G. Matthew Longo MD

• Assistant Professor of Vascular Surgery, University of Nebraska Medical Center,
• Omaha, Nebraska

Embolization versus surgery for peptic ulcer bleeding after failed endoscopic hemostasis: a meta-analysis medicine rising appalachia lyrics cheap 250mg chloroquine with visa. Prophylactic angiographic embolisation after endoscopic control of bleeding to high-risk peptic ulcers: a randomized controlled trial treatment kidney infection order chloroquine with a visa. Surgical complications after open and laparoscopic surgery for perforated peptic ulcer in a nationwide cohort medicine 1900 buy 250mg chloroquine mastercard. Risk stratification in perforated duodenal ulcers: a prospective validation of predictive factors medications diabetes discount generic chloroquine uk. Eradication of Helicobacter pylori prevents recurrence of ulcer after simple closure of 146 medicine ball workouts cheap chloroquine 250mg. Eastern Europe and Central and South America also have high incidence rates treatment 5th finger fracture order cheap chloroquine, with the lowest incidence rates observed in North America, North Africa, South Asia, and Australia. The incidence of gastric cancer in males is approximately twice that in females (Table 54. Native Americans and Hispanics also have a higher risk of developing gastric cancer than whites. The dominant risk factor remains, however, infection with Hp and the associated chronic-active inflammation of the gastric mucosa (see Chapter 52). This type of gastric cancer is more closely linked to environmental and dietary risk factors, tends to be the predominant form in regions with a high incidence of gastric cancer, and is the form of cancer that is now declining worldwide. The diffuse type of cancer lacks glandular structure and consists of poorly cohesive cells that infiltrate the wall of the stomach. Extensive involvement of the stomach by the diffuse type can result in a rigid and thickened stomach, a condition referred to as linitis plastic (Video 54. Another key feature of diffuse type cancers are signet-ring cells, special mucin-filled cells that are not present in intestinal type adenocarcinomas. There are also mixed phenotypes that contain heterogenous areas that feature predominantly either intestinalor diffuse-type characteristics. Characterization of the gastric cancer genomic landscape reveals the presence of multiple alterations in the expression of tyrosine kinase receptors, which in conjunction with their ligands and downstream effector molecules represent potential pathways for future drug development. So far, there are only little data to support the biological relevance of this proposed classification. Previous transcriptome analyses of gastric cancers, on the other hand, have demonstrated phenotypic clusters with either distinct prognostic outcomes or different response to systemic treatment. In colon cancer, the evidence is strong that each step in the transition is associated with a specific gene mutation,14 but the evidence that gastric cancer follows a comparable sequence of genetic events has been lacking. A common feature of the initiation and progression to intestinal-type gastric cancer is chronic inflammation of the gastric mucosa. In a subset of patients, the inflammatory process leads to the development of atrophic gastritis (with loss of glandular tissue) followed by progression to intestinal metaplasia, dysplasia, early gastric cancer, and, eventually, advanced gastric cancer. Although animal models suggested that all stages prior to the development of high-grade dysplasia are potentially reversible, there is still ongoing debate what defines the "point of no return" for humans from which further progression of neoplasia can no longer be prevented. These stromal cells, which also include cancer-associated fibroblasts known to promote tumor growth, have been reported to show distinct genetic and epigenetic changes that may confound tumor analysis. Currently, the role of chronic inflammation in the diffuse type of gastric cancer, as well as the similarities if any to the proposed pathway in. A, the intestinal type of gastric adenocarcinoma is characterized by the formation of gland-like tubular structures mimicking intestinal glands. B, the diffuse type of gastric cancer contains singly invasive tumor cells that frequently contain abundant mucin and that lack any glandular structure. In well-differentiated, intestinal-type gastric cancer, histopathologic studies indicated that chronic Hp infection progresses over decades through stages of chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and cancer. An imbalance between epithelial cell proliferation and apoptosis and, in a milieu of atrophy and achlorhydria, gastric colonization by enteric bacteria with nitrate reductase activity facilitating formation of carcinogenic nitrosamines allow the accumulation of oncogenic genetic alterations. Corpus-predominant atrophy, or the loss of specialized glandular cell types such as parietal and chief cells, appears to be the critical initiating step in the progression toward cancer. Infection with Hp has been found in every population studied, although the prevalence is higher in developing countries and most parts of East Asia. The risk for gastric cancer development varies with the type of background gastritis, but in general, corpusdominant gastritis resulting in a low acid state is mainly associated with an increased risk. Hp-induced duodenal ulcer disease is associated with a high gastric acid output as well as a reduced risk for developing gastric cancer. Although Hp infection is associated with both diffuse-type and intestinal-type adenocarcinomas, we focus in this chapter mainly on the mechanisms responsible for the formation of intestinaltype adenocarcinoma because they have been better studied. The association of Hp with mucosa-associated lymphoid tissue lymphoma is discussed in Chapter 32. The increased risk of development of gastric adenocarcinoma due to Hp infection depends on multiple factors including host genetic factors, the strain of bacteria (including bacterial virulence factors), the duration of infection, and the presence or absence of other environmental risk factors In a Japanese cohort, only those infected with Hp developed gastric adenocarcinoma during follow-up (2. Currently, genetic susceptibility factors of the human host are studied based on individual genes, but new technologies such as next-generation sequencing will enhance the identification of host genetic factors. Nevertheless, the most important factor appears to be the induction of chronic inflammation by Hp infection. This leads to an impairment of the epithelial barrier function of the gastric mucosa, thereby increasing the impact of other pathogenic factors Indeed, chronic inflammation has been linked to a large number of nongastric cancers. Chronic inflammation of the gastric mucosa appears necessary for the progression through atrophy to gastric cancer. Disease mechanisms are difficult to study in human infection, and therefore, much of our understanding of the immune response to Helicobacter organisms comes from work performed in a mouse model. Different inbred strains of mice respond to infection with varying degrees of disease susceptibility, and several knockout models have helped to elucidate the roles of individual components of the immune response in disease. For example, gastric Helicobacter infection in mice deficient in lymphocytes does not result in tissue damage, cell lineage alterations, or the metaplasia-dysplasia-carcinoma sequence. Mouse strains such as the C3H, which has a mixed Th1/Th2 cytokine profile, show intermediate disease, suggesting that cytokines within an immune response interact to form a continuum of disease rather than discrete disease states. These observations in mice led to human studies in Africa and Latin America that confirmed that geographic regions with low gastric cancer rates had much higher Th2/Th1 immune responses to Hp. These findings further stress the importance of the host response to infection and suggest the possibility that manipulation of the genetically predetermined host cytokine profile in response to environmental challenges may lessen or exacerbate the disease process. Studies on human tissue have also demonstrated that the degree of colonization with Hp depends on various factors, such as the presence and activity of regulatory T-cells (Treg) or the initial (naive) parietal cell mass (which reflects the acid-secreting capacity of the gastric body). This is associated with a concomitant increase of the Treg cell compartment in the peripheral blood as well as persistence of CagA positive strains that favors a Treg-mediated chronic inflammation. Gastric cancer almost always occurs in the setting of prolonged gastric atrophy and hypochlorhydria, a condition that predisposes to enteric bacterial overgrowth. Although antibiotic eradication therapy targeting Hp delays and inhibits development of gastric cancer in mice,20,68 antibiotics eradicate not only Hp but also other microorganisms that colonize the atrophic, hypochlorhydric stomach. With regard to these findings, it is also of interest that Hp-when present-dominates the otherwise much more diverse gastric microbiome in humans, as well as mice, prior to cancer development. Several strains may infect a single individual, and existing strains can undergo mutations and change over time. Factors that contribute to carcinogenesis include those that enable the bacteria to effectively colonize the gastric mucosa, those that incite a more aggressive host immune response, and those that affect host cell-growth signaling pathways. Motility toward epithelial cells of the stomach is a vital feature of Hp survival tactics. Spiraling movement is mediated by the FlaA and FlaB proteins, which are designed to navigate the thick gastric mucus. This includes a urease gene cluster consisting of 7 genes, of which UreA/UreB complex (comprising the urease enzyme) codes for 10% of the protein of Hp and is vital for its survival. The terminal gene of this island, cagA, is often used as a marker for the entire cag locus. Compared with cagA-negative (cagA-) strains, cag-positive (cagA+) strains are associated with more severe inflammation, higher degrees of atrophy, and a greater chance of progressing to gastric adenocarcinoma. The remarkable finding that CagA is injected into host cells, where it is phosphorylated by Src- and c-Abl kinases, has raised the possibility that CagA could directly promote growth, migration, and transformation. Approximately 50% of Hp strains express the vacA protein, which has been shown to be a very powerful inhibitor of T cell activation in vitro. Other bacterial virulence factors, such as cagE, may play a role in the modulation of apoptosis and the host inflammatory response, thereby contributing to disease manifestations. Indeed, "virulent strains" (cagA+, cagE+, and VacA+ s1m1) appear to be more potent inducers of proinflammatory mediators than "nonvirulent strains" (cagA-, cagE-, and VacA-), possibly explaining the higher association of cagA+ strains with gastric cancer. Moist snuff is a smokeless tobacco product promoted as an alternative to cigarettes that has reportedly reduced levels of carcinogenic nitrosamines. The decline in gastric cancer rates has coincided with the widespread use of refrigeration and the concomitant higher intake of fresh fruits and vegetables and lower intake of pickled and salted foods. Use of refrigeration for more than 10 to 20 years has been associated with a decreased risk of gastric cancer. Additionally, high intake of highly preserved foods may be associated with increased gastric cancer risk,96 potentially due to higher contents of salt, nitrates, and polycyclic aromatic amines. When nitrates are reduced to nitrite by bacteria or macrophages, they can react with other nitrogenated substances to form N-nitroso compounds that are known mitogens and carcinogens. However, studies trying to link N-nitroso exposure to gastric cancer risk have been inconclusive, perhaps reflecting the fact that nitrate intake does not necessarily correlate with nitrosation levels. High salt intake has been associated with higher rates of atrophic gastritis in humans and animals in the setting of Helicobacter infection and increases the mutagenicity of nitrosated food in animal models. Overall, the risk increase seems to be moderate and influenced by multiple factors (including tobacco consumption and physical activity). Interestingly, alcohol intake may increase the risk of gastric cancer in patients with certain polymorphisms of the alcohol dehydrogenase gene. Generally, intestinal-type gastric cancer is considered largely due to environmental causes. In the case of intestinal-type gastric cancer, however, assigning relative values to environmental and genetic contributions is complex, given that the major environmental factor, Hp, also tends to exhibit familial clustering. Nevertheless, in the future, gastric cancer types might rather be classified by genetic alterations and grouped to molecular subgroups with distinct carcinogenic mechanisms as well as clinical behavior, than to a histologic phenotype. Data from South Korea indicate that individuals with a family history of gastric cancer more frequently have both Hp infection and associated atrophic gastritis or intestinal metaplasia. In a number of model systems, the development of gastric atrophy has been linked to a strong Th1 immune response. Inflammation is modulated by an array of pro- and anti-inflammatory cytokines, and several genetic polymorphisms have been described that influence cytokine response. With the recently started nextgeneration sequencing approaches, we may be able to determine whether families with increased gastric cancer incidence have a genetic predisposition for a more carcinogenic immune response. A large New Zealand kindred was found to have a germline mutation in the E-cadherin gene, and similar mutations have been reported in several additional kindreds, all with diffuse-type gastric cancer. Patients with familial adenomatous polyposis have a prevalence of gastric adenomas ranging from 35% to 100%, and their risk of gastric cancer is close to 10-fold higher than that of the general population. Indeed, gastric cancer most likely arises from stem or progenitor cells present within the gastric mucosa rather than directly from terminally differentiated metaplastic cells. Investigators have for several decades sought to unravel the mutations responsible for gastric cancer initiation and progression to uncover a logical progression of acquired mutations akin to what is seen in colorectal cancer. However, gastric cancer does not follow a pattern like colorectal carcinoma progression, there is no clear-cut linear sequence of mutations in gastric cancers, and there is an even greater heterogeneity in genetic alterations. They demonstrated a good correlation of clustering between different levels of genomic data as well as epigenetic changes and transcriptome and even proteome analyses. The actual genomic changes that have been described in these comprehensive studies are in line with results that have been published previously. Aneuploidy is common in gastric cancer (60% to 75%), but cytogenetic studies have failed to identify any consistent chromosomal abnormality. Genes that inhibit entry into the cell cycle, such as p16 and p27, show diminished expression in nearly one half of gastric cancers. Multiple tumor suppressor genes have been shown to be methylated in gastric cancers. Emerging evidence suggests that these epigenetic changes, including global hypomethylation and promoter hypermethylation, occurs quite early in gastric carcinogenesis. Further evidence supporting a role for E-cadherin in the pathogenesis of gastric cancer comes from studies showing that suppression of E-cadherin expression occurs in 51% of gastric cancers, with a higher percentage found in diffuse-type cancers. For these reasons, the current thinking is that a resident tissue stem cell is the target of genetic mutations and becomes the "cancer stem cell"-capable of autonomous growth and with metastatic potential. Interestingly, Lgr5 shows lineage labeling in some antral gastric glands and in the gastric cardia. Sigal and colleagues demonstrated a direct CagA-dependent activation of Lgr5-positive gastric stem cells, thus reporting a further mechanism by which H. Given that intestinal metaplasia arises in the gastric mucosa and in the esophagus, it is plausible that a similar stem cell gives rise to both. These classifications emerged from data gathered by transcript profiling high throughput study as well as next generation sequencing and transcend the classic histopathological classification (left). Early transcriptome data suggested dichotomous groups that showed similar features to the classic Lauren types (middle, top), before more functional interpretation was enabled by pathway analyses (middle, bottom). A special interest lies in the understanding of factors that drive each phenotype, mostly the interaction with the tumor microenvironment. The more common is environmental multifocal atrophic gastritis, which is associated with Hp infection and more likely to be associated with metaplasia. The presence of Hp infection is associated with an approximately 10-fold increased risk of atrophic gastritis. Gastrin is a known growth factor for gastric mucosal cells, and sustained elevations of gastrin may contribute to abnormal growth and increased risk of neoplastic progression. Although controversy exists as to the sequence and connection of mucosal lineage changes associated with increased risk for gastric cancer, there is a general agreement that the loss of acid-secreting parietal cells, also known as oxyntic atrophy, is a prerequisite for induction of metaplasia. Antralization of the fundus, or the presence of metaplastic glands in the fundus with a general phenotype similar to that of the antral or pyloric glands (also known as pseudopyloric metaplasia), is frequently associated with intestinal-type adenocarcinoma. Nevertheless, it remains to be determined whether either or both these metaplasias can progress to dysplasia or neoplasia.

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As noted earlier medicine keri hilson lyrics buy 250mg chloroquine fast delivery, the pancreas incurs a double risk because most of its proteins are zymogens and trypsin activation will lead to recurrent injury and eventually destruction of the pancreas through progressive fibrosis treatment without admission is known as cost of chloroquine. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation medications identification buy chloroquine in united states online. Instead treatment genital warts cheap chloroquine 250mg mastercard, these features are caused by specific environmental factors or modifier genes medications on airplanes buy chloroquine australia. Q1011E are strongly associated with urolithiasis and hypercalcuria in various populations medicine park lodging 250mg chloroquine with amex. Q1011E (rs1801726) is also widely studied, but a clear role in pancreatic disease has not been established. The pathogenic effects of these variants do not appear to be through causing injury, but rather in altering the response to injury or inflammation caused by other etiologies. Claudins seal the space between epithelial cells, mark the transition between the apical and basolateral membrane, and control the paracellular flux of water and electrolytes. The human genome has up to 27 claudins, which are generally divided into "tight" sealing claudins On one hand the regulation of intra-acinar cell calcium is critical for the prevention of pancreatic injury,176,177 whereas increasing concentrations of calcium in the pancreatic duct increases the risk of sustained trypsin activation and precipitation as calcium-containing stones. The association with this locus and risk of pancreatitis has been replicated in multiple studies in multiple non-African ancestral groups. Males possess one chromosome (hemizygous genotype) and females possess 2 (homozygous or heterozygous genotypes). Although further work needs to be done to better understand the underlying mechanisms, these data are useful for risk stratification and counseling of patients with pancreatitis and alcohol use. The opportunity to target these modifiers to improve patient disease severity is a goal of future research. Third is the "omics" revolution, where millions of analytes can be measured in a patient within a specific clinical context. Fourth, the availability of research and population data sets linked to new computational and analysis tools are needed to provide context and comparisons for the rich data sets to advance biomedical discovery. If no genetic testing, or an inadequate panel of variants was performed, then an extended genetic panel should be ordered after appropriate genetic counseling. Anthropomorphic measures including height, weight, blood pressure, and heart rate should be documented. Genetic testing for Mendelian disease has utility for identifying the disease-causing variant in affected family members, clarifying etiology and prognosis, and providing information for at-risk family members and family planning. However, additional considerations are required for complex genetic disorders, and the role of a qualified genetic counselor in the evaluation process is different than with Mendelian disorders. These are particularly important to interpret in the context of other risk factors. Patients should be specifically counseled prior to testing so that they understand the benefits, risks Patients should be evaluated at least annually, with assessment and documentation of changes in pancreatitis-related symptoms or interval hospitalizations, development of new symptoms (particularly those that may suggest cancer), functional abnormalities (exocrine and/or endocrine insufficiency), morphological changes on imaging (if performed), and laboratory testing. The emergence of new and established drugs and therapies that can be repurposed and used in pancreatic diseases continues to be examined and applied to specific problems. The trauma is usually blunt, associated with injuries to other abdominal viscera, and becomes evident soon after the injury, although injury may apparently precede the manifestation or recognition of pancreatitis by several weeks. Injury to the pancreas is often not considered in a severely injured or battered child. Pancreas divisum is the most common anatomic aberration, although a wide variety of other structural abnormalities of the bile and pancreatic duct also have been observed (see Chapter 55). Gallstone pancreatitis is less common in children than in adults and is probably a reflection of the relative infrequency of cholelithiasis before puberty. This is confirmed only by documentation of pancreatic disease, improvement on drug withdrawal, and return of disease when the drug is reintroduced. Infections, particularly with viruses,248 are frequently associated with childhood pancreatitis. Pancreatitis is occasionally observed in diabetic ketoacidosis242,243,254 and various inborn errors of metabolism. The most common metabolic derangement associated with development of pancreatic disease in children is protein-calorie malnutrition. In severely malnourished children, pancreatic enzyme secretion is often compromised, whereas volume and bicarbonate secretion are preserved. Recovery of pancreatic function is said to occur more promptly after kwashiorkor than after marasmus, but in either case the pancreatic disease may contribute to malabsorption during convalescence. Vigorous early refeeding of malnourished children has been associated with the development of clinically significant pancreatitis. In infants and toddlers, vomiting, fever, irritability, and abdominal distention can be presenting symptoms. Around 10% of all patients were diagnosed after age 10 and a few were diagnosed after age 40. Most infants identified by newborn screening are minimally symptomatic or asymptomatic when screened. However, false-positive as well as falsenegative results may be observed in newborns, in patients with malnutrition, with some medications, or if inadequate sweat is obtained (see Table 57. Environmental factors may include chronic infection with Pseudomonas aeruginosa, nutritional status, tobacco smoke, and environmental allergens,169 whereas genetic factors include variants in inflammatory response genes264,265 and modifier genes. Histologically, hyperplasia and eventual necrosis of ductular and centroacinar cells, together with inspissated secretions, lead to blockage of pancreatic ductules and subsequently encroach on acini, causing flattening and atrophy of the epithelium A mild inflammatory reaction may be present around obstructed acini, and progressive fibrosis gradually separates and replaces the pancreatic lobules. The islets of Langerhans are spared in most cases until late in the process and become concentrated in the shrinking pancreas. However, the severity of the endocrine deficiency lags behind the exocrine deficiency because the islets are relatively spared until later in the course of pancreatic destruction Enteric-coated mini-microspheres are the preferred form of replacement because they protect the digestive enzymes from destruction by gastric acid (pH < 4) and are effective. If the majority of the spheres are too large (>1 mm), emptying of the spheres/enzymes can be delayed until after food is well into the small intestine. Frequent, bulky, and fatty stools; excessive bloating and flatus; and excessive appetite or inadequate growth velocity are signs of inadequate treatment. In large part, inability to normalize fat absorption may reflect decreased uptake of fatty acids by the abnormal intestinal mucosa. Because of the high purine content of pancreatic extracts, hyperuricosuria may develop in some patients taking large doses of enzyme preparations. Colonic strictures and fibrosing colonopathy were reported with very high-dose administration of pancreatic enzymes and led to a withdrawal of all the high-dose formulations of enzymes. Fibrosing colonopathy, first recognized in 1994,278 had nearly disappeared by 1996. Vitamin D levels are affected by dietary intake, sunlight exposure, and genetics, and deficiencies are more complex than intake alone. Its manifestations vary from mildly increased bruising or purpura to catastrophic hemorrhage and affects bone formation. Supplementation of 1 mg vitamin K per day appears to improve osteocalcin levels, a marker of bone metabolism, and no harm was identified with vitamin K supplementation in a systematic review. The changes in small bowel mucosa cause physiological dysfunction of the intestine. However, patients with adult-type hypolactasia and lactose malabsorption may have decreased bone mineral density. Complicated meconium ileus includes intestinal obstruction with segmental volvulus, atresia, necrosis, perforation, meconium peritonitis (generalized), and giant meconium pseudocyst formation. As many as half of the cases of meconium ileus are complicated by volvulus, atresia, or meconium peritonitis from extravasation of meconium into the peritoneal cavity after intestinal perforation; this may manifest clinically merely as intra-abdominal calcifications, a meconium pseudocyst, generalized adhesive meconium peritonitis, or meconium ascites. Characteristic radiologic findings are unevenly distended loops of bowel with absent or scarce air-fluid levels. Abdominal calcification reflects meconium peritonitis, and a meconium pseudocyst may displace loops of bowel. Meconium ileus classically manifests with signs of intestinal obstruction within 48 hours of birth in an infant who is otherwise well; complicated meconium ileus manifests even earlier, and infants appear much sicker. When feedings are initiated, bilious emesis occurs with or without abdominal distention. The infant with meconium peritonitis often presents with additional signs of abdominal tenderness, fever, and shock. Dilated, firm, rubbery loops of bowel may be visible and palpable through the abdominal wall, particularly in the right lower quadrant. More recent reports indicate a very low operative mortality, and long-term survival approaches 90% for uncomplicated meconium ileus. N-acetylcysteine (Mucomyst), which reduces the viscosity of mucoprotein solutions by cleaving disulfide bonds in the mucoprotein molecule, and polysorbate 80 (Tween 80), a mild industrial detergent and preservative, are now generally recognized as safe and effective. In addition, more recent case series suggest that use of Gastrografin enemas only have success rates of 36% to 39%. Treatment of this disorder with balanced intestinal lavage solutions may also be beneficial. Maintenance therapy with polyethylene glycol continues to grow in popularity because it is effective and there are few side effects. Liver injury tests may be moderately elevated and fluctuate over the course of the illness. Fecal bile salt losses are high, often approaching those of patients with ileal resection (see Chapter 64). Pancreatic enzyme replacement improves fat absorption, thereby reducing fecal bile acid excretion and steatorrhea. The fractional turnover rate of the bile acid pool is increased and the total bile acid pool size diminished in the absence of pancreatic enzymes,313 whereas the biliary lipid composition and saturation index approach those of patients with cholelithiasis. Obstruction of the hepatic or bile ducts by mucous plugs does not occur, but intraductal stones sometimes cause obstructive symptoms and predispose to cholangitis. The most striking changes in the male genital tract occur in the epididymis, the vas deferens, and the seminal vesicles. Multiple histologic sections of the spermatic cord rarely show patency at more than 1 level. In addition to these defects, there is a striking increase in abnormalities associated with testicular descent, such as inguinal hernia, hydrocele, and undescended testes. Cancer tended to occur in the third decade of life and involved the esophagus, small and large intestines, stomach, liver, biliary tract, pancreas, or rectum. Adolescents and adults with unexplained complaints, especially relating to the abdominal organs, should be evaluated for occult malignancy. Energy intake can be affected both by disease complications and by psychosomatic issues, psychosocial issues, stress, and treatment noncompliance, especially in children and adolescents. In some patients, clinical depression, physical fatigue, a disordered sense of smell (food is unappetizing), and altered body image can lead to reduced food intake. In general, intake of energy should be age-appropriate and supporting normal weight, noting a wide interindividual range from about 1. This observation implies that better anticipatory planning and early markers of pending nutritional failure are needed. Some adolescents learn to pass soft Silastic feeding tubes nightly in order to administer nasogastric feedings. Gastrostomy feedings may be preferred by some families and patients, especially in younger children. Gastrostomy or jejunostomy feedings are instituted at the first sign of nutritional failure. Nocturnal infusion is encouraged to promote normal eating patterns during the day. Initially, 30% to 50% of the estimated caloric needs should be provided overnight. Very lowfat, elemental formulas may be used without enzyme supplements for patients with an enteral feeding tube, and should be given by continuous infusion. A novel in-line cartridge containing immobilized lipase offers another attractive option. In some cases, parenteral nutrition may be necessary, but it should be reserved for acute support with a return to some form of enteral nutrition as soon as possible. Most of the morbidity and mortality is related to chronic pulmonary disease; respiratory or cardiorespiratory disease contributes to 67% of deaths. These medical problems will include such entities as pancreatitis, malnutrition, cirrhosis with portal hypertension, diabetes mellitus with its long-term complications, osteopenia, and reproductive issues, as well as all of the more common problems seen in childhood. The penetrance of the pancreatitis phenotype in gene mutation carriers is incomplete (80%). Multiple small meals, avoidance of high-fat meals, and use of antioxidants and vitamins are generally recommended. A subset of subjects develops exocrine and/or endocrine failure, usually 20 to 30 years after the first symptoms. The pain experience is highly variable, suggesting the presence of multiple modifying factors. Rather, the recurrent pancreatic injury caused by unregulated trypsinogen activation, and subsequent inflammatory response appears to provide an environment that is oncogenic in nature. The most effective lifestyle target is tobacco smoking, which doubles the risk for pancreatic cancer. Genetic testing results remain unchanged throughout the life of the patient, have implications for future descendants and other family members, and may affect social and reproductive choices, employment, and insurability. Genetic information may also be useful in making life decisions to minimize risk of disease The positive and negative predictive value of a genetic test in identifying specific mutations is almost perfect with properly applied modern techniques. Prognosis can be outlined in general terms from the clinical discussion earlier, noting that there is significant variability and that the effectiveness of future treatments in preventing adverse outcomes is unknown. Finally, the mutation-positive individual has a 50% chance of passing on the mutation to each child. A positive test result in a clinically unaffected person is interpreted as an increased risk of pancreatitis, with this risk possibly diminishing with age.

An uncommon source of upper gastrointestinal bleeding: epiphrenic esophageal diverticulum treatment 8th feb buy chloroquine 250mg otc. Intramural diverticulosis of the oesophagus and Rokitansky-Aschoff sinuses in the gallbladder atlas genius - symptoms discount chloroquine 250mg free shipping. A case of obstructed deglutition from a preternatural dilation of and bag formed in the pharynx medicine 6 year cheap 250mg chloroquine. Hypopharyngeal diverticulum after cervical spine surgery: the role of endoscopic management symptoms 3 days before period cheap 250 mg chloroquine. Hypopharyngeal diverticulum formation following anterior discectomy and fusion: case series treatment resistant anxiety buy discount chloroquine on line. Esophageal intubation with duodenoscope in the presence of pharyngeal pouch by a guidewire and catheter-guided technique treatment yeast infection home generic 250mg chloroquine fast delivery. The endoscopic operation for hypopharyngeal diverticula: a roentgencinematographic study. Intramural pseudodiverticulosis of the esophagus detected on barium esophagograms: increased prevalence in patients with esophageal carcinoma. Rare coincidence of eosinophilic esophagitis with esophageal stenosis and intramural pseudodiverticulosis. Esophageal intramural pseudo-diverticulosis: endoscopic and radiologic correlation. Long-term follow-up after dilation in symptomatic esophageal intramural pseudodiverticulosis: an observational study in 22 cases. Operative management of pulmonary abscess due to spontaneous perforation of diffuse intramural esophageal pseudodiverticulosis. Conversion of vertical banded gastroplasty to Roux-en-Y gastric bypass results in restoration of the positive effect on weight loss and co-morbidities: evaluation of 101 patients. Laparoscopic resection of gastric diverticulum presenting after Roux-en-Y gastric bypass. Gastric diverticulum simulating a left adrenal mass: a case report and review of the literature. Adenocarcinoma arising in an intramural diverticulum presenting as a long-standing submucosal tumor. Juxtapapillary duodenal diverticula risk development and recurrence of biliary stone. Influence of periampullary diverticulum on the occurrence of pancreaticobiliary diseases and outcomes of endoscopic retrograde cholangiopancreatography. Active bleeding from a periampullary duodenal diverticulum that was difficult to diagnose but successfully treated using hemostatic forceps: a case report. Successful side-viewing endoscopic hemoclipping for Dieulafoy-like lesion at the brim of a periampullary diverticulum. Endoscopic sphincterotomy for acute relapsing pancreatitis associated with periampullary diverticula: a long-term follow-up. Influence of juxtapapillary diverticulum on hepatic clearance in patients after endoscopic sphincterotomy. Function of the sphincter of Oddi in patients with juxtapapillary duodenal diverticula: evaluation by intraoperative biliary manometry under a duodenal pressure load. Influence of juxtapapillary diverticula on the success or difficulty of cannulation and complication rate. Intraluminal duodenal diverticula: collective review with report of a laparoscopic excision. Acute bleeding and anemia associated with intraluminal duodenal diverticulum: case report and review. The clinical significance of jejunal diverticular disease diagnosed by double-balloon enteroscopy for obscure gastrointestinal bleeding. Complicated jejunal diverticulitis: a challenging diagnosis and difficult therapy. Enterolith ileus: liberated large jejunal diverticulum enterolith causing small bowel obstruction in the setting of jejunal diverticulitis. Jejunal diverticulum enterolith causing perforation and upper abdominal peritonitis. Intraluminal duodenal diverticulum causing recurrent pancreatitis: treatment by endoscopic incision. Endoscopic removal of entrapped coins from an intraluminal duodenal diverticulum 20 years after ingestion. Congenital duodenal diverticula: a report of three cases and a review of the literature. Endoscopic treatment of intraluminal duodenal ("windsock") diverticulum: varying techniques from five cases. Capsule endoscopy versus push enteroscopy in patients with occult gastrointestinal bleeding. Analysis of clinical manifestations of symptomatic acquired jejunoileal diverticular disease. Technically, all these hernias are hiatal hernias because they pass through the esophageal hiatus of the diaphragm. Etiology and Pathophysiology Sliding hiatal hernias (type I) occur when the gastroesophageal junction and some portion of the stomach are displaced above the diaphragm, but the orientation of the stomach axis is unchanged. The phrenoesophageal membrane anchors the gastroesophageal junction to the diaphragm (see Chapters 43 and 46). Hiatal hernias may be caused by age-related deterioration of this membrane, combined with normal positive intra-abdominal pressure and traction of the esophagus on the stomach as the esophagus shortens during swallowing. The gastroesophageal junction remains in a normal position at the level of the diaphragm, because there is preservation of the posterior phrenoesophageal ligament and normal anchoring of the gastroesophageal junction, and only the stomach moves proximally. When diagnosing a hiatal or paraesophageal hernia, important questions for the radiologist to address include: (1) Does the gastroesophageal junction lie at or above the hiatus Abdominal wall hernias protrude through the muscular and fascial walls of the abdomen and have 2 parts: (1) the orifice or defect in the aponeurotic wall of the abdomen, and (2) the hernia sac, which consists of peritoneum and abdominal, contents. Abdominal wall hernias are external if the sac protrudes through the abdominal wall or interparietal if the sac is contained within the abdominal wall. Internal hernias are contained within the abdominal cavity and do not always have a hernia sac. Hernias are reducible when the protruding contents can be returned to the abdomen and irreducible or incarcerated when they cannot. A hernia is strangulated when the vascular supply of the protruding organ is compromised, and as a consequence the organ becomes ischemic or necrotic. An incarcerated hernia is generally repaired because there is danger of strangulation, which can result in the loss of bowel. Because it can be difficult to determine whether a hernia is incarcerated or strangulated, incarcerated hernias are considered urgent and treated with surgical intervention. Another type of hernia is a Richter hernia, where only one side of the bowel (most often the antimesenteric side) protrudes through the hernia orifice. As opposed to other hernias, strangulation may occur in a Richter hernia without intestinal obstruction, making this type of hernia a diagnostic challenge. Epidemiology Estimates of the prevalence of hiatal hernia vary widely, ranging from 14% to 84% of patients examined, depending on the patient population, method of diagnosis, and symptoms present. Patients with symptomatic paraesophageal hernias are most often middle-aged to older adults. Hiatal and Paraesophageal Hernias the most common diaphragmatic hernias are sliding hernias of the stomach through the esophageal hiatus, which include Clinical Features, Diagnosis, and Complications Many patients with small simple sliding hiatal hernias are asymptomatic. Barium study showing a paraesophageal hernia with a portion of the stomach above the diaphragm. B, this barium study showing a paraesophageal hernia complicated by an organoaxial volvulus of the stomach The gastroesophageal junction remains in a relatively normal position below the diaphragm (arrow). C, the retroflexed endoscopic view of the proximal stomach demonstrates the endoscope traversing a sliding hiatal hernia adjacent to a large paraesophageal hernia. In addition to heartburn and regurgitation, patients with large sliding hiatal hernias may complain of dysphagia or discomfort in the chest or upper abdomen. With chest radiography, a hiatal hernia may be noted as a soft tissue density or an air-fluid level in the retrocardiac area. At endoscopy, the gastroesophageal junction is noted to be proximal to the impression of the diaphragm. Patients with paraesophageal or mixed hiatal hernias are rarely completely asymptomatic if closely questioned. Many patients with paraesophageal hernias have gastroesophageal reflux, particularly those with larger paraesophageal hernias. Cameron lesions or linear erosions may develop in patients with sliding hiatal hernias, particularly large hernias (see Chapter 20). These mucosal lesions are usually found on the lesser curve of the stomach at the level of the diaphragmatic hiatus This is the location of the rigid anterior margin of the hiatus formed by the central tendon of the diaphragm. Mechanical trauma, ischemia, irritation by pills, and peptic injury have been proposed as the cause of these lesions. The prevalence of Cameron lesions in patients with hiatal hernias who undergo endoscopy has been reported to be about 5%, with the highest prevalence in the largest hernias, with rates of approximately 30% in paraesophageal hernias referred for surgical repair. Symptoms include acute abdominal pain and retching, and it can progress rapidly to a surgical emergency (see "Gastric Volvulus"). Endoscopy may be difficult if the hernia is associated with gastric volvulus, and reaching the pylorus may be a challenge due to positioning of the stomach. Patients with symptomatic giant sliding hiatal hernias, paraesophageal, or mixed hernias should be offered surgery. One should pay careful attention to chest pain and postprandial shortness of breath; these may be symptoms related to the paraesophageal hernia. Indeed, patients with pulmonary issues may benefit from having their paraesophageal hernias repaired to create room in the chest and decrease aspiration events. The extent of the preoperative evaluation needed for paraesophageal hernia repair is controversial. Patients often have already had a barium esophagogram or other esophageal study that characterizes the paraesophageal hernia. Many surgeons recommend routine preoperative evaluation with esophageal manometry and ambulatory esophageal pH monitoring because of the high prevalence of associated gastroesophageal reflux and esophageal motility disorders, while others may forgo pH testing and use reflux symptoms as a guide for the type of repair chosen. Options for assessment of esophageal pH include 24-hour impedance/ pH testing and 48-hour wireless capsule pH monitoring. The object of manometric evaluation is to determine whether the patient has a significant motility disorder However, esophageal manometry is challenging in these patients, and anatomic distortions can make it difficult to identify the lower esophageal sphincter, making this measurement unreliable. Many surgeons routinely add a fundoplication to hernia repairs to prevent postoperative reflux esophagitis and to fix the stomach in the abdomen. However, in patients with motility disorders, the surgeon may elect to perform a loose anterior wrap (Dor fundoplication) or use a gastrostomy tube or gastropexy to fix the stomach intra-abdominally. These elements can be accomplished minimally invasively (laparoscopically or robotically), or via open operation performed through the abdomen or chest. Injury to the lung can occur with vigorous traction; however, as the diaphragmatic defect is central (medial) rather than peripheral (lateral), as in a traumatic defect, intense lung adhesions are usually not present. Resection of the hernia sac can result in violation of the left chest, requiring chest tube placement. Reconstruction of the diaphragm can be performed by placing nonabsorbable sutures posterior to the esophagus. However, most surgeons are wary of using synthetic mesh close to the esophagus, and therefore "biological" products are favored. Keyhole mesh can be used, in which the esophagus is completely encircled with mesh, with the concern being dysphagia in this situation. Fixation of the stomach in the abdomen is usually achieved by using a fundoplication, which provides some bolstering effect at the hiatus to keep the stomach in the abdomen and can reduce postoperative gastroesophageal reflux. Additional use of gastropexy, with suturing of the stomach to the abdominal wall or gastrostomy tube placement for 2 weeks to allow the stomach to mature to the abdominal wall, may result in fewer recurrences. Patients with sliding hiatal or paraesophageal hernias may have shortening of the esophagus. This makes it difficult to restore the gastroesophageal junction below the diaphragm without tension, a key factor in decreasing recurrence. In such cases, an extra length of neoesophagus can be constructed from the proximal stomach (Collis-Nissen procedure). Alternatively, transmediastinal dissection of the esophagus for more than 5 cm into the chest will usually result in adequate intra-abdominal length of esophagus without the need for additional stapling. Potential surgical complications include esophageal and gastric perforation, pneumothorax, and liver laceration. Potential long-term complications may include dysphagia if the wrap is too tight or gastroesophageal reflux if the fundoplication breaks down or migrates into the chest. When examined closely, radiographic recurrence after paraesophageal hernia repair is 15% to 25%. The retroflex view from the stomach will demonstrate the presence or absence of a paraesophageal hernia. Morgagni hernias form anteriorly at the sternocostal junctions of the diaphragm, and Bochdalek hernias form posterolaterally at the lumbocostal junctions of the diaphragm. Epidemiology Congenital diaphragmatic hernias occur in about 1/2000 to 1/10,000 births, with some types seen more frequently in males. The presence of intra-abdominal contents in the chest during fetal development results in significant hypoplasia of the lung. Morgagni hernias make up about 2% to 3% of surgically treated diaphragmatic hernias. Newborns with Bochdalek hernia have respiratory distress, absent breath sounds on one side of the chest, and a scaphoid abdomen. The major causes of mortality in infants with Bochdalek hernias are respiratory failure and associated anomalies, which can include cardiac abnormalities and musculoskeletal defects.

Clinical characteristics of congenital esophageal stenosis distal to associated esophageal atresia medications osteoarthritis pain buy 250 mg chloroquine overnight delivery. Congenital esophageal stenosis because of tracheobronchial remnant and treated by circular myectomy: a case report symptoms joint pain and tiredness buy chloroquine 250mg mastercard. Circular myectomy for the treatment of congenital esophageal stenosis owing to tracheobronchial remnant medicine hat horse discount chloroquine online american express. Complete endoscopic management of tubular esophageal duplication in a young woman treatment 20 chloroquine 250 mg without prescription. Presentation and surgical management of bronchogenic and esophageal duplication cysts in adults symptoms definition 250 mg chloroquine visa. Plummer-Vinson syndrome associated with celiac disease and complicated by postcricoid carcinoma and carcinoma of the tongue medicine 95a buy generic chloroquine pills. Heterotopic gastric mucosa of the esophagus: literature review and proposal of a clinicopathologic classification. Prevalence of esophageal inlet patch and clinical characteristics of the patients. Acid secretion from an esophageal inlet patch demonstrated by ambulatory pH monitoring. Helicobacter pylori and heterotopic gastric mucosa in the upper esophagus (the inlet patch). Argon plasma ablation of gastric inlet patches in the cervical esophagus may alleviate globus sensation: a pilot trial. Retrospective analysis of esophageal food impaction: differences in etiology by age and gender. Single dilation of symptomatic Schatzki ring with a large dilator is safe and effective. A randomized prospective study comparing rigid to balloon dilators for benign esophageal strictures and rings. Obliteration of symptomatic Schatzki rings with jumbo biopsy forceps (with video). The intrinsic muscles of the pharynx, the superior, middle, and inferior pharyngeal constrictors The inferior constrictor is composed of the thyropharyngeus (superior part) and the cricopharyngeus (inferior part). The thyropharyngeus arises from the thyroid cartilage, passes posteromedially, and inserts in the median raphe. The cricopharyngeus has superior and inferior components, each of which arise bilaterally from the sides of the cricoid lamina; the superior fibers course posteromedially to the median raphe whereas the inferior fibers loop around the esophageal inlet without a median raphe. Killian triangle, a triangular area of thin muscle, is formed posteriorly between these components and is the most common site of origin for pharyngeal pulsion diverticula. The spaces formed between the lateral insertion of the inferior constrictor and the lateral walls of the thyroid cartilage are the pyriform sinuses that end inferiorly at the cricopharyngeus muscle, separating the pharynx from the esophagus. The larynx and trachea are suspended in the neck between the hyoid bone superiorly and the sternum inferiorly. A number of muscles, categorized as the laryngeal strap muscles, contribute to this suspension and, together with the intrinsic elasticity of the trachea, permit the larynx to be raised and lowered. Laryngeal movement is crucial to the swallow response as the laryngeal inlet is both closed and physically removed from the bolus path in the course of a swallow. The pharyngeal muscles are densely innervated with motor fibers coming from nuclei of the trigeminal, facial, glossopharyngeal, and hypoglossal nuclei, as well as the nucleus ambiguus of the vagus and spinal segments C1 to C3. All motor neurons within nucleus ambiguus participate in swallowing, with those innervating the striated muscle esophagus situated rostrally and those innervating the pharynx and larynx more caudally. As such, the esophagus encompasses the anatomic and physiologic transition from the striated muscle oropharynx and the smooth muscle gut. Neurologically, the oropharynx is controlled by the cerebral cortex and medulla and capable of precise tactile sensation; the distal esophagus is composed entirely of smooth muscle, controlled by the vagus nerve and enteric nervous system, and comparatively insensitive. Although there is a gradual transition between these endpoints, motor function in the oropharynx and esophageal body are quite distinct. With that in mind, the ensuing discussion includes selected aspects of pharyngeal, gastric, and diaphragmatic function that are inextricably entwined with esophageal function. The nasopharynx extends from the base of the skull to the distal edge of the soft palate. Muscles in the nasopharynx elevate the soft palate during swallowing, seal the nasopharynx, and prevent nasopharyngeal regurgitation. The inferior margin of the oropharynx is demarcated by the valleculae anteriorly and the mobile tip of the epiglottis posteriorly. Musculature of the soft palate, tongue, and pharynx all participate during swallowing to collapse and shorten the pharyngeal lumen and then expel its contents into the esophagus. A, Sagittal view of the pharynx showing the musculoskeletal structures involved in swallowing. In the course of a swallow, the laryngeal inlet will be sealed and the mouth of the esophagus will be opened by highly coordinated muscular activity. Note that the hyoid bone is positioned as a fulcrum and is instrumental in directing anterior, superior traction forces critical to closing the larynx and opening the esophageal inlet during a swallow. It also constitutes an additional barrier to refluxed material entering the pharynx from the esophagus and prevents air from entering the esophagus by contracting in synchrony with inspiration. The Pharyngeal Swallow Disorders of the oral phase of swallowing occur with many conditions characterized by global neurologic dysfunction, such as traumatic brain injury, brain tumors, or chorea (see Chapter 37). Detailed discussion of these conditions can be found in texts on swallow evaluation and therapy. Afferent sensory fibers capable of triggering the pharyngeal swallow travel centrally via the internal branch of the superior laryngeal nerve (from the larynx) and the glossopharyngeal nerve (from the pharynx). Although understood physiologically as the patterned activation of motor neurons and their corresponding motor units, swallowing is clinically evaluated in mechanical terms and best evaluated by videofluoroscopic or cineradiographic analysis. The pharyngeal swallow rapidly reconfigures pharyngeal structures from a respiratory to an alimentary pathway and then reverses this reconfiguration within 1 second. Precise coordination of these actions is an obvious imperative, and to some degree the relative timing of these events is affected either by volition or by the volume of the swallowed bolus The most fundamental anatomic reconfiguration required to transform the oropharynx from a respiratory to a swallow pathway is to open the inlet to the esophagus and seal the inlet to the larynx. These events occur in close synchrony, facilitated by laryngeal elevation and anterior traction via the hyoid axis. Bolus transport out of the oropharynx is facilitated by the tongue and pharyngeal constrictors. Tongue motion adapts to varied swallow conditions and propels most of the bolus into the esophagus prior to the onset of the pharyngeal contraction. On the other hand, the pharyngeal contraction is more stereotyped, functioning to strip the last residue from the pharyngeal walls. The time line illustrates the coordination and timing of events within the pharyngeal swallow on fluoroscopy. Esophagus the esophagus is a 20- to 22-cm tube composed of skeletal and smooth muscle. The proportion of each muscle type is species dependent, but in humans, the proximal 5% is striated, the middle 35% to 40% is mixed with an increasing proportion of smooth muscle distally, and the distal 50% to 60% is entirely smooth muscle. The outer longitudinal muscle arises from the cricoid cartilage with slips from the cricopharyngeus passing dorsolaterally to fuse posteriorly about 3 cm distal to the cricoid cartilage. This results in a posterior triangular area devoid of longitudinal muscle, Laimer triangle. Distal to Laimer triangle, the longitudinal muscles form a continuous sheath of uniform thickness around the esophagus. The adjacent, inner muscle layer is formed of circular or, more precisely, helical muscle also forming a sheath of uniform thickness along the length of the esophagus. The extrinsic innervation of the esophagus is via the vagus nerve with motor neurons in nucleus ambiguus (striated muscle portion) and the dorsal motor nucleus of the vagus (smooth muscle portion). A, the 30-mm Hg isobaric contour plot (black lines) demonstrates that progression through the esophagus is not seamless. The proximal striated segment 1 and the distal smooth muscle esophageal contractile segments 2 and 3 are separated by a transition zone (P). The distal esophagus is also divided into 2 distinct contractile segments (2 and 3), separated by a pressure trough (M). Of interest is the concept of concurrent esophageal contraction illustrated by the vertical dashed arrows. The vagus also provide sensory innervation; in the cervical esophagus, this is via the superior laryngeal nerve with cell bodies in the nodose ganglion, whereas in the remainder of the esophagus, sensory fibers travel via the recurrent laryngeal nerve or, in the most distal esophagus, via the esophageal branches of the vagus. The esophagus also contains an autonomic nerve network, the myenteric plexus, located between the longitudinal and circular muscle layers. Myenteric plexus neurons are sparse in the proximal esophagus, and their function is unclear because the striated muscle is directly controlled by nucleus ambiguus motor neurons. On the other hand, in the smooth muscle esophagus preganglionic neurons in the dorsal motor nucleus of the vagus synapse on relay neurons in the myenteric plexus ganglia. A second nerve network, the submucosal or Meissner plexus, is situated between the muscularis mucosa and the circular muscle layer, but this is sparse in the human esophagus. Esophageal Peristalsis the esophagus is normally atonic and its intraluminal pressure closely reflects pleural pressure, becoming negative during inspiration. Primary peristalsis is initiated by a swallow and traverses the entire length of the esophagus; secondary peristalsis can be elicited in response to focal esophageal distention with air, fluid, or a balloon, beginning at the locus of distention. The mechanical correlate of peristalsis is of a stripping wave that milks the esophagus clean from its proximal to distal end. A second swallow initiated while an earlier peristaltic contraction is still progressing in the proximal esophagus completely inhibits the contraction induced by the first swallow. Deglutitive inhibition in the distal esophagus is attributable to hyperpolarization of the circular smooth muscle and is mediated via inhibitory ganglionic neurons in the myenteric plexus. Deglutitive inhibition can be demonstrated experimentally in the esophagus by distending an intraluminal balloon, which stimulates esophageal contraction. The physiologic control mechanisms governing the striated and smooth muscle esophagus differ. The striated muscle receives exclusively excitatory vagal innervation, and its peristaltic contraction results from sequential activation of the musculature. Striated muscle peristalsis is programmed by the medullary swallowing center in much the same way as is the pharyngeal swallow. The vagus nerves also exhibit control of primary peristalsis in the smooth muscle esophagus, but the mechanism of vagal control is more complex than that of the striated muscle because vagal fibers synapse on myenteric plexus neurons rather than directly on muscle cells. However, the myenteric plexus can also orchestrate peristalsis independently of vagal activation; secondary peristalsis can be elicited anywhere along the smooth muscle esophagus despite extrinsic denervation. In contrast, transection across the striated muscle esophagus does not inhibit peristaltic progression across the transection site or distally. Regardless of central or ganglionic control, esophageal smooth muscle contraction is ultimately elicited by ganglionic cholinergic neurons. Less clear are the control mechanisms for the direction and velocity of peristalsis. Nerve conduction studies indicate that neural stimuli initiated by swallowing reach the ganglionic neurons along the length of the esophagus essentially simultaneously. However, the latency between the arrival of the vagal stimulus and muscle contraction progressively increases, moving aborally. The current hypothesis is that peristaltic direction and velocity result from a neural gradient along the esophagus, wherein excitatory ganglionic neurons dominate proximally and inhibitory ganglionic neurons dominate distally. This organization is consistent with the demonstration of 2 subsegments within the smooth muscle segment with pressure topography plotting, the first of which is strongly reactive to cholinergic drugs. Clouse and colleagues pioneered this technology, noting that peristalsis was not a seamless wave of pressurization, but rather a coordinated sequence of 4 contiguous contractile segments A transition zone exists between the first and second segments, characterized by the nadir peristaltic amplitude, slightly delayed progression, and occasional failed transmission. Longitudinal Muscle the longitudinal muscle of the esophagus also contracts during peristalsis, with the net effect of transiently shortening the structure by 2 to 2. Similar to the pattern of circular muscle contraction, longitudinal muscle contraction is propagated distally as an active segment at a rate of 2 to 4 cm/s. However, unlike the circular muscle, nerve stimulation studies suggest the longitudinal muscle to be free of inhibitory neural control. The esophagus then traverses the diaphragmatic hiatus and joins the stomach almost tangentially. Viewed intraluminally, this region extends within the gastric lumen, appearing as a fold that has been conceptually referred to as a "flap valve" because increased intragastric pressure forces it closed, sealing off the entry to the esophagus. The blue circles represent excitatory neurons, and the red circles represent inhibitory neurons. A, In normal subjects, cholinergic neurons are most dense proximally, becoming increasingly sparse distally. Conversely, inhibitory neurons are more prominent distally and relatively sparse proximally. This inverse neural gradient causes increasing latency of the contraction as it progresses distally. With simultaneous vagal stimulation of ganglia along the length of the esophagus, contraction first occurs proximally and propagates distally only as the effects of increasingly dense inhibition wear off. Thus, pharmacologic manipulation can alter both contractile vigor and timing of propagation. Conceptually, esophageal motor pathophysiology can be explained by alterations in these neural gradients. B, Patients with hypercontractility and normal (or fast) propagation may have a relative increase in excitatory neurons. C, Patients with loss of inhibitory neurons will lose deglutitive inhibition, and contractions will occur simultaneously and prematurely. D, Patients with loss of both excitatory and inhibitory neurons may present with absent or weak peristalsis that does not propagate. Vagal influence is similar to that of the esophageal body, with vagal stimulation activating both excitatory and inhibitory myenteric neurons. Crural diaphragm contraction is also augmented during abdominal compression, straining, or coughing.

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