text:
Nerve conduction block treatment
At least one of a plurality of disorders of a patient are treated where the disorders are associated with a gastrointestinal tract of a patient where the disorders are characterized at least in part by hyper-tonal vagal activity innervating at least one of a plurality of alimentary tract organs of the patient at an innervation site. The treatment includes applying a neural conduction block to a vagus nerve of the patient at a blocking site proximal to the innervation site. The neural conduction block is selected to at least partially block nerve impulses on the vagus nerve at the blocking site. A treatment apparatus has an electrically controllable neural conduction electrode adapted to be placed on a vagus nerve of a patient at a blocking site proximal to an innervation site.
Latest Beta Medical, Inc. Patents:
[0001] The present application is a continuation-in-part application of U.S. patent application Ser. No. 10/358,093 filed Feb. 3, 2003 and entitled "Method and Apparatus for Treatment of Gastroesophageal Disease (GERD)". The present application discloses and claims subject matter disclosed in the following commonly assigned and copending U.S. patent applications filed on the same date as the present application and in the name of the same inventors: U.S. patent application Ser. No. not yet assigned, entitled "Enteric Rhythm Management", having Attorney Docket No. 14283.1USI2 and U.S. patent application Ser. No. not yet assigned, entitled "Nerve Stimulation And Conduction Block Therapy", having Attorney Docket No. 14283.1USI3.II. BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention pertains to treatments of disorders associated, at least in part, with neural activity. These may include, without limitation, gastrointestinal, pancreo-biliary, cardio-respiratory and central nervous system disorders (including neurological and psychiatric, psychological and panic disorders). More particularly, this invention pertains to treatment of such disorders through management of neural impulse stimulation and blocking.
[0004] 2. Description of the Prior Art
[0005] A. Functional Gastrointestinal Disorders (FGIDs)
[0006] Functional Gastrointestinal Disorders (FGIDs) are a diagnostic grouping having diagnostic criteria based on symptomatology, because the pathophysiology of these diseases is multifactorial with some pathophysiologic mechanisms in common. FGIDs are thought to be due to altered autonomic nervous system balance and to be pathophysiological combinations of: (1) abnormal GI motility; (2) visceral hypersensitivity; and, (3) brain-gut interactions. Tougas, "The Autonomic Nervous System in Functional Bowel Disorders", Gut, Vol. 47 (Suppl IV), pp. iv78-iv80 (2000) and Drossman, "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders—The Functional Gastrointestinal Disorders and the Rome II Process", Gut, Vol. 45 (Suppl II):II1-II5 (1999). The FGIDs of interest to the present invention are functional dyspepsia (dysmotility-like) and irritable bowel syndrome (IBS).
[0007] 1. Functional Dyspepsia (Dysmotility-Like)
[0008] Functional dyspepsia (dysmotility-like), is diagnosed when a patient's symptoms, in the absence of other organic disease likely to explain the symptoms, include persistent or recurrent pain or discomfort centered in the upper abdomen that may be accompanied by upper abdominal fullness, early satiety, bloating or nausea. Talley et al., "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders—Functional Gastroduodenal Disorders" Gut, Vol. 45 (Suppl II), pp. I37-II42 (1999).
[0009] A spectrum of dysmotilities has been documented in patients with functional dyspepsia. These include delayed gastric emptying of solids and liquids, reduced vagal tone, gastric dysrhythmias and impaired gastric accommodation. Furthermore, some studies have found good correlation between symptoms and indices of dysmotility, while others have not. Stanghellini V, et al., "Delayed Gastric Emptying of Solids in Patients with Functional Dyspepsia", Gastroenterol, (1996) 110:1036-1042. Undeland K A, et al., "Wide Gastric Antrum and Low Vagal Tone in Patients with Diabetes Mellitus Type 1 Compared to Patients with Functional Dyspepsia and Healthy Individuals", Dig Dis Sci, (1996) 41:9-16. Tack J, et al., "Role of Impaired Gastric Accommodation to a Meal in Functional Dyspepsia", Gastroenterol, (1998) 115:1346-1352. Wilmer A, et al., "Ambulatory Gastrojejunal Manometry in Severe Motility-like Dyspepsia: Lack of Correlation between Dysmotility, Symptoms and Gastric Emptying", Gut, (1998) 42:235-242. Tack J, et al., "Symptom Pattern and Gastric Emptying Rate Assessed by the Octanoic Acid Breath Test in Functional Dyspepsia" [abstract]. Gastroenterol, (1998) 114:A301. Cuomo R, et al., "Functional Dyspepsia Symptoms, Gastric Emptying and Satiety Provocation Test: Analysis of Relationships", Scand J Gastroenterol, (2001) 36:1030-1036. Sarnelli G, et al., "Symptoms Associated with Impaired Gastric Emptying of Solids and Liquids in Functional Dyspepsia", Am J Gastroenterol, (2003) 98:783-788.
[0010] 2. Irritable Bowel Syndrome (IBS)
[0011] The second FGID of interest, IBS, is diagnosed when a patient's symptoms include persistent abdominal pain or discomfort, in the absence of other explanatory organic disease, along with at least two of the following: relief of pain with defecation, onset of symptoms associated with a change in frequency of stools and/or onset of symptoms associated with a change in appearance/form of stools. Thompson W G, et al., "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders —Functional Bowel Disorders and Functional Abdominal Pain", Gut, (1999);45(Suppl II):II43-II47.
[0012] In addition to colonic dysmotility, a number of other GI motility abnormalities have been identified, including delayed gastric emptying, gastroparesis, and small intestine motility abnormalities. Vassallo M J, et al., "Colonic Tone and Motility in Patients with Irritable Bowel Syndrome", Mayo Clin Proc, (1992);67:725-731. Van Wijk H J, et al., "Gastric Emptying and Dyspeptic Symptoms in the Irritable Bowel Syndrome", Scand J Gastroenterol, (1992);27:99-102. Evans P R, et al., "Gastroparesis and Small Bowel Dysmotility in Irritable Bowel Syndrome", Dig Dis Sci (1997);42:2087-2093. Cann P A, et al. "Irritable Bowel Syndrome: Relationship of Disorders in the Transit of a Single Solid Meal to Symptoms Patterns", Gut, (1983);24:405-411. Kellow J E, et al., "Dysmotility of the Small Intestine in Irritable Bowel Syndrome", Gut, (1988);29:1236-1243. Evans P R, et al., "Jejunal Sensorimotor Dysfunction in Irritable Bowel Syndrome: Clinical and Psychosocial Features", Gastroenterol, (1996);110:393-404. Schmidt T, et al., "Ambulatory 24-Hour Jejunal Motility in Diarrhea-Predominant Irritable Bowel Syndrome", J Gastroenterol, (1996);31:581-589. Simren M, et al., "Abnormal Propagation Pattern of Duodenal Pressure Waves in the Irritable Bowel Syndrome (IBS)", Dig Dis Sci, (2000);45:2151-2161.
[0013] A related finding is that patients with constipation-predominant IBS have evidence of decreased vagal tone, while diarrhea-predominant IBS is associated with evidence of increased sympathetic activity. Aggarwal A, et al., "Predominant Symptoms in Irritable Bowel Syndrome Correlate with Specific Autonomic Nervous system Abnormalities", Gastroenterol, (1994); 106:945-950.
[0014] There is no cure for IBS. Treatments include supportive palliative care (antidiarrheals, dietary modification and counseling).
[0015] A recently approved drug to treat selected patients with FGIDs is tegaserod maleate sold under the tradename "Zelnorme®" by Novartis Pharmaceuticals Corp., East Hanover, N.J., USA. The product literature on Zelnorm recognizes the enteric nervous system is a key element in treating IBS. The literature suggests Zelnorm® acts to enhance basal motor activity and to normalize impaired motility. Novartis product description, Zelnorm®, July 2002 (T2002-19). Zelnorm's approved use is limited to females with constipation-related IBS. It is for short-term use only.
[0016] B. Gastroparesis
[0017] The third disease indication discussed here, gastroparesis (or delayed gastric emptying) is associated with upper GI symptoms such as nausea, vomiting fullness, bloating and early satiety. Gastroparesis can be caused by many underlying conditions. The most important, because of chronicity and prevalence, are diabetes, idiopathic and post-surgical. Hombuckle K, et al. "The Diagnosis and Work-Up of the Patient with Gastroparesis", J Clin Gastroenterol, (2000);30:117-124. GI dysmotility in the form of delayed gastric emptying is, by definition, present in these patients.
[0018] In patients with Type 1 diabetes mellitus and delayed gastric emptying, there appears to be a relationship between delayed gastric emptying and low vagal tone. Merio R, et al., "Slow Gastric Emptying in Type 1 Diabetes: Relation to Autonomic and Peripheral Neuropathy, Blood Glucose, and Glycemic Control", Diabetes Care, (1997);20:419-423. A related finding is that patients with Type 1 diabetes have low vagal tone in association with increased gastric antral size, possibly contributing to the dysmotility-associated symptoms seen in these patients. Undeland K A, et al., "Wide Gastric Antrum and Low Vagal Tone in Patients with Diabetes Mellitus Type 1 Compared to Patients with Functional Dyspepsia and Healthy Individuals", Dig Dis Sci, (1996);41:9-16.
[0019] The current treatments for gastroparesis are far from satisfactory. They include supportive care, such as dietary modification, prokinetic drugs, and; when required, interventions such as intravenous fluids and placement of a nasogastric tube may be needed.
[0020] C. Gastroesophageal Reflux Disease (GERD)
[0021] The fourth indication, GERD, can be associated with a wide spectrum of symptoms, including dyspepsia, reflux of gastric contents into the mouth, dysphagia, persistent cough, refractory hyperreactive airway disease and even chronic serous otitis media. Sontag S J, et al., "Asthmatics with Gastroesophageal Reflux: Long Term Results of a Randomized Trial of Medical and Surgical Antireflux Therapies", Am J Gastroenterol, (2003);98:987-999. Poelmans J, et al., "Prospective Study on the Incidence of Chronic Ear Complaints Related to Gastroesophageal Reflux and on the Outcome of Antireflux Therapy", Ann Otol Rhinol Laryngol, (2002); 111:933-938.
[0022] GERD is considered to be a chronic condition for which long-term medical therapy and/or surgical therapy is often deemed necessary, in significant part because esophageal adenocarcinoma is sometimes a consequence of GERD. DeVault K R, et al., "Updated Guidelines for the Diagnosis and Treatment of Gastroesophageal Reflux Disease", Am J Gastroenterol, (1999);94:1434-1442. Lagergren J, et al., "Symptomatic Gastroesophageal Reflux as a Risk Factor for Esophageal Adenocarcinoma", New Engl J Med, (1999);340:825-831.
[0023] The underlying pathophysiological mechanisms in GERD are considered to be transient lower esophageal relaxations (TLESRs) in the presence of either an inadequate pressure gradient between the stomach and the esophagus across the lower esophageal sphincter and/or low amplitude esophageal activity at times when gastric contents do reflux into the esophagus. In addition, gastric distention is thought to be associated with an increase in TLESRs. Mittal R K, et al., "Mechanism of Disease: The Esophagogastric Junction", New Engl J Med, (1997);336:924-932. Scheffer R C, et al., "Elicitation of Transient Lower Oesophageal Sphincter Relaxations in Response to Gastric Distension", Neurogastroenterol Motil, (2002);14:647-655.
[0024] GERD is generally considered to be the result of a motility disorder which permits the abnormal and prolonged exposure of the esophageal lumen to acidic gastric contents. Hunt, "The Relationship Between The Control Of pH And Healing And Symptom Relief In Gastro-Oesophageal Reflux Disease", Ailment Pharmacol Ther., 9 (Suppl. 1) pp. 3-7 (1995). Many factors are believed to contribute to the onset of GERD. These include transient lower esophageal sphincter relaxations (as previously described), decreased LES resting tone, delayed stomach emptying and an ineffective esophageal clearance.
[0025] Certain drugs have had some effectiveness at controlling GERD but fail to treat underlying causes of the disease. Examples of such drugs are H2-receptor antagonists (which control gastric acid secretion in the basal state) and proton pump inhibitors (which control meal-stimulated acid secretion). Hunt, id. Both classes of drugs can raise intragastric pH to or about 4 for varying durations. Hunt, supra.
[0026] Surgery treatments are also employed for the treatment of GERD and include techniques for bulking the lower esophageal sphincter such as fundoplication and techniques described in U.S. Pat. No. 6,098,629 Johnson et al, Aug. 8, 2000. Other surgical techniques include placement of pacemakers for stimulating muscle contractions in the esophageal sphincter, the stomach muscles or in the pyloric valve. U.S. Pat. No. 6,104,955 to Bourgeois, U.S. Pat. No. 5,861,014 to Familoni.
[0027] A summary of GERD treatments can be found in DeVault, et al., "Updated Guidelines for the Diagnosis and Treatment of Gastroesophageal Reflux Disease", Amer. J. of Gastroenterology, Vol. 94, No. 6, pp. 1434-1442 (1999).
[0028] Notwithstanding multiple attempts at various types of treatment, GERD continues to be a serious disease proving to be difficult to treat by any of the foregoing prior art techniques. In view of the foregoing and notwithstanding various efforts exemplified in the prior art, there remains a need for an effective treatment for GERD. It is an object of the present invention to provide a novel treatment and novel apparatus for the treatment of GERD.
[0029] D. Electrical Stimulation to Treat GI Disorders
[0030] Treatment of gastrointestinal diseases through nerve stimulation have been suggested. For example, U.S. Past. No. 6,238,423 to Bardy dated May 29, 2001 describes a constipation treatment involving electrical stimulation of the muscles or related nerves of the gut. U.S. Pat. No. 6,571,127 to Ben-Haim et al. dated May 27, 2003 describes increasing motility by applying an electrical field to the GI tract. U.S. Pat. No. 5,540,730 to Terry, Jr. et al., dated Jul. 30, 1996 describes a motility treatment involving vagal stimulation to alter GI contractions in response to a sense condition indicative of need for treatment. The '730 patent also uses a definition of dysmotility more restrictive than in the present application. In the '730 patent, dysmotility is described as hyper- or hypo-contractility. In the present application, dysmotility is a broader concept to refer to all abnormalities of gastric emptying or bowel transfer regardless of cause. U.S. Pat. No. 6,610,713 to Tracey dated Aug. 26, 2003 describes inhibiting release of a proinflammatory cytokine by treating a cell with a cholinergic agonist by stimulating efferent vagus nerve activity to inhibit the inflammatory cytokine cascade.
[0031] A substantial body of literature is developed on nerve stimulation. For example, in Dapoigny et al., "Vagal influence on colonic motor activity in conscious nonhuman primates", Am. J. Physiol., 262: G231-G236 (1992), vagal influence on colonic motor activity was investigated in conscious monkeys. To block antidromic interference, the vagus was blocked via vagal cooling and a vagal stimulation electrode was implanted distal to the vagal block. It was noted that vagal efferent stimulation increased contractile frequency and that the vagus has either a direct or indirect influence on fasting and fed colonic motor activity throughout the colon, and that a non-adrenergic, noncholinergic inhibitory pathway is under vagal control.
[0032] Colonic and gastric stimulation are also described in a number of articles associated with M. P. Mintchev. These include: Mintchev, et al., "Electrogastrographic impact of multi-site functional gastric electrical stimulation", J. of Medical Eng. & Tech., Vol. 23, No. 1 pp. 5-9 (1999); Rashev, et al., "Three-dimensional static parametric modeling of phasic colonic contractions for the purpose of microprocessor-controlled functional stimulation", J. of Medical Eng. & Tech., Vol. 25, No. 3 pp. 85-96 (2001); Lin et al., "Hardware-software co-design of portable functional gastrointestinal stimulator system", J. of Medical Eng. & Tech., Vol. 27, No. 4 pp. 164-177 (2003); Amaris et al., "Microprocessor controlled movement of solid colonic content using sequential neural electrical stimulation", Gut, 50: pp 475-479 (2002) and Rashev et al., "Microprocessor-Controlled Colonic Peristalsis", Digestive Diseases and Sciences, Vol. 47, No. 5, pp. 1034-1048 (2002).
[0033] The foregoing references describe nerve stimulation to stimulate muscular contraction in the GI tract. As will be more fully discussed, the present invention utilizes vagal stimulation to improve vagal tone (similar in concept to improving cardiac electrical tone through cardiac pacing) and/or to treat GI disorders by altering the nature of duodenum contents by stimulation pancreatic and biliary output. The invention is also applicable to treating other diseases such as neuropsychiatric disorders.
[0034] Vagal tone has been shown to be associated with dyspepsia. Hjelland, et al., "Vagal tone and meal-induced abdominal symptoms in healthy subjects", Digestion, 65: 172-176 (2002). Also, Hausken, et al., "Low Vagal Tone and Antral Dysmotility in Patients with Functional Dyspepsia", Psychosomatic Medicine, 55: 12-22 (1993). Also, decreased vagal tone has been associated with irritable bowel syndrome. Heitkemper, et al., "Evidence for Automatic Nervous System Imbalance in Women with Irritable Bowel Syndrome", Digestive Diseases and Sciences, Vol. 43, No. 9, pp. 2093-2098 (1998).
[0035] Also, as will be discussed, the present invention includes, in several embodiments, a blocking of a nerve (such as the vagal nerve) to avoid antidromic influences during stimulation. Cryogenic nerve blocking of the vagus is described in Dapoigny et al., "Vagal influence on colonic motor activity in conscious nonhuman primates", Am. J. Physiol., 262: G231-G236 (1992). Electrically induced nerve blocking is described in Van Den Honert, et al., "Generation of Unidirectionally Propagated Action Potentials in a Peripheral Nerve by Brief Stimuli", Science, Vol. 206, pp. 1311-1312. An electrical nerve block is described in Solomonow, et al., "Control of Muscle Contractile Force through Indirect High-Frequency Stimulation", Am. J. of Physical Medicine, Vol. 62, No. 2, pp. 71-82 (1983) and Petrofsky, et al., "Impact of Recruitment Order on Electrode Design for Neural Prosthetics of Skeletal Muscle", Am. J. of Physical Medicine, Vol. 60, No.5, pp. 243-253 (1981). A neural prosthesis with an electrical nerve block is also described in U.S. Patent Application Publication No. US 2002/0055779 A1 to Andrews published May 9, 2002. A cryogenic vagal block and resulting effect on gastric emptying are described in Paterson C A, et al., "Determinants of Occurrence and Volume of Transpyloric Flow During Gastric Emptying of Liquids in Dogs: Importance of Vagal Input", Dig Dis Sci, (2000);45:1509-1516.III. SUMMARY OF THE INVENTION
[0036] According to a preferred embodiment of the present invention, a method and apparatus are disclosed for treating at least one of a plurality of gastrointestinal disorders of a patient characterized at least in part by an altered autonomic balance or altered motility. The method includes electrically stimulating an enteric nervous system of the patient to enhance a functional tone of the enteric nervous system.
[0037] Enteric rhythm management (ERM) treats GI diseases in which dysmotility is thought to play a major role. This therapy is based on the physiological actions of pancreatic exocrine secretion and bile on the composition (osmolality and pH) and the digestion (enzymatic activity and, in the case of fats, emulsification) of intraduodenal chyme, thereby presenting a novel approach to regulating the motility of the GI tract and, in particular, gastric emptying and the digestion and propulsion of chyme through the duodenum and into the jejunum and ileum.
[0038] ERM as a therapy for GI diseases involving dysmotility is based on the following: (1) pacing the delivery of pancreatic exocrine secretion and bile can be used to either up- or down-regulate at least two aspects of GI motility-gastric emptying and small bowel transit—by modulating the osmolality, the pH and the digestion, including emulsification as needed, of intra-duodenal chyme; (2) pacing the efferent activity of the intra-abdominal vagus nerve as needed while blocking afferent activity of that same nerve as needed can be used to treat GI dysmotility in patients with either increased or decreased vagal tone as a component of their disease; and, (3) treating GI dysmotility disorders can and often does require flexibility in adjusting treatment algorithms based on symptomatic response because of inter-patient differences with a diagnostic group and because of intra-patient variability over time.
[0039] The goals of enteric rhythm management in gastroparesis are: 1) to regulate the composition and digestion of duodenal chyme and, by so doing, to facilitate gastric emptying through the modulatory effect of duodenal chemo- and mechanoreceptors on the pylorus and 2) to up-regulate or down-regulate vagal tone to optimize gastricintestinal motility and symptom relief.
[0040] In patient with GERD, ERM utilizing a physiologic enteric pacing device will, as described earlier, allow pacing of the delivery of pancreatic exocrine secretion and bile, thereby initiating pyloric relaxation, gastric emptying and consequent reduction in gastric distention, leading to a decrease in the underlying mechanism of GERD, that is, TLESRs.
[0041] Kellow J E, et al., "Rome II: A Multinational Consensus Document on Gastrointestinal Disorders—Principles of Applied Neurogastroenterology: Physiology/Motility-Sensation", Gut, (1999);45(Suppl II):II17-II24. Paterson C A, et al., "Determinants of Occurrence and Volume of Transpyloric Flow During Gastric Emptying of Liquids in Dogs: Importance of Vagal Input", Dig Dis Sci, (2000);45:1509-1516. Tougas G, "The Autonomic Nervous System in Functional Bowel Disorders", Gut, (2000);47(Suppl IV):iv78-iv80. Guyton A C, et al., "Propulsion and Mixing of Food in the Alimentary Tract", Textbook of Medical Physiology, 10th ed. Philadelphia: W. B. Saunders and Company, 200:728-737. Guyton A C, et al., "Secretory Functions of the Alimentary Tract", Textbook of Medical Physiology, 10th ed. Philadelphia: W. B. Saunders and Company, 200:738-753. Schwartz M P, et al., "Human Duodenal Motor Activity in Response to Acid and Different Nutrients", Dig Dis Sci, (2001);46:1472-1481. Schwartz M P, et al., "Chemospecific Alterations in Duodenal Perception and Motor Response in Functional Dyspepsia", Am J Gastroenterol, (2001);96:2596-2602.
[0042] ERM involves pacing and thereby regulating the timing and the volume of pancreatic exocrine secretion and bile delivered to the intraluminal contents of the duodenum. In one embodiment, this is accomplished with a small, laparoscopically implantable and programmable medical device called a physiologic enteric pacing device. Three leads are positioned intra-abdominally and then connected to a subcutaneous, programmable pulse generator. A pacing lead may be placed on the anterior vagal trunk and another pacing lead may be placed on the posterior vagal trunk. One or more intra-abdominal electrode, i.e. blocking electrodes, may be placed on the vagus nerve proximal to the pacing leads.
[0043] An additional embodiment of the present invention pertains to treating at least one of a plurality of gastrointestinal disorders of a patient by electrically stimulating a vagus nerve of the patient at a stimulation site proximal to at least one site of vagal innervation of a gastrointestinal organ. The electrical stimulation includes applying a stimulation signal at the stimulation site. A proximal electrical blocking signal is applied to the vagus nerve at a proximal blocking site proximal to the stimulation site. The proximal blocking signal is selected to at least partially block nerve impulses proximal to the proximal blocking site.
[0044] The invention further includes a treatment apparatus having a stimulation electrode adapted for placement on a nerve of a patient at a stimulation site and a stimulation signal generator for generating a stimulation signal at the stimulation electrode and selected to electrically stimulate a nerve to induce bi-directional propagation of nervous impulses in a stimulated nerve. The apparatus includes a blocking member for placement on the nerve at a blocking site and creating localized conditions at the blocking site that at least partially diminish transmission of nerve impulses past the blocking site.
[0045] A still further embodiment of the present invention includes a method for treating at least one of a plurality of disorders of a patient where the disorders are associated with a gastrointestinal tract of a patient where the disorders are characterized at least in part by hyper-tonal vagal activity innervating at least one of a plurality of alimentary tract organs of the patient at an innervation site. The method includes applying a neural conduction block to a vagus nerve of the patient at a blocking site proximal to the innervation site. The neural conduction block is selected to at least partially block nerve impulses on the vagus nerve distal to the blocking site.
[0046] A yet further embodiment pertains to a treatment apparatus having an electrically controllable neural conduction electrode adapted to be placed on a vagus nerve of a patient at a blocking site proximal to an innervation site. A blocking signal generator generates a blocking signal selected to at least partially block nerve impulses on the vagus nerve distal to the blocking site.
[0047] A still additional embodiment of the present invention includes a method for treating at least one of a plurality of disorders of a patient by electrically stimulating a vagus nerve at a stimulation site with a stimulation signal selected to have a therapeutic effect on a target organ. An electrical blocking signal is applied to the vagus nerve at a blocking site on a side of said stimulation site opposite the target organ. The blocking signal is selected to at least partially block nerve impulses to a second organ on a side of said blocking site opposite the stimulation site. In specific examples, the target organ may be gastrointestinal or central nervous with the other organ being cardio-respiratory.IV. BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 is a schematic representation of a gastric-emptying feedback loop with a patient-controlled stimulator for stimulating an organ of the loop;
[0049] FIG. 2 is a view similar to FIG. 1 with an automatic controller replacing the patient-controller of FIG. 1 and with feedback circuits to the automatic controller schematically represented;
[0050] FIG. 3 is a schematic illustration of an alimentary tract (GI tract plus non-GI organs such as the pancreas and liver) and its relation to vagal and enteric innervation;
[0051] FIG. 4 is the view of FIG. 3 showing the application of a pacing electrode according to an embodiment of the present invention;
[0052] FIG. 5 is a schematic representation of pacing system;
[0053] FIG. 6 is the view of FIG. 4 showing the application of a nerve conduction block electrode proximal to the pacing electrode;
[0054] FIG. 7 is the view of FIG. 6 showing the application of a nerve conduction block electrode distal to the pacing electrode; and
[0055] FIG. 8 is the view of FIG. 3 showing the application of a nerve conduction block electrode according to an embodiment of the present invention.V. DESCRIPTION OF THE PREFERRED EMBODIMENT
[0056] With reference now to the various drawing figures in which identical elements are numbered identically throughout, a description of the preferred embodiment of the present invention will now be described.
[0057] A. Invention of Parent Application
[0058] FIGS. 1 and 2 and the description which follow are from the aforementioned U.S. patent application Ser. No. 10/358,093 filed Feb. 3, 2003 filed Feb. 3, 2003 and entitled "Method and Apparatus for Treatment of Gastroesophageal Disease (GERD)".
[0059] With initial reference to FIG. 1, a gastric emptying feedback loop is shown schematically for ease of illustration. The feedback loop illustrates a patient's stomach S which is provided with food from the esophagus E. A lower esophageal sphincter LES is shown positioned between the esophagus E and the stomach S. The lower esophageal sphincter normally provides control of reflux of stomach contents into the esophagus E.
[0060] On a proximal or lower end of the stomach S the stomach discharges into the superior duodenum D which is an upper portion of the intestines. The superior duodenum D and the stomach S are separated by a pyloric valve PV which opens to permit gastric emptying from the stomach into the duodenum D.
[0061] Also schematically illustrated in FIG. 1 are nerve paths N providing signal flow paths from both the superior duodenum D and the stomach S to the brain B. An efferent Vagal nerve VN connects the brain B to the pancreas P of the patient. A conduit (pancreatic duct PD) extends from the pancreas P and discharges into the superior duodenum D.
[0062] The presence of food contents within the duodenum D (such contents being referred to as "chyme") may prevent passage of gastric content of the stomach S past the pyloric valve PV into the duodenum D. As long as such gastric contents cannot be passed into the duodenum D, such contents can be forced retrograde past the lower esophageal sphincter LES and into the esophagus E creating the symptoms and discomfort of GERD. The contents discharging from the stomach S into the duodenum D are acidic (and high osmolality) and reside in the duodenum D until pH is elevated (close to a neutral pH of 6-7) and osmolality is normalized.
[0063] The elevation of pH and reduction of osmolality of chyme in the duodenum D results from exocrine secretion being administered from the pancreas P and from bile from the liver into the duodenum D. This raises the pH and lowers the osmolality of the duodenum D content permitting discharge from the duodenum D and thereby permitting gastric emptying across the pyloric valve PV.
[0064] According to the present invention gastroesophageal reflux disease (GERD) results from a derangement of the feedback loops involved in upper GI digestion and motility control. This problem encompasses receptors and reflexes that regulate the propulsive contractions of the stomach, upper duodenum and biliary tree and the secretions of the exocrine pancreas. The interaction of these receptors and reflexes control gastric emptying (by coordinating gastric propulsive contractions and sphincter [primarily pyloric] tone) and regulate the pH and osmolality of the chyme in the duodenum. This chemo-regulation is mediated through control of bile delivery and stimulation of secretion by the exocrine pancreas of fluid delivered to the superior duodenum. Chey et al., "Neural Hormonal Regulation of Exocrine Pancreatic Secretion", Pancreatology, pp. 320-335 (2001).
[0065] Normally, ingestate delivered to the stomach is mixed by low intensity gastric mixing contractions with the enzymatic, ionic, including hydrogen ion (H+), and water secretions of the glands of the stomach. When the material is adequately reduced in size and is a smooth consistency, the fluid, now called chyme, is delivered to the ampulla of the small intestine by the much stronger propulsive, or emptying, contractions of the stomach coupled with transitory relaxation of the pyloric sphincter. This material is at a very low pH (about 2) and high osmolality, which activates receptors, including those for H+ and osmotic pressure, which are abundant in the wall of the ampulla. This receptor activation initiates the series of reflexes that cause pancreatic exocrine secretion to be delivered into the superior duodenum and ampulla. This fluid contains digestive enzymes, water and buffering compounds to raise the pH, and reduce the osmolality, of the chyme.
[0066] Once a neutral pH and physiological osmolality are achieved, then propulsive contractions in the superior duodenum move the chyme out of the superior portion into the length of the duodenum; At which point the stretch and baro-receptors in the ampulla allow the pyloric sphincter to relax and another bolus of gastric contents is delivered into the ampulla by the peristaltic gastric emptying contractions. This material, at a very low pH (less than 2), activates hydrogen ion (H+) on receptors of the ampulla (upper most portion of the duodenum) causing the pancreatic fluids to be delivered to the material in the ampulla restarting the cycle as described above. Chapter 3, "The Stomach", Gastrointestinal System, 2nd Ed., M. S. Long editor, Mosby Publisher, London (2002).
[0067] If the control system is down regulated by, for example, by increased pH of gastric contents entering the ampulla, feedback may thereby be reduced from the H+ receptors in the duodenum that stimulate pancreatic exocrine secretion and bile delivery to the duodenum, then movement of chyme from the superior duodenum is delayed, causing delay of gastric emptying. Mabayo, et al., "Inhibition of Food Passage by Osmeprazole in the Chicken", European J. of Pharmacology, pp. 161-165 (1995).
[0068] In GERD, this reflex is inhibited in such a way that the stomach empties more slowly so that the gastric emptying contractions force gastric contents to flow retrograde into the esophagus. This is a result of the situation in which the gastric emptying contractions are vigorous but must operate against a contracted pyloric sphincter. These vigorous peristaltic contractions eventually begin to force gastric contents to flow retrograde into the esophagus because of the inherent imbalance between a very strong pyloric sphincter and a much weaker gastroesophageal sphincter. The delay in gastric emptying is directly related to a slow down in the transport of chyme out of the ampulla and superior duodenum. The drugs used to treat this disease raise pH further dampening the hydrogen-receptor-pancreatic secretion loop, further delaying gastric emptying. Benini, "Gastric Emptying and Dyspeptic Symptoms in Patients with Gastroesophageal Reflux", Amer. J. of Gastroenterology, pp. 1351-1354 (1996).
[0069] The present invention is directed towards reestablishing the link between gastric emptying and pancreatic secretion delivery, thereby addressing the main pathology of this disease by shortening chyme residence time in the superior duodenum so that intestinal contents move into the distal digestive tract in a more normal manner. According to a first embodiment, this is done by stimulating the H+ ion receptors or by stimulation of the pancreas directly or via its para-sympathetic innervation (pre-ganglionic Vagal nerves). Stimulation of pancreatic exocrine secretion has been shown by direct stimulation of the thoracic vagus nerves in dogs. Kaminski et al., "The Effect of Electrical Vagal Stimulation on Canine Pancreatic Exocrine Function", Surgery, pp. 545-552 (1975). This results in a more rapid (normal) neutralization of chyme in the ampulla, allowing it move down the duodenum more quickly so that gastric emptying is returned to a more normal pace.
[0070] Acidity (pH) can be assessed by measuring bicarbonate. It will be understood that references to —H includes such indirect measurements. Also, effects of the therapy described herein can be assessed and/or controlled by measuring an indication of pancreatic exocrine secretion or bile (e.g., HCO3−).
[0071] An alternative embodiment uses gastrocopic delivery of a paralyzing agent (e.g. botulism toxin) to the pyloric valve along with use of H2 antagonists or PPI's to manage the acidity of the chyme reaching the duodenum.
[0072] As an additional alternative to pancreatic stimulation, the gall bladder can be stimulated to encourage bile movement into the duodenum. Shown schematically in the figures, the gall bladder GB resides below the liver L. The gall bladder is connected to the small intestine (specifically the duodenum D) via a bile duct BD. The bile duct BD can discharge directly into the duodenum D or via the pancreatic duct PD as shown. The bile can normalize the chyme to accelerate duodenal emptying. Bile consists of bile acids (detergents that emulsify lipids), cholesterol, phospholipids, electrolytes such as (Na+, K+, Ca+2, Cl−, HCO3−) and H2O. Chapter 4, "The Liver and Biliary Tract", Gastrointestinal System, 2nd Ed., M. S. Long editor, Mosby Publisher, London (2002). The gall bladder GB or bile duct can be stimulated indirectly via stimulation of the vagal nerve VN or directly stimulated by an electrode 11 (shown in phantom lines).
[0073] As illustrated in the figures, an electrical stimulator 10, 20 which may be implanted is provided which alternatively may be directly connected to the Vagal nerve VN or the pancreas P to stimulate the pancreas directly or indirectly to excrete exocrine into the duodenum D (or more distally into the small intestine—e.g., into the jejunum) and increase the pH of chyme in the duodenum D as described. Alternatively, the same can be done to promote bile release. The frequency may be varied to maximize the response and selectively stimulate exocrine instead of endocrine secretions. Rösch et al., "Frequency-Dependent Secretion of Pancreatic Amylase, Lipase, Trypsin, and Chymotrypsin During Vagal Stimulation in Rats", Pancreas, pp. 499-506 (1990). See, also, Berthoud et al., "Characteristics of Gastric and Pancreatic Reponses to Vagal Stimulation with Varied Frequencies: Evidence for Different Fiber Calibers?", J. Auto. Nervous Sys., pp. 77-84 (1987) (showed frequency-response relationship with insulin, i.e., significantly less insulin was released at lower frequencies—2 Hz v. 8 Hz—also, frequency-response curves evidenced distinctly different profiles for gastric, pancreatic and cardiovascular responses.) Slight insulin release can maximize pancreatic exocrine secretion. Chey et al., "Neural Hormonal Regulation of Exocrine Pancreatic Secretion", Pancreatology, pp. 320-335 (2001).
[0074] With a patient control stimulation as shown in FIG. 1, the patient may activate the stimulator 10 by remote transmitter to stimulate an electrical charge either after eating (e.g., about 60 to 90 minutes after eating) or on onset of GERD symptoms. It will be appreciated that there are a wide variety of nerve stimulators and organ stimulators available for implantation and are commercially available and which include connectors for connecting directly to nerves.
[0075] FIG. 2 illustrates an additional embodiment where the patient activated loop is replaced with an automatic loop having a programmable stimulator 20 which receives as an input signals from sensors in the duodenum to measure pH, osmolality or strain (e.g., from baro-sensors) on the duodenum indicating filling or may measure acidity in the esophagus or strain on the lower esophageal sphincter LES or stomach S all of which may be provided to the implantable controller 20 which can be provided with desirable software to process the incoming signals and generate a stimulating signal to either the vagal nerve, the pancreas P or the duodenum D (or jejunum) directly in response to such received signals. It will be appreciated that stimulators and controllers are well within the skill of the art. U.S. Pat. No. 5,540,730 teaches a neurostimulator to stimulate a vagus nerve to treat a motility disorder. U.S. Pat. No. 5,292,344 teaches gastrointestinal sensors, including pH sensors.
[0076] B. Application of Parent Application to Treatments Other than GERD
[0077] In addition to treatment of GERD, the foregoing invention is applicable to treatment of a plurality of GI diseases associated with delayed gastric emptying or altered autonomic activity. These include functional gastrointestinal disorders and gastroparesis. Furthermore, applicants have determined that duodenal content impacts a plurality of motility disorders throughout the bowels and can diseases associated with dysmotility (e.g., irritable bowel syndrome). Accordingly it is an object of the present invention to use the teachings of the aforementioned parent application to treat GI disorders associated with delayed gastric emptying and abnormal intestinal transport.
[0078] C. Additional Disclosure of the Present Application
[0079] 1. Enteric Innervation
[0080] FIG. 3 is a schematic illustration of an alimentary tract (GI tract plus non-GI organs such as the pancreas and ball bladder, collectively labeled PG) and its relation to vagal and enteric innervation. The lower esophageal sphincter (LES) acts as a gate to pass food into the stomach S and, assuming adequate function of all components, prevent reflux. The pylorus PV controls passage of chyme from the stomach S into the intestines I (collectively shown in the figures and including the large intestine or colon and the small intestine including the duodenum, jejunum and ileum).
[0081] The biochemistry of the contents of the intestines I is influenced by the pancreas P and gall bladder PG which discharge into the duodenum. This discharge is illustrated by dotted arrow A.
[0082] The vagus nerve VN transmits signals to the stomach S, pylorus PV, pancreas and gall bladder PG directly. Originating in the brain, there is a common vagus nerve VN in the region of the diaphragm (not shown). In the region of the diaphragm, the vagus VN separates into anterior and posterior components with both acting to innervate the GI tract. In FIGS. 3, 5-8, the anterior and posterior vagus nerves are not shown separately. Instead, the vagus nerve VN is shown schematically to include both anterior and posterior nerves.
[0083] The vagus nerve VN contains both afferent and efferent components sending signals away from and to, respectively, its innervated organs.
[0084] In addition to influence from the vagus nerve VN, the GI and alimentary tracts are greatly influenced by the enteric nervous system ENS. The enteric nervous system ENS is an interconnected network of nerves, receptors and actuators throughout the GI tract. There are many millions of nerve endings of the enteric nervous system ENS in the tissues of the GI organs. For ease of illustration, the enteric nervous system ENS is illustrated as a line enveloping the organs innervated by the enteric nervous system ENS
[0085] The vagus nerve VN innervates, at least in part, the enteric nervous system ENS (schematically illustrated by vagal trunk VN3 which represents many vagus-ENS innervation throughout the cut). Also, receptors in the intestines I connect to the enteric nervous system ENS. Arrow B in the figures illustrates the influence of duodenal contents on the enteric nervous system ENS as a feedback to the secretion function of the pancreas, liver and gall bladder. Specifically, receptors in the intestine I respond the biochemistry of the intestine contents (which are chemically modulated by the pancreao-biliary output of Arrow A). This biochemistry includes pH and osmolality.
[0086] In the figures, vagal trunks VN1, VN2, VN4 and VN6 illustrate schematically the direct vagal innervation of the GI organs of the LES, stomach S, pylorus PV and intestines I. Trunk VN3 illustrates direct communication between the vagus VN and the ENS. Trunk VN5 illustrates direct vagal innervation of the pancreas and gall bladder. Enteric nerves ENS 1-ENS4 represent the multitude of enteric nerves in the stomach S, pylorus PV, pancreas and gall bladder PG and intestines I.
[0087] While communicating with the vagus nerve VN, the enteric nervous system ENS can act independently of the vagus and the central nervous system. For example, in patients with a severed vagus nerve (vagotomy—an historical procedure for treating ulcers), the enteric nervous system can operate the gut. Most enteric nerve cells are not directly innervated by the vagus. Gershon, "The Second Brain", Harper Collins Publishers, Inc, New York, N.Y. p. 19 (1998)
[0088] In FIG. 3, the vagus VN and its trunks (illustrated as VN1-VN6) and the enteric nervous system ENS are shown in phantom lines to illustrate reduced vagal and enteric nerve tone (i.e., sub-optimal nerve transmission levels). Reduced vagal and enteric tone contribute directly to the ineffectiveness of the GI organs as well as indirectly (through reduced pancreatic/biliary output). The reduced pancreatic/biliary output is illustrated by the dotted presentation of arrow A. As previously discussed, the vagus can be stimulated to stimulate pancreatic or biliary output. Therefore, the reduced output of arrow A results in a reduced feedback illustrated by the dotted presentation of arrow B.
[0089] 2. Enteric Rhythm Management (ERM)
[0090] The benefits of the present invention are illustrated in FIG. 4 where a stimulating or pacing electrode PE is applied to the vagus VN. While only one electrode is shown in FIG. 4, separate electrodes could be applied to both the anterior and posterior vagus nerves (or to the common vagus or vagal branches). In a preferred embodiment, the electrode PE is placed a few centimeters below the diaphragm and proximal to stomach and pancreo/biliary innervation. While this placement is presently preferred for ease of surgical access, other placement locations may be used.
[0091] By pacing the vagus through the pacing electrode, vagal tone is optimized by either up- or down-regulation. With reference to the parasympathetic and enteric nervous systems, "tone" refers to basal activity of a nerve or nervous system facilitating appropriate physiologic response to a patient's internal environment. For example, low vagal tone implies a reduction in vagus nerve activity resulting in decreased response of the alimentary tract to ingested food. As used in the present application, "pacing" is not limited to mean timed events coordinated with specifically timed physiologic events. Instead, pacing means any electrical stimulation of a nerve trunk to induce bi-directional propagation of nervous impulses in the stimulated nerve.
[0092] The operating effectiveness of the vagus is enhanced so that local physiological signals generated in the enteric nervous system (or sent to the brain from the organs) are more appropriately responded to within the alimentary tract. Due to its innervation of the enteric nervous system, pacing of the vagus enhances the functional tone of the enteric nervous system. By enhancing the functional tone it will be noted that the stimulation pacing is elevating the degree of functionality of the vagus and enteric nerves. In this context, "pacing" is not meant to mean timed pulsed coordinated with muscular contractions or synchronized with other invents. Pacing means elevating the activity level of the nerves.
[0093] Tonal enhancement of the vagus and enteric nerves is illustrated by the solid lines for the nerves VN, ENS in FIG. 4. Vagal trunk VN5 is in solid line to illustrate enhanced tone of the many vagal nerve components communicating with the enteric nervous system ENS. Direct vagal innervation of the LES, stomach S, pylorus PV and intestines I remains shown as low tone indicated by phantom lines VN1, VN2, VN4, VN6. The tonal pacing described herein is not intended to trigger or drive the muscular contractility of these organs. The stimulation is not intended to be timed to trigger contractility and is not provided with an energy level sufficient to drive peristaltic contractions. Instead, these functions remain controlled by the central and enteric nerves systems. The enhanced nerve tone provided by the present invention permits these functions to occur.
[0094] Pacing to enhance vagal tone is not initiated in response to any senses event (or in anticipation of an immediate need to GI activity). Instead, the pacing can be done intermittently over the day to provide an enhanced level of operating functionality to the vagus. By way of non-limiting example, the stimulation pacing can be done during awake hours. For example, every ten minutes, pacing signals can be sent to the pacing electrodes. The pacing signals have a duration of 30 seconds with a current of 4 mA, a frequency of 12 Hz and an impulse duration of 2 msec. These parameters are representative only. A wide range of signal parameters may be used to stimulate the vagus nerve. Examples of these are recited in the afore-referenced literature
[0095] As will be further discussed, the present invention permits ERM to be uniquely designed and modified by an attending physician to meet the specific needs of individual patients. For example, pacing can be limited to discrete intervals in the morning, afternoon and evening with the patient free to coordinate meals around these events.
[0096] In addition to enhancing vagal and enteric tone directly, the pacing also enhances the pancreatic and biliary output for the reasons discussed above. Namely, while ERM does not drive muscular events over nerve trunks VN1, VN2, VN4, VN6, the enhanced tone stimulates pancreo-biliary output over trunk VN5 (illustrated by the solid line of VN5 in FIG. 4). This enhanced output is illustrated as solid arrow A′ in FIG. 4. As a consequence there is a greater feedback to the intestinal receptors as illustrated by solid arrow B′ in FIG. 4. This enhanced biochemistry feedback further enhances the tone of the enteric nervous system ENS.
[0097] 3. Implantable Pacing Circuit
[0098] A representative pacing circuit 100 is schematically shown in FIG. 5. Similar to cardiac pacing devices, an implantable controller 102 contains an induction coil 104 for inductive electrical coupling to a coil 106 of an external controller 108. The implantable controller 102 includes anterior and posterior pulse generators 110, 112 electrically connected through conductors 114, 116 to anterior and posterior pacing electrodes 118, 120 for attachment to anterior and posterior trunks, respectively, of the vagus nerve VN. The implantable controller 102 also includes a battery 122 and a CPU 124 which includes program storage and memory. The timing and parameters of the pulse at the electrodes 118, 120 can be adjusted by inductively coupling the external controller 108 to the implantable controller 102 and inputting pacing parameters (e.g., pulse width, frequency and amplitude).
[0099] While a fully implantable controller 102 is desirable, it is not necessary. For example, the electrodes 118, 120 can be implanted connected to a receiving antenna placed near the body surface. The control circuits (i.e., the elements 124, 110, 112 and 108) can be housed in an external pack worn by the patient with a transmitting antenna held in place on the skin over the area of the implanted receiving antenna. Such a design is forward-compatible in that the implanted electrodes can be later substituted with the implantable controller 102 at a later surgery if desired.
[0100] Although not shown in FIG. 5, the controller 102 can also include circuits generating nerve conduction block signals (as will be described) which connect to electrodes which may be positioned on a nerve proximally, distally (or both) of the electrodes 118, 120.
[0101] 4. Nerve Conduction Block
[0102] FIG. 6 shows an alternative embodiment using a nerve conduction blocking electrode PBE proximal to the pacing electrode for providing a conduction block. A nerve block is, functionally speaking, a reversible vagotomy. Namely, application of the block at least partially prevents nerve transmission across the site of the block. Removal of the block restores normal nerve activity at the site. A block is any localized imposition of conditions that at least partially diminish transmission of impulses.
[0103] The vagal block may be desirable in some patients since unblocked pacing may result in afferent vagal and antidromic efferent signals having undesired effect on organs innervated by the vagus proximal to the GI tract (e.g., undesirable cardiac response). Further, the afferent signals of the pacing electrode PE can result in a central nervous system response that tends to offset the benefits of the pacing electrode on the ENS and pancreo/biliary function. thereby reducing the GI and enteric rhythm management effectiveness of vagal pacing.
[0104] The block may be intermittent and applied only when the vagus is paced by the pacing electrode PE. The preferred nerve conduction block is an electronic block created by a signal at the vagus by an electrode PBE controlled by the implantable controller (such as controller 102 or an external controller). The nerve conduction block can be any reversible block. For example, cryogenics (either chemically or electronically induced) or drug blocks can be used. An electronic cryogenic block may be a Peltier solid-state device which cools in response to a current and may be electrically controlled to regulate cooling. Drug blocks may include a pump-controlled subcutaneous drug delivery.
[0105] With such an electrode conduction block, the block parameters (signal type and timing) can be altered by a controller and can be coordinated with the pacing signals to block only during pacing. A representative blocking signal is a 500 Hz signal with other parameters (e.g., timing and current) matched to be the same as the pacing signal). While an alternating current blocking signal is described, a direct current (e.g., −70 mV DC) could be used. The foregoing specific examples of blocking signals are representative only. Other examples and ranges of blocking signals are described in the afore-mentioned literature (all incorporated herein by reference). As will be more fully described, the present invention gives a physician great latitude in selected pacing and blocking parameters for individual patients.
[0106] Similar to FIG. 4, the vagus VN and enteric nervous system ENS in FIG. 6 distal to the block PBE are shown in solid lines to illustrate enhanced tone (except for the direct innervation VN1, VN2, VN4, VN6 to the GI tract organs). Similarly, arrows A′, B′ are shown in solid lines to illustrate the enhanced pancreo-biliary output and resultant enhanced feedback stimulation to the enteric nervous system ENS. The proximal vagus nerve segment VNP proximal to the block PBE is shown in phantom lines to illustrate it is not stimulated by the pacing electrode PE while the blocking electrode PBE is activated.
[0107] 5. Proximal and Distal Blocking
[0108] FIG. 7 illustrates the addition over FIG. 6 of a nerve conductive block DBE distal to the pacing electrode PE. The proximal block PBE prevents adverse events resulting from afferent signals and heightens the GI effectiveness by blocking antidromic interference as discussed with reference to FIG. 6.
[0109] In FIG. 7, the distal block DBE is provided in the event there is a desire to isolate the pacing effect of electrode PE. For example, a physician may which to enhance the vagus and enteric activity in the region proximal to the duodenum but may wish to avoid stimulating pancreo-biliary output. For example, a patient may have a GI problem without apparent colon dysfunction (e.g., gastroparesis functional dyspepsia without bowel symptoms). Placing the distal block DBE on a branch of the vagus between the pacing electrode PE and the pancreas and gall bladder PG prevents increased pancreo-biliary output and resultant feedback (illustrated by dotted arrows A and B in FIG. 7 and dotted distal vagal nerve segment VND and vagal trunk VN5).
[0110] 6. Blocking As An Independent Therapy
[0111] FIG. 8 illustrates an alternative embodiment of the invention.
[0112] In certain patients, the vagus nerve may be hyperactive contributing to diarrhea-dominant IBS. Use of a blocking electrode alone in the vagus permits down-regulating the vagus nerve VN, the enteric nervous system ENS and pancreo-biliary output. The block down-regulates efferent signal transmission. In FIG. 8, the hyperactive vagus is illustrated by the solid line of the proximal vagus nerve segment VNP. The remainder of the vagus and enteric nervous system are shown in reduced thickness to illustrate down-regulation of tone. The pancreo-biliary output (and resulting feedback) is also reduced. In FIG. 8, the blocking electrode BE is shown high on the vagus relative to the GI tract innervation (e.g., just below the diaphragm), the sole blocking electrode could be placed lower (e.g., just proximal to pancreo/biliary innervation VN5).
[0113] 7. Application to Obesity
[0114] The foregoing discussion has been described in a preferred embodiment of treating FGIDs, gastroparesis and GERD. Obesity is also treatable with the present invention.
[0115] Recent literature describes potential obesity treatments relative to gut hormone fragment peptide YY3-36. See, e.g., Batterham, et al., "Inhibition of Food Intake in Obese Subjects by Peptide YY3-36", New England J. Med., pp. 941-948 (Sep. 4, 2003) and Korner et al., "To Eat or Not to Eat—How the Gut Talks to the Brain", New England J. Med., pp. 926-928 (Sep. 4, 2003). The peptide YY3-36 (PPY) has the effect of inhibiting gut motility through the phenomena of the ileal brake. Vagal afferents create a sensation of satiety.
[0116] The present invention can electrically simulate the effects of PPY by using the vagal block to down-regulate afferent vagal activity to create a desired sensation of satiety. Since the down-regulation does not require continuous blocking signals, the beneficial efferent signals are permitted.
[0117] 8. Application to Other Therapies
[0118] There are numerous suggestions for vagal pacing or stimulation to treat a wide variety of diseases. For example, U.S. Pat. No. 5,188,104 dated Feb. 23, 1993 describes vagal stimulation to treat eating disorders. U.S. Pat. No. 5,231,988 dated Aug. 3, 1993 describes vagal stimulation to treat endocrine disorders. U.S. Pat. No. 5,215,086 dated Jun. 1, 1993 describes vagal stimulation to treat migraines. U.S. Pat. No. 5,269,303 dated Dec. 14, 1993 describes vagal stimulation to treat dementia. U.S. Pat. No. 5,330,515 dated Jul. 19, 1994 describes vagal stimulation to treat pain. U.S. Pat. No. 5,299,569 dated Apr. 5, 1994 describes vagal stimulation to treat neuropsychiatric disorders. U.S. Pat. No. 5,335,657 dated Aug. 9, 1994 describes vagal stimulation to treat sleep disorders. U.S. Pat. No. 5,707,400 dated Jan. 13, 1998 describes vagal stimulation to treat refractory hypertension. U.S. Pat. No. 6,473,644 dated Oct. 29, 2002 describes vagal stimulation to treat heart failure. U.S. Pat. No. 5,571,150 dated Nov. 5, 1996 describes vagal stimulation to treat patients in comas. As previously described, U.S. Pat. No. 5,540,730 dated Jul. 30, 1996 describes vagal stimulation to treat motility disorders and U.S. Pat. No. 6,610,713 dated Aug. 26, 2003 describes vagal stimulation to inhibit inflammatory cytokine production. All of the foregoing U.S. patents listed in this paragraph are incorporated herein by reference.
[0119] All of the foregoing suffer from undesired effects of vagal pacing on cardiovascular, gastrointestinal or other organs. Nerve conduction blocking permits longer pulse durations which would otherwise have adverse effects on other organs such as those of the cardiovascular or gastrointestinal systems. In accordance with the present invention, all of the foregoing disclosures can be modified by applying a blocking electrode and blocking signal as disclosed herein to prevent adverse side effects. By way of specific example, pacing a vagus nerve in the thoracic cavity or neck combined with a blocking electrode on the vagus nerve distal to the pacing electrode can be used to treat neuropsychiatric disorders (such as depression and schizophrenia) and Parkinson's and epilepsy and dementia. In such treatments, the blocking electrode is placed distal to the stimulating electrode 25 shown in FIGS. 4 and 2, respectively, of each of U.S. Pat. Nos. 5,269,303 and 5,299,569. The present invention thereby enables the teachings of the afore-referenced patents listed in foregoing two paragraphs.
[0120] As described, the parameters of the stimulating and blocking electrodes can be inputted via a controller and, thereby, modified by a physician. Also, FIG. 2 illustrates a feedback for controlling a stimulating electrode. Feedbacks for stimulating electrodes are also described in the patents incorporated by reference. The blocking electrode can also be controlled by an implanted controller and feedback system. For example, physiologic parameters (e.g., heart rate, blood pressure, etc.) can be monitored. The blocking signal can be regulated by the controller to maintain measured parameters in a desired range. For example, blocking can be increased to maintain heart rate within a desired rate range during stimulation pacing.
[0121] 9. Opportunity for Physician to Alter Treatment for Specific Patient
[0122] Gastrointestinal disorders are complex. For many, the precise mechanism is of the disorder is unknown. Diagnosis and treatment are often iterative processes. The present invention is particularly desirable for treating such disorders.
[0123] Use of proximal and distal blocking electrodes in combination with one or more pacing electrode permits a physician to alter an operating permutation of the electrodes. This permits regional and local up- or down-regulation of the nervous system and organs. Further, pacing parameters (duty cycle, current, frequency, pulse length) can all be adjusted. Therefore, the treating physician has numerous options to alter a treatment to meet the needs of a specific patient.
[0124] In addition, a physician can combine the present invention with other therapies (such as drug therapies like prokinetic agents).
[0125] With the foregoing detailed description of the present invention, it has been shown how the objects of the invention have been attained in a preferred manner. Modifications and equivalents of disclosed concepts such as those which might readily occur to one skilled in the art, are intended to be included in the scope of the claims which are appended hereto.
1. A method for treating at least one of a plurality of disorders of a patient where the disorders are associated with a gastrointestinal tract of a patient where said disorders are characterized at least in part by hyper-tonal vagal activity innervating at least one of a plurality of alimentary tract organs of said patient at an innervation site, said method comprising:
- applying a neural conduction block to a vagus nerve of said patient at a blocking site proximal to said innervation site with said neural conduction block selected to at least partially block nerve impulses on said vagus nerve at said blocking site.
2. A method according to claim 1 wherein application of said neural conduction block is variable by a controller to alter a characteristic of said block.
3. A method according to claim 1 wherein said neural conduction block is a cryogenic block.
4. A method according to claim 1 wherein said proximal neural conduction block is a pharmacologic block.
5. A method according to claim 1 wherein said proximal neural conduction block is an electrical conductive block.
6. A method according to claim 1 wherein said at least one of a plurality of disorders is obesity.
7. A method according to claim 6 wherein said neural conduction block is regulated to heighten a sensation of satiety of said patient.
8. A method according to claim 1 wherein said at least one of a plurality of disorders is constipation.
9. A method according to claim 1 wherein said at least one of a plurality of disorders is irritable bowel syndrome.
10. An apparatus for treating at least one of a plurality of disorders of a patient where the disorders are associated with a gastrointestinal tract of a patient where said disorders are characterized at least in part by hyper-tonal vagal activity innervating at least one of a plurality of alimentary tract organs of said patient at an innervation site, said apparatus comprising:
- an electrically controllable neural conduction electrode adapted to be placed on a vagus nerve of said patient at a blocking site proximal to said innervation site;
- a blocking signal generator for generating a blocking signal selected to at least partially block nerve impulses on said vagus nerve at said blocking site.
11. An apparatus according to claim 10 comprising a controller for selectively controlling parameters of said blocking stimulation.
12. An apparatus according to claim 11 wherein said controller is implantable within said patient's body.
13. An apparatus according to claim 11 wherein said controller is inductively coupled to said blocking electrode to electrically controlling said electrode and member remote from an interior of said patient's body.
Type: Application
Filed: Sep 29, 2003
Publication Date: Sep 2, 2004
Patent Grant number: 7489969
Applicant: Beta Medical, Inc.
Inventors: Mark B. Knudson (Shoreview, MN), Richard R. Wilson (Arden Hills, MN), Katherine S. Tweden (Mahtomedi, MN), Timothy R. Conrad (Eden Prairie, MN)
Application Number: 10674330
International Classification: A61N001/18;


text:
Quality: Full
Video Game Category: PSP
PSP Game Language:
Download Game ISO: Working
Download Game CSO: Working
Tested in: Firmware 3.xx OE-A
For those of you have are serious in PAC-MAN World 3 addict like myself, and are into video games, have probably seen or heard of the new PAC-MAN World 3 free video game. I saw the PAC-MAN World 3 trailer about a month ago and was really impressed. I took some time to play around with this free full game PAC-MAN World 3 and I was impressed.
PAC-MAN World 3 marks the latest addition to the much loved and effortlessly fun gaming series like Nintendo game, PSP game, PS2 game, PS3 game, WII game, Xbox game etc.
PAC-MAN World 3 can also spark a gamers interest in a particular subject, causing them to not only pick up information throughout the free full game like PAC-MAN World 3, but to seek further details at a later date.
I'm going to tell you some ups and downs the video game has after playing and finishing it, and it'll be up to you to decide if it is worth playing for yourself. Playing these game: PAC-MAN World 3 that combines challenging fun with a little bit of aerobic activity, assists in the growth of thinking and problem-solving skills, as well as reasoning and memory capabilities.
Try to download game for free full PAC-MAN World 3 here.
PAC-MAN World 3 USA FULL CSO 760 MB
Part 1 : http://ifile.it/wife2xb Rar : 125 MB]
Part 2 : http://ifile.it/g09c6qu [Rar : 125 MB]
Part 3 : http://ifile.it/h3x9vrw [Rar : 125 MB]
Part 4 : http://ifile.it/j51lhgw [Rar : 125 MB]
Part 5 : http://ifile.it/6ajn4k2 [Rar : 125 MB]
Part 6 : http://ifile.it/evymq60 [Rar : 125 MB]
Part 7 : http://ifile.it/zn9dg2p [Rar : 11 MB]
Uploader and Tested by jusexe
Password : hako
Ripped : nothing
Tested : 3.90m33-3
Mirror Download Links:
Link 1: Direct Download Full ISO Here!!
Link 2: Direct PSP Download Single Link!!
Link 3: PSP Download Mirror Link!!
Frequently Ask Questions Support - PSP HELP
Note: You've downloaded (all parts) and right click on part 1 "Extract to folder, enter password,then all parts will be extracted and you will see the ISO or CSO file. Put this ISO or CSO file in to, main ISO folder which is on the PSP Memory Stick
This file has been downloaded 2,147 times.

subset: commoncrawl


text:
The Dubai Lynx has removed all of FP7 Doha's winning work for Samsung from its website following a request by the Korean electronics company.
The move has been made in response to the religious fall-out in Lebanon caused by an FP7 Doha ad featuring Jesus taking a photograph of a group of nuns with the new Samsung SL310W.
The ad has been depicted as an attack "against Christian symbols" by certain factions in Lebanon and is causing significant damage to Samsung's image in the Levant.
FP7 Doha's Samsung work is currently under investigation by the Dubai Lynx, as is its work for clients Higeen Mouthwash and Nissan. FP7 is also undertaking its own internal 'fact-finding mission'.
Steve Lane, festival director of the Dubai Lynx, said the presence of the ads on the Lynx website had been fanning the flames of the controversy in Lebanon.
A decision on whether FP7 Doha will be stripped of its awards is expected early next week. If the decisions go against the agency, it could be stripped of its Agency of the Year title. Other FP7 Doha ads have also been removed from the website.
Update: In a statement released by Samsung in Lebanon, the company has categorically distanced itself from the ad.
"The company did not commission, develop or approve the publishing of the religiously insensitive advertisements," said the statement. "This advertising campaign was produced and submitted by marketing agency, FP7 Doha, without the knowledge or consent of Samsung Electronics."
Sunny Hwang, president of Samsung Electronics Levant, added: "At no time was Samsung Electronics aware of these advertisements and the company has not approved or commissioned FP7 to create any advertising campaigns. Samsung has the utmost respect for all cultures and religions and would never produce or approve the use of such culturally insensitive advertisements."
Phillip Thomas, CEO of Cannes Lions, the organisers of the Dubai Lynx, said: "We accept all entries to the Dubai Lynx Awards in good faith and trust the agencies competing to be honest and accurate with their submissions and details of client sign off. It appears in this case that FP7 Doha has knowingly tried to mislead ourselves and our jury regarding work they claimed to have created on behalf of Samsung Electronics, which in reality the client had never seen or approved.
"We have openly stated that any submissions to the awards found to be in breach of our entry criteria will be withdrawn and that will be the case here. We will be vigilant in checking all winning entries meet the criteria in all ways, and if they are found wanting then we will act."


text:
image from nme.com
Release date: 16 June 1997
Tracks: (Click for codes to singles charts.) Airbag / Paranoid Android (6/7/97, #3 UK) / Subterranean Homesick Alien / Exit Music (For a Film) / Let Down (8/16/97 #29 MR) / Karma Police (8/6/97, #69 UK, #14 MR) / Fitter Happier / Electioneering / Climbing Up the Walls / No Surprises (1/24/98 #4 UK) / Lucky (11/4/95, --) / The Tourist
Sales (in millions): 2.0 US, 0.9 UK, 3.0 Europe, 7.5 world
Peak: 21 US, 12 UK
Review: OK Computer "is art-rock at its most rewarding and contradictory." BN Its "astonishing emotional and compositional complexity" BN established "Radiohead as one of the most inventive and rewarding guitar-rock bands of the '90s," AMG even invoking some to call them "The Only Band That Matters." TL
The album "vigorously defies fast analysis, flip judgment and easy interpretation" RS and "becomes even more impressive with repeated listens." AMG Radiohead eschewed "many of the obvious elements of guitar rock, creating music that is subtle and textured, yet still has the feeling of rock & roll." AMG The album is marked by "countless schizophrenic twists and turns." BN It is "subtly layered but startlingly bombastic, melancholic but beautifully serene, fractured and chaotic but completely sure of its own sonic ambition." BN It "rejects speed and hooks in favor of languorous texture and morose details." AZ "It's a thoroughly astonishing demonstration of musical virtuosity" AMG in which "it's not always easy to determine which instrument makes which noise. The melodies are unorthodox and tangentia" QM and the "more planetarium-compatible noises" QM garnered comparisons to Pink Floyd. AZ
Thematically, it is a "spooky, atmospheric, intense and paranoid rumination" TL on "the debilitating clutter of modern life and the desire to escape from it." BN It explores the idea that "the past is being perpetually deleted (with the future yet to be downloaded)." URB It "would be insufferable if it didn't float along on a procession of gorgeous melodies…punctuated by Thom Yorke's elastic tenor" TL and ability to shift his voice "effortlessly…from a sweet falsetto to vicious snarls." AMG
Paranoid Android
Highlights include the "sighing" AMG and "superb Karma Police" QM as well as "the complex, multi-segmented Paranoid Android." AMG It is packed with "alternating time signatures, wild dynamic shifts, drama and adrenaline to spare" VH1 is "a 'Bohemian Rhapsody' for the nineties." AD Finally, "the slow and emotionally draining closing five minute long epic" AD "No Surprises is Radiohead's prettiest moment to date." QM
Karma Police
Resources and Related Links:
- Radiohead's DMDB Encyclopedia entry
- album page on DMDB website (even more in-depth look at album)
- AMG All Music Guide review by Stephen Thomas Erlewine
- AZ Amazon.com review by Douglas Wolk
- BN Barnes & Noble review by Colin Helms
- AD Adrian Denning
- QM Q magazine review by David Cavanaugh. Was at Q4music.com. Review no longer online.
- RV The Review "100 Greatest Albums of All Time" by Clarke Speicher (October – November 2001; Vol. 128: numbers 12-23).
- RS RollingStone.com review by David Fricke
- TL Time Magazine's All-TIME 100 Albums by Josh Tyrangiel and Alan Light (11/13/06).
- URB URB magazine. "The 50 Greatest Albums Ever" (July 2003).
- VH1 VH1. (2003). 100 Greatest Albums. Edited by Jacob Hoye. Pocket Books: New York, NY.


text:
Photo of junior defender Baba Omosegbon
courtesy of David Silverman.
Live Statistics (vs. UC Santa Barbara)
Live Statistics (at New Mexico)
Live Video at New Mexico (with subscription)
The Matchups:
The sixth-ranked Harvard men's soccer team heads to New Mexico for the Lobo Classic, as the Crimson will face UC Santa Barbara and New Mexico Sept. 17 and 19, respectively.
Harvard enters the weekend unbeaten with a 2-0-1 mark, while the Gauchos stand at 0-2-2 and the Lobos are 3-1-1.
Follow From Home:
Live statistics will be available for both games this weekend and most road contests this fall.
Live statistics vs. UC Santa Barbara
Live statistics at New Mexico
In addition, live video will be available with a subscription for the game against New Mexico.
A History Lesson:
Harvard and UC Santa Barbara have met once, a 1-1 tie, on Sept. 23, 2007. Meanwhile, the Crimson and Lobos have never met on the soccer field.
Moving On Up:
Harvard started the season ranked 10th in the National Soccer Coaches Association of America (NSCAA) national poll, and has since moved up to No. 6. In addition, the Crimson appears 17th in the Top Drawer Soccer and CollegeSoccerNews rankings.
About No. 6 Harvard:
For the second straight year, the Crimson is unbeaten after three games, as Harvard earned a 1-1 tie at then-No. 10 Connecticut Sept. 11. Zack Wolfenzon supplied the Harvard offense with a goal in the 19th minute, while Austin Harms finished the tie with three saves in 110 minutes.
Through three games, Brian Rogers is Harvard's leading scorer with two goals and four points. Wolfenzon, Scott Prozeller and Ross Friedman have also supplied offense for the Crimson with a goal apiece. Kyle Henderson has handed out a team-high two assists, while Rogers has fired a Harvard-best 10 shots.
Harms is off to a strong start in net, going 2-0-1 with a 1.24 goals-against average and eight saves to his credit.
Harvard is outscoring teams by a 6-4 margin, but trails in shots, 47-38, and corner kicks, 17-7.
About UC Santa Barbara:
The Gauchos are hoping to improve on their 0-2-2 start, tying Davidson, 2-2, in their last game Sept. 10. UC Santa Barbara has also tied New Mexico, 1-1, while falling to Cal State Bakersfield, 1-0, and Creighton, 1-0, earlier this fall.
Sam Garza (two goals, one assist) and Michael Tetteh (one goal) have found the back of the net for the Gauchos, who have only scored three goals in four games. Sam Hayden has played all 406 minutes in net, and is 0-2-2 with a 1.11 goals-against mark and 15 stops.
Opponents are outscoring UC Santa Barbara, 5-3, but the Gauchos have a sizable lead in shots, 56-39, and corner kicks, 30-16.
About New Mexico:
The Lobos, who will face Buffalo in the Lobo Classic Sept. 17, are coming off a 2-1 loss at home to Portland Sept. 12. UNM has earned wins this season against Saint Louis, 3-2, and Georgetown, 3-1.
Six different players have scored goals, led by Lance Rozeboom and Levi Rossi, who have tallied two goals apiece and have netted a game-winning tally each. Goalkeeper Justin Holmes has made five saves in four games and owns a 1.44 goals-against average to go along with a 2-1-1 record.
The Lobos have netted eight goals, compared to six for opponents, but are considerably outshooting teams by a 65-25 margin. UNM also has earned 24 corner kicks, while opponents have 18.
Quest For Five Straight:
Harvard has reached the NCAA tournament four straight seasons, advancing to the second round three times. The Crimson reached the tournament in five consecutive seasons from 1968-1972, a program record.
Up Next:
The Crimson returns East to visit Stony Brook Friday, Sept. 24 at 7 p.m.


text:
Eva Longoria: Shimon Peres Latino & Jewish Leaders Meeting!
Eva Longoria strikes a pose with the President of Israel, Shimon Peres, at the Latino and Jewish Leaders meeting held at the Beverly Hilton Hotel on Sunday (March 11) in Beverly Hills, Calif.
The 36-year-old actress (in Zara) was joined by Edward James Olmos and Andy Garcia as Shimon recognized the Latino and Jewish leaders for their relationships and strong historical ties between their communities.
PHOTOS: Check out the latest pics of Eva Longoria
"I can't wait to meet President Peres from Israel tomorrow," Eva wrote on her Twitter the day before. "Looking forward to learning more about the situation in Israel. #peace."
FYI: Eva is wearing "Goldy" pumps by Brian Atwood.


text:
Past Time: Geology in European and American Art
Friday, December 7, 2018Time
10:00 amLocation
Frances Lehman Loeb Art Center Temporary Exhibition Galleries
Past Time: Geology in European and American Art
September 21¬–December 9, 2018
Temporary Exhibitions Gallery
Past Time looks at sketches and studies made by European and American artists from the 1770s to the 1890s who were engaged with a new scientific investigation of the earth. In this arguably golden age of art and science, artists traveled and explored the land internationally, taking keen note of earth's prominent surface features in their watercolors, drawings, and oil sketches. The exhibition features loans from major institutions, and benefits from the generous support of the Art Dealers Association of America Foundation, the Evelyn Metzger Exhibition Fund, and from the Lucy Maynard Salmon Research Fund, awarded by the Vassar College Research Committee. Included are works by Asher B. Durand, Frederic Church, John Singer Sargent, J. M. W. Turner, and Joseph Wright of Derby.
Margaret Vetare
(845) 437-7745
The Frances Lehman Loeb Art Center
- This Month
- Events This Week
- Events Today
- Academic Calendar
- Sign up to receive VassarEvents
This calendar contains a selection of events open to the public, unless otherwise noted. For the full campus calendar, visit: Master Calendar


text:
Main navigation | Main content
Registration has begun for the "Hands-on Fluorescence Workshop for Students in the Biological Sciences." The workshop will be held June 7-9th in the Tate Lab of Physics.
Registration is free, but limited to 8 participants. The workshop is designed for advanced undergraduates and beginning graduate students. Students outside the area of biology with an interest in fluorescence may also apply. The deadline to register is May 31st, 2007.


text:
Monday, 22 September 2008
50 Mile Race Report
We had taken the Milwaukee, WI to Muskeegon, MI ferry with my parents and The Bois. It was a couple hours from the ferry to our little cabin at Pine Creek Lodge, just four miles from the race start. It seemed like the closest lodging to the race.
We eventually found a bar for dinner, called Jackie's in Irons, MI, where pickup trucks lined the parking lot. And almost all the patrons donned cowboy hats.
There was plenty of dancing and karaoke. The Bois was as mesmerized as we were. The food was really good, but I for one was really nervous about the race. I started to feel nauseated.
Back at the cabin we tried to get to bed quickly. And we actually did. But it was so warm and the little Lorax was kicking and moving right next to me in our little bed. I kept thinking about how I just wanted to start the race. I was so antsy to run. I finally fell asleep around 2 am. Normally I would be bothered by this, but I rarely get much sleep before races and it actually doesn't seem to affect how I feel the next day.
We woke up at 6:15 to a beautiful, cool morning. I kept imaging the dark woods and winding trails. I drank lots of coffee and think I managed to eat about 1000 calories worth of chocolate chip coconut brownie bars before the start.
I wore a water belt around my waist with water in it. And I had my ipod. I regret immensely that I didn't bring my camera. I made two trips to the outhouse and, happily, I managed to avoid bowel problems the rest of the day.
This race has a marathon and a 50 miler. Both start at once. There is one loop for the half marathon and the 50 milers do that loop twice. There were about 300 participants there.
It had been a week since my last good run. My entire body was aching to start. I was walking back from saying good luck to SR when the gun went off. For the first mile or so, I went way too fast, just until I could let all of the people at the front pass me. One man was kind enough to tell me that if I was running the 50 miler, I was going too fast :). Strangely, I was a bit hurt by that, but I, of course, slowed down.
At around mile 5, I heard a pack coming up behind me. They were shouting out their pace and seemed to know what they were doing. I latched on to them. Initially, everyone made fun of my accent, which according to my parents has become the same strange mix of a Upper Midwestern-Danish accent that SR has. I was surprised it stood out so much among Michiganites.
I would stay with two of those girls from the pack for the next 3/4 of the race. Their names were Mandy and Rachel. Both from around Ann Arbor, they knew each other from a running club and a running store that Rachel ran. Mandy had a garmin-type device and we were aiming for around a 9 minute pace when we weren't walking hills or stopping at aid stations. Our stops at aid stations were brief. And they convinced me to replace my water with Gatorade to get more calories, which I did.
It sounded like both Rachel and Mandy had had experience winning 50k races in the area (I began thinking I'd do anything just to hang on to them). This was Mandy's first 50 miler and Rachel's second. They did a great job keeping an even pace. After a while we switched off taking the lead. We had such a wonderful time talking about famous ultra runners, enjoying the scenery and sharing bits and pieces about our lives. I would love to run with them more often.
I ate 1 or 2 peanut butter sandwich squares at each aid station and had a cup or two of water or Gatorade.
The second half of the first loop (starting around mile 12) was quite hilly. We walked all of the hills. By the end of the first half, I felt great. I wasn't sore anywhere. This was despite having already taken two tumbles. We did the first 25 miles in 4:15 and found out we were in 3rd, 4th and 5th for the women.
At this point, my parents told me SR was in fifth for the men. The Lorax was looking at his toy fish and wouldn't give me the time of day.
After a brief refueling, the three girls were off again. It was staring to get a bit warmer, but luckily 95% of the course is in the shade of the enormous and amazingly varied trees of the forest. At the start of the first loop, we walked a very gradual incline and I considered pulling ahead. But I knew I had 25 miles to go, so I held back. Then we picked up Jeff (also from Michigan). I knew he would be a lot of fun when he said half of the people he knows call him Tim because of a misunderstanding he never bothered to correct.
At mile 30, Rachel began to feel ill and dropped back. Mandy, Jeff and I made it to the 50k mark at just over 5 hours. I couldn't believe I was ahead of my 50k PR time. I entertained the idea of trying a gu at the aid station, but Mandy warned me not to try anything new on race day.
At around mile 37, I got a big second wind. I took off ahead of Mandy and Jeff. I even thought I might catch SR if I went fast enough. I saw my dad at the next aid station and he said that SR was 1 hour and 20 minutes ahead of me. Wow. I was so proud of him.
I reached a sign that said 3.9 miles to go. I couldn't believe how quickly time had gone! Wow. I put on my music for the first time and mustered up a sprint, knowing I had just over a 5k left. I then reached another aid station at the point I thought would be the finish and they said there were 5 miles to go. There's no crying in baseball, though. (The last sign must have said 3.9 miles to the next aid station)
I told myself over and over "It's just a fun run in the woods." I tried to convince myself I hadn't run at all yet. I listened to music and kept my spirits up. Over and over I heard the crowd at the finish line, but when I took off my headphones, I would realize it was my ears playing tricks. I passed one guy, who served as reassurance that I hadn't gotten off path. He asked me when I dropped the girls. Apparently he was one of the 19 members of their Ann Arbor running club there that day.
The trails were soft dirt winding through one mini ecosystem after another. All of the hills I walked the first time around I ran. I didn't walk at all the last 9 miles, with the exception of one very steep hill. I was a bit sore from my accidental 5k sprint, but not too bad. I finally saw the sign saying there were 0.9 miles left. This last stretch was eternal.
As I saw the finish line, I turned around to see a woman in a white T-shirt and black spandex pants right behind me. My heart nearly jumped out of my chest. I turned back again and she had disappeared. Wow. A real hallucination. As I crossed the finish line, the announcer said "Here's Sealegsgirl... the mom of that cute baby!"
And I was done. It took 8 hours and 49 minutes. I hugged SR. He had finished 3rd for the men and I had finished 3rd for the women. Spectators commented on the dirt covering every inch of my body. It was from the 5 tumbles, most of which were cushioned by my lactating boobs.
Then my parents came up to us with The Lorax. He was smiling and yelling and holding out his arms to me when he saw me. It was a moment I may remember for the rest of my life.
One of the race directors came up to me to congratulate me and handed me a $50 check! And I received a sweatshirt for first in my age group. On top of that, every finisher receives a really nice mug.
I was so happy. It was a wonderfully organized event on a gorgeous course. And I made some friends. I wanted to stick around to see them finish, but after trying to stomach some food, I became quite ill and we all retreated to the Pine Creek Lodge.
What did I learn? Running 4 miles a day for the 6 days before the race is enough tapering. Drinking Gatorade during the race is a great way to get calories. You don't need gu to do well. Walking the hills during the first 30 miles is probably essential to prevent getting sore. Running with a group is great incentive to keep going at a good, even pace.
Thanks Rachel, Mandy and Jeff if you guys are reading this! A huge thanks to my parents for watching The Lorax. And, of course, I couldn't have done this without SR, my running partner and the love of my life.
We would do this race again in a heartbeat and would recommend it to anyone looking for a 50 mile run.
9 comments:
- Danni said...
Congrats!!! That's awesome!!!
- 22 September 2008 at 20:46
- Bec said...
Way to go! Kudos to you both!
- 22 September 2008 at 21:13
- H said...
Congrats! You're a superstar!
Love the report too and the finish line story.
CONGRATS again! totally awesome
- 23 September 2008 at 09:52
- Kate said...
Congrats! Amazing.
As someone who's been more of a lactater (lactator?) over the last year than a runner, I am truly impressed with your ability to do both. You are inspiring.
- 23 September 2008 at 17:05
- SteveQ said...
You learned things in one race that took me many years to learn (well, actually I'm still working on some of them). When I read you PR'ed at 50K, I was expecting a bad crash. Third place! That's great.
I want a toy fish, too.
- 23 September 2008 at 17:52
- Olga said...
What an awesome experience! So happy for both of you guys!
- 23 September 2008 at 17:55
- Meghan said...
Hey Sealegs!
Congrats on finishing your first 50 miler, and for doing it sooooo well! You and your family look great in the photos as well.
- 24 September 2008 at 03:14
- holly said...
Congratulations! What a lovely day for you and your family.
- 24 September 2008 at 05:45
- Lisa said...
Woman, you are a true Rock Star. For real. Way to GO!
Flight of the Conchords? OMG, we love that show.
and yes, that kid is cute....
- 25 September 2008 at 18:18


text:
https://slotsdad.com/ - casino online slots
A blog for storage administrators and data managers.
[Show picture list]
You must log in to post a comment.
The entire contents of this site are Copyright © 2010 by The Data Management Institute, LLC. All rights reserved.
For permission to reprint any materials on this site, please forward your request to firstname.lastname@example.com.
WordPress Admin


text:
MELBOURNE, Australia (AP) Two-time major winner Svetlana Kuznetsova has defeated former No. 1 Caroline Wozniacki 6-2, 2-6, 7-5 to advance to the quarterfinals of the Australian Open.
Kuznetsova, winner of the 2004 U.S. Open and 2009 French Open, broke her Danish opponent in the 11th game of the third set and finished the match with a backhand winner down the line.
Kuznetsova saw her streak of 40 straight Grand Slam appearances broken last year when a right knee injury forced her out of the U.S. Open.
Wozniacki lost her No. 1 ranking to Victoria Azarenka last year after falling in the quarterfinals at Melbourne Park to Kim Clijsters.


text:
-%mf ^fi.V*
•-= • v
In July of 1951, Touche, Ross, Bailey & Smart came to
Kansas City. The firm of Hull & Crouch merged with
TRB&S, and the Kansas City office was opened.
Kansas City . . . a city a little more than 100 years old,
a city noted for its beautiful residential areas, its stately
elm trees; its wide, tree-bordered boulevards. Visitors to
the city are delighted by the quiet beauty of the Country
Club Plaza, the oldest of the shopping centers, with its
Spanish architecture, numerous fountains and smart shops
and dining places. The Nelson Gallery of Art, the Starlight
Theatre and the American Royal, a famous livestock
and horse show, are places of interest to see and
Into this environment came TRB&S. Howard D. Hull
started his own practice in Kansas City in 1937. He was
a native of Ohio, having graduated from Oberlin College
in 1919. Prior to forming his own firm he was employed
in the Kansas City office of Arthur Andersen & Co.
In 1947, Howard D. Hull and John D. Crouch formed
the partnership of Hull & Crouch and this was the firm
that merged with Touche, Ross, Bailey & Smart.
John D. Crouch graduated from the University of
Kansas School of Business in 1938 and in 1941 received
his law degree from the University of Kansas. He entered
the United States Navy the next year and was discharged
as a Lieutenant in 1945. Having started with Arthur


text:
Over the last few decades, one of the most important basic restoration references we attempted to compile and create was how to correctly refurbish, re-plate and restore all or most of the small, underhood sub-assembly parts on a typical 1950s-1970s Chevrolet. Finding answers was, at best, extremely time-consuming. We've asked a lot of shops and also read a lot of factory reference books. So, this all-encompassing story is as complete as we presently know. If by chance we have missed something, feel free to jump in and let us know, c/o Editor Jim Campisano at email@example.com.
Luckily, over the years, we have met some of the best Chevy restoration veterans anywhere, such as Florida's Harold Louisiana, Don Ruhff, Wendell Snowden, Warren Shafer and Denny Williams; Pennsylvania's Vince Dimezza and Frank Incremona; New York's Gary Pronesti; Maryland's Jerry MacNeish, John Hopper and D.M. Crispino; Rhode Island's Matt Prendergast; Indiana's Brian Caudell; South Carolina's Tommy Brooks; Virginia's Mike Arnold; Tennessee's Floyd Garrett and D.J. Gentry; Georgia's Lamar Walden and the late Tom Trainor; Arizona's John Chambers; Illinois' Barry Wallner, Bill Skarupinski and the late Keith Bacon; California's Noland Adams; Michigan's Bob Webster, Al Maynard and the late Sam Folz; Ohio's Joe Johnson; Missouri's Phil Reed and Donnie Shaffer; Minnesota's Vince Emme; Wisconsin's Jim Carlson, plus many more Chevy and Corvette hands-on experts from both restoration businesses and clubs alike.
Our goal in this story was to note what we believe is the accurate coating process (or non-process) of each small part. We have left out special models with chrome valve covers, etc. We also won't tax your gray matter with how each coating process is performed. Reference books and/or actual shop owners can best explain this to you. All we wanted to accomplish here was to give you the correctly named process used on each part/assembly so you at least know what to tell the shop who is about to restore or refurbish your parts.
Also, when you box your parts to send to the restorer, we highly suggest you box them "by process," as-listed. This way, nothing will be incorrectly restored, re-plated or refurbished. Read on. Much story credit goes to GM Service Manuals, with technical terminology from Al Colvin's multi-book series, "Chevrolet By The Numbers" from GM Archives material.
Heater Box Horn Assemblies, Ignition Coil Assembly, Oil Fill Tube (exc. Z/28), Open Element Air Cleaner Base Assembly Power Steering Pump Cannister, Radiator Top, Water Pump's Radiator Fan Blade Assembly
Black/Semi-Gloss (Satin)
Air Injection Pump support brace ('69-up), Air Injection Reactor pump pulley ('69-up), Alternator Brackets, Alternator Fan (Pre-'68), Battery Tray, Crankshaft Pulley, Front Control Arms, Master Cylinder (some models Natural), Power Steering Pulley, Power Steering Pump Bracket, Pre-'68 Oil Filler Tube (Cars), Radiator Core Support Starter Motor, Solenoid & Brace, Water Pump Pulley
Gold Cadium (Also spelled CADMIUM)
Brake Proportioning Valve Bracket Assembly, Air Injection Reactor, Backfire Valve, Holley Carb Accelerator Pump, Arm Master Cylinder Top Cover
Gold Dichromate
Carburetor Main Body
Gold Iridite
Power Brake Booster
Air Injection Reactor Housing, Alternator Housing, Alternator Bracket Spacer, Aluminum Intake Distributor Hold-Down, Aluminum Intake, Thermostat Housing, Bellhousing (later models often painted), Cast Iron Exhaust Manifolds, Disc Brake Proportioning Valve, Distributor Housing, Q-Jet Carb, Throttle Arm Thermal Fan Clutch Assembly, L & R Upper Control Arm Shaft
Orange Gloss Paint
Air Injection Reactor Pump support brace (pre-'69), Alternator Bracket ('67-68 Z/28-only), Harmonic Balancer, Iron Intake Distributor Hold-Down, Iron Intake Manifold Heater Hose Nipple Fitting, Iron Intake Thermostat Housing, Oil Pan, Spark Plug Wire Looms, Bolts on Steel Intake Manifold, Timing Chain Cover & Bolts, Water Pump Heater Hose Nipple Fitting
Air Injection Reactor pump muffler, Air Injection Reactor installation bolt, Air Injection Reactor pump pulley (pre-'69), Alternator Main Bolt, Battery Hold-Down Clamp, Control Arm Mounting Bolts, Fender Bolts (Inner & Outer), Hood Hinges/bolts, Hood Latch Assembly, Manual Trans Clutch Linkage, Radiator Core Support Bolts, Throttle Linkage
Silver Cadium (also spelled CADMIUM)
Alternator Adjusting Bolt, Aluminum Intake Bolts, Aluminum Intake Heater Hose Nipple Fittings, Alternator Fan ('68-up), Carb Air Cleaner Stud, Coil Bracket & bolts, Horn Relay, Hose Clamps, Master Cylinder Top Cover Tension Wires, Starter Bolts


text:
Portion Sizes for Babies, Toddlers, and Preschoolers
By Katherine M. Tomlinson
Mounting research links childhood diet to everything from brain development and mental stability to risk for obesity and other health conditions. So how can make sure your child gets enough—yet not too much—of the nutrients he needs? When it comes to portion sizes for babies, toddlers, and preschoolers, experts say the little ones themselves know best.
If he turns away, he's full.
"Children do not need to be taught how much to eat," writes Eileen Behan, RD, in The Baby Food Bible, "but you must support this by showing them how to recognize feelings of hunger and satiety by feeding them when [they're] hungry and allowing them to stop eating when they indicate a sense of fullness."
Little ones need small, frequent meals.
When feeding your baby, keep in mind, however, that she may get full quickly and soon show signs of hunger again. Because little ones' stomachs are small, they need to nibble on demand. As your child grows, he will gradually eat more at one time and extend the time between feedings. Ultimately, you'll want to feed him at regular meal times, but it's likely that he will not be ready for just three meals and two snacks a day until he is at least a year old.
What and how much to offer
You can and should see to it that your child is offered the most nutritious foods appropriate for his age. The concentration of nutrients required to fuel his rapid growth and development leaves no room in his tiny stomach for sweets and junk food. To demonstrate this, we've assembled the following chart of guideline portion sizes for babies, toddlers, and preschoolers based on recommendations from the USDA and the Academy of Nutrition and Dietetics.
Since needs vary widely depending on a child's size, growth rate and activity level, these examples should be used only as rough idea for how much to prepare and make available to your child as he grows. Remember that your little one's internal cues are the most accurate indicators of the amount of food he needs to eat. Never restrict your child's supply of healthful food or force him to eat anything. Once your child is old enough to enjoy an assortment of foods, the best way to foster healthy eating habits is to offer him a variety of nutritious fare in a relaxed way, then let him decide what and how much to eat.
Click through to see guideline portion sizes for babies, toddlers, and preschoolers.