMT of Enschede, The Netherlands). For example, when electrodes of SCU 160 are implanted in or adjacent to pallido-subthalamic tracts 106, a stimulating electrode of SCU 160, or other sensing means contained in the electrode lead, catheter, IPG, microstimulator, or any part of the system may be used to sense changes in neural firing frequency of the pallido-subthalamic tracts 106 resulting from the electrical and/or drug stimulation applied to the pallido-subthalamic tracts 106. (As used herein, "adjacent" or "near" means as close as reasonably possible to targeted tissue, including touching or even being positioned within the tissue, but in general, may be as far as about 150 mm from the target tissue.)
Alternatively, an "SCU" dedicated to sensory processes communicates with an SCU providing stimulation pulses. The implant circuitry 154 may, if necessary, amplify and transmit these sensed signals, which may be digital or analog. Other methods of determining the required electrical and/or drug stimulation include measuring impedance, acidity/alkalinity (via a pH sensor), muscle EMG, head or limb acceleration (e.g., via accelerometer), EEG, ENG, other methods mentioned herein, and others that will be evident to those of skill in the field upon review of the present disclosure. The sensed information may be used to control stimulation parameters in a closed-loop manner.
For instance, in several embodiments of the present invention, a first and second "SCU" are provided. The second "SCU" periodically (e.g. once per minute) records firing rate of neurons in GPi 110 (or the level of a substance, e.g., dopamine or L-Dopa, or an amount of electrical activity, etc.), which it transmits to the first SCU. The first SCU uses the sensed information to adjust electrical and/or drug stimulation parameters according to an algorithm programmed, e.g., by a physician. For example, the amplitude and/or frequency of electrical stimulation may be increased in response to increased firing rate of neurons in GPi 110. In some alternatives, one SCU performs both the sensing and stimulating functions, as discussed in more detail presently.
While an SCU 160 may also incorporate means of sensing symptoms or other prognostic or diagnostic indicators of movement disorders, e.g., via sensing of tremor (e.g., via accelerometer), sensing of dopamine or dopamine agonist levels (e.g., L-dopa), and/or sensing of neural electrical activity (e.g., firing rate of neurons in pallido-subthalamic tracts 106), it may alternatively or additionally be desirable to use a separate or specialized implantable device to record and telemeter physiological conditions/responses in order to adjust electrical stimulation and/or drug infusion parameters. This information may be transmitted to an external device, such as external appliance 220, or may be transmitted directly to implanted SCU(s) 160. However, in some cases, it may not be necessary or desired to include a sensing function or device, in which case stimulation parameters are determined and refined, for instance, by patient feedback, or the like.
Thus, it is seen that in accordance with the present invention, one or more external appliances may be provided to interact with SCU 160, and may be used to accomplish, potentially among other things, one or more of the following functions:
By way of example, a treatment modality for movement disorders, e.g., Parkinson's disease, may be carried out according to the following sequence of procedures:
In another example, a treatment for movement disorders, e.g., essential tremor, may be carried out according to the following sequence of procedures:
For the treatment of any of the various types and severities of movement disorders, it may be desirable to modify or adjust the algorithmic functions performed by the implanted and/or external components, as well as the surgical approaches, in ways that would be obvious to skilled practitioners of these arts. For example, in some situations, it may be desirable to employ more than one SCU 160, each of which could be separately controlled by means of a digital address. Multiple channels and/or multiple patterns of electrical and/or drug stimulation might thereby be programmed by the clinician and controlled by the patient in order to, for instance, deal with complex or multiple symptoms or conditions, such as Parkinson's disease coupled with side effects from medication, e.g., dyskinesia.
In some embodiments discussed earlier, SCU 160, or a group of two or more SCUs, is controlled via closed-loop operation. A need for and/or response to stimulation is sensed via SCU 160, or by an additional SCU (which may or may not be dedicated to the sensing function), or by another implanted or external device. If necessary, the sensed information is transmitted to SCU 160. In some cases, the sensing and stimulating are performed by one SCU. In some embodiments, the parameters used by SCU 160 are automatically adjusted based on the sensed information. Thus, the electrical and/or drug stimulation parameters are adjusted in a closed-loop manner to provide stimulation tailored to the need for and/or response to the electrical and/or drug stimulation.
For instance, as shown in the example of
A drug infusion stimulator made in accordance with the invention may incorporate communication means for communicating with one or more external or site-specific drug delivery devices, and, further, may have the control flexibility to synchronize and control the duration of drug delivery. The associated drug delivery device typically provides a feedback signal that lets the control device know it has received and understood commands. The communication signal between the implanted stimulator and the drug delivery device may be encoded to prevent the accidental or inadvertent delivery of drugs by other signals.
An SCU made in accordance with the invention thus incorporates, in some embodiments, first sensing means 268 for sensing therapeutic effects, clinical variables, or other indicators of the state of the patient, such as head acceleration, limb acceleration, limb EMG, and/or discharge frequency of a neural population, or the like. The stimulator additionally or alternatively incorporates second means 269 for sensing neurotransmitter levels and/or their associated breakdown product levels, medication levels and/or other drug levels, hormone, enzyme, ketone, electrolytes, interleukin, cytokine, lymphokine, chemokine, and/or growth factor levels and/or changes in these or other substances in the blood plasma, local interstitial fluid, and/or cerebrospinal fluid. The stimulator additionally or alternatively incorporates third means 270 for sensing electrical current levels and/or waveforms supplied by another source of electrical energy. Sensed information may be used to control infusion and/or electrical parameters in a closed loop manner, as shown by control lines 266, 267, and 265. Thus, the sensing means may be incorporated into a device that also includes electrical and/or drug stimulation, or the sensing means (that may or may not have stimulating means), may communicate the sensed information to another device(s) with stimulating means.
According to some embodiments of the invention, the electrical and/or drug stimulation decreases activity of one or more areas of the brain that exhibit chronic increased activity, relative to control subjects, in patients experiencing a movement disorder(s). These areas may include one or more of the pallido-thalamic axons 107, putamen to GPe fibers 108, and/or subthalamo-pallidal fibers. Such inhibitory stimulation is likely to be produced by relatively high-frequency electrical stimulation (e.g., greater than about 100–150 Hz), an excitatory neurotransmitter antagonist(s) (e.g. prazosin, metoprolol, atropine), an inhibitory neurotransmitter(s) (e.g., GABA), an agonist thereof, an agent that increases the level of an inhibitory neurotransmitter, an agent that decreases the level of an excitatory neurotransmitter (e.g., DCG-IV), a local anesthetic agent (e.g., lidocaine), and/or an analgesic medication. This stimulation may be applied to one or more of the pallido-thalamic axons 107, putamen to GPe fibers 108, and subthalamo-pallidal fibers to treat movement disorder(s).
According to other embodiments of the invention, the electrical and/or drug stimulation increases activity of one or more of those areas of the brain that exhibit chronic decreased activity, relative to control subjects, in patients experiencing a movement disorder(s), thereby treating or preventing such disorder(s) and/or the symptoms and/or pathological consequences thereof. These areas may include one or more of the NTS 100, pallido-subthalamic tracts 106, and putamen to GPi fibers. Such excitatory stimulation is likely to be produced by relatively low-frequency electrical stimulation (e.g., less than about 100–150 Hz), an excitatory neurotransmitter (e.g., glutamate, acetylcholine), an excitatory cortical neurotransmitter agonist (e.g., glutamate receptor agonist, L-aspartic acid, N-methyl-D-aspartic acid (NMDA), bethanechol, norepinephrine), an inhibitory neurotransmitter antagonist(s) (e.g., bicuculline), an agent that increases the level of an excitatory neurotransmitter (e.g., edrophonium), and/or an agent that decreases the level of an inhibitory neurotransmitter. This stimulation may be applied to one or more of the NTS 100, pallidosubthalamic tracts 106, and putamen to GPi fibers to treat movement disorder(s).
According to certain embodiments, the stimulation selectively increases neural activity of the relatively large diameter fibers of the nucleus tractus solitarius (NTS 100). Relatively low amplitude (e.g., about 0.05 mA to about 5.0 mA) electrical current pulses are likely to produce such selective excitation.
According to various embodiments, one or more stimulating drugs, possibly in combination with electrical stimulation, are infused into the brain. For instance, a growth factor, such as glial cell line-derived neurotrophic factor (GDNF) may be infused into the putamen 116, possibly while providing electrical stimulation as described above. Other stimulating drugs are described previously herein and include brain cell line-derived neurotrophic factor (BDNF), naloxone, and levodopa.
In various embodiments, sensing means described earlier may be used to orchestrate first the activation of SCU(s) targeting an area(s) of the brain, and then, when appropriate, SCU(s) targeting another area(s) and/or by different means. Alternatively, this orchestration may be programmed, and not based on a sensed condition.
While the invention herein disclosed has been described by means of specific embodiments and applications thereof, numerous modifications and variations could be made thereto by those skilled in the art without departing from the scope of the invention set forth in the claims.
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Fire alarm with LED read-out?
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Last night, at 1am, everyone in the house was woken up by the loud beep of our networked fire alarms. A single beep means something different from a short sequence of 2 or 3 beeps (which is different from the constant beeping I assume you hear when there's an actual fire). The problem is, at 1am it's hard to remember what a single beep means. Does anyone know of a fire alarm that has some kind of display that would tell you what the issue is? EG, it beeps once and the display says "unit 3 -- low battery".0
Yes, get a "real" alarm system with wireless or smart hardwired smoke detectors. An esay to install residential system could include:
http://www.security.honeywell.com/hsc/products/wireless/sm/201968.html http://www.security.honeywell.com/hsc/products/control/wi/ly/283765.html
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Blue smoke from your exhaust may mean your car needs a complete engine overhaul. Black smoke usually means a maladjusted carburetor. White smoke: Ignore it if the engine is cold, but if it keeps up after the engine has warmed, you may have a leaking head gasket. — Reader's Digest, reported in Bottom Line Personal

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Preheat oven to 350°F. Line bottom of a buttered 9- by 2-inch springform pan with a round of wax paper or parchment and butter paper. Dust pan with flour, knocking out excess.
To make cake layer:
In a bowl whisk together whole eggs and yolk. Into another bowl sift together flour, baking powder, and salt. In a glass measuring cup stir together milk and Amaretto. In a bowl with an electric mixer on medium speed beat butter 1 minute and beat in sugar in a steady stream, scraping bowl occasionally, until light and fluffy, about 4 minutes. Beat in egg, a little at a time, beating well after each addition, until pale and fluffy. Stir in flour mixture in 3 batches alternately with milk mixture, beginning and ending with flour mixture and stirring until smooth after each addition.
Turn batter into pan, smoothing top, and bake in middle of oven until a tester comes out clean, about 25 minutes. Cool cake layer in pan on a rack 10 minutes. Run a thin knife around edge of pan and remove side of pan. Invert cake layer onto rack. Remove paper carefully and cool cake completely. With a long serrated knife halve cake horizontally. Clean springform pan and line with 2 sheets plastic wrap, leaving at least a 1-inch overhang. Put bottom half of cake, cut side up, in pan.
Make raspberry frozen yogurt:
In a food processor purée raspberries with sugar and water and force through a fine sieve into a large bowl. Add frozen yogurt and stir until purée is well incorporated.
Working quickly, spoon about half of frozen yogurt over cake in pan, spreading evenly. Top with other half of cake layer, cut side down, and spoon remaining frozen yogurt on top, spreading evenly.
Arrange raspberries decoratively on top of cake, pushing slightly into frozen yogurt, and sprinkle almonds over top of cake. Freeze cake, covered, at least until frozen hard, about 6 hours, and up to 1 week.
Let cake soften in refrigerator at least 30 minutes and up to 45 minutes before serving. Remove cake from pan, discarding plastic wrap. Serve cake with sauce.
To make the sauce:
In a food processor purée raspberries with sugar and Amaretto and force through a fine sieve into a bowl. Sauce may be made 3 days ahead and chilled, covered. Makes about 1 1/2 cups.


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When Lights Are Low by Benny Carter - Digital Sheet Music
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When Lights Are Low digital sheet music. Contains printable sheet music plus an interactive, downloadable digital sheet music file.
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Originally written on Hoop Fantasies Fantasy Basketball Blog | Last updated 2/13/13
Utah Jazz forward Paul Millsap is drawing interest from the Brooklyn Nets. ESPN New York (citing the New York Daily News) reports that the Nets want Millsap as their starting power forward. No word on who Brooklyn is offering, but the franchise has been trying to unload Kris Humphries and MarShon Brooks. The Nets have been mentioned as a possible destination for Josh Smith and Ben Gordon, but neither deal is imminent. Acquiring Millsap would reunite him with pick-and-roll partner Deron Williams. A deal would also potentially open up minutes in Salt Lake City for Derrick Favors and Enes Kanter.
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Mike Krieglstein is production manager for The Giving Tree Band from Yorkville, IL. The band has received international recognition and plans to tour as far as Australia, with other international dates to follow.
Jeremy Ceja is a psychology teacher at Eisenhower High School in Blue Island, IL.
Rob Bassett is principal of Oak Park Elementary School in Oak Park, IL.
Grant Swanson teaches sixth grade at St. Francis Indian School on the Rosebud Lakota Reservation in South Dakota. After his first year of teaching under contract with Teach For America, he worked as a teacher-ranger at Yellowstone National Park. As a result, he was able to take his students on a weeklong field trip to Yellowstone through the program Expedition: Yellowstone! a curriculum-based educational program about the importance of the park.
Shannon Juenger is a fourth-grade teacher at West Lane Elementary in Jackson, MO. Juenger earned her English as a second language certification from Methodist University in Fayetteville, NC. She may be reached at email@example.com.
Scott Drucker visited North Central College for a screening of his documentary "Between the Harvest," which was also nominated in the Naperville Film Festival. The documentary is about the controversy surrounding the Costa Rican government's decision to legalize the harvest of endangered sea turtle eggs.
Maureen Szweda Mann started her own business with Rodan and Fields, a direct sales company that specializes in skincare and anti-aging products. To learn more visit momann.myrandf.com.
Michelle Arb is an English and honors English teacher and assistant cheerleading coach at Freeport High School in Freeport, IL. She may be contacted at firstname.lastname@example.com.
Joe Norton is full-time head coach for the Knox College wrestling program, located in Galesburg, IL. He served as a graduate assistant for the wrestling program at North Central College. As a student-athlete at North Central, he had 94 career victories on the mat and was a four-time NCAA regional place winner. He was ranked as high as ninth as an individual and was recipient of the Hammer Award in recognition of outstanding commitment and work ethic in NCAA Division III.
Michael Swengel was appointed director of vocal music and show choir for Mt. Zion High School in Mt. Zion, IL. He will lead Swingsations, Les Femmes, Sound System and Vocal Trax show choirs. Swengel is a Harvard, IL, native and previously worked in Milton, WI, where he spent three years teaching vocal music and show choir to grades 7 through 12. In 2007, he completed his student teaching experience at Bednarcik Junior High in Oswego, IL and Waubonsie Valley High School in Aurora, IL. He brings to Mt.
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- The Big Picture: What's AAP
- A year later, the tweak: Desh to Dilli
- Bus from Burari laden with volunteers and hope
- Rare day out for AAP families
- Riot of support for AAP in communal hot spots
- Hunt on for CM house, will not accept Z-plus security
- No word from high command, Delhi Congress in a paralysis
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- Second time at Ramlila Maidan: Hope overrides their doubts
- Kejriwal has no portfolio, will keep an eye on others
- In sea of white caps, BJP troika plans to be 'forceful opposition'
- MP, MLA see Punjab as the next AAP stop
- A year later, the tweak: Desh to Dilli
- Arvind Kejriwal repeats his advice to sting the corrupt, asks police to act against 'goondagardi'
- Proud that one of our volunteers has become Delhi CM: Anna Hazare
- Arvind Kejriwal not to keep any portfolio
- Now an Aam Aadmi Party Cola by beverage-maker inspired by Arvind Kejriwal's party
- New chief minister Arvind Kejriwal holds meetings at Delhi Secretariat
- Cong's Ajay Maken blames Sheila Dikshit for Delhi polls debacle
- Left, right, AAP
Battleground Amethi: Narendra Modi ups the ante; takes battle to Gandhi den
The BJP's prime ministerial candidate Narendra Modi took his Lok Sabha election campaign to the home turf of the Nehru-Gandhi family in Amethi Monday, attacking Rajiv Gandhi, Sonia, Rahul and Priyanka and promising voters success where he said they had failed — turn Amethi into a model of development.
Responding to the barbs thrown at him by Sonia, Rahul and Priyanka in recent days during campaigning, Modi said that ensuring the victory of BJP candidate Smriti Irani — who he said was like his younger sister — was now a "question of his respect".
Countering Priyanka's remark that Modi does not understand the dignity of the post of prime minister and Rahul's allegation that he indulges in the politics of anger, Modi cited examples of what he said were instances of the Gandhi family members, Rajiv onwards, engaging in the politics of anger and how Rahul had belittled Prime Minister Manmohan Singh by terming an ordinance cleared by the cabinet as "nonsense".
"When the prime minister was out of the country, he tears apart a cabinet decision in anger and after calling it nonsense. Now who showed disrespect to the prime minister?" Modi asked during his 50-minute speech at a ground in the Gauriganj area of Amethi.
He also referred to the incident of Rajiv, who was a general secretary in the Congress when his mother Indira Gandhi was prime minister, scolded Andhra Pradesh Chief Minister T Anjaiah in public at an airport, reducing the senior leader to tears.
Targeting Sonia next, Modi alleged that she had not allowed the funeral of former prime minister P V Narasimha Rao to be held in Delhi "out of her anger", just like the British colonial rulers refused to allow the last Mughal emperor Bahadur Shah Zafar to be buried in Delhi.
Former Congress president Sitaram Kesri, he alleged, was insulted and thrown out of the party office again because of Sonia's anger.
Referring to Rahul as "Rahul bhaiya" and Sonia as "Sonia madam" through his speech, Modi repeatedly asked the crowd, "what kind of a family is this?" as he chose to focus on "family politics" and the "under-development of Amethi".
Criticising Rahul and his frequent references to his family in his speeches, Modi asked if the country can be run by saying, "I am part of your family. You know my father". He said "your MP…your Rahul bhaiya" did not ask a single question about Amethi in Parliament in the last 10 years.
He told voters that Amethi had blindly voted for the Gandhi family for the last 40 years but had not got even basic facilities such as roads, drinking water and electricity in return.
Countering the Congress claim that the party could not do much in Uttar …continued »


text:
Minimal Surfaces
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more"Minimal Surfaces" is the first volume of a three volume treatise on minimal surfaces (Grundlehren Nr. 339-341). Each volume can be read and studied independently of the others. The central theme is boundary value problems for minimal surfaces. The treatise is a substantially revised and extended version of the monograph Minimal Surfaces I, II (Grundlehren Nr. 295 & 296). The first volume begins with an exposition of basic ideas of the theory of surfaces in three-dimensional Euclidean space, followed by an introduction of minimal surfaces as stationary points of area, or equivalently, as surfaces of zero mean curvature. The final definition of a minimal surface is that of a non-constant harmonic mapping X: \Omega\to\R^3 which is conformally parametrized on \Omega\subset\R^2 and may have branch points. Thereafter the classical theory of minimal surfaces is surveyed, comprising many examples, a treatment of Bjorling's initial value problem, reflection principles, a formula of the second variation of area, the theorems of Bernstein, Heinz, Osserman, and Fujimoto. The second part of this volume begins with a survey of Plateau's problem and of some of its modifications.One of the main features is a new, completely elementary proof of the fact that area A and Dirichlet integral D have the same infimum in the class C(G) of admissible surfaces spanning a prescribed contour G. This leads to a new, simplified solution of the simultaneous problem of minimizing A and D in C(G), as well as to new proofs of the mapping theorems of Riemann and Korn-Lichtenstein, and to a new solution of the simultaneous Douglas problem for A and D where G consists of several closed components. Then basic facts of stable minimal surfaces are derived; this is done in the context of stable H-surfaces (i.e. of stable surfaces of prescribed mean curvature H), especially of cmc-surfaces (H = const), and leads to curvature estimates for stable, immersed cmc-surfaces and to Nitsche's uniqueness theorem and Tomi's finiteness result. In addition, a theory of unstable solutions of Plateau's problems is developed which is based on Courant's mountain pass lemma. Furthermore, Dirichlet's problem for nonparametric H-surfaces is solved, using the solution of Plateau's problem for H-surfaces and the pertinent estimates. less
Springer; August 2010
698 pages; ISBN 9783642116988
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Title: Minimal Surfaces
Author: Ulrich Dierkes; Stefan Hildebrandt; Friedrich Sauvigny; Ruben Jakob; Albrecht Kuster
698 pages; ISBN 9783642116988
Read online, or download in secure PDF format
Title: Minimal Surfaces
Author: Ulrich Dierkes; Stefan Hildebrandt; Friedrich Sauvigny; Ruben Jakob; Albrecht Kuster
Buy, download and read Minimal Surfaces (eBook) by Ulrich Dierkes; Stefan Hildebrandt; Friedrich Sauvigny; Ruben Jakob; Albrecht Kuster today!
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2001 Jeep Cherokee Q&A
2001 Jeep Cherokee Question: will stop leak damage a/c
Last year my a/c quit working and the mechanic used stop leak and it worked for a year, then the mechanic I learned did it again this summer, it stopped and I added freon, it worked for a while then stopped and stop leak was used again, will it clog up my system? The a/c has blown cold for several days but the pressure tht I told at home shows it just around 25-30? Also I was told it could be an evaporator could the stop leak have damaged a compressor, it still clicks on and off? Are there any signs it if damages a condensor, compressor, or evaporator, like it won't keep a charge for long, or won't recharge past a certain psi depsite the amount added? Tahnks - jackpa
4 Answers
Answer 1
The last part of your question is a bit hard to understand so I hope this answer helps. I do not think that adding stop leak three time over the last year or so would damage any of your A/C system components. It is a bit excessive however. It may be time for the A/C system in your 2001 Jeep Cherokee to be completely diagnosed by an A/C professional. If there is still a leak it must be found and repaired - it seems that the stop leak did not work to seal your A/C leak. Once the leak is found and repaired the system can be fully charged and inspected for other issues. - Oakman
Answer 2
I don't like using stop leak additives unless it is an emergency or you really aren't interested in putting money into the vehicle. You system still has a leak, it will need to be located and repaired. It can be a hose, evaporator, condenser, basically can be from anywhere. What the repair shop should do is add fluorescent dye into the system to help locate the leak. As far as all that stop leak damaging the compressor, I don't have any experience with it to know, but my feeling is that it can't be good. Either was, focus on finding and fixing the leak, recharge the system and see how the compressor is working. Good luck! - munkyrench
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Oven Baked Jambalaya
22 Oct 2009
You'll simply love Jambalaya from the Spainish cusine. An easy to make main course meal, the Jambalaya is one of the best recipes that you can mouth! Please let us know if you agree with us.
|2 Tablespoon
|Finely chopped onion
|1 Cup (16 tbs)
|Finely chopped green pepper
|1 Cup (16 tbs)
|2 Clove (10 gm), minced fine
|Diced cooked chicken
|1 Cup (16 tbs)
|Diced cooked ham
|1 Cup (16 tbs)
|Pork sausages
|12 Small, cut into pieces
|Canned tomatoes
|2 1⁄2 Cup (40 tbs), undrained
|Raw white rice
|1 Cup (16 tbs)
|Chicken broth
|1 1⁄2 Cup (24 tbs)
|1⁄2 Teaspoon
|Chopped parsley
|1 Tablespoon
|Chili powder
|1⁄4 Teaspoon
|1 1⁄2 Teaspoon
|Fresh ground black pepper
|1⁄4 Teaspoon
1. Preheat oven to moderate (350° F.).
2. Melt the fat in a large skillet and add the onion, green pepper and garlic. Cook slowly, stirring often, until the onion and pepper are tender. Add the chicken, ham and sausages and cook five minutes.
3. Add the tomatoes with their liquid, the rice, broth, thyme, parsley, chili, salt and pepper. Turn the mixture into a large casserole. Cover and bake until the rice is tender, about one and one quarter hours.
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Oven Baked Jambalaya Recipe


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Saturday, July 4, 2015
Goodbye, Dali
It has been 10 years now since the release of the longest-in-production film in history, Disney's animated short Destino. Begun in 1945 as a collaboration between Disney Studios ... Continue Reading →
Anyone Remember 'Budgie?'
Animation has become such a juggernaut within the film industry that it seems as though everyone has tried their hand in it at one point or other, up to and including British Royalty. ... Continue Reading →
A Non-Technical Chat with Ed Catmull
In Tom Sito's excellent and exhaustively researched new book, Moving Innovation: A History of Computer Animation, no one has quite as many index listings as Dr. Ed Catmull, current ... Continue Reading →
The Art of Being Peter Chung
Whenever I begin to despair that animation has fallen into a rut (which usually happens after watching the latest major-studio sequel), I start thinking about Peter Chung. Not quite ... Continue Reading →
It's Good to Be the 'King's' New Guy
Every now and then I find a surprise in my garage. On bad days, it's a baby rattlesnake or a black widow. On good days, it's an interview with someone I don't recall ... Continue Reading →
The Acknowledged Art of Gary Baseman
Even with the growing awareness of cartooning as an actual art, it is still rare that a popular cartoonist is honored with an exhibition of his work in an established museum. Graphic ... Continue Reading →
Saturday Morning Fab Four Flashback
One of the hard truths about animated cartoons is that many of them simply do not stand the test of time very well. For every Bugs Bunny there are multiple Flip the Frogs, characters ... Continue Reading →
3-D or Not 3-D
Show business seems to thrive on marking anniversaries for marketing purposes––25th or 50th or 75th Anniversary DVD releases of something, for example––but here's one that ... Continue Reading →
You Think Your Film Was a Challenge?
Any discussion of the different styles of animation invariably cover traditional, digital, stop-motion, paper cut-out, sometimes even puppetry. But there is one style that is rarely ... Continue Reading →
The Tale of 'The Tale of Tillie's Dragon'
One of these years I'm going to sit down and put together an entire book-length history of the "Toon Boom." I'm not speaking of the Canadian software company by that name, but ... Continue Reading →


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CBS Wins Tuesday in Viewers and Key Demos
CBS won Tuesday in viewers, adults 18-49 and adults 25-54 with VEGAS, the season's number one freshman series in viewers, notching its best adult 18-49 rating since early October, according to Nielsen preliminary live plus same day ratings for Nov. 20.
At 10PM, VEGAS was first in households (6.5/11), viewers (10.20m), adults 25-54 (2.4/06) and adults 18-49 (1.8/05). VEGAS beat NBC (4.52m) and ABC (4.14m) combined in by more than +1.5 million viewers (10.20m, vs. 8.66m, +18%). VEGAS posted its best adults 18-49 delivery since October 9, 2012.
NCIS: LOS ANGELES was first in households (9.5/15), viewers (15.06m), adults 25-54 (3.9/09) and adults 18-49 (2.8/08). NCIS LOS ANGELES beat NBC (5.28m), ABC (4.03m) and FOX (3.39m) combined by over +2.3 million viewers (15.06m vs. 12.70m, +19%).
NCIS was first in households (10.1/16), viewers (16.47m), adults 25-54 (4.3/11) and second in adults 18-49 (3.3/09). NCIS was the night's number one program in viewers and adults 25-54, and number one scripted program in adults 18-49.
For the night, CBS was first in households (8.7/14), viewers (13.91m), adults 25-54 (3.6/09) and adults 18-49 (2.5/07).
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text:
Press release from PR Newswire
Record Quarterly Earnings of R2.1 Billion
Thursday, November 10, 2011
Record Quarterly Earnings of R2.1 Billion01:39 EST Thursday, November 10, 2011JOHANNESBURG, November 10, 2011 /PRNewswire/ --Gold Fields Limited (Gold Fields) (JSE, NYSE, NASDAQ Dubai: GFI) today announced record net earnings for the September quarter of R2,055 million compared with R1,267 million in the June quarter and earnings of R701 million in the September 2010 quarter. In US dollar terms net earnings for the September quarter were US$293 million, compared with US$186 million in the June quarter and earnings of US$95 million in the September 2010 quarter.September 2011 quarter salient features:Group attributable equivalent gold production of 900,000 ounces, 3 per cent higher than the June quarter;Operating margin increased from 47 per cent to 51 per cent and NCE margin from 21 per cent to 29 per cent;Loans repaid of US$195 million funded from operating activities; andSecond down payment of US$66 million made in the Far Southeast project in the Philippines, on positive drilling results.The full results are available on the Gold Fields website: http://www.goldfields.co.zaNotes to editorsAbout Gold FieldsGold Fields is one of the world's largest unhedged producers of gold with attributable annualised production of 3.5 million gold equivalent ounces from eight operating mines in Australia, Ghana, Peru and South Africa. Gold Fields also has an extensive and diverse global growth pipeline with four major projects in resource development and feasibility, with construction decisions expected in the next 18 to 24 months. Gold Fields has total attributable gold equivalent Mineral Reserves of 76.7 million ounces and Mineral Resources of 225.4 million ounces. Gold Fields is listed on the JSE Limited (primary listing), the New York Stock Exchange (NYSE), NASDAQ Dubai Limited, Euronext in Brussels (NYX) and the Swiss Exchange (SWX).Sponsor: J.P. Morgan Equities LimitedEnquiries Investor Enquiries Zakira Amra Tel +27-11-562-9775 Mobile +27(0)79-694-0267 email email@example.com Willie Jacobsz Tel +508-839-1188 Mobile +857-241-7127 email email@example.com Media Enquiries Sven Lunsche Tel +27-11-562-9763 Mobile +27(0)83-260 9279 email firstname.lastname@example.com Gold Fields LimitedFor further information: .


text:
Texas grows but city shrinks
Of 25 metro areas, Wichita Falls loses 1,217
While the first national population estimate since the 2010 Census shows some significant changes in patterns, one thing remained consistent: Texas continued to grow. The annual estimate of populations of counties and metropolitan statistical areas since the official 2010 Census count indicated Texas had four of the fastest growing metro areas in the nation.
Austin, San Antonio, Dallas and Houston remained leaders in the pack in population growth. Dallas-Fort Worth and Houston added more people between 2010 and 2011 than any other metro areas in the country, adding 155,000 and 140,000 people respectively. Houston passed the 6 million mark between 2010 and 2011 and Odessa was among the top 50 metros in growth in the nation during the same period.
Of Texas' 25 metropolitan statistical areas, Wichita Falls was the only one to show a loss of population rather than growth, losing an estimated 1,217 people. Likewise, Wichita County registered an estimated loss of 802 residents during the same period. The Census Bureau did not release estimates of individual incorporated cities Thursday. Wichita Falls showed a slight increase in population — 356 people — in that category in the official 2010 Census.
Some local community leaders have challenged the validity of Census Bureau estimates since they began showing population declines in the Wichita Falls area after the 2000 Census.
Another trend that persisted in the latest estimates was growth in the South and Southwest. Nearly all of the fastest growing metros were located either entirely or partially in those two regions.
For some parts of the country, the 2011 estimates were a marked contrast between the trends seen in the first decade of the 21st century.
One such example was Palm Coast, Fla., which was the fastest-growing metro area between 2000 and 2010, but fell to 55th place between 2010 and 2011. Similarly, Las Vegas, the third fastest-growing metro area between 2000 and 2010, fell to 151st place.
"Our nation is constantly changing, and these estimates provide us with our first measure of how much substate areas have grown or declined in total population since Census Day," Census Bureau Director Robert Groves said. "We're already seeing different patterns of population growth than we saw in the last decade."
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|8 posts found
Apprentice Member
Joined: 2/08/12
website: http://dragona.sc.gameclub.com/drmain.asp
Free MMORPG Gamers love games that come with features that a different, even if that game doesn't offer a ton of things that are different, a feature that isn't seen a hundred times before is very welcome. When that feature allows the gamer to transform themselves into a dragon, and become a powerful force. Things really get interesting.
Dragona Online, a free to play MMORPG from GameClub, is offering players just this opportunity. This is one of a few features that Dragon Online has put together to allure players to the gaming world of Bartan. Is it enough that you should pay attention to Dragona? We will take a look at this and many of the other features that the game brings to the table below.
Character Creation
Getting started in Dragona can be an interesting affair. For me I had a few issues getting the game to send me a confirmation email. I ended up having to abandon my gaming email and register a free account with a free service which finally allowed me to register and get the confirmation email. This was a very minor inconvenience, but one that should be noted in the event that someone else has a similar situation.
Once logged in, the standard process of logging in, selecting a secondary password, and then selecting a server were all there. At this time the game only has one server, so not many options there.
After we were logged in, we moved quickly to the character creation process. The games options here can be disappointing to some users as the character classes are gender locked. So, while there is a good amount of variety, there are still some gameplay types that may not be available to a player unless one is willing to play the opposite sex.
Also, not all classes are playable by all races, this is something that players are a bit more accustomed to though. There are four races, each with two character classes. With classes ranging the gambit of the standard archetypes that players are use to, Tanks, Healers, DPS, and Ranged DPS.
During the character creation process you will have several aesthetic choices, face, hair style, and hair color, and one transformation choice. When choosing your initial dragon transformation choice, a play will want to pay attention to their character class of choice as well as playing style. The initial dragon transformation selection will give players the opportunity to determine which body part they will be able to transform from the start of their adventures. With this decision comes specific bonuses that can be very helpful to players as they start their journey. So choose wisely.
Interface and Combat
Now that we have our character created we jumped into the game and quickly into the action. Dragona wastes no time running you around the game world on mundane tasks to learn controls or interface options. They have tips that show you the basics, but these come up as you are in the thick of battle and leveling your character. Leveling up comes regularly and with it comes skill points. You will have many skill options, so once again the player will get to pick and choose how they build their character. This is nice as the character creation process seemed to lack options, the skill system more than makes up for deficiency.
The games interface is also nice and clean and easy to use. It isn't overly cluttered with options and leaves the screen open for the player to focus their attention on the gaming world and the action. If you have played any free MMORPG in the past, you will quickly find your way around the hotkey shortcuts and have no problem quickly immersing yourself into the gaming world.
Right from the start a player is also given quests to accomplish. One of the nicest features here is that you do not have to find an NPC or travel long distances to turn in quests. You establish a communication link that allows you to communicate and complete quests from where ever you are in the world and quickly gain your rewards. Some quests will require you to find certain NPCs, but the games autopathing system quickly will take you to where you need to go, so you are not endlessly searching.
Dragon Transformation
Who doesn't want to turn into an all powerful fire breathing flying dragon. Well, you are going to have to tame your expectations a bit on the fire breathing and flying part. While the game does boast dragon transformations, the dragons are a bit different in this world. You will start out only being able to transform one body part, and as previously mentioned, you will want to choose which body part wisely. Each body part has bonuses that will help you during your adventures. As you gain more transformations you will be able to have multiple body parts transformed, until you are able to do a full transformation and really take advantage of the bonuses that come with this feature.
PvP in Dragona is not only fun, but it is highly rewarding. You will have to level up to 15 before you can take part in the action, but this does not take more than a few hours of gameplay to accomplish. Once you are able to participate in the PvP action, you will find yourself able to earn not only PvP gear rewards, but also Experience.
PvP battles happen every 2 hours in the game world and players are notified approximately 1 minute before a battle is able to begin. Selecting to participate will add the player to a battle where they will combat against other players to reap the rewards as the victor of the battle. As the winner you will earn points that can be redeemed for gear and other items. With PvP being a great way to earn experience, expect many of the games players to be taking part in every battle, and it to become the focus of almost every players leveling scheme.
Graphics and Sounds
Graphically, Dragona Online is gorgeous! The game world looks amazing, the skill and spell animations are very well done. With many different environments to see as a player travels through the world there will always be something to catch your eye. The character models are not too hard on the eyes as well. With most of the female characters sporting some form of fleshy enticement through their armor, whether it be cleavage, side boob, under boob, or a mix of all of the above. It was clear that the female toons were meant to allure the male audience.
The Final Word
While being able to transform into a dragon is a really neat feature, it is actually not the best feature that Dragona has to offer. This is a positive in our eyes, as the game has so many quality features, and truly shows that the developers took the time to see what gamers enjoy and built a game with that in mind. Creating a beautiful gaming world is just half the battle for a developer. Throwing in a few unique features and you really have something. Then put together a highly rewarding and fun PvP system, quality crafting and item enhancement system, and much more.
Dragona is a solid offering to a list of free MMORPGs that is getting very long. Long gone are the days of being able to just spit out anything and gamers will flock to it. It is nice to see that Dragona's developers and publisher took that to heart and made sure to deliver a quality product that gamers will love for a long time.
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Advanced Member
Joined: 10/03/06
Life Liberty and the Pursuit of those that would threaten It
Apprentice Member
Joined: 7/15/08
I played a game called Isteria (I think) where the players could play as dragons......I remember alot of them jsut sitting in town doing nothing, but hey they were dragons......Alot of them said the only reason they were there was because they could play as a dragon, so this game will get a few to try jsut for that reason alone.
Novice Member
Joined: 11/16/03
American by Birth
Originally posted by Theocritus
I played a game called "Horizons", years ago. Is this the same game or a new one?
Elite Member
Joined: 8/13/09
"It is double pleasure to deceive the deceiver". - Niccolo Machiavelli
i like Dragona online but i stopped playing it because theres some issues with in game resolution. No matter to what resolution i set the game (i use 1280 x 720 and it looks like i have like 1024 x 768 no matter to what res i change it) i still get huge UI eating more than half of my screen and i hate that.... It doesnt happen with any other game. The resolution in that game doesnt change at all for me... so i just quit.
i dont have monitor so i use my 32" 720p hdtv
Elite Member
Joined: 8/13/09
"It is double pleasure to deceive the deceiver". - Niccolo Machiavelli
Originally posted by outfctrl
yes i believe horizon is istaria, name change or a new version of it, but the same game
Novice Member
Joined: 2/28/12
i played any simply F2p games.my skill is very bad
Novice Member
Joined: 7/27/11
Good and thorough review.
Terrible game though.
I played Dragona a month ago and uninstalled it within a week. I got to around level 25 or so. And yes, while the feature of turning into a dragon may be considered unique and the game being nice to look at, it really does nothing innovative for the genre. Auto pathing takes away any need for exploration and the world felt derivative and generic.


text:
An album by the Backstreet Boys
The band's goofy charm and sure-footed melodic sense is in full flower here, and the singalongs on "Brian Wilson" and "If I Had $1000000" are proof of the bond between band and audience. A hidden rap tribute to Ed Robertson's "Uncle … see full wiki
Rock Spectacle is a fine live recording which includes many of their great early tunes. Brian Wilson and Jane are super recordings and Hello City, Break Your Heart, and Straw Hat And Old Dirty Hank are very pleasant surprises. The rap about Uncle Elwin at the end of the CD is quite amusing.
Also very noteworthy are the arrangements of each song especially in a live setting. Sometiems the focus is on the keyboards, other times more the guitars, bit most often are the little touches given to the vocals. Love the harmonies on Hello City.
A very nice account of the Barenaked Ladies pre-Stunt days. Quite worthy indeed.
What did you think of this review?
An Album by Pink Floyd
An album by the Backstreet Boys
2006 rap song by American rapper E-40.
2003 rap song by American rapper 50 Cent.


text:
Big Problemo.
Bought One today and I have not been able to shoot it yet. Maybe tonight.
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