The esophageal propulsive force: esophageal response to acute obstruction.

The response of the normal human esophagus to an obstructing intraluminal bolus was investigated and compared to the response evoked by transient intraluminal distention. A balloon, immobilized within the esophagus by external attachment to a force transducer, was inflated with from 3 to 25 ml of air for from 3 to 210 sec. Pressure phenomena occurring in the esophagus were simultaneously recorded from the body of the esophagus above and below the balloon. Transient distention (5 sec or less) with small volumes (5 ml or less) often evoked a secondary peristaltic wave in the esophagus distal to the balloon, but infrequently resulted in the registration of any force exerted upon the balloon to drive it downward. Conversely, distentions of longer duration and with greater volume elicited an esophageal propulsive force exerted upon the balloon oriented to propel it aborally, and much less often evoked a propagated wave of secondary peristalsis. The propulsive force, obviously resulting from esophageal muscular contraction, occurred promptly, and once initiated, was sustained until deflation of the balloon. It varied widely in magnitude, from 4 to 200 g, and was associated with no motor phenomena recorded from the body of the esophagus proximal or distal to the balloon which could account for its presence, onset, magnitude, or duration. The force was inhibited by deglutition, but arrival of the primary peristaltic wave at the bolus resulted in augmentation of the force. When the obstructing balloon was freed from its attachment, the persistent, stationary force was converted to a propagated one that propelled the balloon before it. It the balloon was arrested before entering the stomach, the moving contraction was also arrested and the persistent propulsive force acting upon the balloon was maintained. The velocity of the moving contraction wave was determined in great part by the resistance offered by the bolus. Unrestrained, the balloon was propelled aborally at 4-8 cm/sec by the esophageal propulsive force; when restrained by 50 g, the rate of passage was reduced to 0.2-0.8 cm/sec. The esophageal response to intraluminal distention is thus not limited to the uninterrupted wave of secondary peristalsis but is versatile and is determined by the nature of the distending bolus. Transient distention by a mobile or collapsible bolus elicits the propagated secondary peristaltic wave.

Influence of bolus temperature on human esophageal motor function.

Hot and cold water, in comparison to room temperature water, ingested by normal young men, profoundly alters esophageal motor function. Cold water slows or abolishes esophageal peristalsis, prolongs the contraction wave in the distal esophagus, produces a delayed but prolonged relaxation of the lower esophageal sphincter, and regularly causes a lower esophageal sphincteric contraction of increased amplitude. It does not, however, diminish the frequency of response of the lower esophageal sphincter even when the peristaltic wave above is abolished. Hot water, on the other hand, accelerates the response of the esophagus to the swallow; this change is reflected by increased speed of wave propagation, waves of shorter duration, a more brief relaxation of the lower esophageal sphincter, and a lower esophageal sphincter contraction of less amplitude. Hot water may even increase the frequency of peristalsis at least in the proximal esophagus. In spite of these changes, however, neither extreme of temperature altered the rapid passage of the water swallows through the more proximal portions of the esophagus. Hot water tended to traverse the lower esophageal sphincter more rapidly than did room temperature water, but cold water was often delayed in entering the stomach and tended to pool in the distal esophagus even though sphincteric relaxation was manometrically complete and prolonged.

Restructuring medical schools to better manage their three missions in the face of financial scarcity.

The leaders of schools of medicine face a major financial and management challenge as they approach the end of the twentieth century. The new environment for the practice of medicine is diminishing the clinical income that schools have used for so long to supplement their operations. Deans and their staffs must discover new ways to manage their schools and their schools' finances. In particular, schools that continue to rely on subsidies from their health care operations will very likely face the prospect of having to defend themselves as pressures for more cost-effective operations increase and clinical and other subsidies dwindle. In sum, for deans to remain captains of their own ships, preserve their schools' three missions, and balance their books, it is essential that they lead their schools in change toward better administrative, information, and financial management systems. Stritch School of Medicine at Loyola University of Chicago is reinventing itself in response to this challenge. The organizational and management models being used there have been partially guided by the two approaches to redesigning schools of medicine described in detail in this article, the service line management matrix (SLMM) and the fractal management (FM) method. In turn, the experience of implementing the education and research service lines at Loyola has permitted a refinement of the approaches, reflected in the descriptions in this article. These approaches constitute a new model that provides for the development of three administrative service lines-teaching, research, and clinical service (not implemented at Loyola). Each service line has its own leaders and managers, who are responsible for balancing income against expenses. Each service line is a profit-and-loss center, an approach that highlights how effectively the service line is being managed and leads to greater accountability and productivity of faculty and staff. This new approach makes it possible for the school to answer the question, "Can research and teaching pay for themselves?" If they cannot, any subsidies that are needed from clinical income are identified as such. This businesslike approach supplants the traditional one of commingling all income streams to pay for operations, a strategy that worked well enough when research and clinical income constantly increased but now places medical schools in harm's way.

Are dipyridamole (sensitive) calcium channels present in esophageal smooth muscle?

UNLABELLED: Calcium (Ca2+) entry from the extra-cellular space into the cytoplasm through voltage-dependent Ca2+ channels, specifically dipyridamole (DHP) sensitive ones (L-type), control a variety of biological processes, including excitation-contraction coupling in vascular and GI muscle cells. It has also been proposed that these channels may control esophageal contractility. However, DHP-sensitive Ca2+ channels in esophagus have not been well characterized biochemically. Thus, it is not known if these channels are similar in number or affinity to those in vascular or neural tissues--organs for which clinical use of calcium channel blockers has been successful. Thus, the purpose of this study was to identify and characterize DHP-sensitive calcium channels in esophagus and compare them to vascular, neural, and other GI tissues. METHODS: We carried out in vitro receptor binding assays on lower esophageal muscle homogenates, gastric and intestinal and colonic homogenates, and aortic muscle homogenates from ca; and on brain homogenates from rat. We used a radio-labeled dihydropyridine derivative [3H]nitrendipine, to label these sites and co-administration of unlabeled nimodipine to define specific binding. RESULTS: As expected, ligand binding to L-type Ca2+ channels in aortic vascular smooth muscle and brain was readily detectable: brain, Bmax=252 fmol/mg protein, Kd=0.88 nM; aorta, Bmax=326 fmol/mg protein, Kd=0.84 nM. For esophagus (Bmax=97; Kd=0.73) and for other GI tissues, using the same assay conditions, we detected a smaller signal, suggesting that L-type Ca2+ channels are present in lower quantities. CONCLUSION: L-type Ca2+ channel are present in esophagus and in other GI muscles, their affinity is similar, but their density is relatively sparse. These findings are consistent with the relatively limited success that has been experienced clinically in the use of calcium channel blockers for treatment of esophageal dysmotility.

Cimetidine in the treatment of duodenal ulcer: review and commentary.

The published world literature on the efficacy of cimetidine, a histamine H2-receptor antagonist, in the treatment of duodenal ulcer is reviewed. In eight prospective randomized double blind placebo-controlled studies, cimetidine was administered to 348 duodenal ulcer patients with an incidence of endoscopically verified healing incidence of 37 percent in 300 placebo-treated patients. Healing rates were similar in patients receiving cimetidine in doses ranging from 0.8 to 2.0 g per day. It appears that at least 3 to 4 weeks of cimetidine therapy are needed to achieve healing rates of about 70 percent. In most trials, cimetidine was superior to placebo in achieving symptom relief in patients with duodenal ulcer. The drug has not been shown to result in acid rebound after cessation of therapy. There are no published prospective studies on the question of whether treatment with cimetidine results in increased ulcer for the short term treatment of duodenal ulcer. More data are required for an assessment of long term therapy with cimetidine.

Lipolysosomes in human liver: distribution in livers with fatty infiltration.

In this study we investigated whether lipolysosomes--lysosomes containing large lipid droplets--were present in livers of patients with various forms of hepatic injury. Organelles which displayed the same morphological characteristics and enzymatic activity as those originally described in the hamster and those found in the hepatocytes of patients with Wolman's or Wilson's disease were also found in hepatocytes of 13 of 14 randomly selected biopsy specimens from patients with minimal to severe fatty infiltration of the liver. The numbers and sizes of the lipolysosomes seemed to increase with the degree of fatty infiltration while their proportion in relation to the total number of lipid droplets remained below 5%. Based on these observations of a virtually constant association of lipolysosomes with excess lipid accumulation in liver cells we suggest that lysosomes probably play an important role in hepatic lipid metabolism and that various pathogenetic mechanisms may trigger their proliferation.

The role of nitric oxide in ethanol-induced gastrointestinal dysfunction.

We recently showed that acute ethanol inhibits contractility of the lower esophageal sphincter (LES) and the lower esophageal body (LEB) both in vivo and in vitro. To evaluate the mechanism of this inhibitory effect of ethanol, we investigated the role of nitric oxide (NO) on contractility of isolated LES and LEB circular muscle strips using inhibitors of NO synthase (NOS), NG-nitro-L-arginine methyl ester and NG-nitro-L-arginine. Ethanol significantly decreased LES basal tone. This effect was not mediated by NO, because inhibition was not prevented by inhibitors of NOS. Electrical field stimulation caused an On-response relaxation from LES strips, and an Off-response contraction from both LES and LEB strips. Inhibitors of NOS prevented the On-response relaxation of LES, but had no significant effect on LES Off-response contraction. Ethanol potentiated the On-response relaxation of the LES Off-response contraction. Ethanol potentiated the On-response relaxation of LES, but had no significant effect on Off-response contraction. Ethanol's potentiating effect of the On-response relaxation is NO-mediated, because it was abolished by NOS inhibitors. Ethanol also inhibited carbachol-induced LES contractility. This inhibitory affect was NO-mediated, because NOS inhibitors abolished it. Ethanol inhibited both the Off-response contraction and carbachol-induced contraction of LEB strips. These effects were not NO-mediated, because they were not affected by NOS inhibitor. These data suggest that NO is not a mediator for the inhibitory effect of ethanol on LEB contractility, and that NO seems to be a mediator of ethanol inhibition of some aspects of LES motor functions.

Ethanol inhibits contractility of esophageal smooth muscle strips.

Acute ethanol (EtOH) in vivo decreases both the pressure of the lower esophageal sphincter (LES) and the amplitude of contractions of the smooth muscle of the lower esophageal body (LEB) in both man and cat. However, the mechanism of this inhibitory effect of EtOH is unclear. This inhibitory effect could be caused by a direct effect of EtOH on the esophagus or be secondary to known inhibitory effects of EtOH on the central nervous system. To this end, we evaluated the in vitro effect of EtOH on contractility of smooth muscle strips from both LES and LEB. Circular muscle strips from LES and LEB were isolated from cats. Changes in resting tension of LES strips and changes in stimulant-induced tension of LES or LEB strips were measured in the presence of up to five concentrations of EtOH (12.5- 100 mM). Stimulants included electric field stimulation (EFS) and carbachol. EtOH at 75 mM significantly decreased resting LES tension. EtOH also decreased maximal contractile responses to carbachol in both LES and LEB and increased the EC50 of carbachol for LES, but not LEB. EtOH also modulated EFS-induced esophageal contractility; EtOH potentiated EFS-induced "on-response relaxation" in LES and decreased EFS-induced "off-response contractions" In LEB. EtOH-induced inhibition of esophageal contractility seemed to be reversible. EtOH did not result in muscle fatigue. Thus, EtOH can directly inhibit contractility of the esophagus, and does so reversibly and at pharmacologically relevant concentrations.

Acute ethanol inhibits calcium influxes into esophageal smooth but not striated muscle: a possible mechanism for ethanol-induced inhibition of esophageal contractility.

In both humans and cats, EtOH administered in vivo and acutely decreases contractility of smooth muscle of lower esophageal sphincter (LES) and lower esophagus (LE), but not striated muscle of upper esophagus. To see if these effects are associated with perturbation of Ca++ homeostasis, esophageal muscle slices were incubated in vitro with EtOH and then 45Ca++. At steady-state Ca++ uptake, some slices were exposed to 1 microM carbachol (CCH). Although 100 mM EtOH had no effect on Ca++ uptake into resting or stimulated striated muscle of upper esophagus, it significantly inhibited Ca++ uptake into smooth muscle of LES and LE. For unstimulated LE and resting LES, 100 mM EtOH significantly inhibited both initial uptake and steady-state levels, whereas lower doses had no significant effect. EtOH at 100 mM also affected changes in Ca++ content induced by CCH stimulation. CCH increased total exchangeable tissue Ca++ content in LE, whereas it decreased Ca++ content in LES. EtOH at 100 mM blunted these CCH-induced effects in both LES and LE. In contrast to resting muscle, inhibition of CCH-stimulated LE muscle was not limited to 100 mM EtOH, because substantial and significant inhibition was also seen at EtOH doses of 25 and 50 mM, doses which are relevant even in social drinking. Thus, EtOH inhibition of Ca++ influx into esophageal muscle is selective for smooth muscle, can occur at pharmacologically relevant EtOH doses and could be the underlying mechanism for EtOH's inhibition of contractility of esophageal smooth muscle.

Excessive production of reactive oxygen metabolites by inflamed colon: analysis by chemiluminescence probe.

Reactive oxygen metabolites (ROMs) are involved in inflammatory diseases and are postulated to contribute to tissue injury in colitis. To determine whether excessive ROMs are generated by inflamed colonic mucosa and to identify possible sources and type of ROMs, mucosal ROMs were estimated in rats and humans using a chemiluminescence probe. Colitis was induced in rats by intracolonic injection of acetic acid or intraperitoneal injection of mitomycin C. Intact, inflamed colon in rats produced more ultraweak chemiluminescence than normal colon. Inflamed mucosal scrapings from both rat models produced significantly more luminol-enhanced chemiluminescence. Addition of catalase, an H2O2 scavenger, or azide, a myeloperoxidase inhibitor, into the media significantly decreased chemiluminescence from inflamed mucosal scrapings. Indomethacin, an antioxidant cyclo-oxygenase inhibitor, also decreased chemiluminescence, but MK-866, a 5-lipoxygenase inhibitor, had no effect. Colonic biopsy specimens obtained during colonoscopy from patients with ulcerative colitis also produced more catalase-inhibitable chemiluminescence than normal colonic mucosa. These data indicate that excessive ROMs are produced by inflamed colonic mucosa in both humans and rats, which may contribute to tissue injury.

Human neutrophil functions are inhibited in vitro by clinically relevant ethanol concentrations.

Neutrophils [polymorphonuclear neutrophils (PMNs)] play a pivotal role in host defense in man. These defenses may be compromised, however, in alcohol users and abusers. We therefore evaluated the effect of ethanol levels (12.5 to 500 mg/dl), on key functions of human PMNs-chemotaxis and production of reactive oxygen species-and on changes in cytosolic-free calcium ([Ca2+]i), a pivotal intracellular mechanism of PMN activation. Ethanol significantly inhibited chemotaxis as evaluated by formyl-methionyl-leucyl-phenylalanine (fMLP)-induced upregulation of surface adhesion molecules (CD11b). fMLP-induced PMN elongation was only inhibited by a very high ethanol concentration of 500 mg/dl. Production of reactive oxygen species by normal PMNs was assessed by either chemiluminescence (CL) for hypochlorous acid or ferricytochrome c reduction (FCR) for superoxide anions. For PMN stimulated by fMLP, ethanol inhibited CL but not FCR. For PMNs activated by phorbol myristate acetate, ethanol inhibited both CL and FCR. Ethanol did not alter baseline [Ca2+]i, as assessed by videomicroscopy using the Ca(2+)-sensing fluorescent dye Fura-2-AM, but did significantly potentiate the increase in peak [Ca2+]i levels that occurs in response to stimulation by fMLP. Calcium channel blockers attenuated ethanol's inhibition of CL. Thus, acute in vitro ethanol, at clinically relevant concentrations, can inhibit several critical aspects of PMN functions. But, in PMNs, unlike neural cells, these inhibitory effects do not seem to be mediated by decreases in Ca2+ influx or in [Ca2+]i.

Esophageal dysfunction in esophagopharyngeal regurgitation.

Esophageal manometry was performed in 20 patients with esophagopharyngeal regurgitation, in 20 patients with severe chronic heartburn but without regurgitation, and in 20 normal subjects. The purpose of the procedure was to identify possible differences between these groups in upper esophageal sphincter and lower esophageal sphincter resting pressures, and in amplitude of peristaltic contraction in the distal esophagus. The mean peak upper esophageal sphincter pressures in normal subjects and in patients with chronic heartburn were significantly greater than in the patients with esophagopharyngeal regurgitation (101 and 108 vs. 54 mmHg, respectively). In the normal subjects, the mean lower esophageal sphincter resting pressure (19 mmHg) was significantly greater than for the heartburn group (14 mmHg) and for the patients with esophagopharyngeal regurgitation (10 mmHg). The amplitude of peristalsis was significantly lower in the group with regurgitation than in both normal subjects and the group with chronic heartburn. Nine normal subjects responded to intraesophageal infusion of 0.9% NaCl and 0.1 N HCl with a significant increase in upper esophageal sphincter resting pressure, but the group with esophagopharyngeal regurgitation showed no significant change. Patients with esophagopharyngeal regurgitation have lower esophageal sphincter hypotension, diminished peristaltic amplitude, upper esophageal sphincter hypotension, and diminished upper esophageal sphincter response to intraesophageal fluid. We conclude there is in these patients a breakdown of several normal esophageal mechanisms which ordinarily serve as barriers to esophagopharyngeal regurgitation.

Human upper esophageal sphincter pressure profile.

The pressure profile of the upper esophageal sphincter was characterized in nine normal subjects. Directionally oriented intraluminal pressures were recorded, at 0.5-cm intervals over a 6-cm segment that encompassed the sphincter, by a high-fidelity low-compliance recording system. The peak resting pressure was directed posteriorly, and the lowest pressures were recorded from the lateral orientations. Significant axial asymmetry was observed with peak posterior pressure 0.55 cm more distal than the anterior pressure. Calculations of variability of pressures recorded at each interval showed the peak pressure to be the most reproducible measurement for each subject. Isotonic saline and acid infusions into the esophagus distal to the sphincter resulted in increased sphincteric peak resting pressure (acid greater than saline). There was axial lengthening of the sphincteric pressure zone with infusion of acid and saline, but this observed increase in length was not significant except at the 50 mmHg level. Pressure profiles recorded during 0.5-cm station pull-throughs were virtually identical to those obtained by a rapid continuous pull-through technique.

Modulation of neutrophil function by novel colonic factors: possible role in the pathophysiology of ulcerative colitis.

Tissue damage in acute ulcerative colitis (UC) may be triggered by neutrophils (PMNs) and their inflammatory mediators such as reactive oxygen species (ROS). Because circulating PMNs appeared normal in subjects with UC, we hypothesized that the critical abnormality that attracts and activates PMNs in UC is a local colonic factor. Accordingly, the colonic milieu was sampled by using in vivo rectal dialysis (mol wt < or = 12 kd). Normal PMNs were exposed in vitro to rectal dialysates (RD) from control subjects (cRD) or subjects with active UC (aRD) or inactive UC (IRD). PMN-derived ROS were measured by chemiluminescence. cRD did not increase ROS production by unstimulated PMNs; aRD significantly and concentration-dependently increased ROS; IRD gave intermediate results. cRD inhibited the PMN-stimulating effects of both the bacterial peptide formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA). aRD and IRD blunted the effect of fMLP and PMA significantly less than did cRD. Rectal dialysates from 44% of subjects with active UC exaggerated the fMLP effect, whereas potentiation occurred for only 13% of cRDs and 18% of iRDs. cRD preconditioned with either activated or nonactivated PMNs was not significantly different than unconditioned cRD. We thus infer the existence of colonic factors in UC that (1) can trigger PMNs to produce ROS and (2) have a proinflammatory modulatory effect on bacterial peptide-induced, PMN-mediated ROS production, thereby initiating or perpetuating inflammation and eventually causing tissue damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of neutrophils in ulcerative colitis by colonic factors: a possible mechanism of neutrophil activation and tissue damage.

The mucosal injury of active ulcerative colitis (UC) could involve enhanced migration and activation of neutrophils (PMNs). Because, in vitro, PMNs from patients with UC appear normal and are not therefore a likely cause for the enhancements, we hypothesized an abnormal colonic milieu. We previously found that factors in the UC colonic milieu markedly increase production of reactive oxygen species (ROS) by control PMNs. We now hypothesize that these factors also regulate PMN surface integrins, that regulation of UC PMNs is different than that of control PMNs, and that the integrin regulation is consistent with the ROS regulation. Using rectal dialysis, we sampled the colonic milieu in patients with active UC, in patients with inactive UC, and in control subjects. We monitored a key PMN adhesion molecule, CD11b. When control PMNs were tested, active UC rectal dialysate was almost as effective (+115%) as N-formyl-methionyl-leucyl-phenylalanine (+132%) in up-regulating CD11b. When inactive UC PMNs were tested, baseline CD11b was 50% higher than that for control PMNs. In contrast, rectal dialysates failed to up-regulate CD11b of inactive UC PMNs and in fact down-regulated CD11b. Preincubating control PMNs with UC rectal dialysates converted their CD11b response to PMN activators from up-regulation to down-regulation, mimicking inactive UC PMNs. Changes in intracellular calcium levels paralleled these changes in CD11b. Rectal dialysate-induced changes in both CD11b and calcium paralleled our previous findings on rectal dialysate-induced changes in ROS production. Thus the net overall effect of factors in the colonic milieu is a consistent and predictable regulation of PMN function--proinflammatory in UC, anti-inflammatory in control subjects. These factors may be a critical part of the pathophysiology of UC.