Towards an integrative model of irritable bowel syndrome.
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Colon↗
Biomedical subjects
L Chang
Publications and source records attributed to L Chang.
Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia.
BACKGROUND: Irritable bowel syndrome (IBS) and fibromyalgia (FM) are considered chronic syndromes of altered visceral and somatic perception, respectively. Because there is a significant overlap of IBS and FM, shared pathophysiological mechanisms have been suggested. Although visceral perception has been well studied in IBS, somatic perception has not. AIMS: To compare hypervigilance and altered sensory perception in response to somatic stimuli in patients with IBS, IBS+FM, and healthy controls. METHODS: Eleven IBS females (mean age 40), 11 IBS+FM females (mean age 46), and ten healthy female controls (mean age 39) rated pain perception in response to pressure stimuli administered to active somatic tender points, non-tender control points and the T-12 dermatome, delivered in a predictable ascending series, and delivered in an unpredictable randomized fashion (fixed stimulus). RESULTS: Although IBS patients had similar pain thresholds during the ascending series compared with controls, they were found to have somatic hypoalgesia with higher pain thresholds and lower pain frequency and severity during fixed stimulus series compared with IBS+FM patients and controls (P<0.05). Patients with IBS+FM were more bothered by the somatic stimuli and had somatic hyperalgesia with lower pain thresholds and higher pain frequency and severity. CONCLUSIONS: Both hypervigilance and somatic hypoalgesia contribute to the altered somatic perception in IBS patients. Co-morbidity with FM results in somatic hyperalgesia in IBS patients.
Adult↗
Differential contribution of the conserved tyrosine residues to activity and structural stability of Ophiophagus hannah alpha-neurotoxins.
Two alpha-neurotoxins, Oh-4 and Oh-7, from king cobra (Ophiophagus hannah) venom were subjected to Tyr modification with tetranitromethane. Selective nitration of Tyr4 in Oh-4 caused a slight decrease in lethal toxicity of 11% and a decrease in nicotinic acetylcholine receptor (nAchR)-binding activity of 28%, whereas nitration of Tyr4 in Oh-7 resulted in an approximately equal 60% decrease in lethality and nAchR-binding activity. When the Tyr23 in Oh-4 or Tyr22 in Oh-7 appears to be 'buried' in the toxin following further modification, the toxins lost their biological activity and conformational change concurrently. Nevertheless, the dinitrated Oh-4 retained a beta-sheet structure as revealed by CD spectra and exhibited a precipitin reaction with anti-Oh-4 sera. These results indicate that both Tyr4 and Tyr22 play a crucial role in the neurotoxicity of Oh-7, whereas intact Tyr23 is involved in the manifestation of the toxicity of Oh-4 to a greater extent. In contrast to Oh-4, the conformational stability of Oh-7 depends heavily upon the integrity of Tyr22.
Circular Dichroism↗
Modulating conjunctival wound healing.
Advances in molecular and cell biology have led to an expansion in our knowledge and understanding of the processes involved in wound healing. We review existing and potential therapies modulating the conjunctival scarring response, with particular reference to glaucoma filtration surgery. We discuss how the refinement of present antimetabolite regimens can minimise complications and improve surgical results, and advocate their use in carefully selected patient groups. Perhaps the most promising approach is targeting biological molecules. Hence, use of fully human neutralising monoclonal antibodies to the growth factor TGF beta has potential as a useful strategy for modifying conjunctival scarring. Combination therapies may also afford an improved therapeutic index. It is hoped that future therapies can offer safer, more specific, focal and titratable treatment, with far-reaching clinical applications.
Antimetabolites↗
Gender differences in regional brain response to visceral pressure in IBS patients.
In two experiments including a total of 30 irritable bowel syndrome patients, symptom-mimicking rectal pressure stimuli elicited changes in regional neural activation as measured by positron electron tomography (PET) cerebral blood flow images. Although most stimuli were not rated as painful, rectal pressure increased regional cerebral blood flow (rCBF) in areas commonly associated with somatic pain, including the anterior cingulate, insula, prefrontal cortex, thalamus, and cerebellum. Despite similar stimulus ratings in male and female patients, regional activations were much stronger for males. In both experiments, rectal pressure activated the insula bilaterally in males but not in females. Insula activation was associated most strongly with objective visceral pressure, whereas anterior cingulate activation was associated more with correlated ratings of subjective discomfort. The insula is discussed as a visceral sensory cortex. Several possible reasons for the insula gender effect are proposed.
Adult↗
Preoperative versus postoperative endoscopic retrograde cholangiopancreatography in mild to moderate gallstone pancreatitis: a prospective randomized trial.
OBJECTIVE: To determine whether endoscopic retrograde cholangiopancreatography (ERCP) and common bile duct (CBD) stone extraction should be performed routinely before surgery or'selectively after surgery in patients with mild to moderate gallstone pancreatitis. SUMMARY BACKGROUND DATA: The role and timing of ERCP in mild to moderate gallstone pancreatitis remains controversial. Routine preoperative ERCP identifies persisting CBD stones but carries risks of complications and may delay definitive care. Selective postoperative ERCP, performed only if a CBD stone is seen on intraoperative cholangiography (IOC), avoids unnecessary ERCP but risks unsuccessful stone extraction. METHODS: A prospective, randomized study of consecutive patients with gallstone pancreatitis was conducted. Using previously determined criteria, patients with acute cholangitis or necrotizing pancreatitis were excluded. Patients considered at high risk for persisting CBD stones (CBD size > or =8 mm on admission ultrasound, serum total bilirubin > or = 1.7 mg/dL, or serum amylase > or = 150 U/L on hospital day 4) were randomly assigned to routine preoperative ERCP followed by laparoscopic cholecystectomy, or laparoscopic cholecystectomy with selective postoperative ERCP and endoscopic sphincterotomy only if a CBD stone was present on IOC. Primary end points were costs, length of hospital stay, and the combined treatment failure rates (failure of diagnostic ERCP and IOC, complications of ERCP and endoscopic sphincterotomy, and complications of surgery). RESULTS: One hundred fifty-four consecutive patients with gallstone pancreatitis were evaluated prospectively for study eligibility. Sixty patients met the randomization criteria. Thirty patients were randomized to routine preoperative ERCP and 29 patients to selective postoperative ERCP (1 patient refused). Age, admission laboratory values, and APACHE II and Imrie scores were similar in both groups. By protocol, ERCP was performed in all patients in the preoperative ERCP group. In the postoperative ERCP group, ERCP was necessary in only 7 of 29 patients (24%). Mean hospital stay was significantly longer in the routine preoperative ERCP group (11.7 days) than in the selective postoperative ERCP group (9.0 days). Mean total cost was higher in the preoperative ERCP group ($9,426) than in the postoperative ERCP group ($7,798). The combined treatment failure rate was 10% in both groups. CONCLUSIONS: In patients with mild to moderate gallstone pancreatitis without cholangitis, selective postoperative ERCP and CBD stone extraction is associated with a shorter hospital stay, less cost, no increase in combined treatment failure rate, and significant reduction in ERCP use compared with routine preoperative ERCP.
APACHE↗
Wound healing modulation after glaucoma surgery.
Recent developments in molecular and cell biology have made a major impact on our understanding of the wound healing process and its modification. In this article, the spectrum of therapies that are either currently available or have potential application as modulators of the scarring response following glaucoma surgery are reviewed. Refinement of existing antimetabolite regimens can improve surgical results, especially in carefully selected patient groups. However, the most promising new approach appears to be using molecular-based therapies, such as fully human neutralizing monoclonal antibodies, designed to target specific molecules in the scarring response. Such strategies ultimately offer the potential of safer, more specific, focal, and titratable treatment, with far-reaching clinical applications.
Animals↗
Correlation of symptom criteria with perception thresholds during rectosigmoid distension in irritable bowel syndrome patients.
OBJECTIVE: Due to a lack of reliable biological markers, the diagnosis of irritable bowel syndrome (IBS) is based on symptom criteria. The possible physiological correlates of these criteria are not known. Our aims were to identify correlations of currently used IBS symptom criteria with distinct alterations in visceral perception. METHODS: Forty-two IBS patients (51% women) with a mean age of 39.5+/-1.4 yr, were included; 64% of patients were recruited from advertisement and 36% were clinic referrals. Patients completed a bowel symptom questionnaire, which included the Rome criteria and symptom severity ratings. Rectal discomfort thresholds were evaluated in all patients and in 19 controls, using a nonbiased tracking protocol consisting of phasic rectal balloon distensions before (PreTh) and after (PostTh) repetitive, high-pressure sigmoid distensions. We assessed the effect of each Rome criteria and symptom severity on PreTh and PostTh. RESULTS: IBS symptom severity was reported as moderate in 38.1% and as severe in 61.9% of patients. Overall, lower thresholds were observed in IBS patients than in controls (PreTh: 28.2+/-1.7 vs. 36.3+/-2.8 mm Hg, p<0.05; PostTh: 25.3+/-1.5 vs. 34.2+/-2.7 mm Hg, p<0.01). When assessing the effect of Rome criteria on rectal thresholds, we found that patients with hard/lumpy stools had lower thresholds than those without them, whereas patients with loose watery stools had higher thresholds than those who lacked them (both p<0.05). The lowering of rectal discomfort thresholds after sigmoid stimulation was observed regardless of the presence or absence of any Rome criteria or symptom severity. CONCLUSION: Although a decrease in rectal discomfort thresholds after sigmoid stimulation is seen in IBS regardless of specific symptoms, baseline and postsigmoid stimulation thresholds are lower in IBS patients with constipation-related symptoms.
Adult↗
Tumor stroma as the main source of inhibin production in ovarian epithelial tumors.
PROBLEM: Elevated serum inhibin levels have been found in ovarian cancer patients; however, the source of the elevated inhibin is uncertain. Previous studies of activin in human ovarian cancer suggest that activin may promote the growth of the tumor. The aims of this study were to examine the source of elevated inhibin from ovarian epithelial tumors (OETs) and to preliminarily investigate the role of the gonadotropin-inhibin/activin relationship in the development of OET. METHOD OF STUDY: The protein and mRNA expression of alpha and betaA subunits of inhibin/activin were examined by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) in 120 OETs, including 30 benign cystadenomas, 30 borderline tumors, and 60 carcinomas. Stromal and epithelial cells were microdissected from 23 OETs to further examine the expression of alpha and betaA subunits by RT-PCR. Dimeric inhibin A and activin A production were measured by using the two-site ELISA from three OET cell lines in culture under treatment of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). RESULTS: betaA subunit was expressed in the epithelial component of 100% of the cystadenomas, in 80% of borderline tumors, and in 75% of the carcinomas, but not in tumor stroma. Inhibin alpha expression was not found in the epithelium of all OETs studied, but focal inhibin alpha immunoreactivity was seen in the tumor stroma (mainly luteinized stromal cells) in the majority of cases. Dimeric activin A was produced by all of the three OET cell lines with a 1.5-1.9-fold increment after FSH stimulation. However, activin A production was not augmented by LH treatment. No inhibin A was produced by the three OET cell lines with or without gonadotropin stimulation. CONCLUSIONS: The stroma of OET is the major source in the production of inhibin alpha (monomer). Dimeric inhibin A production may be the result of combined efforts of the tumor stroma (alpha subunit) and epithelium (betaA subunit). Cellular, compartmental expression of inhibin and activin subunits may play a role in the development of OET, although the mechanism remains undefined. The unopposed activin A production stimulated by FSH in OET cell lines suggests that activin production may represent one of the cellular mechanisms of growth promotion by FSH.
Activins↗
Perceptual responses in patients with inflammatory and functional bowel disease.
BACKGROUND AND AIMS: Enhanced visceral sensitivity following a transient inflammatory process in the gut has been postulated as an aetiological mechanism of irritable bowel syndrome (IBS). In this study we compared perceptual responses to rectosigmoid distension in patients with mild chronic inflammation of the rectum (ulcerative colitis (UC)) and patients without mucosal inflammation (IBS) to determine if chronic low grade mucosal inflammation may be a plausible explanation for rectosigmoid hypersensitivity reported in both IBS and UC patients. METHODS: UC disease activity was quantified using activity index scores. Perception thresholds for discomfort during rectosigmoid distension were compared between 11 UC patients with quiescent or mild disease activity, 18 IBS patients, and 13 healthy controls. RESULTS: Although UC activity index scores negatively correlated with perceptual thresholds for discomfort (r=-0.76, p=0.016), UC patients had higher discomfort thresholds compared with IBS patients and controls before (p=0.02) and after (p<0.001) a noxious sigmoid conditioning stimulus. CONCLUSIONS: Rectal perception was attenuated in UC but enhanced in IBS. In chronic mild inflammation, activation of antinociceptive mechanisms may prevent the development of visceral hyperalgesia. Low grade mucosal inflammation alone is unlikely to be responsible for symptoms in functional gastrointestinal disorders.
Adult↗
85 kDa cytosolic phospholipase A2 is a target for chronic lithium in rat brain.
The mechanism by which chronic lithium exerts its therapeutic effect in brains of bipolar patients is not known. One possibility, suggested by our demonstration in the rat brain, is that chronic lithium inhibits turnover of arachidonic acid (AA) by reducing the activity of an AA-specific phospholipase A2 (PLA2). To test this further, mRNA levels of two AA-specific PLA2s, cytosolic PLA2 (cPLA2) type IV and intracellular PLA2 (iPLA2) type VIII, and protein level of cPLA2 were quantified in the brain of rats given lithium for 6 weeks. Chronic lithium markedly reduced brain mRNA and protein level of cPLA2, but had no effect on mRNA level of iPLA2. These results suggest that the final common path effect of chronic lithium administration is to reduce turnover of AA in brain by down-regulating cPLA2.
Animals↗
Diagnostic approach to the patient with irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a common chronic functional bowel disorder characterized by abdominal pain or discomfort and alterations in bowel habits. In clinical practice, diagnosis is based on positive symptoms known as the Rome criteria and limited diagnostic screen, taking into account warning features suggestive of organic disease. Minimal diagnostic tests are warranted to rule out structural lesions in a cost-effective manner and to convince the patient of the diagnosis of IBS. An initial diagnosis of IBS is safe and rarely needs revision over time. Persistence of symptoms is to be expected and does not justify suspicion of other diagnoses. Only change in the clinical pattern over time justifies additional investigations. Other diagnostic evaluations depend on predominant symptoms, namely constipation, diarrhea, and pain or discomfort. It should be emphasized that although an initial "positive diagnosis" is safe to exclude other diseases with similar symptoms, a common disorder such as IBS may often coexist with other asymptomatic disorders.
Colonic Diseases, Functional↗
Genetic organization of alpha-bungarotoxins from Bungarus multicinctus (Taiwan banded krait): evidence showing that the production of alpha-bungarotoxin isotoxins is not derived from edited mRNAs.
Two genomic DNAs with a size of approximately 2.8 kb, isolated from the liver of Bungarus multicinctus (Taiwan banded krait), encode the precursors of the long neurotoxins, alpha-Bgt(A31) and alpha-Bgt(V31), respectively. Both genes share virtually identical overall organization with three exons separated by two introns, which were inserted in the same positions in the coding regions of the genes. Moreover, their nucleotide sequences share approximately 98% identity. This result indicates that the two genes co-exist in the genome of B.multicinctus, and probably arose from gene duplication. The exon/intron structures of the alpha-Bgt genes were essentially the same as those reported for the short neurotoxins. This reflects that the long and short neurotoxins should share a common evolutionary origin. Comparative analyses on long neurotoxin and short neurotoxin genes showed that the protein coding regions of the exons were more diverse than the introns except for the signal peptide domain. This implies that the protein coding regions of the neurotoxins may have evolved via accelerated evolution. PCR amplification of venom gland cDNA mixtures revealed that only two amino acid sequences corresponding to alpha-Bgt(A31) and alpha-Bgt(V31) could be deduced from the cDNAs. The results of chromatographic analyses and protein sequencing again emphasized the view that, with the exception of alpha-Bgt(A31) and alpha-Bgt(V31), no other alpha-Bgt isotoxins with amino acid substitutions were present in B.multicinctus venom. In contrast to the proposition of Liu et al. ( Nucleic Acids Res., 1998,26, 5624-5629), our findings strongly suggest that each alpha-Bgt isotoxin is derived from the respective gene, and that alpha-Bgt RNA polymorphism does not originate from one single, intronless gene by the mechanism of RNA editing.
Animals↗
Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia.
OBJECTIVE: To determine whether cerebral metabolite abnormalities normalize with highly active antiretroviral therapy (HAART). BACKGROUND: Patients with HIV-cognitive motor complex (HIV-CMC) show cerebral metabolite abnormalities in the early stages of dementia. METHODS: Sixteen patients with HIV-CMC were evaluated before and after HAART, and compared with 15 HIV-negative healthy volunteers. Cerebral metabolite ratios and concentrations in the frontal lobe and basal ganglia were measured using proton MRS (1H MRS). RESULTS: In 14 of 16 patients who tolerated HAART, CD4 count increased by 133+/-101 cells/mm3 (p = 0.0003), HIV Dementia Scale score increased by 1.8+/-2.4 points (p = 0.02), and AIDS dementia complex (ADC) stage decreased by 0.54+/-0.54 points (p = 0.003). The initially increased choline/creatine (CHO/CR) reversed in the midfrontal cortex (-8.0%; p = 0.02) and in the basal ganglia (-14.7%; p = 0.01). The initially elevated myoinositol (MI)/CR and myoinositol concentration [MI] in the basal ganglia also decreased (MI/CR: -14.1%; p = 0.005; [MI]: 11.8%; p = 0.02), along with normalization of [MI] in the frontal white matter (11.4%; p = 0.05). Furthermore, the change in [MI] in the frontal white matter correlated with the change in CD4 count (r = -0.67, p = 0.03) and with the change in ADC stage (p = 0.04). CONCLUSIONS: HAART improves HIV-CMC in addition to systemic measures of HIV infection. 1H MRS detects improvement of brain injury measured by cerebral metabolites, particularly the glial marker [MI], in patients with early HIV-CMC after HAART. In addition, the degree of improvement in clinical severity of HIV-CMC is related to the degree of recovery with [MI].
AIDS Dementia Complex↗
A beta-tubulin leucine cluster involved in microtubule assembly and paclitaxel resistance.
Analysis of beta-tubulin alleles from nine paclitaxel-resistant Chinese hamster ovary cell lines revealed an unexpected cluster of mutations affecting Leu-215, Leu-217, and Leu-228. Six of the mutant alleles encode a His, Arg, or Phe substitution at Leu-215; another mutant allele has an Arg substitution at Leu-217; and the final two mutant alleles have substitutions of His or Phe at Leu-228. Using plasmids that allow tetracycline regulated expression, the L215H, L217R, and L228F mutations were introduced into a hemagglutinin antigen-tagged beta-tubulin cDNA and transfected into wild-type Chinese hamster ovary cells. In all three cases, low to moderate expression of the transfected mutant gene conferred paclitaxel resistance. Higher levels of expression caused disruption of microtubule assembly, cell cycle arrest at mitosis, and failure to proliferate. Consistent with reduced microtubule stability, cells expressing mutant hemagglutinin beta-tubulin had fewer acetylated microtubules than nonexpressing cells in the same population. These data, together with previous studies showing that the paclitaxel-resistant mutant cell lines have less stable microtubules, indicate that the leucine cluster represents an important structural motif for microtubule assembly.
Animals↗
Chiral resolution and stereospecificity of 6-phenyl-4-phenylethynyl- 1,4-dihydropyridines as selective A(3) adenosine receptor antagonists.
Racemic 6-phenyl-4-phenylethynyl-1,4-dihydropyridine derivatives have been shown to be highly selective A(3) adenosine receptor antagonists (Jiang et al. J. Med. Chem. 1997, 40, 2596-2608). Methods for resolving the optical isomers at the C4 position, involving selective crystallization or chromatographic separation of diastereomeric ester derivatives, have been developed. Optically pure glycerol and threitol derivatives were used as chiral auxiliary groups for ester formation at the 3-position, resulting in diastereomeric mixtures of dihydropyridines. Esterification of a 6-phenyl-4-phenylethynyl-1,4-dihydropyridine derivative at the 3-position with a chiral, protected glycerol moiety, (S)-(+)-2, 2-dimethyl-1,3-dioxolane-4-methanol, allowed the selective crystallization of a pure diastereomer, 9. The (1)H NMR spectrum of 9 using the lanthanide shift reagent Eu(fod)(3) indicated optical purity, and the (4S,2'R)-configuration was assigned using X-ray crystallography. The noncrystalline (4R,2'R)-isomer 10 was also isolated and shown to be 3-fold more potent than the (4S,2'R)-isomer in binding to A(3) receptors. The 2,2-dimethyl-1,3-dioxolane moiety also served as a protected form of a diol, which showed selective reactivity versus a 5-ethyl ester in basic transesterification reactions. A racemic 5-carboxylic acid derivative could not be resolved through crystallization of diastereomeric salts. Enantiomers of 5-benzyl 3-ethyl 2-methyl-6-phenyl-4-phenylethynyl-1, 4-dihydropyridine-3,5-dicarboxylate (2) were obtained via an ester derived from (4R,5R)-(-)-2,3-O-isopropylidene-D-threitol at the 3-position, which was resolved using HPLC, and each diastereomer was subsequently deprotected in acidic conditions. The resulting diols were exchanged for ethyl ester groups by base-catalyzed transesterification. The binding of pure enantiomers of 2 at A(3) adenosine receptors indicated a 35-fold stereoselectivity for the (4S)-isomer 21. A receptor docking hypothesis, using a previously derived human A(3) receptor model, shows the bulkier of the two ester groups (5-Bn) of 21 oriented toward the exofacial side and the 4-position phenylethynyl group situated between transmembrane helical domain TM6 and TM7.
Animals↗
Does upregulation of inducible nitric oxide synthase (iNOS) render the stomach more susceptible to damage?
Nitric oxide from constitutive nitric oxide synthase (NOS) augments gastric mucosal blood flow and is important in mucosal defense. However, the function of the inducible isoform of NOS (iNOS) in the gastric mucosa remains to be fully elucidated. This study was done to examine the role of iNOS in gastric mucosal blood flow and gastric injury following endotoxemia. Conscious rats were given intraperitoneal saline or lipopolysaccharide (LPS, 5 or 20 mg/kg). Five hours later, rats were anesthetized, a laparotomy made, gastric fluid aspirated, and 3 ml of 20% ethanol introduced into the forestomach. Rats were sacrificed 10 min later for assessment of macroscopic injury (mm2) to the gastric mucosa. Other rats did not receive 20% ethanol, but instead, gastric mucosal blood flow was determined with laser Doppler, followed by sacrifice and removal of stomachs for determination of gastric mucosal iNOS immunoreactivity (Western immunoblot). Lipopolysaccharide dose dependently increased gastric injury, decreased gastric mucosal blood flow, and increased gastric mucosal iNOS immunoreactivity compared to rats receiving saline. In additional experiments and using a similar protocol, intraperitoneal administration of aminoguanidine (45 mg/kg), an iNOS inhibitor, reversed lipopolysaccharide-induced gastric injury and restored gastric mucosal blood flow to baseline, whereas the nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (5 mg/kg) did not. Taken together, these data suggest that upregulation of iNOS is in part responsible for the detrimental effects of LPS on the gastric mucosa, possibly from a reduction in gastric mucosal blood flow.
Animals↗
Brain biochemistry in Williams syndrome: evidence for a role of the cerebellum in cognition?
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Brain Chemistry↗