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J R Mathias

Publications and source records attributed to J R Mathias.

At least 19 recordsLinked to original sources
PubMed2001

Altering the DNA-binding specificity of the yeast Matalpha 2 homeodomain protein.

Homeodomain proteins are a highly conserved class of DNA-binding proteins that are found in virtually every eukaryotic organism. The conserved mechanism that these proteins use to bind DNA suggests that there may be at least a partial DNA recognition code for this class of proteins. To test this idea, we have investigated the sequence-specific requirements for DNA binding and repression by the yeast alpha2 homeodomain protein in association with its cofactors, Mcm1 and Mata1. We have determined the contribution for each residue in the alpha2 homeodomain that contacts the DNA in the co-crystal structures of the protein. We have also engineered mutants in the alpha2 homeodomain to alter the DNA-binding specificity of the protein. Although we were unable to change the specificity of alpha2 by making substitutions at residues 47, 54, and 55, we were able to alter the DNA-binding specificity by making substitutions at residue 50 in the homeodomain. Since other homeodomain proteins show similar changes in specificity with substitutions at residue 50, this suggests that there is at least a partial DNA recognition code at this position.

Amino Acid Substitution↗
PubMed2000

Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial.

INTRODUCTION: Motilin-receptor agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the motilin agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying. METHODS: Patients were randomized with postprandial symptoms and documented functional dyspepsia by endoscopy (n=589 in intention-to-treat analysis). Patients were assigned to either the delayed or normal gastric emptying strata, based on a validated 13C octanoic acid breath test. Patients were then further randomized within each strata, to receive one of four doses of ABT-229 (1.25, 2. 5, 5 or 10 mg b.d. before breakfast and dinner) or placebo for 4 weeks, following a 2-week baseline. The primary outcome was the assessment of change in symptom severity over the 2 weeks from baseline to final visit, based on a self-report questionnaire measuring severity on visual analogue scales. RESULTS: Baseline characteristics across the treatment arms were very similar. No significant differences in the upper abdominal discomfort severity score (maximum 800 mm) were observed for any active treatment arm vs. placebo (mean change from baseline -139, -141, -145, -160 and -134 mm for placebo, 1.25, 2.5, 5, and 10 mg, respectively, at 4 weeks by intention-to-treat). More patients on placebo reported a good or excellent global response than patients on 1.25 or 5 mg of active therapy (both P < 0.05). The results were very similar in those with and without delayed gastric emptying. Helicobacter pylori status did not predict response. Excluding patients with any baseline heartburn (total remaining n=240), ABT-229 10 mg was inferior to placebo in relief of upper abdominal discomfort. CONCLUSIONS: ABT-229 was of no value for relief of symptoms in functional dyspepsia, compared with placebo.

Adult↗
PubMed1998

Relation of endometriosis and neuromuscular disease of the gastrointestinal tract: new insights.

OBJECTIVE: To investigate the neuromuscular activity of the gastrointestinal tract by antroduodenal manometry in women with endometriosis documented by laparoscopy, to assess the effects of diet and drug therapy on symptoms, and to assess the bacterial overgrowth that is commonly associated with these nerve diseases. DESIGN: Prospective, open-label study. SETTING: A clinical center for the care of women's health. PATIENT(S): Fifty women with endometriosis documented by laparoscopy and gastrointestinal tract symptoms characterized by chronic abdominal pain, nausea, vomiting, early satiety, bloating and distention, and altered bowel habits. INTERVENTION(S): Motility of the gastrointestinal tract was recorded and bacterial overgrowth was assessed. Treatment consisted of dietary changes, including reduction of glycemic carbohydrates, balancing with omega 9 oils, elimination of foods with caffeine and tyramine, and addition of omega 3 fatty acids, as well as drug therapy with clonazepam (0.25 mg 3 times per day). RESULT(S): All 50 women showed a characteristic motility change (ampulla of Vater-duodenal wall spasm, a seizure equivalent of the enteric nervous system). Forty of the women showed bacterial overgrowth. There was a significant reduction in the total symptom score after 8 weeks of treatment. CONCLUSION(S): This study suggests that endometriosis and gastrointestinal tract symptoms are a result of the dysfunction of hollow organs. Correction of the biochemical imbalance of the eicosanoid system and the hypersecretion of insulin that results from excessive intake of glycemic carbohydrates and lack of essential fatty acids significantly decreases symptoms in patients with endometriosis and associated neuromuscular disease of the gastrointestinal tract.

Adult↗
PubMed1998

Effect of leuprolide acetate in treatment of abdominal pain and nausea in premenopausal women with functional bowel disease: a double-blind, placebo-controlled, randomized study.

We have previously reported impressive results in using a gonadotropin-releasing hormone analog, leuprolide acetate (Lupron), in the treatment of moderate to severe symptoms (especially abdominal pain and nausea) in patients with functional bowel disease (FBD). Pain is the hallmark of patients with FBD, and there is no consistent therapy for the treatment of these patients. The purpose of the present study was to expand the investigation to study similar patients (menstruating females) in a multicenter, double-blind, placebo-controlled, randomized study using Lupron Depot (which delivers a continuous dose of drug for one month), 3.75 mg (N = 32) or 7.5 mg (N = 33), or placebo (N = 35) given intramuscularly every four weeks for 16 weeks. Symptoms were assessed using daily diary cards to record abdominal pain, nausea, vomiting, early satiety, anorexia, bloating, and altered bowel habits. Additional assessment tools were quality of life questionnaires, psychological profile, oral-to-cecal transit using the hydrogen breath test, antroduodenal manometry, reproductive hormone levels, and global evaluations by both patient and investigator. Patients in both Lupron Depot-treated groups showed consistent improvement in symptoms; however, only the Lupron Depot 7.5 mg group showed a significant improvement for abdominal pain and nausea compared to placebo (P < 0.001). Patient quality of life assessments and global evaluations completed by both patient and investigators were highly significant compared to placebo (P < 0.001). All reproductive hormone levels significantly decreased for both Lupron Depot-treated groups by week 4 and were significantly different compared to placebo at week 16 (P < 0.001). This study shows that leuprolide acetate is effective in controlling the debilitating symptoms of abdominal pain and nausea in patients with FBD.

Abdominal Pain↗
PubMed1996

Myoelectric activity of the cecum in fed and fasted domestic fowl (Gallus sp.).

To study cecal motility and its relation to the fed and fasted condition in domestic fowl, we sutured 7 miniature electrodes onto the ceca and ileum of 4 roosters. After recovery from the surgery, the birds received recordings of myoelectric activity for a total of 169 h while fasted and for 28 h while in the fed state. We found that single or brief clusters of action potentials (APs) occurred in the cecal smooth muscle at mean frequencies of 10.8 to 25.0/h, with the fewest when the lumen contained little food (after fasting > 24 h). Virtually all APs propagated, whether orad (toward the ileocecocolic junction) or retrograde (toward the cecal tip), with retrograde activity significantly more frequent (P < 0.001). Propagation velocity was rapid, varying from 8 to 750 cm/min (mean = 106 cm/min), being slower when birds were in the fed state. Thus, fasting resulted in fewer and more rapid APs and more that propagated toward the cecal tip. Motor activity was well coordinated between ceca, both organs showing essentially simultaneous spike activity; 72% of APs occurred within 8.1 s of each other. No relationship between ileal and cecal activity was apparent. Prominent slow waves were recorded in the ceca (5 to 5.5/min), the same slow-wave frequency as in the ileum (small intestine). From the results obtained here and from earlier studies, we conclude that the single or brief clusters of APs represent contractions that produce mixing of the luminal contents; occasional periods of protracted APs represent evacuation of cecal contents.

Action Potentials↗
PubMed1996

Presence of gonadotropin-releasing hormone (GnRH) receptor mRNA in rat myenteric plexus cells.

Idiopathic neuromuscular disease of the gastrointestinal tract (functional bowel disease) is thought to result from the malfunction of neurons within the enteric nervous system. Gonadotropin-releasing hormone (GnRH) analogs have recently been shown to organize the disordered motility patterns typical in these patients and to produce significant, long-term symptomatic improvement. To determine whether GnRH analogs might bind to an endogenous enteric nervous system GnRH receptor, reverse transcription-polymerase chain reaction (RT-PCR) was performed using cultured neonatal rat enteric neuron RNA and rat GnRH receptor primers. A PCR product of the predicted size was cloned and nucleotide sequence analysis demonstrated that the myenteric plexus PCR product encoded a portion of the GnRH receptor sequence previously identified in rat pituitary. These results suggest that cells in the myenteric plexus express GnRH receptors that may bind exogenously administered GnRH analogs. The expression of GnRH receptors in enteric neurons would provide an explanation for the effectiveness of GnRH analogs in treatment of idiopathic neuromuscular disease of the gastrointestinal tract.

Amino Acid Sequence↗
PubMed1996

Luteinizing hormone and human chorionic gonadotropin fragment the migrating myoelectric complex in rat small intestine.

We hypothesized that sex hormones may affect motility disorders because these diseases occur more often in women than in men, and symptoms often occur or worsen after ovulation. Luteinizing hormone (LH) is predominantly secreted by the anterior pituitary midway through the menstrual cycle; it results in the development of the corpus luteum. LH levels also increase after bilateral gonadectomy. LH and human chorionic gonadotropin (hCG) bind to the same receptor, but rats lack hCG. To assess how LH and hCG influence myoelectric activity of the small intestine and to test the specificity of the LH receptor, we implanted electrodes on the jejunum of female rats. LH (0.1 or 0.5 NIH units) was administered intraperitoneally to intact and gonadectomized rats and 0.5 NIH units to rats that had been both hypophysectomized and gonadectomized; intact animals were treated with 100 units USP of hCG. Recordings were made with the rats in fasted and in fed states, and their intestinal motility was analysed. The most striking effects of LH, hypophysectomy, and hCG were the same: phase III of the migrating myoelectric complex was markedly fragmented and its duration lengthened (P < 0.0001). Gonadectomy alone and gonadectomy with hypophysectomy also increased fragmentation and phase III duration (P < 0.01 or better). LH receptors respond similarly to LH and hCG, and both hormones alter myoelectric activity of the rat small intestine in comparable ways.

Animals↗
PubMed1995

Effect of cloned Salmonella typhimurium enterotoxin on rabbit intestinal motility.

We analysed the small intestine myoelectric responses of anesthetized New Zealand albino rabbits to Escherichia coli lysates containing an entertoxin cloned from Salmonella typhimurium. Migrating action potential complex, which consisted of rapid bursts of actions potentials and secretion of fluid, was observed only in ileal loops, injected with the enterotoxin-containing lysate. Migrating action potential complex produced by Stn usually propagated aborally, which was typical of cholera toxin, but orad or bidirectional propagation occurred from a single point of origin when activity was intense. Cell lysates from an E. coli clone containing vectors alone, as well as proximal control segments injected with phosphate-buffered saline, gave neither a change in motility nor fluid secretion. These results show that Stn caused dramatic changes in intestinal motility and substantial fluid production.

Action Potentials↗
PubMed1995

Ampulla of Vater/duodenal wall spasm diagnosed by antroduodenal manometry.

Patients with chronic epigastric to right upper quadrant pain are often considered to have gallbladder of sphincter of Oddi dysfunction, but standard tests are nondiagnostic. In 62 consecutive patients with this compliant undergoing antroduodenal manometry, we correlated a change on duodenal motility with spasm of the ampulla of Vater/duodenal wall. This distinctive motility pattern occurred and was analyzed in 35% of patients. It is characterized by increased duodenal wall tone with phasic contractions of 19-22 or 41-44 contractions/min or by phasic activity alone. The subjects with spasm also underwent cholecystokinin cholescintigraphy, and 50% showed either significantly delayed gallbladder emptying of hilum to small intestine emptying, or both. The disorder appears to be secondary to a loss of neural inhibitory control and a dysfunctional small-bowel pacemaker. Antroduodenal manometry is an essential diagnostic procedure that complements sphincter of Oddi manometry in evaluation of unexplained right upper quadrant pain.

Abdominal Pain↗
PubMed1995

Neuromuscular diseases of the gastrointestinal tract. Specific disorders that often get a nonspecific diagnosis.

Gastrointestinal motor dysfunction, intestinal pseudo-obstruction syndromes, and hollow visceral neuropathy and myopathy were previously considered functional bowel diseases but are now recognized to be organic disorders. They may alter the muscle of the intestinal wall or the nerves of the myenteric plexus, or both. Their symptoms of chronic unexplained abdominal pain, abdominal distention and bloating, early satiety, nausea, vomiting, and alternating diarrhea and constipation are the most common and perhaps the most difficult problems encountered by gastroenterologists. New intestinal recording devices assess motility and allow objective classification of neuromuscular disease, permitting accurate diagnosis and better treatment.

Digestive System↗
PubMed1994

Effect of leuprolide acetate in patients with moderate to severe functional bowel disease. Double-blind, placebo-controlled study.

Moderate to severe functional bowel disease results in debilitating abdominal pain, nausea, intermittent vomiting, early satiety, bloating, abdominal distension, and/or altered bowel habits. Because it occurs approximately 20-30 times more frequently in women than in men and its symptoms often coincide with the menstrual cycle, we hypothesized that reproductive steroids may antagonize diseased nerves of the gastrointestinal tract, enhancing the expression of symptoms. No effective or consistent therapy has existed for these patients. We prospectively investigated the effect of a gonadotropin-releasing hormone analog, leuprolide acetate, in 30 women with symptoms of moderate to severe functional bowel disease. The study was phase II, randomized, double blind, and placebo controlled. Lupron Depot 3.75 mg (which delivers a continuous low dose of drug for one month) or placebo were given intramuscularly monthly for three months. Symptom scores were assessed at each four-week visit. Follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone levels were assessed before and after therapy. Patients treated with low-dose leuprolide improved progressively and significantly in scores for nausea, vomiting, bloating, abdominal pain, and early satiety, and for overall symptoms (P < 0.01-0.05). All hormone levels decreased significantly (P < 0.05) except luteinizing hormone (P = 0.054).

Adult↗
PubMed1994

Effect of leuprolide acetate in patients with functional bowel disease. Long-term follow-up after double-blind, placebo-controlled study.

We initially investigated the effects of a gonadotropin-releasing hormone analog, leuprolide acetate, in 28 patients with moderate to severe functional bowel disease in a phase-II, randomized, double-blind, and placebo-controlled study using Lupron Depot 3.75 mg (which delivers a continuous low dose of drug for one month) or placebo given intramuscularly. After completing that 12-week study period during which their symptoms had improved significantly (P < 0.01-0.5), the 28 patients were allowed to continue receiving leuprolide acetate; they were monitored for an additional 40 weeks. Of those 28, 25 (89%) finished the 52-week treatment. Drug administration was changed from the monthly low-dose form of leuprolide acetate to a daily subcutaneous dose that was gradually increased from 0.5 mg daily to an effective therapeutic dose (1.0-1.5 mg). All subjects received estrogen replacement during this period. Continued use of leuprolide acetate at maximum therapeutic dosage and over longer periods of time produced even more striking and significant changes in the disabling and debilitating symptoms of functional bowel disease. Nausea, abdominal pain, early satiety, anorexia, and abdominal distension decreased markedly (P < 0.0001) and vomiting was also reduced (P < 0.01) more than in the short-term, low-dosage, double-blind study. Combined total symptom scores and overall assessment also changed significantly in the long-term phase (both P < 0.0001).

Adult↗
PubMed1992

Chronic intestinal pseudoobstruction in a patient with heart-lung transplant. Therapeutic effect of leuprolide acetate.

After orthotopic heart-lung transplantation and immunosuppression, a patient developed intractable nausea and vomiting in association with chronic cytomegalovirus infection. Chronic intestinal pseudoobstruction was documented by antroduodenal manometric study. The patient was treated with leuprolide acetate with resolution of symptoms and improvement of intestinal motility abnormality. This case demonstrates an association of chronic viral infection with acquired intestinal motor disorders. Gastrointestinal complications that are common after organ transplantation might be due to acquired neuromuscular disease. The potential efficacy of leuprolide in such neuromuscular disorders provides a rationale for diagnostic motility studies in patients with "functional" gastrointestinal disorders.

Adolescent↗
PubMed1992

Roux-limb motility after total gastrectomy and Roux-en-Y anastomosis in patients with Zollinger-Ellison syndrome.

The Roux-en-Y syndrome was defined as chronic nausea, intermittent vomiting, and chronic abdominal pain worsened by eating in patients who have undergone a gastrojejunostomy Roux-en-Y reconstruction for peptic ulcer. When these patients fasted, the Roux limb showed striking abnormalities in motor function; when postprandial, they failed to convert to normal fed-state motor activity. In contrast, patients with Zollinger-Ellison syndrome do well after similar surgery; they can eat most foods and maintain their body weight. We studied the motility of the Roux limb and jejunum in six patients with Zollinger-Ellison after an esophagojejunostomy Roux-en-Y anastomosis. Roux-limb motor activity in these patients, as characterized by the migrating motor complex, was more frequent, well organized, and in synchrony with the remaining jejunum; most subjects also converted to the fed state after a liquid meal. We suggest that the enteric nervous system is intact and functions normally in patients who have had a Roux-en-Y reconstruction for ulcer disease secondary to Zollinger-Ellison, but not in patients with idiopathic peptic ulcer disease.

Adult↗
PubMed1992

Leuprolide acetate affects intestinal motility in female rats before and after ovariectomy.

Leuprolide acetate, a gonadotropin-releasing hormone (GnRH) analogue, is currently being proposed to control debilitating symptoms in women with functional bowel disease. Whether leuprolide alters gastrointestinal motility as part of its actions is unknown. This study was designed to assess, using myoelectric techniques in an animal model, the effects of leuprolide on potential mechanisms of neuromuscular function of small intestine. Female rats with (n = 6) or without (n = 8) bilateral ovariectomy were used to study jejunal motility before and after leuprolide therapy. Throughout the study, daily leuprolide dosages of 0.02, 0.2, or 0.4 micrograms/kg were injected into intact rats and 0.02, 0.2, 0.4, 1.0, or 2.5 micrograms/kg into ovariectomized rats. Recordings were made while the rats were fasted and postprandial and before and after leuprolide administration. Under control conditions, migrating myoelectric complexes (MMCs) were found in intact female rats, whether fasted or postprandial. After ovariectomy, postprandial controls and those treated with low-dose leuprolide (0.02, 0.2, and 0.4 micrograms) had typical fed-state patterns and no MMCs, but at 1.0 and 2.5 micrograms the fed state was inhibited and cycling MMCs occurred at a frequency similar to that of fasted controls. Reproductive hormones thus have a significant effect on gastrointestinal motility.

Animals↗
PubMed1992

A complex avian intestinal motility response to fasting.

The rhythmic oscillating complex (ROC) is described from a series of experiments that surveyed the myoelectric activity of the avian small intestine as recorded from chronically implanted bipolar electrodes. A highly organized myoelectric event in the fasting avian small intestine, the ROC is demonstrated in detail in chickens (Gallus); it is also found in other gallinaceous birds but not in owls (Strix) or mammals. The ROC comprises rapidly propagating bursts of spike potentials (SPBs) that occur in a regular and predictable pattern: single orad SPBs alternate with groups of aborad SPBs. An average ROC in a chicken contains a mean of 78.9 +/- 2.0 (mean +/- SE) SPBs (37% orad, 63% aborad) that rapidly traverse the full length of the small intestine. The aborad SPBs move at mean velocities of 25.0 +/- 0.5 cm/s and last a mean of 0.9 +/- 0.0 s at an electrode site; the orad SPBs are faster (41.2 +/- 2.3 cm/s) and longer in duration (1.3 +/- 0.0 s). ROC activity continues for a mean of 7.6 +/- 0.2 min. ROCs occur only in a well-fasted gut as often as every 3 h and apparently for as long as the bird remains without food. Because ROCs restimulate fed-state activity in the stomach and small intestine, we hypothesize that they recycle nutritive material for further digestive activity in the distal tract.

Action Potentials↗