Patterns of mucin secretion in neoplastic and non-neoplastic diseases of the colon

Changes in the pattern of sulfomucin and sialomucin secretion and height of large bowel mucosa have been described adjacent to primary colonic adenocarcinomas and adenomas, and called “transitional” mucosa. These-changes were initially thought to be specific preneoplastic changes. In this study “transitional” changes in colonic and rectal mucosa were found in some cases overlying benign mesenchymal tumors, metastatic tumors from noncolonic sites, and sites of endometriosis, as well as adjacent to primary colonic and rectal neoplasms. These findings suggest that although these changes may be found adjacent to primary large bowel neoplasms, they are frequently secondary reactive rather than primary preneoplastic phenomena. In addition, the thickness of the mucosa and the accompanying pattern of mucin secretion usually seen in transitional mucosa may be dissociated.     

Problems with the interpretation of gastric pH measurement

Summary The present study examines some of the assumptions underlying the use of intragastric pH-metry for assessing the degree of therapeutic gastric inhibition. Three separate studies were performed to determine the relationship between pH and titratable hydrogen ion concentration in gastric juice and to assess the relationship between the concentration of acid and the rate of gastric secretion. The concentration of acid derived from pH measurements tended to be lower than the titrated hydrogen ion concentration. The difference between the two readings — the buffered hydrogen ion concentration — was increased by the presence of food and was reduced during gastric secretory inhibition with ranitidine. The titrated hydrogen ion concentration reflected more accurately the amount of hydrochloric acid added to a container in vitro than pH measurement. However, in vivo even the measurement of titratable acidity was poorly correlated with the volume of secreted gastric juice so that measurement of gastric acid concentration does not permit inferences about the rate of gastric secretion. The results of the present study indicate that measurement of intragastric pH is unsatisfactory for assessing gastric secretion, particularly in response to a food stimulus, so that measurement of gastric acidity alone does not reflect the rate, or changes in the rate, of gastric acid secretion.     

Stimulation of gastric acid secretion and suppression of VIP-like immunoreactivity by bombesin in the Atlantic codfish,Gadus morhua

Cods were equipped with cannulae for drainage of the stomach and for separate perfusion of the stomach (pure sea-water) and intestine (diluted sea-water). Acidity and volume of gastric effluence were measured. Plasma immunoreactive gastrin and vasoactive intestinal polypeptide (VIP) were assayed in some experiments. The high rate of “basal” acid secretion was further elevated by i.m. administration of bombesin, but not by pentagastrin. Exogenous VIP inhibited acid secretion. Following 5 h of bombesin infusion, plasma gastrin-IR was unaffected while VIP-IR was depressed compared to saline-treated controls. The possibility that bombesin stimulates acid secretion by inhibiting VIP-release is discussed.     

Effect of Atropine and SC-15396 on Stimulated Gastric Acid Secretion in the Atlantic Cod,Gadus morhua

Gastric acid secretion was measured in swimming codfish surgically equipped with a catheter draining the stomach. Gastric acid secretion was stimulated by histamine (5 or 15μg/kg-h) or by carbachol (5μg/kg-h). Pretreatment with atropine (1 μmol/kg-h) completely prevented the acid secretion induced by carbachol, but did not influence the secretion induced by histamine. Atropine had marked effects on the motor functions of the stomach, and seriously reduced the volume draining from the stomach. Infusion of phenol red indicated that the decrease in volume was due to a decrease in recovery of ingested water. SC-15396, “antigastrin”, significantly depressed acid secretion induced by histamine, and reduced carbachol-stimulated secretion, although the latter was statistically insignificant. The effects of SC-15396 is discussed with reference to the absence of receptors for gastrin related to gastric acid secretion in the codfish stomach.     

Dissecting primary and secondary senescence to enable new senotherapeutic strategies

Cellular senescence is a state of stable cell cycle arrest that is known to be elicited in response to different stresses or forms of damage. Senescence limits the replication of old, damaged, and precancerous cells in the short-term but is implicated in diseases and debilities of aging due to loss of regenerative reserve and secretion of a complex combination of factors called the senescence-associated secretory phenotype (SASP). More recently, investigators have discovered that senescent cells induced by these methods (what we term “primary senescent cells”) are also capable of inducing other non-senescent cells to undergo senescence — a phenomenon we call “secondary senescence.” Secondary senescence has been demonstrated to occur via two broad types of mechanisms. First, factors in the SASP have been shown to be involved in spreading senescence; we call this phenomenon “paracrine senescence.” Second, primary senescent cells can induce senescence via an additional group of mechanisms involving cell-to-cell contacts of different types; we term this phenomenon “juxtacrine senescence.” “Secondary senescence” in our definition is thus the overarching term for both paracrine and juxtacrine senescence together. By allowing cells that are inherently small in number and incapable of replication to increase in number and possibly spread to anatomically distant locations, secondary senescence allows an initially small number of senescent cells to contribute further to age-related pathologies. We propose that understanding how primary and secondary senescent cells differ from each other and the mechanisms of their spread will enable the development of new rejuvenation therapies to target different senescent cell populations and interrupt their spread, extending human health- and potentially lifespan.     

The role of cellular senescence in aging through the prism of Koch-like criteria

Since Hayflick’s discovery of cellular senescence (CS), a great volume of knowledge in the field has been accumulated and intensively discussed. Here, we attempted to organize the evidence “for” and “against” the hypothesized causal role of CS in aging. For that purpose, we utilized robust Koch-like logical criteria, based on the assumption that some quantitative relationships between the accumulation of senescent cells and aging rate should exist. If so, it could be expected that (i) the “CS load” would be greater in the premature aging phenotype and lesser in longevity phenotype; (ii) CS would promote age-related diseases, and (iii) the interventions that modulate the levels of senescent cells should also modulate health/lifespan. The analysis shows that CS can be considered a causal factor of aging and an important player in various age-related diseases, though its contribution may greatly vary across species. While the relative impact of senescent cells to aging could overall be rather limited and their elimination is hardly expected to be the “fountain of youth”, the potential benefits of the senolytic strategy seems a promising option in combating age-related diseases and extending healthspan.     

Osmotic flow of water in isolated frog gastric mucosa.

A gravimetric procedure was used to measure net volume flow across bullfrog gastric mucosa mounted between chambers. A portion of the net volume flow towards the lumen was coupled to acid production. With an isotonic solution instilled on the luminal surface, the secreted acidity (ratio of increase in acid output to increase in volume flow) was hypertonic, in agreement with previous reports in mammalian stomach. Dilution of the secretory solution to 10% of normal nearly abolished the net volume flow coupled to acid production so that the mean secreted acidity rose to 1.87 M. Other experiments in which gastric juice was collected from this preparation showed that secretion into an initially empty lumen was only slightly hypertonic, as in mammalian stomach. The results indicate that instillation of secretory solution dilutes the endogenous osmotic gradient due to secreted HC1. This gradient is probably just outside the apical surface of the oxyntic cells of stomach.     

Effects of combined use of roxatidine and pirenzepine on gastric secretion in humans

We examined the effects of the combined use of H2-receptor antagonist (roxatidine) and muscarinic receptor antagonist (pirenzepine) by oral administration on gastric juice and acid secretion in humans. The volume, pH level, and acidity of gastric juice were determined in the sample collected at 9:00 AM 10 hr after either the oral administration of 150 mg of roxatidine or the combined administration of 150 mg of roxatidine and 50 mg of pirenzepine. Significant decrease in volume and acidity and increase in pH were observed in both roxatidine group and combined group compared with control placebo group, but significant difference were not observed in gastric pH and acidity between roxatidine group and combined group. The volume of gastric juice was decreased significantly by the combined administration in comparison with the sole administration of roxatidine. Consequently, the combined oral administration of the two agents was considered to be more effective than the sole administration of roxatidine for clinical cases which require stronger suppression of gastric secretion at the night.     

Gastric blood flow in anaesthetized cats

1. The gastric mucosal blood flow has been measured by the amidopyrine clearance technique in anaesthetized cats. The total gastric blood flow has been (a) measured directly and (b) calculated by the Fick principle from the amidopyrine concentrations in gastric arterial and venous blood and the gastric output of amidopyrine.2. Observations on the recovery of added amidopyrine from arterial and venous blood and plasma, and on the rate of transfer of amidopyrine from corpuscles to plasma, support the underlying assumptions of the amidopyrine method of measuring mucosal blood flow.3. If acid solutions are instilled into the stomach the mucosal blood flow of the non-secreting stomach may be measured by the amidopyrine technique.4. Total gastric and mucosal blood flow increased linearly with increase in H(+) secretion, stimulated by histamine or gastrin. The increase in total flow was entirely due to the increase in mucosal flow.5. The relationship between mucosal blood flow and H(+) secretion was the same for histamine and gastrin responses, and was unaffected by maintaining the total flow at a constant level, or by reduction of the circulating blood volume. Increase in blood volume altered the relationship so that there was a greater increment in mucosal blood flow for any increase in H(+) secretion.6. It is concluded that valid observations may be made on secretion and blood flow relationships in acute anaesthetized preparations.     

Propene polymerization in the presence of MgCl2-supported Ziegler-Natta catalysts, 4.. Effects of Lewis bases on polymer stereochemistry

The stereochemistry of polypropenes obtained in the presence of several MgCl₂-supported Ziegler-Natta catalyst systems comprising different Lewis bases has been investigated by ¹³C NMR spectroscopy, with special attention paid to the “less tactic” (heptane-soluble) fractions. These have been found to consist of “tendentially isotactic” and “tendentially syndiotactic” stereosequences, in largely variable amounts (depending on the catalyst system). The microstructure of the former is in accordance with the enantiomorphic site model, whereas that of the latter suggests a stereocontrol arising from the asymmetry of the growing chain end. In both cases, propene insertion is primary (1–2). Polymerization conditions leading to the formation of “syndiotacticrich” polymers showing syndiotactic crystallinity have been identified.     

The role of DNA damage and repair in aging through the prism of Koch-like criteria

Since the first publication on Somatic Mutation Theory of Aging (Szilárd, 1959), a great volume of knowledge in the field has been accumulated. Here we attempted to organize the evidence “for” and “against” the hypothesized causal role of DNA damage and mutation accumulation in aging in light of four Koch-like criteria. They are based on the assumption that some quantitative relationship between the levels of DNA damage/mutations and aging rate should exist, so that (i) the longer-lived individuals or species would have a lower rate of damage than the shorter-lived, and (ii) the interventions that modulate the level of DNA damage and repair capacity should also modulate the rate of aging and longevity and vice versa. The analysis of how the existing data meets the proposed criteria showed that many gaps should still be filled in order to reach a clear-cut conclusion. As a perspective, it seems that the main emphasis in future studies should be put on the role of DNA damage in stem cell aging.     

Mechanism of inhibition of gastric acid secretion by vagal denervation in the rat

Acute bilateral subdiaphragmatic vagotomy in the conscious fistula rat greatly reduced gastric acid secretion, stimulated by the combined intravenous infusion of pentagastrin (10 μg/kg/h), histamine dihydrochloride (3 mg/kg/h) and carbachol (50 μg/kg/h). The reduction of acid output was immediate (within 15 min after vagotomy). The greatly reduced acid response to these secretagogues persisted for at least 8 weeks after vagal denervation (longest time studied). The sudden and dramatic effect of vagotomy on acid secretion is not related to a possible deficiency of either acetylcholine or histamine at the respective receptor site since the combined infusion of gastrin, histamine and carbachol did not prevent the suppression of acid secretion. Since the decline in acid output following vagal denervation was immediate, it probably reflects a sudden inaccessibility rather than loss of muscarinic or H₂-receptors. The acid output obviously depends upon intramural “transducer” systems that respond to and transmit the vagal input. It is likely that the intramural ganglia represent such “transducer” systems. In the absence of a vagal drive these neuronal “transducers” cease to fire and as a result the parietal cells become almost unresponsive to stimuli.     

The secretion of electrolytes and enzymes by the pancreas of the anaesthetized cat

1. The bicarbonate concentration in cat pancreatic juice falls and the chloride concentration increases at slow secretory rates. The concentration of sodium and potassium remain constant at all secretory rates.2. Acetazolamide reduces the maximal rate of secretion markedly, and the maximal bicarbonate concentration slightly, but does not alter the reciprocal relationship between bicarbonate and chloride at slow rates of flow.3. By perfusion of the main duct it has been shown that there is a loss of bicarbonate and a gain of chloride across the duct wall due to a passive process of exchange diffusion. It is suggested that this may account for a substantial part of the flow-dependent changes in bicarbonate and chloride concentrations in the intact gland.4. The enzyme content of pancreatic juice is made up of a small continuous basal output, to which may be added a much larger secretion in response to hormonal stimulation.5. From analysis of successive small samples of juice it has been found that the response to single injections of pancreozymin lasts a very short time, during which the secretory cells release enzymes in a small volume of chloride-containing fluid.6. It is concluded that in the cat pancreatic secretion consists of an isosmolar primary secretion mostly of sodium bicarbonate, to which is added small amounts of a chloride-containing enzyme secretion. This fluid is modified, particularly at slow flow rates, by transductal exchange of chloride and bicarbonate which, at least in the main duct, is passive in nature.     

Opening up of plasmalemma type-1 VDAC to form apoptotic “find me signal” pathways is essential in early apoptosis — Evidence from the pathogenesis of cystic fibrosis resulting from failure of apoptotic cell clearance followed by sterile inflammation

Cell membrane-standing type-1 VDAC is involved in cell volume regulation and thus apoptosis. The channel has been shown to figure as a pathway for osmolytes of varying classes, ATP included. An early event in apoptotic cell death is the release of “find me signals” by cells that enter the apoptotic process. ATP is one of those signals. Apoptotic cells this way attract phagocytes for an immunologically silent cell clearance. Thus, whenever apoptosis fails by a blockade of plasmalemma type-1 VDAC processes of sterile inflammation must be assumed for cell elimination. This is evident from a close look on the pathogenetic process of cystic fibrosis (CF). However, in normal airway epithelia two different anion channels cooperate to guarantee an appropriate volume of airway surface liquid (ASL) necessary for surface clearing: the cystic fibrosis conductance regulator (CFTR) and the outwardly rectifying chloride channel (ORCC) complex also called “alternate chloride channel” and under the control of the CFTR. There are arguments, that type-1 VDAC forms the channel part of the ORCC complex, and it has been shown that CFTR and type-1 VDAC co-localize in the apical membranes of human surface respiratory epithelium. In cystic fibrosis, the central cAMP-dependent regulation of ion and water transport via functional CFTR is lost. Here, CFTR molecules do not reach the apical membranes of airway epithelia anymore or work in an insufficient way, respectively. In addition, type-1 VDAC is no longer available to work as a “find me signal” pathway. In consequence, clearing away of apoptotic cells is blocked. There are experimental data on the channel characteristics of type-1 VDAC under the anion channel blocker DIDS (4,4-diisothiocyanato-stilbenedisulphonic acid) that argue in favor of this hypothesis. Together, type-1 VDAC should be kept as a “find me signal” pathway, which may give way to several classes of such signals.     

A microperfusion investigation of bicarbonate secretion by the rat submaxillary gland

Summary Bicarbonate transport in the rat submaxillary main duct has been studied by microperfusion. Bicarbonate was concentrated in the duct lumen against an electrochemical gradient and the equilibrium concentration was estimated to be 56.5 mEq/l±3.1 (S.E.M.,n=11). The secretory mechanism could not be inhibited by 6 mMolar cyanide although such concentrations caused marked inhibition of both net sodium efflux and net potassium influx. Bicarbonate secretion in the main duct was not inhibited by acetazolamide whether applied from the duct lumen or given intravenously. Similarly, the drug was without effect on bicarbonate excretion by the intact gland even when maximum excretory rates had been induced with carbachol. It was concluded that catalytic hydration of carbon dioxide to carbonic acid was not a rate-limiting step in the bicarbonate secretory process. The data did not permit a distinction to be made between a bicarbonate secretory processper se and a process of either H⁺ reabsorption or OH^– secretion.The parasympathomimetic agent, carbachol, when given parenterally was found to increase sharply the net influx of bicarbonate into the microperfused main duct as well as to reduce net sodium efflux and net potassium influx. Previously it had been postulated that final saliva was formed in two stages. First a plasma-like primary secretion was formed at a rate depending on the degree of stimulation, and second, the primary secretion was modified in the gland duct system by reabsorptive and secretory processes whose transport rates were presumed to be independent of the degree of stimulus. It now becomes necessary to postulate that stimulation can act on electrolyte transport at both primary and secondary levels; at present, however, no data are available to show whether appreciable net water influx can ever occur at the secondary level.Preliminary reports of this study have been presented to the Australian Physiological and Pharmacological Society [28, 31].     

The pattern of glycogen distribution in the liver

The behaviour of glycogen in the rat liver under conditions of fasting, refeeding, and cortisone administration has been investigated in a combined chemical and histochemical study. In contrast to the observations of others the distribution of glycogen in the liver was found to be reasonably uniform. Histochemically, the periodic acid-Schiff reaction was considered to be the method of choice for the assessment of glycogen, particularly at low levels. In sections from frozen dried liver, however, reasonably good results could also be obtained with Best's carmine stain, although this stain was not very sensitive at the lower, and was thought to be too dense for accurate visual assessment at the higher levels of glycogen. As far as the intralobular distribution of glycogen was concerned, no fixed zones of “glycogen deposition” and “glycogen withdrawal” were found, since the intralobular gradient could be altered by varying the experimental conditions. This observation led to the postulate of a “glycogenic wave,” which not only helps to explain some of the contradictory findings in the literature on the localization of glycogen in the liver, but which can also be reconciled with the traditional concept of the liver lobule. The “heterogeneity of the cell population” in the liver lobule was considered to be a function of time rather than of fixed anatomical features.     

Alterations in the gastro-intestinal functions during the development of adjuvant disease in rats

Gastric biliary and pancreatic secretions were examined in Lewis rats with adjuvant-induced polyarthritis. By application of the pylorus-ligation technique according to Shay for 4 h, a marked increase in gastric secretion was detected from day 11 to day 54 after adjuvant injection. The changes were manifest by a decrease of pH and an increase of secretory volume as well as total acid output. Maximum values were reached at the 23rd day with an acid secretion 4 times higher than in healthy animals. The enhanced hydrochloric acid secretion in adjuvant arthritic rats was confirmed with the aid of the gastric perfusion technique according to Ghosh and Schild and by the finding that the gastric contents of conscious arthritic rats under standard feeding conditions showed a statistically significant higher acidity (pH 2.5) than normal rats (pH 4.0).Adjuvant arthrltic rats with acute bile fistulas exhibited a basal and stimulated bile and pancreatic secretion like normal rats.The gastric mucosa of rats with adjuvant disease is highly sensitive to the irritant effect of gastric hypersecretion in the pylorus-ligation technique. The ulcer rate increases during the progress of the disease with a maximum of 70% at the 37th day. Normal rats with 4 h-pylorus ligation showed no macroscopically visible lesions. Increased sensitivity of the gastric mucosa against the ulcerogenic activity of non-steroidal anti-rheumatic drugs was demonstrated for aspirin and indomethacin. The etiological role of disease stress for the high susceptibility of the arthritic rat to gastric ulceration is discussed.To whom correspondence should be addressed.     

Original antigenic sin at the cellular level. I. Antibodies produced by individual cells against cross-reacting haptens

“Original antigenic sin” has been studied in the mouse at the cellular level using two cross-reacting haptens: m-aminobenzoic acid (mB) and m-sulfanilic acid (mS). The number of antibody-forming cells (AFC) was measured by the local hemolysis technique using red blood cells coupled to the haptens. Immunization was performed with the haptens coupled to a carrier protein (human γ-globulin) in Freund's adjuvant. It was found that a heterologous booster was always followed by an increase of the AFC specific of the primary antigen, larger than what could be expected from the cross-reactivity of the two haptens. In the case of primary stimulation by mS and secondary stimulation by mB, it was observed that the absolute number of AFC against mS was greater than the AFC against mB.     

Is the evidence for ectopic antidiuretic hormone watertight?

The clinical syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with malignancy cannot be distinguished from a similar metabolic abnormality found in patients with non-malignant conditions. It is, nevertheless, widely accepted that SIADH associated with malignancy is due to the “ectopic” tumour production of arginine vasopressin (AVP). This view is challenged after scrutiny of available data. Since some malignant or non-malignant tissues may produce neurophysins, the presence of “ectopic” AVP in tumour tissue may be explained by active binding of AVP from the circulation by neurophysins. On the other hand, the absence of detectable AVP in tumour accompanied with SIADH suggests excess AVP secretion from the posterior pituitary or hyponatraemia due to other, as yet unidentified, antidiuretic factors. The concept of “ectopic” AVP may be false.