Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis

Background & Aims: Nitric oxide (NO) is well accepted as an inhibitory neurotransmitter in the gastrointestinal tract; however, its role in the triggering of transient lower esophageal sphincter relaxations (TLESRs) in humans remains to be determined. Therefore, the effect of N^G-monomethyl-L-arginine (L-NMMA), a specific NO synthase blocker, on gastric distention–induced TLESRs was investigated. Methods: Esophageal manometry was performed using a perfused sleeve assembly. The effect of L-NMMA was evaluated on water swallow–evoked primary peristalsis (n = 8; single-blind, placebo-controlled) and on the rate of TLESRs during gastric distention (n = 8; double-blind, placebo-controlled). Results:L-NMMA increased the amplitude of peristaltic pressure waves in the distal esophagus and increased peristaltic velocity in the proximal esophagus. In contrast, L-NMMA had no effect on basal lower esophageal sphincter pressure, nadir pressure, duration, and area under the curve of lower esophageal sphincter relaxation. L-NMMA significantly inhibited the increase in TLESRs during gastric distention. L-NMMA also increased the intraballoon pressure during distention. Conclusions: NO is one of the neurotransmitters involved in the reflex arc mediating the triggering of TLESRs. NO is involved in the timing of human esophageal peristalsis and may exert a tonic inhibition on the proximal stomach.GASTROENTEROLOGY 1998;115:1374-1380     

The Fate of Retained Gallstones Following Laparoscopic Cholecystectomy in a Prairie Dog Model

Background and Objectives:

Reported complications of retained gallstones following laparoscopic cholecystectomy (LC) are increasing. This study was undertaken to evaluate the effects of retained gallstones following LC in a prairie dog model.

Methods:

Twenty-seven prairie dogs with diet-induced gallstones were divided into three groups of nine. Group I (control) had LC with removal of stones. Group II had LC followed by return of native stones intra-abdominally. Group III had LC followed by return of infected stones (stones dipped in Escherichia coli) intra-abdominally. Animals were euthanized at two months and the character and extent of intra-abdominal adhesions were scored.

Results:

Adhesions were present in 56% of animals in Group I, 89% in Group II, and 100% in Group III. The character and extent of adhesions in groups II & III were significantly greater than the control group (p < 0.03). Group III exhibited the highest degree of adhesions when compared to control (p < 0.007). Histopathology revealed evidence of micro-abscess formation, foreign body giant cell reaction, and fat necrosis adjacent to retained stones.

Conclusion:

Retained intra-abdominal gallstones, especially if infected, are associated with increased adhesions and inflammatory response in this LC model. Further investigation into the long-term consequences of this entity is warranted.     

Heterogeneous intracellular localization and expression of ataxin-3

Spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disorder caused by an unstable and expanded CAG trinucleotide repeat that leads to the expansion of a polyglutamine tract in a protein of unknown function, ataxin-3. We have generated and characterized a panel of monoclonal and polyclonal antibodies raised against ataxin-3 and used them to analyze its expression and localization. In Hela cells, multiple isoforms are expressed besides the major 55-kDa form. While the majority of ataxin-3 is cytosolic, both immunocytofluorescence and subcellular fractionation studies indicate the presence of ataxin-3, in particular, of some of the minor isoforms, in the nuclear and mitochodrial compartments. We also show that ataxin-3 can be phosphorylated. In the brain, only one ataxin-3 isoform containing the polyglutamine stretch was detected, and normal and mutated proteins were found equally expressed in all patient brain regions analyzed. In most neurons, ataxin-3 had a cytoplasmic, dendritic, and axonal localization. Some neurons presented an additional nuclear localization. Ataxin-3 is widely expressed throughout the brain, with a variable intensity specific for subpopulations of neurons. Its expression is, however, not restricted to regions that show intranuclear inclusions and neurodegeneration in SCA3/MJD.     

c-fos protein-like immunoreactivity: distribution in the human brain and over-expression in the hippocampus of patients with Alzheimer's disease.

c-fos protein-like immunoreactivity was investigated in the human brain post mortem, using a polyclonal antiserum raised against the N-terminal conserved peptide of c-fos protein. Immunostaining was found in the cerebral cortex, hippocampus, striatum, thalamus and cerebellum but not in the upper brainstem and the adrenal gland. c-fos-like immunoreactivity predominated in neuronal elements, but was also observed in neuropil and glial cells. In addition to a nuclear localization, the staining could be seen in neuronal dendrites (i.e. in the pyramidal cells of hippocampus or in some cortical areas). In order to analyse the effect of brain injury on c-fos expression, the characteristics of the immunostaining were analysed in the hippocampus of patients deceased with Alzheimer's disease known to be associated with a preferential vulnerability of the pyramidal neurons. No staining was observed in the senile plaques or in neurofibrillary tangles, the histopathological stigmata of the disease. Densitometric measurement of the intensity of c-fos-like staining revealed a significant increase in the hilus, the fimbria and the CA1 field of the pyramidal layer in brains of patients with Alzheimer's disease compared to controls. These modifications may result from a suffering stage of hippocampal cells or from a compensatory mechanism in the still surviving neurons not yet affected by the pathological process.     

Serological monitoring of previously treated lepromatous patients during a course of multiple immunotherapy treatments with heat-killed Mycobacterium leprae and BCG.

Two-hundred and seventy lepromatous patients who had completed treatment received multiple treatments with heat-killed M. leprae and BCG and were monitored for changes in humoral responses to M. leprae-specific antigens. These patients were divided into four treatment groups: placebo (n = 69); BCG (n = 68); M. leprae only (n = 71); and BCG + M. leprae (n = 62). They were monitored for 15 months, receiving five inoculations for each treatment regimen. Two ELISA systems, one measuring antibodies to M. leprae-specific epitopes of the phenolic glycolipid I (NDO-ELISA) and the other of 36-kD protein antigens (INH-ELISA) were used to measure serological changes during this period of immunotherapy. We found no significant increase in serological reactivity with the different treatments, as measured by NDO-ELISA. INH-ELISA similarly showed no significant changes, with the exception of increased values in a small group 13% (36/270) which became skin test-positive during the course of the study. The NDO-ELISA results indicate that use of heat-killed M. leprae or BCG + heat-killed M. leprae did not stimulate the humoral response to the semi-synthetic PG-I antigens of M. leprae. Thus, the NDO-ELISA may be useful in monitoring the outcome of vaccine trials in which killed M. leprae or M. leprae fractions are used, since seroconversion may indicate disease, rather than a response to the vaccine material.     

Responses of neurons in the cat's superior colliculus to acoustic stimuli. II. A model of interaural intensity sensitivity

Most neurons in the deep and intermediate layers of the superior colliculus (SC) that respond to acoustic stimuli are sensitive to interaural intensity disparities (IIDs). We examine a model for the generation of sensitivity to IIDs that depends upon temporal coincidence of the inputs from each ear at a given binaural neuron. Because the neural response latency decreases with increasing stimulus intensity, IIDs affect the relative timing of arrival of the inputs. If this model were true, the neurons sensitive to IIDs should also respond to interaural time differences (ITDs) of isointensive stimuli, provided that the magnitude of the delays reflect the neural latency-intensity relationship. For both major classes of binaural cells in the SC, namely those that exhibit binaural inhibition (BI) and binaural facilitation (BF), our results support the model in that the detection of IIDs is largely due to their sensitivity to the temporal overlap of inputs from each ear. The shapes of the IID and ITD functions for each class are similar. The summation of inputs includes inhibitory as well as facilitatory interactions. Estimates of the durations of the subliminal excitatory events in BF cells using the model indicate that they are relatively short (1-4 ms), whereas the durations of the inhibitory processes in BI cells are much longer. The model specifies a common neuronal mechanism for comparison of interaural disparities of time and intensity and does not separate the processing of IIDs and ITDs, as the classic duplex theory suggests. The model provides a physiological explanation for certain features of the psychophysical phenomenon of time-intensity trading. It is also consistent with recent experiments that have shown that the auditory system is sensitive to behaviorally significant ITDs of high-frequency complex signals. The model applies only to the processing of transient stimuli and does not address neural sensitivity to IIDs of continuous high-frequency tones.     

Adenokarzinoid der Appendix vermiformis

Zusammenfassung Adenokarzinoide sind seltene Tumoren mit histologischen Merkmalen sowohl von Karzinoiden, als auch von Adenokarzinomen. Sie besitzen ein aggressiveres biologisches Verhalten als klassische Karzinoide. Wir berichten über eine 64-jährige Patientin mit einer diffusen Infiltration der Appendixwand durch ein Adenokarzinoid. Aufgrund des Befalls des chirurgischen Absetzungsrandes und der Tumorausbreitung wurde eine Hemikolektomie durchgeführt. Es existieren keine eindeutigen Kriterien, welche die operative Wahl zwischen Appendektomie und Hemikolektomie vorschreiben. Es wird vermutet, dass bei kleinen Tumoren in der Appendixspitze die alleinige Appendektomie ausreichend ist. Patienten mit einer diffusen Appendixbeteiligung bedürfen einer aggressiveren chirurgischen Intervention.     

Inhibition of vein graft intimal proliferative lesions in the rat by heparin.

The authors investigated the effect of heparin on the development of myointimal proliferative lesions in a rat vein graft model. Intimal thickening in this model was most pronounced in the anastomotic regions, and was composed principally of vascular smooth muscle cells, as identified by immunocytochemistry with anti-muscle actin antibody, HHF-35. Medial thickening was less cellular, and evenly distributed throughout the grafts. Continuous, intravenous infusion of whole heparin at 0.3 mg/kg/hr effectively inhibited the development of myointimal proliferative lesions, although with no effect on medial thickening. The authors suggest that heparin, through its antiproliferative activity for vascular smooth muscle cells, may have a potentially important pharmacologic role in preventing vein graft failure, which most commonly results from the development of myointimal proliferative lesions.     

Assessment of the practicality and safety of thrombolysis with anistreplase given by general practitioners.

BACKGROUND--Recent guidelines recommend that patients with obvious acute myocardial infarction receive thrombolysis, unless contraindicated, within 60-90 minutes of summoning assistance. If this target is to be achieved, an increasing number of general practitioners are likely to be involved in the administration of thrombolytic agents. AIM--This study aimed to assess the practicality and safety of thrombolysis with anistreplase when given by general practitioners. METHOD--An observational study was conducted in 805 general practices throughout the United Kingdom. Between March 1991 and September 1992, a total of 3383 patients with a clinical diagnosis of myocardial infarction were recruited--888 by 344 general practitioners who wished to include anistreplase in their management of myocardial infarction ('user' group) and 2495 by 776 general practitioners who did not wish to use anistreplase but who were willing to provide information about their cases ('comparison' group). RESULTS--More than half the patients were seen within two hours of onset of symptoms. A high frequency of contra-indications to thrombolysis, diagnostic uncertainty, and other, mainly practical, reasons limited the number of occasions on which anistreplase was administered. Thus, only 310 patients were given anistreplase in the community. The general practitioners in the study used anistreplase safely. Their diagnostic accuracy was high (of the 310 patients given anistreplase 69% had a definite, possible or probably myocardial infarction, 4% a definite non-cardiac diagnosis), the number of patients given anistreplase in spite of a documented contraindication was small (seven patients), and the doctors appeared to be aware of potential bleeding problems associated with thrombolysis. In all cases, the complications of acute myocardial infarction appeared to be managed appropriately. CONCLUSION--General practitioners can use anistreplase both appropriately and safely in the early management of acute myocardial infarction. Recognized contraindications to thrombolysis and practicalities of diagnosis and drug administration may, however, limit the number of occasions on which anistreplase is used.