Prevention and reversal of cholera enterotoxin effects in rabbit jejunum by nicotinic acid.

The cholera enterotoxin produces intestinal secretion associated with an elevation of tissue levels of cyclic adenosine 3',5'-monophosphate levels of cyclic adenosine 3',5'-monosphosphate (cAMP). The objectives of this study were to determine whether intestinal secretion and cAMP elevation induced by cholera toxin could be prevented, or once initiated, reversed by nicotinic acid, an agent known to lower tissue levels of cAMP. In rabbits, four jejunal loops were constructed as alternating control (3-ml isotonic electrolyte solution) and cholera toxin (same solution containing 50 mug purified cholera toxin) loops. Net intestinal secretion was determined by measuring fluid accumulation, after which intestinal biopsies were taken for cAMP assay. The animals were pretreated either subcutaneously with 50 mg/kg nicotinic acid in saline 3 h and 1 h before the introduction of cholera toxin, or intraluminally with 200 mg/kg nicotinic acid in Ringer's lactate solution 15 min before the instillation of cholera toxin. Under these conditions, nicotinic acid blocked the cholera toxin-induced secretion and the rise in cAMP measured 3 h after the loops were exposed to cholera toxin. The effect of the nicotinic acid administered within the lumen on net intestinal secretion was studied. Maximal inhibition of net intestinal secretion was achieved with an intraluminally administered dose of nicotinic acid of 100 mg/kg. This dose was chosen for testing the ability of nicotinic acid to reverse the effects of cholera toxin. When nicotinic acid was instilled into a fifth loop constructed distally to the four experimental loops 3 h after exposure of these loops to cholera toxin, both intestinal secretion and elevation of cAMP were reversed. These results suggest that nicotinic acid can prevent and reverse the secretory effects of cholera toxin and may have a role in the therapy of cholera and other cAMP-associated diarrheal diseases.

Characterization of interactions between the mammalian polycomb-group proteins Enx1/EZH2 and EED suggests the existence of different mammalian polycomb-group protein complexes.

In Drosophila melanogaster, the Polycomb-group (PcG) and trithorax-group (trxG) genes have been identified as repressors and activators, respectively, of gene expression. Both groups of genes are required for the stable transmission of gene expression patterns to progeny cells throughout development. Several lines of evidence suggest a functional interaction between the PcG and trxG proteins. For example, genetic evidence indicates that the enhancer of zeste [E(z)] gene can be considered both a PcG and a trxG gene. To better understand the molecular interactions in which the E(z) protein is involved, we performed a two-hybrid screen with Enx1/EZH2, a mammalian homolog of E(z), as the target. We report the identification of the human EED protein, which interacts with Enx1/EZH2. EED is the human homolog of eed, a murine PcG gene which has extensive homology with the Drosophila PcG gene extra sex combs (esc). Enx1/EZH2 and EED coimmunoprecipitate, indicating that they also interact in vivo. However, Enx1/EZH2 and EED do not coimmunoprecipitate with other human PcG proteins, such as HPC2 and BMI1. Furthermore, unlike HPC2 and BMI1, which colocalize in nuclear domains of U-2 OS osteosarcoma cells, Enx1/EZH2 and EED do not colocalize with HPC2 or BMI1. Our findings indicate that Enx1/EZH2 and EED are members of a class of PcG proteins that is distinct from previously described human PcG proteins.

Energetics of structural domains in alpha-lactalbumin.

alpha-Lactalbumin is a small, globular protein that is stabilized by four disulfide bonds and contains two structural domains. One of these domains is rich in alpha-helix (the alpha-domain) and has Cys 6-Cys 120 and Cys 28-Cys 111 disulfide bonds. The other domain is rich in beta-sheet (the beta-domain), has Cys 61-Cys 77 and Cys 73-Cys 91 disulfide bonds, and includes one calcium binding site. To investigate the interaction between domains, we studied derivatives of bovine alpha-lactalbumin differing in the number of disulfide bonds, using calorimetry and CD at different temperatures and solvent conditions. The three-disulfide form, having a reduced Cys 6-Cys 120 disulfide bond with carboxymethylated cysteines, is similar to intact alpha-lactalbumin in secondary and tertiary structure as judged by its ellipticity in the near and far UV. the two-disulfide form of alpha-lactalbumin, having reduced Cys 6-Cys 120 and Cys 28-Cys 111 disulfide bonds with carboxymethylated cysteines, retains about half the secondary and tertiary structure of the intact alpha-lactalbumin. The remaining structure is able to bind calcium and unfolds cooperatively upon heating, although at lower temperature and with significantly lower enthalpy and entropy. We conclude that, in the two disulfide form, alpha-lactalbumin retains its calcium-binding beta-domain, whereas the alpha-domain is unfolded. It appears that the beta-domain does not require alpha-domain to fold, but its structure is stabilized significantly by the presence of the adjacent folded alpha-domain.

Selective nonoperative management of contained intrathoracic esophageal disruptions.

Eight patients with intrathoracic esophageal disruptions were managed nonoperatively and without pleural drainage. Criteria for nonoperative treatment included the following: disruption contained in the mediastinum or between the mediastinum and visceral lung pleura; drainage of the cavity back into the esophagus; minimal symptoms; and minimal signs of clinical sepsis. Cause of the esophageal perforation was pneumostatic dilatation (1 patient), vomiting (2), and a leak following esophageal operation (5). Antibiotics were administered intravenously to all patients; hyperalimentation was accomplished intravenously in 5, and nasogastric suction was used in only 1. The cavities contracted and the esophageal leaks sealed in all instances. Time before oral intake was resumed ranged from 7 to 38 days (average, 18 days). Days until discharge ranged from 15 to 52 days (average, 28 days).

A calorimetric study of the influence of calcium on the stability of bovine alpha-lactalbumin.

Bovine alpha-lactalbumin has been studied by differential scanning calorimetry with various concentrations of calcium to elucidate the effect of this ligand on its thermal properties. In the presence of excess calcium, alpha-lactalbumin unfolds upon heating with a single heat-absorption peak and a significant increase of heat capacity. Analysis of the observed heat effect shows that this temperature-induced process closely approximates a two-state transition. The transition temperature increases in proportion with the logarithm of the calcium concentration, which results in an increase in the transition enthalpy as expected from the observed heat capacity increment of denaturation. As the total concentration of free calcium in solution is decreased below that of the proteins, there are two temperature-induced heat absorption peaks whose relative area depends on the calcium concentration, such that further decrease of calcium concentration results in a increase of the low-temperature peak and a decrease of the high-temperature one. The high-temperature peak occurs at the same temperature as the unfolding of the holo-protein, while the low-temperature peak is within the temperature range associated with the unfolding of the apo-protein. Statistical thermodynamic modeling of this process shows that the bimodal character of the thermal denaturation of bovine alpha-lactalbumin at non-saturated calcium concentrations is due to a high affinity of Ca2+ for alpha-lactalbumin and a low rate of calcium exchange between the holo- and apo-forms of this protein. Using calorimetric data, the calcium-binding constant for alpha-lactalbumin has been determined to be 2.9 x 10(8) M-1.

Can restrictions on reimbursement for anti-ulcer drugs decrease Medicaid pharmacy costs without increasing hospitalizations?

OBJECTIVE: To examine the impact of a policy restricting reimbursement for Medicaid anti-ulcer drugs on anti-ulcer drug use and peptic-related hospitalizations. DATA SOURCES/STUDY SETTING: In addition to U.S. Census Bureau data, all of the following from Florida: Medicaid anti-ulcer drug claims data, 1989-1993; Medicaid eligibility data, 1989-1993; and acute care nonfederal hospital discharge abstract data (Medicaid and non-Medicaid), 1989-1993. STUDY DESIGN: In this observational study, a Poisson multiple regression model was used to compare changes, after policy implementation, in Medicaid reimbursement for prescription anti-ulcer drugs as well as hospitalization rates between pre- and post-implementation periods in Medicaid versus non-Medicaid patients hospitalized with peptic ulcer disease. PRINCIPAL FINDINGS: Following policy implementation, the rate of Medicaid reimbursement for anti-ulcer drugs decreased 33 percent (p < .001). No associated increase occurred in the rate of Medicaid peptic-related hospitalizations. CONCLUSIONS: Florida's policy restricting Medicaid reimbursement for anti-ulcer drugs was associated with a substantial reduction in outpatient anti-ulcer drug utilization without any significant increase in the rate of hospitalization for peptic-related conditions.

Reconstructions of efferent fibers in the postnatal hamster cochlea.

It is well known that adult-like physiological functioning of the mammalian postnatal cochlea occurs coincidentally with the presence of efferent synapses on outer hair cells (OHCs). This study described the cochlear innervation patterns of thick efferent fibers traveling in the vestibular nerve in postnatal hamsters ranging in age from day zero to day 10. At least three kinds of efferent fibers were labeled via an in vitro horseradish peroxidase (HRP) technique: varicose, thin efferents; nonvaricose, thin efferents; and nonvaricose, thick efferents. Nonvaricose thick efferents were reconstructed from the basal third of the cochlea. Reconstructed efferent fibers traversed in the intraganglionic spiral bundle (IGSB) on the peripheral edge of the spiral ganglion and branched profusely in the osseous spiral lamina (OSL). From day zero to day five, large (greater than 1.0 microns) diameter nonvaricose efferent fibers gave rise to branches that either terminated underneath inner hair cells or appeared to end blindly in the OSL. Efferent fibers also had branches that traveled in the inner spiral bundle (ISB) and tunnel spiral bundle (TSB). In cochleae from hamsters six to eight days old, some thin and thick diameter efferent fibers contacted both inner and outer hair cells. By the tenth day, large diameter fibers traveled radially across the tunnel of Corti to terminate on one to five OHCs. As early as day seven, large diameter fibers also appear to terminate preferentially on OHCs in row one. These observations are consistent with the notion that the end of the first postnatal week represents a critical period in the formation of adult-like synapses on the OHCs. The data also suggest a developmental transition period when efferent fibers contact both hair cell types before contacting OHCs separately.

Postnatal maturation of spiral ganglion neurons: a horseradish peroxidase study.

Using an in vitro cochlear preparation from postnatal hamsters, spiral ganglion cells (SGCs) were labeled retrogradely following extracellular injections of HRP into the cochlear nerve. In 24 cochleae from hamsters between postnatal days (P) 0 and 10, the neuronal morphology of 201 SGCs and their peripheral axons were analyzed. From P 0 to 3, labeled SGCs had few distinguishable features. Although SGCs could be traced separately to inner hair cells (IHCs) and outer hair cells (OHCs), they all had roughly bipolar-shaped cell bodies. Approximately half of the labeled SGCs had peripheral axons that spiraled some distance before entering radial fiber bundles. From P 3 to 7, SGCs increased in size by nearly 30% and the number of SGCs with spiraling peripheral axons decreased to near zero. At P 10, the central axon diameter to peripheral axon diameter ratios distinguished two populations of SGCs. The hair-cell innervation patterns of SGCs also changed morphologically as a function of postnatal age. At P 0, radial fiber (RF) terminals of peripheral axons contacted as many as 8 IHCs; by P 3, RFs contacted typically one or two IHCs. The terminal portions of peripheral axons contacting OHCs did not show any appreciable spiral until P 2. By P 5, individual outer spiral fibers (OSFs) had greater spiral lengths underneath row-3 OHCs and the number of OHC contacts was also greatest for row-3 OSFs. These data suggest that SGCs undergo a systematic maturational process. Furthermore, the morphological differentiation of SGCs occurs after they have established separate inner and outer hair cell innervations.

Esophageal reflux. Diagnosis and therapy.

Diagnosis of esophageal reflux often can be made on the basis of the characteristic symptoms of heartburn and regurgitation. When the picture is not so typical, acid reflux testing and esophageal biopsy appear to be the best indicators of esophageal reflux. Medical management is directed toward preventing reflux, neutralizing refluxed gastric contents, and enhancing clearance of refluxed material. Antacids are a mainstay of therapy, along with restrictions on diet and certain types of activity. If conservative therapy fails to control symptoms and stricture is likely to develop, surgery may be indicated.

[Adenocarcinoma in a cystic duplication of the ileum]. / Adenocarcinoma optredend in een cystische duplicatie van het ileum.

A case of adenocarcinoma arising in a cystic duplication of the ileum of a 34 year old woman is described. Only one case of adenocarcinoma in ileal duplication has been recorded previously. The adenocarcinoma arose from gastric mucosa of a tubular duplication. In this case the adenocarcinoma arose from primitive type intestinal mucose in a cystic duplication.

pH monitoring: is it the gold standard for the detection of gastroesophageal reflux disease?

Ambulatory, long term (24-h) intraluminal esophageal pH monitoring is the "gold standard" for detection and quantification of gastroesophageal reflux. Is it, however, the "gold standard" for the diagnosis of gastroesophageal reflux disease (GERD)? The answer depends in part on how GERD is defined. Is it to be defined on the basis of symptoms, inflammatory changes in the esophageal mucosa, extent of the exposure of the esophagus to acid or some combination of these factors? Since the correlation between acid exposure of the esophageal mucosa and either symptoms or histologic changes is poor at best, it seems there must be factors in addition to acid exposure that determine the severity of symptoms and histologic damage. One such is the resistance of the individual patient's mucosa to injury by acid exposure. In view of the above, it is not surprising that no specific value for acid exposure of the esophagus can be equated with the diagnosis of GERD. The addition of the symptom index, the frequency with which symptoms coincide with reflux episodes, has done little to increase the sensitivity and specificity of pH recording in the diagnosis of GERD. Another variable only occasionally considered is the day to day variation in the frequency and duration of acid reflux. Finally, intraesophageal pH recording measures only the intensity of acid exposure but we have no clinical measure of mucosa resistance to acid-induced injury, the other factor contributing to the pathogenesis of GERD.

Art and science of history taking in the patient with difficulty swallowing.

History taking is the first step in the evaluation of a patient. An analysis of the information obtained provides the basis for the choice and order of diagnostic tests. In addition, it provides the clinician with the necessary information to determine the relevance of "abnormal tests" to the patient's problem. Dysphagia is a reliable symptom that indicates an abnormality in the swallowing mechanism. The history should contain a detailed description of the symptoms associated with dysphagia from the onset. Especially relevant are questions to determine if dysphagia is experienced every day or intermittently, with solid food or liquids or both, as well as presence and timing of associated symptoms such as, choking, coughing and regurgitation, changes in speech, heartburn and chest pain. It is clinically useful to divide swallowing into three phases: oral, pharyngeal and esophageal. Oral dysphagia is usually due to a neurologic disorder, decreased salivary flow or painful oropharyngeal lesions. Pharyngeal dysphagia is most frequently caused by neuromuscular disorders and less frequently by a Zenker's diverticulum, neoplasm or a mucosal web. Esophageal dysphagia is caused by a structural narrowing, such as produced by a peptic stricture, neoplasm or a Schatzki's ring or by a primary motility abnormality, such as achalasia or diffuse esophageal spasm or by motility abnormalities produced by inflammation caused by gastroesophageal reflux, medication-induced esophageal ulceration or infectious esophagitis.

Coordination of peristalsis in pharynx and esophagus.

When a swallowed liquid bolus is followed from mouth to stomach in man by contrast studies or manometry, it traverses its course without hesitation even though the bolus is propelled by striated muscle contraction in the first part of its journey and smooth muscle in the latter part. The striated muscle is innervated by excitatory cholinergic nicotinic cranial nerves whereas the smooth muscle of the esophagus is innervated by the enteric nervous system (ENS) through excitatory and inhibitory nerves. These differences can be demonstrated by observing the inhibitory effects of curare and atropine, the first blocking nicotinic receptors and the second muscarinic receptors. Early students of esophageal motility recognized that peristalsis could be initiated in two ways. The first is initiated by a swallow and is called primary peristalsis and the second called secondary peristalsis is initiated by distension of the esophagus. It was proposed that primary peristalsis was initiated by a single sensory input activated by the bolus entering the pharynx which in turn activated a motor program in the brain stem. Secondary peristalsis was believed to be stimulated by multiple afferent impulses arriving from the esophagus as the bolus passed down the esophagus. More recent studies using manometric techniques have suggested that the only difference between primary and secondary peristalsis is the afferent stimuli and the effector mechanism is the same. Subsequent studies of carefully timed, paired swallows, transection of vagus nerves and esophagus, and single nerve recordings suggest that the answer lies between the two extremes noted above.(ABSTRACT TRUNCATED AT 250 WORDS)

Campylobacter gastritis and associated disorders.

Our review of evidence that Campylobacter pylori is an important factor in gastritis, peptic ulcer disease, and "nonulcer dyspepsia" suggests that C pylori is the most common cause of chronic active gastritis. The association between C pylori gastritis and duodenal ulcer, which approaches 100%, leads to the suggestion that this infection plays an important role in the pathogenesis of duodenal ulcer. Evidence supporting a central role in the pathogenesis of gastric ulcer and nonulcer dyspepsia is less compelling.

Health plan accreditation: NCQA, JCAHO, or both?

Currently the National Committee for Quality Assurance (NCQA) and the Joint Commission on the Accreditation of Healthcare Organizations (the Joint Commission) accredit managed care organizations (MCOs), but is competition in the market for plan accreditation beneficial or counterproductive? This paper presents the results from two surveys that were administered to a group of large public and private purchasers, and representatives from the American Association of Health Plans and the Centers for Disease Control, who attended the Lovelace Health System (LHS) "Accreditation Experience" program. The LHS program was designed to inform purchasers about the NCQA and Joint Commission accreditation processes. The surveys captured purchaser views about the advantages and disadvantages of both accreditation processes, the value of accreditation, and the use of plan performance measures.

Gastric aspiration in localization of gastrointestinal hemorrhage.

We compared the findings from gastric aspiration for blood with the site of gastrointestinal (GI) hemorrhage ultimately identified by endoscopy or angiography in 1,190 patients whose cases were analyzed retrospectively and prospectively during a six-year period. Gastric aspirates were positive for blood in 837 patients. An upper GI site proximal to Treitz' ligament was identified in 93%, and none had a lower GI site. A negative aspirate was found in 353 patients; a lower GI site was identified in 60%, and 1% (three patients) had an upper GI site. In these three patients, hemorrhage occurred in clinical settings suggesting ulcer disease, and bleeding duodenal ulcers were found in all three. All of the other 180 patients with a bleeding duodenal ulcer had a positive gastric aspirate.