0
edits
Changes
no edit summary
<p><strong>Gastroesophageal Reflux Disease</strong> (<strong>GERD</strong>; or <strong>GORD</strong> when spelling <em>œsophageal</em>, the <a title="British English" href="http://en.wikipedia.org/wiki/British_English">BrE</a> form) is defined as chronic symptoms or <a title="Mucosa" href="http://en.wikipedia.org/wiki/Mucosa">mucosal</a> damage produced by the abnormal reflux in the <a title="Esophagus" href="http://en.wikipedia.org/wiki/Esophagus">esophagus</a><sup class="reference" id="_ref-0"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-0">[1]</a></sup>.</p><p>This is commonly due to transient or permanent changes in the barrier between the esophagus and the <a title="Stomach" href="http://en.wikipedia.org/wiki/Stomach">stomach</a>. This can be due to incompetence of the <em><a title="Lower esophageal sphincter" href="http://en.wikipedia.org/wiki/Lower_esophageal_sphincter">lower esophageal sphincter</a></em> (LES), transient LES relaxation, impaired expulsion of gastric reflux from the esophagus, or a <a title="Hiatal hernia" href="http://en.wikipedia.org/wiki/Hiatal_hernia">hiatal hernia</a>.</p>
<p><a id="Symptoms" name="Symptoms"></a></p>
<h2><span class="editsection"></span><span class="mw-headline">Symptoms</span></h2>
<p><a id="Adults" name="Adults"></a></p>
<h3><span class="editsection"></span><span class="mw-headline">Adults</span></h3>
<p><a title="Heartburn" href="http://en.wikipedia.org/wiki/Heartburn">Heartburn</a> is the major symptom of acid in the esophagus, characterized by burning discomfort behind the breastbone (<a title="Sternum" href="http://en.wikipedia.org/wiki/Sternum">sternum</a>). Findings in GERD include <strong><a title="Esophagitis" href="http://en.wikipedia.org/wiki/Esophagitis">esophagitis</a></strong> (<em>reflux esophagitis</em>) — <a title="Inflammation" href="http://en.wikipedia.org/wiki/Inflammation">inflammatory</a> changes in the esophageal lining (mucosa) —, <a title="Stenosis" href="http://en.wikipedia.org/wiki/Stenosis">strictures</a>, difficulty swallowing (<a title="Dysphagia" href="http://en.wikipedia.org/wiki/Dysphagia">dysphagia</a>), and chronic <a title="Chest pain" href="http://en.wikipedia.org/wiki/Chest_pain">chest pain</a>. Patients may have only one of those findings. Typical GERD symptoms include cough, hoarseness, voice changes, chronic ear ache, burning chest pains, nausea or <a title="Sinusitis" href="http://en.wikipedia.org/wiki/Sinusitis">sinusitis</a>. GERD complications include stricture formation, <a title="Barrett's esophagus" href="http://en.wikipedia.org/wiki/Barrett%27s_esophagus">Barrett's esophagus</a>, <a class="new" title="Esophageal ulcer" href="http://en.wikipedia.org/w/index.php?title=Esophageal_ulcer&action=edit">esophageal ulcers</a>, and possibly even lead to <a title="Esophageal cancer" href="http://en.wikipedia.org/wiki/Esophageal_cancer">esophageal cancer</a>, especially in adults over 60 years old.</p><p>Occasional heartburn is common but does not necessarily mean one has GERD. Patients with heartburn symptoms more than once a week are at risk of developing GERD. A hiatal hernia is usually <a title="Asymptomatic" href="http://en.wikipedia.org/wiki/Asymptomatic">asymptomatic</a>, but the presence of a hiatal hernia is a risk factor for developing GERD.</p>
<p><a id="Children" name="Children"></a></p>
<h3><span class="editsection"></span><span class="mw-headline">Children</span></h3>
<p>GERD may be difficult to detect in <a title="Infant" href="http://en.wikipedia.org/wiki/Infant">infants</a> and <a title="Child" href="http://en.wikipedia.org/wiki/Child">children</a>. Symptoms may vary from typical adult symptoms. GERD in children may cause repeated <a title="Vomiting" href="http://en.wikipedia.org/wiki/Vomiting">vomiting</a>, effortless spitting up, <a title="Coughing" href="http://en.wikipedia.org/wiki/Coughing">coughing</a>, and other respiratory problems. Inconsolable crying, failure to gain adequate weight, refusing food, bad breath, and belching or burping are also common. Children may have one symptom or many — no single symptom is universal in all children with GERD.</p>
<p>It is estimated that of the approximately 8 million babies born in the U.S. each year, up to 35% of them may have difficulties with reflux in the first few months of their life. Most of those children will outgrow their reflux by their first birthday. However, a small but significant number of them will not outgrow the condition.</p>
<p>Babies' immature digestive systems are usually the cause, and most infants stop having acid reflux by the time they reach their first birthday. Some children do not outgrow acid reflux, however, and continue to have it into their teen years. Children that have had heartburn that does not seem to go away, or any other GERD symptoms for a while, should talk to their parents and visit their doctor.</p>
<h2><span class="editsection"></span><span class="mw-headline">Diagnosis</span></h2>
<div class="thumb tright">
<div class="thumbinner" style="WIDTH: 202px"><a class="image" title="Endoscopic image of peptic stricture, or narrowing of the esophagus near the junction with the stomach. This is a complication of chronic gastroesophageal reflux disease, and can be a cause of dysphagia or difficulty swallowing" href="http://en.wikipedia.org/wiki/Image:Peptic_stricture.png"><img class="thumbimage" height="195" alt="Endoscopic image of peptic stricture, or narrowing of the esophagus near the junction with the stomach. This is a complication of chronic gastroesophageal reflux disease, and can be a cause of dysphagia or difficulty swallowing" width="200" border="0" src="http://upload.wikimedia.org/wikipedia/commons/thumb/1/16/Peptic_stricture.png/200px-Peptic_stricture.png" /></a>
<div class="thumbcaption">
<div class="magnify" style="FLOAT: right"><a class="internal" title="Enlarge" href="http://en.wikipedia.org/wiki/Image:Peptic_stricture.png"><img height="11" alt="" width="15" src="http://en.wikipedia.org/skins-1.5/common/images/magnify-clip.png" /></a></div><a title="Gastroscopy" href="http://en.wikipedia.org/wiki/Gastroscopy">Endoscopic</a> image of peptic stricture, or narrowing of the <a title="Esophagus" href="http://en.wikipedia.org/wiki/Esophagus">esophagus</a> near the junction with the <a title="Stomach" href="http://en.wikipedia.org/wiki/Stomach">stomach</a>. This is a complication of chronic gastroesophageal reflux disease, and can be a cause of <a title="Dysphagia" href="http://en.wikipedia.org/wiki/Dysphagia">dysphagia</a> or difficulty swallowing</div>
</div>
</div>
<p>A detailed history taking is vital to the diagnosis. Useful investigations may include <a title="Barium" href="http://en.wikipedia.org/wiki/Barium">barium</a> swallow <a title="X-ray" href="http://en.wikipedia.org/wiki/X-ray">X-rays</a>, esophageal manometry, 24 hour esophageal <a title="PH" href="http://en.wikipedia.org/wiki/PH">pH</a> monitoring and <a title="Esophagogastroduodenoscopy" href="http://en.wikipedia.org/wiki/Esophagogastroduodenoscopy">Esophagogastroduodenoscopy</a> (EGD). In general, an EGD is done when the patient does not respond well to treatment, or has alarm symptoms including: dysphagia, anemia, blood in the stool (detected chemically), <a title="Asthma" href="http://en.wikipedia.org/wiki/Asthma">wheezing</a>, weight loss, or voice changes. Some physicians advocate once-in-a-lifetime endoscopy for patients with longstanding GERD, to evaluate the possible presence of <a title="Barrett's esophagus" href="http://en.wikipedia.org/wiki/Barrett%27s_esophagus">Barrett's esophagus</a>, a precursor lesion for <a title="Esophageal cancer" href="http://en.wikipedia.org/wiki/Esophageal_cancer">esophageal adenocarcinoma</a>.</p><p><a title="Esophagogastroduodenoscopy" href="http://en.wikipedia.org/wiki/Esophagogastroduodenoscopy">Esophagogastroduodenoscopy</a> (EGD) (a form of <a title="Endoscopy" href="http://en.wikipedia.org/wiki/Endoscopy">endoscopy</a>) involves insertion of a thin scope through the mouth and throat into the esophagus and stomach (often while the patient is sedated) in order to assess the internal surfaces of the esophagus, stomach, and <a title="Duodenum" href="http://en.wikipedia.org/wiki/Duodenum">duodenum</a>.</p><p><a title="Biopsy" href="http://en.wikipedia.org/wiki/Biopsy">Biopsies</a> can be performed during gastroscopy and these may show:</p>
<ul>
<li>Edema and basal hyperplasia (non-specific inflammatory changes) </li>
<li>Lymphocytic inflammation (non-specific) </li>
<li>Neutrophilic inflammation (usually due to reflux or <em><a title="Helicobacter" href="http://en.wikipedia.org/wiki/Helicobacter">Helicobacter</a></em> <a title="Gastritis" href="http://en.wikipedia.org/wiki/Gastritis">gastritis</a>) </li>
<li>Eosinophilic inflammation (usually due to reflux) </li>
<li>Goblet cell intestinal metaplasia or Barretts esophagus. </li>
<li>Elongation of the papillae </li>
<li>Thinning of the squamous cell layer </li>
<li><a title="Dysplasia" href="http://en.wikipedia.org/wiki/Dysplasia">Dysplasia</a> or pre-cancer. </li> <li><a title="Carcinoma" href="http://en.wikipedia.org/wiki/Carcinoma">Carcinoma</a>. </li>
</ul>
<p><a id="Pathophysiology" name="Pathophysiology"></a></p>
<p>GERD is caused by a failure of the Anti-Reflux Barrier (ARB) and its primary component, the GastroEsophageal valve (GEV). The understanding of the GEV has continued to progress in recent years, and more focus is currently being placed on the GEV, rather than the Lower Esophageal Sphincter (LES), as the largest contributor to the ARB. Researchers have shown the GEV's robust nature and have shown that the intact GEV alone is highly competent to stop reflux. For example, in cadavers, where no muscle tone or LES pressure is present, the stomach ruptures when filled with water before reflux can occur. This shows the GEV's power to stop reflux even in the absence of any LES pressure.</p>
<p>In healthy patients, the "Angle of His," the angle at which the esophagus enters the stomach, is intact creating a valve that prevents duodenal bile, enzymes, and stomach acid from traveling back into the esophagus where it can cause burning and inflammation of sensitive esophageal tissue.</p>
<p>Another paradoxical cause of GERD-like symptoms is not enough stomach acid (<a title="Hypochlorhydria" href="http://en.wikipedia.org/wiki/Hypochlorhydria">hypochlorhydria</a>). The valve that empties the stomach into the intestines is triggered by acidity. If there is not enough acid, this valve does not open and the stomach contents are churned up into the esophagus. However, there is still enough acidity to irritate the esophagus.</p>
<p>Factors that can contribute to GERD are:</p>
<ul>
<li><a title="Hiatus hernia" href="http://en.wikipedia.org/wiki/Hiatus_hernia">Hiatus hernia</a>, which increases the likelihood of GERD due to mechanical and motility factors<sup class="reference" id="_ref-pmid17573791_0"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid17573791">[2]</a></sup> </li> <li><a title="Obesity" href="http://en.wikipedia.org/wiki/Obesity">Obesity</a>: increasing <a title="Body mass index" href="http://en.wikipedia.org/wiki/Body_mass_index">body mass index</a> is associated with more severe GERD<sup class="reference" id="_ref-pmid175737910_0"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid175737910">[3]</a></sup> </li> <li><a title="Zollinger-Ellison syndrome" href="http://en.wikipedia.org/wiki/Zollinger-Ellison_syndrome">Zollinger-Ellison syndrome</a>, which can be present with increased gastric acidity due to <a title="Gastrin" href="http://en.wikipedia.org/wiki/Gastrin">gastrin</a> production </li> <li><a title="Hypercalcemia" href="http://en.wikipedia.org/wiki/Hypercalcemia">Hypercalcemia</a>, which can increase <a title="Gastrin" href="http://en.wikipedia.org/wiki/Gastrin">gastrin</a> production, leading to increased acidity </li> <li><a title="Scleroderma" href="http://en.wikipedia.org/wiki/Scleroderma">Scleroderma</a> and <a title="Systemic sclerosis" href="http://en.wikipedia.org/wiki/Systemic_sclerosis">systemic sclerosis</a>, which can feature esophageal dysmotility </li>
</ul>
<p>GERD has been linked to <a title="Laryngitis" href="http://en.wikipedia.org/wiki/Laryngitis">laryngitis</a>, chronic <a title="Cough" href="http://en.wikipedia.org/wiki/Cough">cough</a>, <a title="Pulmonary fibrosis" href="http://en.wikipedia.org/wiki/Pulmonary_fibrosis">pulmonary fibrosis</a>, <a title="Earache" href="http://en.wikipedia.org/wiki/Earache">earache</a>, and <a title="Asthma" href="http://en.wikipedia.org/wiki/Asthma">asthma</a>, even when not clinically apparent, as well as to <a class="new" title="Laryngopharyngeal reflux" href="http://en.wikipedia.org/w/index.php?title=Laryngopharyngeal_reflux&action=edit">laryngopharyngeal reflux</a> and ulcers of the <a title="Vocal cords" href="http://en.wikipedia.org/wiki/Vocal_cords">vocal cords</a>. There appears to be an association with <a title="Sleep apnea" href="http://en.wikipedia.org/wiki/Sleep_apnea">obstructive sleep apnea</a>, although its conjectural relationship with GERD remains unproven.<sup class="reference" id="_ref-1"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-1">[4]</a></sup> and <a class="external" title="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17198758" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17198758">PMID 17198758</a>.</p>
<p><a id="Treatment" name="Treatment"></a></p>
<h2><span class="editsection"></span><span class="mw-headline">Treatment</span></h2>
<p>The rubric "lifestyle modifications" is the term physicians use when recommending non-drug GERD treatments. A 2006 review suggested that evidence for most dietary interventions is anecdotal; only <a title="Weight loss" href="http://en.wikipedia.org/wiki/Weight_loss">weight loss</a> and elevating the head of the bed were supported by evidence<sup class="reference" id="_ref-pmid16682569_0"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid16682569">[5]</a></sup>. A subsequent randomized <a title="Crossover study" href="http://en.wikipedia.org/wiki/Crossover_study">crossover study</a> showed benefit by avoiding eating two hours before bed.<sup class="reference" id="_ref-pmid17573791_1"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid17573791">[2]</a></sup></p>
<p><a id="Foods" name="Foods"></a></p>
<h3><span class="editsection">[<a title="Edit section: Foods" href="http://en.wikipedia.org/w/index.php?title=Gastroesophageal_reflux_disease&action=edit&section=7">edit</a>]</span> <span class="mw-headline">Foods</span></h3>
<p>Certain foods and lifestyle are considered to promote gastroesophageal reflux:</p>
<ul>
<li><a title="Coffee" href="http://en.wikipedia.org/wiki/Coffee">Coffee</a>, <a title="Alcoholic beverage" href="http://en.wikipedia.org/wiki/Alcoholic_beverage">alcohol</a>, and excessive amounts of <a title="Vitamin C" href="http://en.wikipedia.org/wiki/Vitamin_C">Vitamin C</a> supplements stimulate gastric acid secretion. Taking these before bedtime especially can cause evening reflux. (Although a study published in 2006 by <a title="Stanford University" href="http://en.wikipedia.org/wiki/Stanford_University">Stanford University</a> researchers disputes the effect of coffee, acidic, spicy foods etc. as a myth.<sup class="reference" id="_ref-pmid16682569_1"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid16682569">[5]</a></sup>) </li> <li><a title="Antacids" href="http://en.wikipedia.org/wiki/Antacids">Antacids</a> based on <a title="Calcium carbonate" href="http://en.wikipedia.org/wiki/Calcium_carbonate">calcium carbonate</a> (but not <a title="Aluminum hydroxide" href="http://en.wikipedia.org/wiki/Aluminum_hydroxide">aluminum hydroxide</a>) were found to actually increase the acidity of the stomach. However, all antacids reduced acidity in the lower esophagus, so the net effect on GERD symptoms may still be positive.<sup class="reference" id="_ref-2"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-2">[6]</a></sup>. </li> <li>Foods high in fats and <a title="Tobacco smoking" href="http://en.wikipedia.org/wiki/Tobacco_smoking">smoking</a> reduce lower esophageal sphincter competence, so avoiding these tends to help. Fat also delays stomach emptying. </li>
<li>Eating shortly before bedtime (For clinical purposes, this usually means 2-3 hours before going to bed). </li>
<li>Large meals. Having more but smaller meals reduces GERD risk, as it means there is less food in the stomach at any one time. </li>
<li>Soda or pop (regular or diet). </li>
<li><a title="Chocolate" href="http://en.wikipedia.org/wiki/Chocolate">Chocolate</a> and <a title="Peppermint" href="http://en.wikipedia.org/wiki/Peppermint">peppermint</a>. </li> <li><a title="Acid" href="http://en.wikipedia.org/wiki/Acid">Acidic</a> foods, such as oranges and tomatoes </li> <li><a title="Cruciferous vegetables" href="http://en.wikipedia.org/wiki/Cruciferous_vegetables">Cruciferous vegetables</a>: onions, cabbage, cauliflower, broccoli, spinach, <a title="Brussel sprouts" href="http://en.wikipedia.org/wiki/Brussel_sprouts">brussel sprouts</a> </li> <li><a title="Milk" href="http://en.wikipedia.org/wiki/Milk">Milk</a> and milk-based products contain calcium and fat, and should be avoided before bedtime. </li>
</ul>
<p><a id="Positional_therapy" name="Positional_therapy"></a></p>
<h3><span class="editsection">P</span><span class="mw-headline">ositional therapy</span></h3>
<p>Sleeping on one's left side has been shown to drastically reduce nighttime reflux episodes in patients.<sup class="reference" id="_ref-3"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-3">[7]</a></sup>.</p><p>Elevating the head of the bed is also effective. When combining drug therapy, food avoidance before bedtime, and elevation of the head of the bed, over 95% of patients will have complete relief<sup class="noprint Template-Fact"><span title="This claim needs references to reliable sources since June 2007" style="WHITE-SPACE: nowrap">[<em><a title="Wikipedia:Citing sources" href="http://en.wikipedia.org/wiki/Wikipedia:Citing_sources">citation needed</a></em>]</span></sup>. Additional conservative measures may be considered if there is incomplete relief. Another approach is to apply all conservative measures for maximum response. A <a title="Meta-analysis" href="http://en.wikipedia.org/wiki/Meta-analysis">meta-analysis</a> suggested that elevating the head of bed is an effective therapy, although this conclusion was only supported by nonrandomized studies <sup class="reference" id="_ref-pmid16682569_2"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid16682569">[5]</a></sup>.</p>
<p>Elevating the head of the bed can be done by using various items: plastic or wooden bed risers that support bed posts or legs, a bed wedge pillow, or a wedge or an inflatable mattress lifter that fits in between mattress and box spring. The height of the elevation is critical and must be at least 6 to 8 inches (15 to 20 cm) in order to be at least minimally effective to prevent the backflow of gastric fluids. It should be noted that some innerspring mattresses do not work well when inclined and tend to cause back pain, thus foam based mattresses are to be preferred. Moreover, some use higher degrees of incline than provided by the commonly suggested 6 to 8 inches (15 to 20 cm) and claim greater success.</p>
<p><a id="Drug_treatment" name="Drug_treatment"></a></p>
<h3><span class="editsection"></span><span class="mw-headline">Drug treatment</span></h3>
<p>A number of drugs are registered for GERD treatment, and they are among the most-often-prescribed forms of <a title="Medication" href="http://en.wikipedia.org/wiki/Medication">medication</a> in most Western countries. They can be used in combination with other drugs, although some antacids can interfere with the function of other drugs:</p>
<ul>
<li><a title="Proton pump inhibitor" href="http://en.wikipedia.org/wiki/Proton_pump_inhibitor">Proton pump inhibitors</a> are the most effective in reducing gastric acid secretion. These drugs stop acid secretion at the source of acid production, i.e., the proton pump. </li> <li><a title="Antacid" href="http://en.wikipedia.org/wiki/Antacid">Antacids</a> before meals or symptomatically after symptoms begin can reduce gastric acidity (increase <a title="PH" href="http://en.wikipedia.org/wiki/PH">pH</a>). </li> <li><a title="Alginic acid" href="http://en.wikipedia.org/wiki/Alginic_acid">Alginic acid</a> (<a title="Gaviscon" href="http://en.wikipedia.org/wiki/Gaviscon">Gaviscon</a>) may coat the mucosa as well as increase pH and decrease reflux. A <a title="Meta-analysis" href="http://en.wikipedia.org/wiki/Meta-analysis">meta-analysis</a> of <a title="Randomized controlled trials" href="http://en.wikipedia.org/wiki/Randomized_controlled_trials">randomized controlled trials</a> suggests <a title="Alginic acid" href="http://en.wikipedia.org/wiki/Alginic_acid">alginic acid</a> may be the most effective of non-prescription treatments with a <a title="Number needed to treat" href="http://en.wikipedia.org/wiki/Number_needed_to_treat">number needed to treat</a> of 4 <sup class="reference" id="_ref-pmid17229239_0"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid17229239">[8]</a></sup>. </li> <li>Gastric <a title="H2 antagonist" href="http://en.wikipedia.org/wiki/H2_antagonist">H<sub>2</sub> receptor blockers</a> such as <a title="Ranitidine" href="http://en.wikipedia.org/wiki/Ranitidine">ranitidine</a> or <a title="Famotidine" href="http://en.wikipedia.org/wiki/Famotidine">famotidine</a> can reduce gastric secretion of acid. These drugs are technically <a title="Antihistamine" href="http://en.wikipedia.org/wiki/Antihistamine">antihistamines</a>. They relieve complaints in about 50% of all GERD patients. Compared to placebo (which also is associated with symptom improvement), they have a <a title="Number needed to treat" href="http://en.wikipedia.org/wiki/Number_needed_to_treat">number needed to treat</a> of eight (8) <sup class="reference" id="_ref-pmid17229239_1"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid17229239">[8]</a></sup>. </li> <li><a title="Prokinetic" href="http://en.wikipedia.org/wiki/Prokinetic">Prokinetics</a> strengthen the LES and speed up gastric emptying. <a title="Cisapride" href="http://en.wikipedia.org/wiki/Cisapride">Cisapride</a>, a member of this class, was withdrawn from the market for causing <a title="Long QT syndrome" href="http://en.wikipedia.org/wiki/Long_QT_syndrome">Long QT syndrome</a>. </li> <li><a title="Sucralfate" href="http://en.wikipedia.org/wiki/Sucralfate">Sucralfate</a> (Carafate®) is also useful as an adjunct in helping to heal and prevent esophageal damage caused by GERD, however it must be taken several times daily and at least two (2) hours apart from meals and medications. </li>
</ul>
<p><a id="Posture_and_GERD" name="Posture_and_GERD"></a></p>
<h3><span class="editsection"></span><span class="mw-headline">Posture and GERD</span></h3>
<p>In adults, a slouched posture is an important factor contributing to GERD. With a slouched posture there is no straight path between the stomach and esophagus; muscles around the esophagus go into a spasm. Gas and acidity get blocked in the spasm, causing coughing and other asthma-like symptoms. A <a title="Meta-analysis" href="http://en.wikipedia.org/wiki/Meta-analysis">meta-analysis</a> suggested that elevating the head of the bed is an effective therapy, although this conclusion was only supported by nonrandomized studies.<sup class="reference" id="_ref-pmid16682569_3"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-pmid16682569">[5]</a></sup></p>
<p><a id="Surgical_treatment" name="Surgical_treatment"></a></p>
<h3><span class="editsection"></span><span class="mw-headline">Surgical treatment</span></h3>
<p>The standard surgical treatment, sometimes preferred over longtime use of medication, is the <em><a title="Nissen fundoplication" href="http://en.wikipedia.org/wiki/Nissen_fundoplication">Nissen fundoplication</a></em>. The upper part of the stomach is wrapped around the LES to strengthen the sphincter and prevent acid reflux and to repair a hiatal hernia. The procedure is often done <a title="Laparoscopic surgery" href="http://en.wikipedia.org/wiki/Laparoscopic_surgery">laparoscopically</a>.<sup class="reference" id="_ref-Abbas_2004_0"><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_note-Abbas_2004">[9]</a></sup></p><p>An obsolete treatment is <a title="Vagotomy" href="http://en.wikipedia.org/wiki/Vagotomy">vagotomy</a> ("highly selective vagotomy"), the surgical removal of <a title="Vagus nerve" href="http://en.wikipedia.org/wiki/Vagus_nerve">vagus nerve</a> branches that innervate the stomach lining. This treatment has been largely replaced by medication.</p>
<p><a id="Endoluminal_fundoplication" name="Endoluminal_fundoplication"></a></p>
<h3><span class="editsection"></span><span class="mw-headline">Endoluminal fundoplication</span></h3>
</tbody>
</table>
<p>In June 2006 EndoGastric Solutions introduced <a class="external text" title="http://www.egseurope.eu" rel="nofollow" href="http://www.egseurope.eu/">EsophyX ELF</a> in the Europe Union as an alternative to surgical and pharmaceutical approaches for GERD treatment. EsophyX ELF is intended to deliver similar benefits as the time-proven laparoscopic fundoplication procedures, by reducing hiatal hernia, recreating the Angle of His, and creating a GastroEsophageal Valve (GEV). The key differences are that EsophyX ELF is an endoscopic non-invasive procedure that is performed transorally (through the mouth), does not require incisions, and does not dissect any part of the natural anatomy.</p><p>Previous endoluminal treatments focused predominantly on the LES. However, failure to effectively treat reflux long-term with endoluminal therapies that focused only on the Lower Esophageal Sphincter (LES) combined with the fact that surgical approaches like Nissen fundoplication recreate the GEV and have excellent long-term efficacy, has led to an awareness that the GEV is probably the most powerful component of the Anti-Reflux Barrier. The device has been designed to deploy multiple tissue fasteners to create a robust and durable valve and is intended to restore the geometry of the GastroEsophageal Junction and recreate the natural, unidirectional valve mechanism necessary to prevent GERD. <a class="external text" title="http://www.endogastricsolutions.com/index.php?src=news&submenu=News&refno=19" rel="nofollow" href="http://www.endogastricsolutions.com/index.php?src=news&submenu=News&refno=19">EsophyX ELF has recently been cleared by the US FDA</a> and is now available in the U.S.</p>
<p><a id="Other_treatments" name="Other_treatments"></a></p>
<h3><span class="editsection"></span><span class="mw-headline">Other treatments</span></h3>
<p>In 2000 , the U.S. <a title="Food and Drug Administration" href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration">Food and Drug Administration</a> (FDA) approved two <a title="Endoscopy" href="http://en.wikipedia.org/wiki/Endoscopy">endoscopic</a> devices to treat chronic heartburn. One system, Endocinch, puts stitches in the LES to create little pleats that help strengthen the muscle. Another, the <a title="Stretta procedure" href="http://en.wikipedia.org/wiki/Stretta_procedure">Stretta Procedure</a>, uses electrodes to apply radio frequency energy to the LES. The long term outcomes of both procedures compared to a Nissen fundoplication are still being determined.</p><p>Subsequently the NDO Surgical Plicator was FDA cleared for the endoscopic GERD treatment. The Plicator creates a plication, or fold, of tissue near the gastroesophageal junction, and fixates the plication with a suture-based implant. The Plicator is currently marketed by NDO Surgical, Inc. <a class="external autonumber" title="http://www.ndosurgical.com" rel="nofollow" href="http://www.ndosurgical.com/">[1]</a>.</p>
<p>Another treatment that involved injection of a solution during endoscopy into the lower esophageal wall was available for about one year ending in late 2005. It was marketed under the name Enteryx. It was removed from the market due to several reports of complications from misplaced injections.</p>
<p><a id="Barrett.27s_esophagus" name="Barrett.27s_esophagus"></a></p>
<h2><span class="editsection"></span><span class="mw-headline">Barrett's esophagus</span></h2>
<p><a title="Barrett's esophagus" href="http://en.wikipedia.org/wiki/Barrett%27s_esophagus">Barrett's esophagus</a>, a type of <a title="Dysplasia" href="http://en.wikipedia.org/wiki/Dysplasia">dysplasia</a>, is a precursor high-grade dysplasia, which is in turn a precursor condition for carcinoma. The risk of progression from Barrett's to dysplasia is uncertain but is estimated to include 0.1% to 0.5% of cases, and has probably been exaggerated in the past. Due to the risk of chronic heartburn progressing to Barrett's, EGD every 5 years is recommended for patients with chronic heartburn, or who take drugs for chronic GERD.</p>
<p><a id="References" name="References"></a></p>
<h2><span class="editsection"></span><span class="mw-headline">References</span></h2>
<div class="references-small" style="-moz-column-count: 2">
<ol class="references">
<li id="_note-0"><strong><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-0">^</a></strong> DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. <em>Am J Gastroenterol</em> 1999;94:1434-42. PMID 10364004. <a class="external/li> <li id=" title=_note-pmid17573791"http:>^ <sup><em><strong>a</strong></www.ncbi.nlm.nih.govem></sup> <sup><em><strong>b</strong></entrezem></query.fcgi?cmdsup> <cite style=Retrieve&db=pubmed"FONT-STYLE: normal">Piesman M, Hwang I, Maydonovitch C, Wong RK (2007). &quot;Nocturnal reflux episodes following the administration of a standardized meal. Does timing matter?"dopt=Abstract&list_uids=10364004" href="http://www.ncbi<em>Am.nlmJ.nihGastroenterol.gov</entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10364004"em>PMID 10364004</astrong>. 102</listrong> <li id="_note(10): 2128-pmid17573791">^ <a title="" href="http2134. DOI:10.1111//enj.1572-0241.wikipedia2007.01348.x. PMID 17573791.org/wiki/Gastroesophageal_reflux_disease#_ref-pmid17573791_0"><sup><em><strong>a</strongcite></em></sup></a> <a titlespan class="Z3988" title="" hrefctx_ver="http://enZ39.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref88-pmid17573791_1"><sup><em><strong>b</strong></em></sup></a> <cite style2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle="FONT-STYLE: normal">Piesman M, Hwang I, Maydonovitch C, Wong RK (2007). "Nocturnal reflux episodes following the administration Nocturnal+reflux+episodes+following+the+administration+of +a +standardized +meal. +Does +timing +matter?%3F"amp;rft. <em>jtitle=Am. +J. +Gastroenterol.</em> <strong>102</strong> (10): 2128-2134&rft.date=2007&rft. <a titlevolume="Digital object identifier" href102&rft.issue="http://en10&rft.wikipedia.org/wiki/Digital_object_identifier">DOI</a>:<a classau="external text" title="httpPiesman+M%2C+Hwang+I%2C+Maydonovitch+C%2C+Wong+RK&rft.pages=2128-2134&rft_id=info:pmid//dx.doi.org17573791&rft_id=info:doi/10.1111/j%2Fj.1572-0241.2007.01348.x" rel> </span> </li> <li id="nofollow_note-pmid175737910" href="http:><strong>^<//dx.doi.org/10.1111/j.1572strong> <cite style="FONT-0241.2007.01348.xSTYLE: normal">10.1111/j.1572-0241.Ayazi S, Crookes P, Peyre C, (2007).01348.x</a>"Objective documentation of the link between gastroesophageal reflux disease and obesity". <a class="external" title="http://wwwem>Am.ncbiJ.nlmGastroenterol.nih.gov</entrez/queryem> <strong>102</strong> (S): 138-139.fcgi?cmd</cite><span class=Retrieve&db"Z3988" title=pubmed&"ctx_ver=Z39.88-2004&doptrft_val_fmt=Abstractinfo%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&list_uidsrft.genre=17573791" hrefarticle&rft.atitle="http://wwwObjective+documentation+of+the+link+between+gastroesophageal+reflux+disease+and+obesity&rft.ncbijtitle=Am.nlm+J.nih+Gastroenterol.gov/entrez/query&rft.fcgi?cmddate=Retrieve2007&dbrft.volume=pubmed102&doptrft.issue=AbstractS&list_uidsrft.au=17573791">PMID 17573791</aAyazi+S%2C+Crookes+P%2C+Peyre+C%2C&rft.pages=138-139">. </citespan><span class/li> <li id="Z3988_note-1" title><strong>^</strong> <cite style="ctx_ver=Z39.88FONT-2004STYLE: normal">Morse CA, Quan SF, Mays MZ, Green C, Stephen G, Fass R (2004). &quot;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3AjournalIs there a relationship between obstructive sleep apnea and gastroesophageal reflux disease?&quot;rft.genre=article&<em>Clin. Gastroenterol. Hepatol.</em> <strong>2</strong> (9): 761–rft8.atitle=Nocturnal+reflux+episodes+following+the+administration+of+a+standardized+mealPMID 15354276.+Does+timing+matter%3F&rft.jtitle</cite><span class="Z3988" title="ctx_ver=Am.+J.+GastroenterolZ39.88-2004&rft.daterft_val_fmt=2007&rft.volume=102info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.issuegenre=10article&rft.auatitle=PiesmanIs+M%2Cthere+Hwanga+I%2Crelationship+Maydonovitchbetween+C%2Cobstructive+sleep+apnea+and+gastroesophageal+Wongreflux+RKdisease%3F&rft.pagesjtitle=2128-2134Clin.+Gastroenterol.+Hepatol.&rft_idrft.date=info:pmid/175737912004&rft_idrft.volume=info:doi/102&rft.1111%2Fjissue=9&rft.1572-0241.2007.01348.x"> </span> </li> <li idau="_note-pmid175737910"><strong><a title="" href="http://enMorse+CA%2C+Quan+SF%2C+Mays+MZ%2C+Green+C%2C+Stephen+G%2C+Fass+R&rft.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-pmid175737910_0">^pages=761%E2%80%938&rft_id=info:pmid/15354276"> </aspan></strongli> <cite styleli id="FONT_note-STYLE: normalpmid16682569">Ayazi S, Crookes P, Peyre C, (2007). "Objective documentation of the link between gastroesophageal reflux disease and obesity". ^ <emsup>Am. J. Gastroenterol.</em> <strong>102a</strong> (S): 138-139.</citeem></sup> <sup><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Objective+documentation+of+the+link+between+gastroesophageal+reflux+disease+and+obesity&rft.jtitleem><strong>b</strong></em></sup> <sup><em><strong>c</strong></em></sup> <sup><em><strong>d</strong></em></sup> <cite style=Am.+J.+Gastroenterol"FONT-STYLE: normal">Kaltenbach T, Crockett S, Gerson LB (2006).&quot;rft.date=2007Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach&quot;rft.volume=102&rft<em>Arch. Intern.issue=SMed.</em> <strong>166</strong> (9): 965&ndash;rft71. DOI:10.au=Ayazi+S%2C+Crookes+P%2C+Peyre+C%2C&rft1001/archinte.166.9.965. PMID 16682569.pages=138-139"> </spancite> </li> <li idspan class="_note-1Z3988"><strong><a title="" hrefctx_ver="http://enZ39.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref88-1">^</a></strong> <cite style2004&rft_val_fmt="FONT-STYLE: normal">Morse CA, Quan SF, Mays MZ, Green C, Stephen G, Fass R (2004). "Is there a relationship between obstructive sleep apnea and gastroesophageal reflux disease?"info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft. <em>Clin. Gastroenterol. Hepatol.</em> <strong>2</strong> (9): 761–8. <a classatitle="external" title="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=RetrieveAre+lifestyle+measures+effective+in+patients+with+gastroesophageal+reflux+disease%3F+An+evidence-based+approach&dbrft.jtitle=pubmedArch.+Intern.+Med.&doptrft.date=Abstract2006&list_uidsrft.volume=15354276" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve166&dbrft.issue=pubmed9&doptrft.au=Abstract&list_uids=15354276">PMID 15354276</a>Kaltenbach+T%2C+Crockett+S%2C+Gerson+LB&rft.</cite><span classpages="Z3988" title="ctx_ver=Z39.88-2004965%E2%80%9371&rft_val_fmtrft_id=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal:pmid/16682569&rftrft_id=info:doi/10.1001%2Farchinte.166.9.genre=article965">&nbsp;rft.atitle=Is+there+a+relationship+between+obstructive+sleep+apnea+and+gastroesophageal+reflux+disease%3F&rft</span> </li> <li id="_note-2"><strong>^</strong> Decktor DL, Robinson M, Maton PN, Lanza FL, Gottlieb S.jtitle=ClinEffects of Aluminum/Magnesium Hydroxide and Calcium Carbonate on Esophageal and Gastric pH in Subjects with Heartburn.+Gastroenterol.+Hepatol.&<em>Am J Ther</em> 1995;rft2:546-552.date=2004&rftPMID 11854825.volume</li> <li id=2&rft"_note-3"><strong>^</strong> Khoury RM, Camacho-Lobato L, Katz PO, Mohiuddin MA, Castell DO.issue=9&rftInfluence of spontaneous sleep positions on nighttime recumbent reflux in patients with gastroesophageal reflux disease.au=Morse+CA%2C+Quan+SF%2C+Mays+MZ%2C+Green+C%2C+Stephen+G%2C+Fass+R&rft.pages<em>Am J Gastroenterol</em> 1999;94:2069-73. PMID 10445529. </li> <li id=761%E2%80%938&rft_id=info:pmid/15354276"_note-pmid17229239"> ^ <sup><em><strong>a</spanstrong> </liem> <li id="_note-pmid16682569">^ <a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-pmid16682569_0"sup><sup><em><strong>ab</strong></em></sup></a> <a titlecite style="" href="httpFONT-STYLE://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-pmid16682569_1normal">Tran T, Lowry A, El-Serag H (2007). "Meta-analysis: the efficacy of over-the-counter gastro-oesophageal reflux disease drugs". <sup><em><strong>b</strongem>Aliment Pharmacol Ther</em></supstrong>25</astrong> <a title="" href="http(2)://en143-53.wikipedia.orgDOI:10.1111/wiki/Gastroesophageal_reflux_disease#_refj.1365-pmid16682569_2"><sup><em><strong>c2036.2006.03135.x. PMID 17229239.</strongcite></em></sup></a> <a titlespan class="Z3988" hreftitle="http://enctx_ver=Z39.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref88-pmid16682569_3"><sup><em><strong>d</strong></em></sup></a> <cite style2004&rft_val_fmt="FONT-STYLE: normal">Kaltenbach T, Crockett S, Gerson LB (2006). info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal"amp;Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approachrft.genre=article"amp;rft. <em>Arch. Internatitle=Meta-analysis%3A+the+efficacy+of+over-the-counter+gastro-oesophageal+reflux+disease+drugs&rft. Med.</em> <strong>166</strong> (9): 965jtitle=Aliment+Pharmacol+Ther&ndashamp;71rft. <a titledate="Digital object identifier" href2007&rft.volume="http://en25&rft.wikipediaissue=2&rft.org/wiki/Digital_object_identifier">DOI</a>:<a classau=Tran+T%2C+Lowry+A%2C+El-Serag+H&rft.pages="external text" title143-53&rft_id="httpinfo://dx.doi.org/10.1001/archinte1111%2Fj.1365-2036.1662006.903135.965x" rel="nofollow" href="http:> <//dx.doi.org/10.1001/archinte.166.9.965"span>10.1001/archinte.166.9.965</ali>. <a classli id="external_note-Abbas_2004" title><strong>^</strong> <cite style="httpFONT-STYLE://www.ncbinormal">Abbas A, Deschamps C, Cassivi SD, et al.nlm.nih(2004).gov/entrez/query.fcgi?cmd=Retrieve&quot;db=pubmedThe role of laparoscopic fundoplication in Barrett&rsquo;dopt=Abstracts esophagus&quot;list_uids=16682569" href="http://www.ncbi.nlm.nih.gov<em>Annals of Thoracic Surgery</entrezem> <strong>77</query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16682569">PMID 16682569</a>.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Are+lifestyle+measures+effective+in+patients+with+gastroesophageal+reflux+disease%3F+An+evidence-based+approach&rft.jtitle=Arch.+Intern.+Med.&rft.date=2006&rft.volume=166&rft.issue=9&rft.au=Kaltenbach+T%2C+Crockett+S%2C+Gerson+LB&rft.pages=965%E2%80%9371&rft_id=info:pmid/16682569&rft_id=info:doi/10.1001%2Farchinte.166.9.965"> </span> </li> <li id="_note-2"><strong><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-2">^</a></strong> Decktor DL, Robinson M, Maton PN, Lanza FL, Gottlieb S. Effects of Aluminum/Magnesium Hydroxide and Calcium Carbonate on Esophageal and Gastric pH in Subjects with Heartburn. <em>Am J Ther</em> 1995;2:546-552. <a class="external" title="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11854825" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11854825">PMID 11854825</a>. </li> <li id="_note-3"><strong><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-3">^</a></strong> Khoury RM, Camacho-Lobato L, Katz PO, Mohiuddin MA, Castell DO. Influence of spontaneous sleep positions on nighttime recumbent reflux in patients with gastroesophageal reflux disease. <em>Am J Gastroenterol</em> 1999;94:2069-73. <a class="external" title="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10445529" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10445529">PMID 10445529</a>. </li> <li id="_note-pmid17229239">^ <a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-pmid17229239_0"><sup><em><strong>a</strong></em></sup></a> <a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-pmid17229239_1"><sup><em><strong>b</strong></em></sup></a> <cite style="FONT-STYLE: normal">Tran T, Lowry A, El-Serag H (2007). "Meta-analysis: the efficacy of over-the-counter gastro-oesophageal reflux disease drugs". <em>Aliment Pharmacol Ther</em> <strong>25</strong> (2): 143-53. <a title="Digital object identifier" href="http://en.wikipedia.org/wiki/Digital_object_identifier">DOI</a>:<a class="external text" title="http://dx.doi.org/10.1111/j.1365-2036.2006.03135.x" rel="nofollow" href="http://dx.doi.org/10.1111/j.1365-2036.2006.03135.x">10.1111/j.1365-2036.2006.03135.x</a>. <a class="external" title="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17229239" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17229239">PMID 17229239</a>.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Meta-analysis%3A+the+efficacy+of+over-the-counter+gastro-oesophageal+reflux+disease+drugs&rft.jtitle=Aliment+Pharmacol+Ther&rft.date=2007&rft.volume=25&rft.issue=2&rft.au=Tran+T%2C+Lowry+A%2C+El-Serag+H&rft.pages=143-53&rft_id=info:doi/10.1111%2Fj.1365-2036.2006.03135.x"> </span> </li> <li id="_note-Abbas_2004"><strong><a title="" href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease#_ref-Abbas_2004_0">^</a></strong> <cite style="FONT-STYLE: normal">Abbas A, Deschamps C, Cassivi SD, et al. (2004). "The role of laparoscopic fundoplication in Barrett’s esophagus". <em>Annals of Thoracic Surgery</em> <strong>77</strong> strong> (2): 393-396. <a class="external" title="http)://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14759403" href="http://www.ncbi.nlm393-396.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14759403">PMID 14759403</a>.</cite><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+role+of+laparoscopic+fundoplication+in+Barrett%E2%80%99s+esophagus&rft.jtitle=Annals+of+Thoracic+Surgery&rft.date=2004&rft.volume=77&rft.issue=2&rft.au=Abbas+A%2C+Deschamps+C%2C+Cassivi+SD%2C+et+al.&rft.pages=393-396&rft_id=info:pmid/14759403"> </span> </li>
</ol>
</div>