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Biomedical subjects

M W Smith

Publications and source records attributed to M W Smith.

At least 181 records · Page 10Linked to original sources
PubMed1990

Relation between toxicity and carcinogenesis in the kidney: an heuristic hypothesis.

Cellular toxicity and cellular carcinogenesis are closely linked. In the kidney, this relationship has been emphasized by the recent discovery of a number of putatively non-mutagenic chemicals that result in acute and chronic toxicity and ultimately in carcinogenesis, especially in the male rat. Many, but not all such compounds, result in renal PTE phagolysosomal overload. At the same time, known metabolites of other carcinogens, e.g., HCBD and FBPA, result in acute renal injury and/or necrosis, followed by chronic tubular disease, interstitial nephritis, and ultimately carcinogenesis. A series of cell mechanisms have been suggested that lead from acute cell injury to altered control of cell division. These mechanisms appear to involve ion deregulation, (especially [Ca2+]i) resulting from a variety of continued injuries, (e.g., oxidative stress from inflammatory cells) and ultimately leading to altered gene expression.

Animals↗
PubMed1989

Hospital discharge diagnoses: how accurate are they and their international classification of diseases (ICD) codes?

The accuracy of the discharge diagnoses recorded in hospital medical records, and the accuracy of their ICD codes, were retrospectively examined in 174 randomly chosen hospital patients. There was a 29% error rate in the recorded ICD codes when compared at a three digit level to the results obtained by retrospectively reviewing the records, establishing diagnoses and coding them. The error rate increased when medical records coders, rather than medically trained personnel, undertook the task of establishing the discharge diagnoses.

Diagnosis↗
PubMed1989

Effects of serum, transforming growth factor type beta, or 12-O-tetradecanoyl-phorbol-13-acetate on ionized cytosolic calcium concentration in normal and transformed human bronchial epithelial cells.

Fluctuations in ionized cytosolic calcium ([Ca2+]i) are considered important signals for induction of growth or differentiation in mammalian cells. The resting concentrations of [Ca2+]i in normal and adenovirus 12-SV40 hybrid virus-transformed (BEAS-2B) human bronchial epithelial cells were 63 +/- 15 nM (SD) and 44 +/- 15 nM, respectively. Eight % calcium-free fetal bovine serum rapidly caused a significant increase in [Ca2+]i, while causing both cell types to undergo squamous differentiation. When treated with 8% calcium-free fetal bovine serum, a serum-sensitive subclone of BEAS-2B cells exhibited a higher elevation of [Ca2+]i than a serum-resistant (i.e., not stimulated to differentiate by serum) subclone. However, a serum component involved in the induction of squamous differentiation, transforming growth factor type beta, did not increase [Ca2+]i in either normal cells or BEAS-2B cells. 12-O-Tetradecanoyl-phorbol-13-acetate, an exogenous inducer of squamous differentiation and activator of protein kinase C, did not increase [Ca2+]i, but did attenuate serum-induced elevation of [Ca2+]i. These results suggest that while an increase in [Ca2+]i is associated with serum-induced squamous differentiation, a cytosolic ionized calcium signal is not required for the initiation of the squamous differentiation pathway induced by either transforming growth factor type beta or 12-O-tetradecanoylphorbol-13-acetate.

Blood Physiological Phenomena↗
PubMed1989

The relationship between cellular ion deregulation and acute and chronic toxicity.

Cell injury proceeds through a predictable series of stages as it progresses from reversible to irreversible injury (or "point of no return") and ends eventually in cell death. Ion deregulation is strongly implicated in this process and, in particular, the deregulation of cytosolic Ca2+ ([Ca2+]i) which is thought by most to be a critical step in the transition from reversible to irreversible injury. [Ca2+]i is normally maintained at approximately 100 microM, a level 10,000 times lower than for extracellular Ca2+ [( Ca2+]e). Deregulation may affect any of three Ca2+ buffering systems: the plasma membrane, the mitochondria, and the endoplasmic reticulum. Perturbation of [Ca2+]i is intimately related to perturbation of other ions, including, H+, Na+, and K+. In normal cells, [Ca2+]i elevation is also linked to activation of oncogenes as well as cell division, initiation, wound repair, differentiation, and possibly tumor promotion. In all models of acute injury for which we have measured [Ca2+]i, including ischemia, HgCl2 and calcium inophores, [Ca2+]i always became elevated. This elevation results from influx of [Ca2+]e (ionomycin), redistribution from intracellular stores (NEM, KCN), or from both sources (HgCl2). The degree of [Ca2+]i elevation is correlated with the degree of injury (as determined by blebbing and morphological changes) and cell killing. More recently, much work has been focused on the role of [Ca2+]i in neoplasia. Many stimuli, including the promoter TPA and transforming growth factor beta have been shown to affect normal and transformed cells differently. Both cause differentiation in normal human bronchial epithelial cells but stimulate growth in transformed cells. We propose that deregulation of ions, especially [Ca2+]i, plays an important role, if not a key role, in the initiation of acute and chronic cell injury, including neoplasia. Increases in [Ca2+]i appear to accelerate degradative processes and, unless regulated, lead to cell death.

Animals↗
PubMed1989

Comparative aspects of microvillus development in avian and mammalian enterocytes.

1. Pieces of chicken mid-jejunum have been used to determine microvillus length in enterocytes located at different points along the crypt-villus axis to determine the positional dependence of microvillus elongation. 2. The rate at which enterocytes migrate along the crypt-villus axis has also been measured, by injecting tritiated thymidine into the same animals, to determine the time course of microvillus elongation. 3. In mammals it had been shown previously that the maximal rate of microvillus elongation correlated closely with the physical size of the intestinal crypt (Smith et al., 1984). Comparison of crypt size with maximal rate of microvillus growth in chickens showed this correlation to apply to both animal classes. 4. The maximal microvillus length of a chicken enterocyte was much longer (3.3 microns) and the rate of enterocyte migration much less (4.0 microns/hr) than values reported previously for mammalian intestines. 5. The possibility that some other factor in addition to crypt size is affecting microvillus growth is discussed.

Animals↗
PubMed1989

Dual control over microvillus elongation during enterocyte development.

1. Previously determined logistic growth constants describing enterocyte microvillus development for a variety of species were analysed for possible interactions taking place between enterocyte migration rate (R) and the size of individual crypts (CD). 2. Microvillus elongation, the c-value of a logistic growth curve, was found to increase linearly with crypt depth and reciprocally with decreasing migration rate. The starting microvillus length of a basal crypt enterocyte, the a-value, also increased linearly with CD without being affected by R. 3. The mathematical equation describing the effects of CD and R on M, the maximal microvillus length, was M = 0.0016 CD + 0.073 CD/R, where M and CD are measured in micron and R in micron/hr. 4. The relationship found between R, CD and M is explained by suggesting that the crypt environment enables enterocytes to respond to an initiating signal imposed on cells as they begin to migrate onto villi. The possible nature of this putative signal is also discussed.

Animals↗
PubMed1989

Intestinal infection with Nematospiroides dubius selectively increases lactase expression by mouse jejunal enterocytes.

1. Intestinal structure, lactase (beta-galactosidase; EC 3.2.1.23) activity and alkaline phosphatase activity have been determined in mouse jejunal and ileal tissues before and during infection with the intestinal parasite Nematospiroides dubius. 2. Oral infection with small numbers of N. dubius larvae caused villus height, crypt depth and enterocyte migration rate to increase in the mouse jejunum. None of these effects occurred in ileal tissue. 3. Lactase activity also increased in jejunal, but not ileal, tissue of infected mice. This increase was associated with a doubling of the rate at which activity appeared in the brush-border membrane of enterocytes during migration over the basal regions of jejunal villi. Alkaline phosphatase activity in jejunal tissue remained unchanged in infected mice. 4. Attention is drawn to the fact that this is the first occasion when crypt cell hyperplasia has been found to be positively correlated with an increase in lactase activity and a decrease in cytotoxic/suppressor T-cells. Further work is needed to establish the primary cause of these effects.

Alkaline Phosphatase↗
PubMed1989

Enterocyte-lymphocyte interactions in the follicle-associated epithelium of the mouse Peyer's patch.

1. Measurements of membrane potential (Vm) have been carried out in the follicle-associated epithelium of the mouse Peyer's patch to investigate possible site-dependent anomalies in enterocyte development. Initial heterogeneity in Vm values obtained from carrying out random impalements in the upper third of the follicle-associated epithelium could be described as arising from the presence of three different cell populations. 2. The predominant cell type in this epithelium (T1) had a mean Vm of -35.3 mV which was partly depolarized by increasing concentrations of K+. These cells were not stained with the vital dye Neutral Red. Two other types of cell (T2L and T2H) were recorded together as consecutive negative jumps in Vm, but only in areas of the epithelium previously stained with Neutral Red. T2L behaved like T1 cells to K+ but with a low Vm of -23.3 mV. T2H cells had a high mean Vm of -47.5 mV showing transient hyperpolarization to increasing K+ concentration. 3. The electrophysiological and non-staining properties of T1 cells are similar to those expected from mature enterocytes. The anatomical size, site, staining properties and Vm of T2H cells correspond to those expected for intraepithelial lymphocytes. The low Vm, K+ depolarization and close association of T2L with T2H cells are typical of properties predicted for an immature-type of antigen-transporting enterocyte known to be present in this type of epithelium. 4. The possibility that intraepithelial lymphocytes either slow or reverse a more normal process of development of enterocytes in their immediate vicinity is discussed along with wider aspects of enterocyte-lymphocyte interactions leading to the transfer to enteric antigens across these modified cells.

Animals↗
PubMed1989

Sugar-dependent selective induction of mouse jejunal disaccharidase activities.

1. Sugar-containing diets chosen not to affect intestinal structure or enterocyte turnover have been fed to mice previously maintained on a low carbohydrate diet in order to determine their ability to induce disaccharidase enzymes in the small intestine. 2. Glucose-, fructose- and 3-O-methyl-glucose-containing diets increased sucrase and maltase but not lactase activities in mouse jejunal homogenates. These effects were either absent or negligible in more distal regions of the small intestine. 3. Placing mice on glucose-, fructose- or 3-O-methyl-glucose-containing diets was further shown, by quantitative cytochemistry, to cause a 1.6-, 2.6- and 3.2-fold increase in the initial rate at which alpha-glucosidase activity (sucrase + maltase) appeared in the brush-border membrane of developing enterocytes. 4. The time during which alpha-glucosidase activity increased in enterocyte brush-border membranes fell from 30 h for low carbohydrate fed mice to 21, 19 and 17 h in mice fed glucose, fructose and 3-O-methyl-glucose respectively. Change of diet had no effect on the kinetics of lactase expression by developing enterocytes. 5. Maximal alpha-glucosidase activity detected in enterocyte brush-border membranes is equal to RT, where R is the initial rate of enzyme appearance and T is the time during which this rate operates. The ability of sugars to increase R selectively, but only at the expense of T, defines unexpected limits to the capacity of enterocytes to adapt to changes in luminal nutrition. 6. The above results are discussed in relation to other aspects of enterocyte differentiation recently subjected to quantitative analysis. The need to standardize other aspects of intestinal physiology and redefine the energy content of diets containing non-metabolizable substrates in this type of work is also emphasized.

3-O-Methylglucose↗
PubMed1989

Cytosolic ionized calcium and bleb formation after acute cell injury of cultured rabbit renal tubule cells.

Changes in cytosolic calcium ([Ca2+]i) and cell blebbing of cultured rabbit kidney proximal tubule cells were studied in response to injury induced through a variety of mechanisms. [Ca2+]i was measured in Fura 2-loaded cells and blebbing was observed by phase microscopy. The severity of injury was evaluated by electron microscopy and cell killing was estimated by trypan blue dye uptake. The types of injury included interaction with sulfhydryl groups (HgCl2, N-ethylmaleimide, p-chloromercuribenzene sulfonic acid, inhibition of energy metabolism (carbonyl cyanide m-chlorophenylhydrazone, KCN, KCN + iodoacetate) and ion deregulation (ouabain, ionomycin, A23187). The role of extracellular calcium ([Ca2+]e) in injury was also studied. HgCl2, N-ethylmaleimide and ionomycin + [Ca2+]e caused the highest elevations of [Ca2+]i, the most extensive blebbing, and most rapid cell death. P-chloromercuribenzene sulfonic acid treatment resulted in a moderate increase in [Ca2+]i, as well as less extensive blebbing and slower cell death. Ouabain and inhibitors of mitochondrial and cellular energy metabolism caused only a 2-fold increase in [Ca2+]i, a few blebs and delayed cell death. Ionomycin - [Ca2+]e caused a transient elevation of [Ca2+]i, minimal blebbing and very slow cell killing. The increase in [Ca2+]i may result from redistribution of intracellular stores (N-ethylmaleimide, p-chloromercuribenzene sulfonic acid, KCN, carbonyl cyanide m-chlorophenylhydrazone, ionomycin - [Ca2+]e), from influx of extracellular [Ca2+]e (ionomycin + [Ca2+]e, ouabain), or from both redistribution and influx (HgCl2). Therefore, removing [Ca2+]e is protective only in certain types of injury, (HgCl2, ionomycin). Cytoplasmic blebbing was seen with all the types of injury studied and occurred before to cell death. Blebs formed rapidly, enlarged, and sometimes detached with membrane sealing. Our results indicate that cell injury which initiates a 3-fold or greater sustained elevation in [Ca2+]i, resulting from either an influx of [Ca2+]e or by Ca2+ release from intracellular pools, is also associated with abundant bleb formation and rapid cell death.

Animals↗
PubMed1988

Interactions of porphyrins and transfer RNA.

The interactions of the free base porphyrin, tetra-(4N-methylpyridyl)porphyrin and its copper(II), manganese(III) and zinc(II) complexes with brewer's yeast type V phenylalaninyl tRNA were evaluated by UV-visible spectroscopy, circular dichroism and melting temperature studies over a range of magnesium ion concentrations and ionic strengths. Scatchard analysis of absorption spectra of the porphyrins in the presence of tRNA showed the free base, copper and zinc porphyrins to have binding constants of 7.3 X 10(7), 1.7 X 10(6) and 2.3 X 10(8), respectively; the manganese(III) complex did not demonstrate changes in its electronic spectra that enable the calculation of a binding constant. The results of the spectroscopic studies indicate a mode of binding for the free base, copper(II) and zinc(II) complexes that is neither intercalative nor simply outside electrostatic. The magnitude of the binding constants and the UV-visible results support intercalation, but the analyses of the thermal denaturation studies and the circular dichroism evaluations suggest that the porphyrins are associating at a single site in a fold of the tertiary structure of the tRNA close to several crucial hydrogen bonds, perhaps in the vicinity of the P10 loop. That the manganese(III) complex does not bind in this site points to constraints on the axial thickness of a molecule that may be accommodated in this locus.

Cations, Divalent↗
PubMed1988

Automated histochemical analysis of cell populations in the intact follicle-associated epithelium of the mouse Peyer's patch.

A new technique of quantitative histochemistry has been developed to study the cellular composition of the follicle-associated epithelium of the mouse Peyer's patch. This technique involves applying naphthol AS-BI phosphate to the surface of intact tissue where it is hydrolysed by alkaline phosphatase present in the luminal membrane of the epithelial cells. Naphthol AS-BI produced by this reaction is then coupled to Fast Red TR diazonium salt at the site of hydrolysis. M cells present in the epithelium contain little alkaline phosphatase activity and, therefore, remain white. Treatment with Alcian Blue is finally used to label goblet cells. Subsequent quantitative analysis of alkaline phosphatase-rich cells is carried out by scanning microdensitometry. Using this technique it is possible to detect two populations of alkaline phosphatase-containing cells in mice reared in a normal animal house environment. These results are discussed in relation to possible interactions taking place between enteric antigens and the gut-associated lymphoid tissue which could reduce the ability of follicle-associated enterocytes to express alkaline phosphatase.

Alkaline Phosphatase↗
PubMed1988

Structure of vertebrate genes: a statistical analysis implicating selection.

This paper conducts a statistical analysis of the size distribution of exons and six other gene parts [the transcription unit, introns, intervening DNA (sum of introns), mRNA (sum of exons), and leader and trailer regions of mRNA] as well as the number of exons, the percentage of introns, the placement of introns within the gene, and the potential for frameshifts from coding exon shifts. The first seven variables measured in base pairs fit log-normal distributions. Significant correlations between the sizes of intervening DNA and mRNA, the sizes of leader and trailer regions, and the sizes of introns and flanking exons exist. Introns occur at nonrandom frequencies within the codon frame, in untranslated regions, and relative to the frameshift potential from exon movement or duplication. These nonrandom patterns in gene structure demonstrate that models of gene evolution must incorporate selective processes.

Animals↗
PubMed1988

Postnatal development of transport function in the pig intestine.

1. In the newborn pig it appears that only prenatally produced enterocytes are capable of absorbing large amounts of protein. 2. The ability of the small intestine to transport sodium, lysine, lysine containing dipeptides and glucose declines markedly during the first week of post natal life. 3. Dexamethosone causes a doubling of the sodium dependent portion of alanine uptake. 4. EGF given between days three and six of postnatal life increases sucrase and maltase activity in the distal region of the small intestine. 5. Weaning induced problems are probably not due to direct inhibition of transport properties.

Animals↗
PubMed1988

A comparison of paramedic versus basic emergency medical care of patients at high and low risk during acute myocardial infarction.

This prospective study compares the outcome of patients with acute myocardial infarction managed by mobile intensive care (paramedic phase) with that of similar patients managed by basic emergency medical care (control phase) in the same community before the introduction of paramedics. All paramedic-transported patients were managed according to a standard chest pain protocol with use of prophylactic lidocaine and, as needed, treatment for sinus bradycardia, hypotension and life-threatening ventricular arrhythmia. There were no specific interventions for supraventricular tachyarrhythmia or hypertension. All patients were treated under similar in-hospital protocols. Percent mortality in patients with hypotension, the highest risk subgroup in the control phase, was significantly lowered with paramedic-level care (69 versus 10%, p = 0.01). Patients with hypertension, a relatively low risk subgroup during the control phase (16% mortality), were also at lower risk during the paramedic phase (10% mortality). In fact, there was no mortality in either study phase for patients with an initial systolic blood pressure greater than 180 mm Hg. During the combined study phases, patients with normotension and tachycardia demonstrated a tendency toward higher percent mortality (33%) than either patients with normotension without tachycardia (10%) or those with hypertension and tachycardia (6%). Although the overall percent mortality was reduced by 24% (from 21 to 16%), this decrease was largely due to the improvement of patients with hypotension. Investigation into the feasibility of prehospital interventions for the high risk patient with acute myocardial infarction normotension and tachycardia appears warranted.

Aged↗
PubMed1988

Selective alteration of brush-border hydrolases in intestinal diseases in childhood.

1. Biochemical estimates of lactase, sucrase and maltase activities, carried out on intestinal biopsies appearing histologically normal, were compared with those obtained from children suffering from coeliac disease, cow's milk protein intolerance/postenteritis syndrome and the intractable diarrhoea syndrome of infancy. Lactase deficiency in these children was found to be more pronounced than sucrase or maltase deficiencies. 2. Quantitative cytochemical investigations showed characteristic disease-induced changes in the ability of enterocytes to express alpha- and beta-glucosidases, but not alkaline phosphatase activities, during migration along stunted villi. 3. Separate estimates of the time course describing hydrolase development in normal and coeliac tissue showed the initial rate of lactase appearance to be halved in coeliac patients, while that for alpha-glucosidases remained constant and that for alkaline phosphatase increased by a factor of four. Enteroblastic replacement of mature enterocytes cannot provide a general explanation for hydrolase deficiency in diseased intestine.

Adolescent↗
PubMed1988

Single-villus analysis of disaccharidase expression by different regions of the mouse intestine.

1. The present results describe how a new technique of whole-tissue cytochemistry can be combined with automatic scanning of microdissected villi to measure the capacity of individual villi to hydrolyse disaccharides in different parts of the small intestine. 2. Intact villi from the mouse proximal jejunum are found to be eight times more effective than ileal villi in hydrolysing 2-naphthyl-alpha-D-glucoside, an artificial substrate for enzymes normally hydrolysing sucrose, maltose, isomaltose and trehalose in adult intestine. Homogenates of jejunal scrapings are four times more effective than ileal homogenates in hydrolysing this substrate. This discrepancy arises from relating enzyme activities to homogenate protein in cases where intestinal structure changes. 3. The eightfold difference in villus alpha-glucosidase activity is associated with a threefold difference in villus surface area. This discrepancy in turn reflects changes in the capacity of individual enterocytes to express alpha-glucosidase during migration along the crypt-villus axis. These results emphasize the futility of trying to gauge intestinal function from measurement of intestinal structure. 4. Differences between ileal and jejunal villus alpha-glucosidase activities have been further partitioned into those depending on villus structure and those depending on enterocyte development. Present results are discussed in relation to the ability of luminal nutrition to maintain a proximal-distal gradient of digestive enzyme function in the small intestine. The general applicability of this method of analysis to other studies of adaptive response is also emphasized.

Animals↗