G-protein β3 subunit 825CC genotype is associated with postprandial distress syndrome with impaired gastric emptying and with the feeling of hunger in Japanese

Background G‐protein dysfunction related alteration of intracellular signal transduction might be linked to various abnormalities of functional gastrointestinal (GI) disorders. Serotonin (5‐hydroxytryptamine; 5‐HT) as well as G‐protein is also key signaling molecule sensorimotor functions in the GI tract. Thus, this study aims to evaluate the correlation between gastric emptying and GNβ3 and 5‐HTs polymorphisms in functional dyspepsia (FD) as defined by Rome III classification. Methods Seventy‐four patients presenting with typical symptoms of FD (epigastric pain syndrome: EPS, n = 24; postprandial distress syndrome: PDS, n = 51) and sixty‐four healthy volunteers were enrolled. Gastric motility was evaluated with the T_max value using the ¹³C‐acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and SRQ‐D scores to determine depression status. GNβ3‐C825T, 5‐HT_1A‐C1019G, 5‐HT_2A‐G1438A, 5‐HT_3A‐C42T, and 5‐HT_4A‐G353 + 6A polymorphisms were analyzed in DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. Key Results There was a significant relationship (P = 0.045) between GNβ3 825CC genotype and PDS patients without gastro‐esophageal reflux symptoms with impaired gastric emptying. In Japanese, GNβ3 825CC genotype in FD patients was significantly associated (P = 0.0485) with the feeling of hunger compared with GNβ3 825CT and TT genotypes. Conclusions & Inferences Our results suggest that the GNβ3 825CC genotype is significantly associated with PDS patients without gastro‐esophageal reflux with impairments of gastric emptying and also with the feeling of hunger in patients with FD. Further studies are needed to clarify whether the GNβ3 825CC genotype is linked to disturbances of gastric emptying via altered signal transduction responses.     

Generalized neuromuscular hypoplasia,reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging

Background Gastrointestinal symptoms, particularly constipation, increase with aging, but their underlying mechanisms are poorly understood due to lack of experimental models. Previously we established the progeric klotho mouse as a model of aging‐associated anorexia and gastric dysmotility. We also detected reduced fecal output in these animals; therefore, the aim of this study was to investigate in vivo function and cellular make‐up of the small intestinal and colonic neuromuscular apparatus. Methods Klotho expression was studied by RT‐PCR and immunohistochemistry. Motility was assessed by dye transit and bead expulsion. Smooth muscle and neuron‐specific gene expression was studied by Western immunoblotting. Interstitial cells of Cajal (ICC) and precursors were analyzed by flow cytometry, confocal microscopy, and three‐dimensional reconstruction. HuC/D⁺ myenteric neurons were enumerated by fluorescent microscopy. Key Results Klotho protein was detected in neurons, smooth muscle cells, and some ICC classes. Small intestinal transit was slower but whole‐gut transit of klotho mice was accelerated due to faster colonic transit and shorter intestinal lengths, apparent only after weaning. Fecal water content remained normal despite reduced output. Smooth muscle myosin expression was reduced. ICC, ICC precursors, as well as nitrergic and cholinergic neurons maintained their normal proportions in the shorter intestines. Conclusions & Inferences Progeric klotho mice express less contractile proteins and develop generalized intestinal neuromuscular hypoplasia mainly arising from stunted postweaning growth. As reduced fecal output in these mice occurs in the presence of accelerated colonic and whole‐gut transit, it likely reflects reduced food intake rather than intestinal dysmotility.     

Effect of 5‐HT4 receptor agonist mosapride citrate on rectosigmoid sensorimotor function in patients with irritable bowel syndrome

Background The 5‐HT₄ receptor agonist, mosapride citrate, accelerates gastric emptying. However, the effect of mosapride on colonic function has not been well investigated. We examined whether mosapride changes rectosigmoid motility and perception in patients with irritable bowel syndrome (IBS). Methods Thirty‐seven patients with IBS and 18 healthy subjects were studied. All subjects underwent a rectosigmoid barostat test to measure pain perception to intraluminal distention and resting smooth muscle motility for 20 min in the fasting state. Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (n = 19) or placebo (n = 18) orally with 200 mL water. Rectosigmoid motility and perception were measured again for 60 min following dosing. Rectosigmoid tone and contractility were evaluated in each 10‐min period. Key Results The pain threshold in the patients was significantly lower than that in controls (P < 0.01). There were no differences between mosapride and placebo groups in pain threshold, barostat bag volume, or number of contractions at baseline. Mosapride significantly decreased the mean bag volume (P < 0.01; group × period interaction by two‐way anova ) and increased the mean number of contractions (P < 0.05) compared with placebo, but did not affect the perception. In IBS patients with constipation (i.e., excluding diarrhea‐predominant subjects), mosapride (n = 13) increased rectosigmoid tone (P < 0.01) and contractions (P < 0.05) more than placebo (n = 14). Conclusions & Inferences Mosapride stimulates colonic motility without any adverse effect. These findings suggest that mosapride may have the potential to treat IBS patients with constipation and/or functional constipation. Further clinical trials are warranted to confirm the efficacy of this agent.     

Nitric oxide in enteric nervous system mediated the inhibitory effect of vasopressin on the contraction of circular muscle strips from colon in male rats

Background Arginine vasopressin (AVP) is widely used in the treatment of critical diseases with hypotension, but the reports about its effect on gastrointestinal motility are controversial. The purpose of this study was to characterize the role of AVP in the regulation of colonic motility and the underlying mechanism. Methods The contraction of the circular muscle strips (CM) of colon in male rats was monitored by a polygraph. The expressions of cytoplasmic inducible nitric oxide synthase (iNOS), I‐κB, and the nuclear P65 in proximal colon were measured by Western blot. The V₁ receptors (V₁Rs) and iNOS were localized by immunohistochemistry. The content of nitric oxide (NO) in the colon was measured by Griess reagent at the absorbance of 560 nm. Key Results Arginine vasopressin (10^?10–10^?6 mol L^?1) caused a concentration‐dependent inhibition on CM contraction. Pretreatment with one of the following chemicals, including V‐1880 (10^?7 mol L^?1), TTX (10^?5 mol L^?1), l ‐NAME (10^?4 mol L^?1), NPLA (10^?7 mol L^?1), SMT (10^?3 mol L^?1), and PDTC (10^?3 mol L^?1), attenuated the inhibitory effect of AVP on CM contraction. Arginine vasopressin increased the expression of iNOS and the content of NO in proximal colon. These effects were attenuated by pretreatment with PDTC (10^?3 mol L^?1). Following AVP administration, the amount of cytoplasmic I‐κB decreased, but that of nuclear P65 increased. Double immunofluorescence labeling revealed that V₁Rs and iNOS were co‐localized on the cells of myenteric plexus in proximal colon. Conclusions & Inferences Arginine vasopressin inhibited the contraction of CM in proximal colon. This effect was mediated by NO produced from NF‐κB–iNOS pathway and neuronal NOS activation in myenteric plexus.     

Familial intestinal degenerative neuropathy associated with chronic intestinal pseudo‐obstruction

Background Few families with autosomal dominant forms of chronic idiopathic pseudo‐obstruction (CIP) have been identified and reported. Methods We compared two families by clinical, laboratory, histopathologic, and genealogical investigations. Ten patients (pts) (five women) from two families, A and B, both with a family history suggesting autosomal dominant CIP, were investigated. Key Results All pts had chronic diarrhea, nine of ten pts had chronic abdominal pain and seven of ten chronic vomiting. Median age for onset of symptoms was 23 (A) and 34 years (B). None had dysphagia, urogenital, neurologic, or ocular symptoms. Small bowel transit and jejunal culture were abnormal in eight of nine. Manometry showed severe jejunal hypomotility in the fasting and fed state and absence of normal phase III in all nine pts and neuropathy‐like duodenal alterations in eight of nine. Progress to overt CIP had occurred in six pts. Histopathologic re‐evaluation (three pts) showed that criteria of visceral degenerative neuropathy were fulfilled in both families including intranuclear inclusions in all three pts. Genealogic exploration using the unique Swedish Register for Catechetical Meetings disclosed that the two families with all likelihood shared a male ancestor in the 1890s. Conclusions & Inferences The compiled results with striking similarities between family A and B together with genealogy findings indicate that this is one, large kindred with a familial autosomal dominant form of intestinal degenerative neuropathy often progressing to CIP but without extra‐intestinal manifestations. This is the fourth and, so far, the largest family reported with these characteristics.     

计算机辅助精子分析与常规精液分析的比较研究

目的研究计算机辅助精子分析（CASA）和常规精液分析（SRA）各项参数是否具有可比性。方法对213例精液标本同时行CASA和SRA分析。CASA采用西班牙SCA精液质量分析仪进行检测,SRA按世界卫生组织（WHO）推荐的标准化方法进行检测。结果当精子密度介于（5-80）×10^6/mL时,CASA和SRA分析的平均精子密度、精子活动力的差异无统计学意义（P〉0.05）;当精子密度〈5×10^6/mL时,CASA分析的平均精子密度高于SRA（P〈0.05）,精子活动力的差异无统计学意义（P〉0.05）;当精子密度〉80×10^6/mL时,CASA分析的平均精子密度高于SRA（P〈0.05）,且CASA检测a级精子比例偏高,d级精子比例偏低（P〈0.05）;用生理盐水按一定比例将精液稀释后分别进行CASA和SRA,平均精子密度、精子活动力的差异均无统计学意义（P〉0.05）。结论当精子密度介于（5-80）×10^6/mL时,CASA和SRA对精子密度和活动力的分析具有可比性;当精子密度〈5×10^6/mL时,CASA的误差较大,需进行SRA;当精子密度〉80×10^6/mL时,需用生理盐水稀释精液后行CASA或SRA分析,两者结果具有可比性。因此,当用CASA进行精液分析时,应同时结合显微镜镜检。     

A 21st century look at the spectrum of gastrointestinal motility disorders. What is dysmotility; what is functional?

Taken together, the above examples indicate that physiology-based diagnosis has a substantial overlap with symptom-based diagnosis. Neither symptomatic treatment nor therapy aimed at restoring normal physiology has had much success. It is still uncertain if measurement of physiologic parameters facilitates the doctor-patient relationship, whether results are abnormal or normal. However, the addition of physiology parameters to the evaluation of therapeutic interventions aimed at symptom reduction in FGIDs can possibly facilitate the identification of subgroups with a higher probability of treatment success. Unfortunately, our experience from clinical trials in this area is that physiology testing usually disappears as a new drug moves from phase II to phase III trials. In the ideal situation, the development of measurement methods with better availability and standardization, like different ingestible capsules, will help us to merge physiology and symptoms regarding both diagnosis and treatment evaluation.     

Gastric electrical stimulation with long pulses in humans and animals: can data obtained in animals be replicated in humans?

Aims: The aim of this study was to investigate and compare effective parameters for gastric electrical stimulation (GES) to modulate gastric muscle functions in different species. Methods: Four species: Pigs, dogs, rats, and mice implanted with two pairs of electrodes on the serosal surface of the stomach were studied, respectively. Experiment 1 was designed to entrain/pace gastric slow waves and included a series of 5‐min periods with long‐pulse GES of different pulse widths and frequencies. Experiment 2 was designed to induce gastric dysrhythmia with long‐pulse GES of different frequencies. Gastric slow waves were recorded during the entire experiment. Results: 1) The minimum pulse width for GES to completely entrain the slow waves was similar (100–400 msec) in all four species. 2) With fixed amplitude (4 mA) and pulse width (400 msec), the highest frequency at which slow waves could be paced was similar (about 10–60% higher than the intrinsic slow wave frequency) in all species. 3) With fixed pulse width of 400 msec and amplitude of 6 mA, GES with nine to 18 cycles per min (cpm) was able to induce dysrhythmia in dogs. In addition, there was no significant difference among these frequencies of 9–18 cpm. 4) GES with 400 msec, 6 mA, and 9 cpm was able to induce dysrhythmia in all species. These effective GES parameters in results 1–4 were similar to those used in humans in the literature. Conclusions: There is no significant difference in stimulation parameters when GES is applied to alter gastric slow waves in different animal models. Furthermore, the effective parameters for GES to alter slow waves are similar between the humans and various animal models. These findings suggest that stimulation parameters obtained from animal studies are applicable in humans.     

Lack of serotonin 5‐HT2B receptor alters proliferation and network volume of interstitial cells of Cajal in vivo

Background Normal gastrointestinal motility requires intact networks of interstitial cells of Cajal (ICC). Interstitial cells of Cajal numbers are maintained by a balance between cell loss factors and survival/trophic/growth factors. Activation of 5‐HT_2B receptors expressed on ICC increases ICC proliferation in vitro. It is not known whether 5‐HT_2B receptors on ICC are activated in vivo. The aims of this study were to investigate if adult ICC proliferate, whether the proliferation of ICC in vivo is affected by knocking out the 5‐HT_2B receptor, and if alterations in proliferation affect ICC networks. Methods Proliferating ICC were identified by immunoreactivity for Ki67 in both the myenteric and deep muscular plexus regions of the jejunum in mice with a targeted insertion of a neomycin resistance cassette into the second coding exon of the htr2b receptor gene. Key Results Adult ICC do proliferate. The number of proliferating ICC was lower in the myenteric plexus region of Htr2b^?/? compared to Htr2b^+/+ mice. The volume of Kit‐positive ICC was 30% lower in the myenteric plexus region and 40% lower in the deep muscular plexus region in Htr2b^?/? mice where the number of ICC was also reduced. Conclusions & Inferences Interstitial cells of Cajal proliferate in adult mice and activation of 5‐HT_2B receptors results in increased proliferation of ICC in vivo. Furthermore, lack of 5‐HT_2B receptor signaling reduces the density of ICC networks in mature mice. These data suggest that 5‐HT_2B receptor signaling is required for maintenance of ICC networks, adding 5‐HT to the growing number of factors shown to regulate ICC networks.     

Bowel preparation affects the amplitude and spatiotemporal organization of colonic propagating sequences

Background Colonic manometry is performed using either colonoscopically assisted catheter placement, after bowel preparation, or nasocolonic intubation of the unprepared bowel. There has been little systematic evaluation of the effects of bowel cleansing upon colonic propagating pressure wave sequences. Methods Eight healthy volunteers underwent nasocolonic placement of a water‐perfused silicone catheter which recorded pressures at 16 recording sites each spaced 7.5 cm apart in the unprepared colon for 24 h. These measures were compared with those obtained in another eight healthy volunteers in whom the catheter was placed to the caecum at colonoscopy in the prepared colon. Key Results The colonic motor responses to meals and morning waking, and the normal nocturnal suppression did not differ between the two groups, nor were the overall frequency, regional dependence nor extent of propagating sequences (PS) influenced by bowel preparation. Bowel preparation did result in a significant increase in the frequency of high amplitude PS (22 ± 7 vs 8 ± 4 HAPS/24 h; P = 0.003). Additionally, a number of the measures of spatiotemporal organization among consecutive PS (linkage among sequences and predefecatory stereotypical patterning) were significantly altered by bowel preparation. Conclusions & Inferences The overall frequency of PSs, the colonic responses to physiological stimuli such a meal and morning waking and nocturnal suppression, are not influenced by prior bowel preparation. However, investigators wishing to study HAPS frequency, or the more complex spatiotemporal relationships among consecutive PSs, should control for bowel preparation when making comparisons among study groups.