Etiology and pathogenesis of achalasia: The current understanding
ABSTRACT Idiopathic achalasia is an inflammatory disease of unknown etiology characterized by esophageal aperistalsis and failure of LES relaxation due to loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus. Proposed causes of achalasia include gastroesophageal junction obstruction, neuronal degeneration, viral infection, genetic inheritance, and autoimmune disease. Current evidence suggests that the initial insult to the esophagus, perhaps a viral infection or some other environmental factor, results in myenteric plexus inflammation. The inflammation then leads to an autoimmune response in a susceptible population who may be genetically predisposed. Subsequently, chronic inflammation leads to destruction of the inhibitory myenteric ganglion cells resulting in the clinical syndrome of idiopathic achalasia. Further studies are needed to better understand the etiology and pathogenesis of achalasia-such an understanding will be important in developing safe, effective, and possibly curative therapy for achalasia.
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ABSTRACT: This study was to generate phasic and tonic stress-strain curves for evaluation of smooth muscle function in the obstructed guinea pig jejunum. Partial and sham obstruction of the jejunum in guinea pigs was created surgically, with guinea pigs not being operated on served as normal controls. The animals survived 2, 4, 7, and 14 days, respectively. The jejunal segment was distended to 10 cm H(2)O. The pressure and outer diameter changes were recorded. Passive conditions were obtained by using papaverine. Total phasic, tonic, and passive circumferential stress and strain were computed from the diameter and pressure data with reference to the zero-stress-state geometry. The active phasic and tonic stresses were defined as the total phasic and tonic stress minus the passive stress. The thickness of intestinal muscle layers increased in a time-dependent manner after obstruction. The amplitude of passive, total phasic, total tonic, active phasic, and active tonic circumferential stresses increased as function of strain 7 days after obstruction. However, when normalized to muscle layer thickness, the amplitude of active stresses did not differ among the groups. In conclusion, the long-term-obstructed intestine exhibits increased total smooth muscle contraction force. However, the contraction force per smooth muscle unit did not increase.BioMed Research International 11/2011; 2011:489720. DOI:10.1155/2011/489720 · 2.71 Impact Factor
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ABSTRACT: Previous studies have demonstrated morphological and biomechanical remodeling in the intestine proximal to an obstruction. The present study aimed to obtain stress and strain thresholds to initiate contraction and the maximal contraction stress and strain in partially obstructed guinea pig jejunal segments. Partial obstruction and sham operations were surgically created in mid-jejunum of male guinea pigs. The animals survived 2, 4, 7 and 14 days. Animals not being operated on served as normal controls. The segments were used for no-load state, zero-stress state and distension analyses. The segment was inflated to 10 cmH(2)O pressure in an organ bath containing 37°C Krebs solution and the outer diameter change was monitored. The stress and strain at the contraction threshold and at maximum contraction were computed from the diameter, pressure and the zero-stress state data. Young's modulus was determined at the contraction threshold. The muscle layer thickness in obstructed intestinal segments increased up to 300%. Compared with sham-obstructed and normal groups, the contraction stress threshold, the maximum contraction stress and the Young's modulus at the contraction threshold increased whereas the strain threshold and maximum contraction strain decreased after 7 days obstruction (P<0.05 and 0.01). In conclusion, in the partially obstructed intestinal segments, a larger distension force was needed to evoke contraction likely due to tissue remodeling. Higher contraction stresses were produced and the contraction deformation (strain) became smaller.Journal of Biomechanics 05/2011; 44(11):2077-82. DOI:10.1016/j.jbiomech.2011.05.017 · 2.50 Impact Factor
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ABSTRACT: Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.Human Genetics 10/2010; 128(4):353-64. DOI:10.1007/s00439-010-0874-8 · 4.52 Impact Factor