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Biomedical subjects

E Maher

Publications and source records attributed to E Maher.

At least 37 records · Page 2Linked to original sources
PubMed1992

Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients.

We report here the result of a screening for germ-line mutations in the adenomatous polyposis coli (APC) gene in 61 new familial adenomatous polyposis (FAP) patients as well as a summary of the results of 150 patients. Examination of the entire coding region of the APC gene, based on a ribonuclease protection assay coupled with the polymerase chain reaction (PCR), disclosed mutations that were considered to cause significant defects in the APC product in 97 of 150 unrelated FAP patients. Our findings revealed the following characteristics of the germ-line mutations of APC: 1) the great majority of the mutations were found to truncate the APC product; 2) almost all of the mutations were located within the first half of the coding region; 3) no correlation was observed between the locations of germ-line mutations and extracolonic manifestations in FAP patients; 4) more than 80% of base substitutions in the APC gene were from cytosine to other nucleotides, nearly one-third of which occurred at the GpG site. Our results provide information helpful to an understanding of the APC gene and will also contribute to presymptomatic diagnosis of members in FAP families.

Adenomatous Polyposis Coli↗
PubMed1992

Endothelin-induced calcium responses in human vascular smooth muscle cells.

The effects of endothelin-1 (ET) on the cytosolic free Ca (Cai) and cytosolic pH (pHi) were examined in primary cultures of human umbilical artery (HUA) vascular smooth muscle cells (VSMCs), respectively, loaded with fura-2 and 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. In 1 mM Ca, ET produced a dose-dependent, biphasic increase in the signal with a maximal effect at 400 nM ET. At this concentration, ET produced a Cai transient (mean +/- SE; a rise from basal Cai of 86 +/- 16 to 216 +/- 33 nM) that lasted for approximately 50-60 s. The Cai transient was followed by a slow but sustained increase in Cai. Both ET-induced Cai transient and posttransient Cai were attenuated in Ca deficient medium or by verapamil and nicardipine. In contrast to ET, thrombin elicited only a monophasic Cai response in HUA VSMCs. This response was also partially sensitive to Ca removal or verapamil. KCl (45 mM) depolarization did not elicit a Cai response. However, the presence of voltage sensitive Ca channels in HUA VSMCs was demonstrated by enhanced Mn uptake in cells depolarized with KCl. Both ET and thrombin treatment did not alter pHi. HUA VSMCs demonstrated a single class of ET receptors (approximately 13,000 sites/cell) with an equilibrium dissociation constant of 0.34 nM. Nicardipine did not alter ET binding. These observations suggest a dual effect of ET on the Cai profile in HUA VSMCs that is mediated by Ca mobilization and Ca entry through Ca channels. The Ca entry could include influx through receptor-operated Ca channels, voltage-sensitive Ca channels, or both, but without a direct interaction between ET and these channels.

Calcium↗
PubMed1992

Renal tubular responsiveness to atrial natriuretic peptide in sodium-retaining chronic caval dogs. A possible role for kinins and luminal actions of the peptide.

60% of chronic caval dogs with ascites did not respond to atrial natriuretic peptide (ANP) (75 ng.kg-1.min-1) with a natriuresis (TIVC-NR; delta UNaV = 2 +/- 0.8 mu eq/min) whereas the remaining 40% responded normally (TIVC-R; delta UNaV = 216 +/- 50 mu eq/min). Since proximal tubule neutral endopeptidase 24:11 (NEP) destroys most of intrarenal luminal ANP and kinins, we attempted to convert TIVC-NR into TIVC-R by providing NEP inhibition with SQ 28603 at 30 mg/kg. This potent and specific NEP inhibitor produced a natriuresis when administered alone to nine TIVC-NR dogs (delta UNaV = 67 +/- 2 mu eq/min) and permitted a natriuresis in the presence of ANP (delta UNaV = 97 +/- 18 mu eq/min). A natriuretic response to ANP could also be induced in TIVC-NR dogs by providing renal arterial bradykinin or intravenous captopril, a kininase inhibitor. Urodilatin, a natriuretic peptide not destroyed by intrarenal NEP was without effect in TIVC-NR dogs but increased UNaV when given to TIVC-R and normal dogs. Providing bradykinin to TIVC-NR now permitted an increment in delta UNaV (62 mu eq/min) when urodilatin was reinfused. TIVC-R dogs could be converted into TIVC-NR by pretreating with a specific bradykinin antagonist before infusing ANP. We conclude that TIVC-NR dogs are deficient in intrarenal kinins but are converted to responding dogs after NEP inhibition because of increased kinin delivery to the inner medullary collecting duct.

Alanine↗
PubMed1991

Dynamics of neurotensin stores in the stellate ganglion of the cat.

Neurotensin (NT) within the stellate ganglion (SG) of the cat is present in axon terminals of extrinsic, presumably preganglionic, neurons and may play a role in ganglionic transmission. NT content of the SG, and of the preganglionic axons which innervate it, was determined by radioimmunoassay in the anesthetized cat under various experimental conditions in order to understand the factors determining the size of the ganglionic NT stores. The immunoreactive NT (iNT) from extracts of SG and its preganglionic inputs (white rami T2 and T3, sympathetic trunk between SG and T4 white ramus) coeluted with synthetic NT(1-13) on RP-HPLC. NT accumulated proximal to ligatures on the preganglionic inputs of the SG. The daily rate of axonal transport of NT, estimated from the accumulation, represents 28.7% of the ganglionic stores of NT. Preganglionic stimulation at 2 Hz for 100 min did not change ganglionic NT content. Preganglionic stimulation at 40 Hz reduced the NT content to 70.4 +/- 1.8% of control in 10 min and to 34.7 +/- 4.2% of control in 20 min. Additional 100 min of 40 Hz stimulation produced no further depletion. The residual iNT, which coeluted with NT1-13, presumably represents a pool of unreleasable NT. Post-depletion recovery was complete in 7 days and showed an initial rapid phase over the first 24 h followed by a slower phase over the remaining 6 days. Pepsin treatment, which has previously been shown to generate iNT from NT precursor in liver and other tissues, provided no evidence of the NT precursor in extracts of SG and its preganglionic input.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1991

Endothelin- and oxytocin-induced calcium signaling in cultured human myometrial cells.

The demonstration that endothelin (ET) induces rat uterine contraction, coupled with the observation that ET is present in human amniotic fluid, suggests that the myometrium may be an important target organ for this hormone. We show that in quiescent human myometrial cells ET produced a dose-dependent increase in cytosolic free Ca2+ (Cai2+), which was markedly attenuated when the cells were studied in Ca2(+)-free media. Preincubation with nicardipine, diltiazem, or verapamil reduced the ET-evoked Cai2+ transient by 30, 40, and 65%, respectively. The presence of voltage sensitive Ca2+ channels was demonstrated by Mn2+ quenching of fura-2. Activation of the Na+/H+ antiport could not be demonstrated with ET stimulation. In nonquiescent cells, the ET-evoked Cai2+ transient was significantly reduced, while the response to oxytocin was retained. This is at least partially explained by a reduction in Bmax (maximal binding capacity) for ET (mean +/- SEM) from 3,506 +/- 268 binding sites/cell in quiescent cells to 2,411 +/- 300 binding sites/cell, as well as 72% increase in Kd (equilibrium dissociation constant), in the nonquiescent cells. We conclude that, in human myometrial cells, ET and oxytocin modulate Cai2+ through independent receptors and propose that ET, like oxytocin, is an important endogenous modulator of uterine contractility.

Actins↗
PubMed1990

Serial natriuretic response to atrial peptide in preascitic bile duct ligated dogs.

We determined if nine precirrhotic unanaesthetized dogs with chronic bile duct ligation (CBDL) responded uniformly to atrial natriuretic peptide (ANF) by infusing this peptide sequentially over 8-12 weeks at 175 ng.kg-1.min-1 and observing the natriuretic response. ANF was administered every 2 weeks post-CBDL until the 8th week and given again during the cirrhotic phase with ascites present (10-12 weeks post-CBDL). Sodium balance studies were conducted at similar time intervals. During the control period and at weeks, 2, 6, and 8 post-CBDL all dogs responded to ANF with a significant change in sodium excretion (delta UNaV, 50-240 mu equiv./min). At these times, all dogs were in sodium balance. At week 4 and during the ascitic period, heterogeneity of response to ANF was observed. In the former interval, five dogs responded (delta UNaV,75-230 mu equiv./min) and four did not, while in the latter interval, five dogs responded (delta UNaV, 50-240 mu equiv./min) and three did not (one dog died). In both time periods, there was severe urinary sodium retention (daily UNaV, 11 +/- 3 and 2 +/- 1 mequiv./day, respectively) while the dogs were ingesting 45 mequiv.Na+/day. The heterogeneity of natriuretic response was not correlated to plasma immunoreactive ANF, renin, or aldosterone levels. Plasma volume was significantly expanded from control during both intervals. We conclude that there is transient sodium retention during the 4th week post-CBDL, and that this period is associated with the heterogeneity of natriuretic response to ANF, despite the absence of ascites or edema.

Aldosterone↗
PubMed1990

Physiological features of edematous dogs unresponsive to atrial natriuretic peptide.

Sodium-retaining cirrhotic and chronic caval dogs with ascites show a heterogeneous natriuretic response to atrial natriuretic factor (ANF) infusions such that half will increase their urinary excretion of sodium and half will show no natriuretic response whatsoever. In these studies we have examined several physiological variables that might discriminate between these two experimental populations. We studied 22 caval dogs (11 natriuretic responders, 11 nonresponders) and 19 cirrhotic dogs (9 responders, 10 nonresponders). After an infusion of rat ANP-(1-28), 125 ng.kg-1.min-1, differences in glomerular filtration rate, blood pressure, or urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP) could not differentiate between the two types of dogs. When the left kidney of nonresponding dogs in both the caval and cirrhotic groups was either denervated or vasodilated with acetylcholine bromide (60-80 micrograms/min), the attenuation of the natriuretic response to ANF was not reversed. Papillary plasma flow (PPF) after ANF infusion was measured by a Lillienfield technique and averaged 36 +/- 4 ml.min-1.100 g-1 in normal dogs, 10.7 +/- 0.7 ml.min-1.100 g-1 in both responding and nonresponding caval dogs, and 48.3 +/- 1.1 ml.min-1.100 g-1 for each group of cirrhotic dogs. We conclude that differences in renal perfusion, PPF, cGMP generation, or the presence of intact renal nerves cannot explain the lack of a post-ANF natriuretic response in half of caval or cirrhotic dogs. Other physiological determinants must explain the heterogeneity of natriuretic response to ANF observed in edematous dogs.

Animals↗
PubMed1989

Calcium mobilization and Na+/H+ antiport activation by endothelin in human skin fibroblasts.

Endothelin (ET-1) has been shown to exert vasoconstrictor activity in vivo and mobilize Ca2+ in vascular smooth muscle cells in culture. In this paper we show that the human skin fibroblast exhibits specific receptors to ET-1 and that activation of these receptors results in increased intracellular Ca2+ (Ca2+i) and accelerated Na+/H+ antiport activity. ET-1 raised Ca2+i in a dose-response manner; the peak Ca2+i rise was from basal levels of 112.2 +/- 21.9 to 299.2 +/- 49.7 nM at 300 nM ET-1. This rise was attenuated by removal of extracellular Ca2+i0. Although ET-1 did not alter basal intracellular pH, it enhanced Na+/H+ antiport activity of acidified cells. Fibroblasts demonstrated 156 +/- 18 (mean +/- SE) ET-1 receptors per unit cell and an equilibrium dissociation constant of 203.4 +/- 35.6 pM. Inasmuch as ET-1 plays a role in the metabolism of cells such as the undifferentiated fibroblast, an important action of this peptide may be to act as a growth factor.

Biological Transport↗
PubMed1989

Heterogeneous renal responses to atrial natriuretic factor. I. Chronic caval dogs.

Atrial natriuretic factor (ANF) (175 ng.kg-1.min-1) was administered to 14 normal, alert dogs and again after constriction of the thoracic vena cava. The average natriuresis observed in the dogs when they were normal was blunted by 55% when they developed ascites and were avidly retaining sodium. Of the 14 caval dogs, 7 showed a natriuretic response no different from the control phase while 7 showed no natriuresis at all in response to the ANF. Ten dogs were restudied when they entered a phase of sodium balance despite the persistence of ascites. All 10 dogs now responded to ANF, and 5 dogs previously not responding now showed a mean change of urinary sodium excretion rate (delta UnaV) of 204 mu eq/min. The two groups could not be differentiated in terms of plasma volume, systemic or renal hemodynamics, or plasma levels of renin and aldosterone. We conclude that there is reversible attenuation of the ANF natriuretic effect in 50% of chronic caval dogs, which disappears when they lose avidity for sodium retention.

Aldosterone↗
PubMed1989

Heterogeneous renal responses to atrial natriuretic factor. II. Cirrhotic dogs.

The renal response to atrial natriuretic factor (ANF) (175 ng.kg-1.min-1) was tested in nine dogs during a control period and again after the appearance of experimental cirrhosis, ascites, and avid sodium retention. During the cirrhotic phase, plasma volume had increased by 28.4% (P less than 0.05), renal perfusion and glomerular filtration rate (GFR) were unchanged from control values, and plasma immunoreactive ANF (iANF) had declined from 71.6 +/- 9.5 to 34.7 +/- 5.4 pg/ml (P less than 0.05). During the control phase, change of urinary sodium excretion rate (delta UNaV) increased by 132 +/- 22 mu eq/min but was attenuated in the cirrhotic phase (delta UNaV = 29 +/- 12.5 mu eq/min). Of these nine cirrhotic dogs, five responded with a delta UNaV ranging from 20 to 114 mueq/min (mean delta UNaV = 59.6 +/- 10.6 mu eq/min), whereas 4 were nonresponders (delta UNaV = 1.3 +/- 0.6 mu eq/min). In neither group could delta UNaV be correlated to changes in GFR, clearance of p-aminohippurate, or filtration fraction. In an additional 10 dogs studied only during cirrhosis, 5 were natriuretic responders and 5 were nonresponders. Atrial content of ANF, half time of infused ANF, and plasma levels of iANF did not differentiate the two groups. We conclude that, like chronic caval dogs with ascites, salt-retaining cirrhotic dogs show heterogeneity of natriuretic response to infused ANF, which is unexplained by differences in renal perfusion.

Animals↗
PubMed1988

Restriction of tumor growth in mice by sodium-deficient diet.

Generalized malnutrition results in inhibition of tumorigenesis and tumor growth in experimental animal models. Neither the specific nutrient deficiency nor the mechanism has been definitely elucidated. We have shown previously that dietary sodium deprivation in rapidly growing rats retards protoplasmic growth. This effect was correlated to the extracellular fluid (ECF) volume expansion which is dependent on sodium accumulation. Since solid tumors are composed of a large quantity of ECF (which includes plasma volume) it was postulated that preventing the accumulation of new ECF by means of sodium restriction would influence tumor growth. The present study was designed to determine the effects of salt restriction on tumor growth and to relate these effects to ECF volume. Approximately 10(6) viable B16 melanoma cells were injected into C57BL/6 x DBA/2 F1 and C57 mice. A salt restricted diet (sodium less than 3 microeq/g) was provided ad libitum. The drinking solution was distilled water for the experimental group and 0.45% saline solution for the controls. There was a significant decrease in tumor growth rates during sodium restriction. The total body ECF volume increased when dietary sodium was supplied but did not change during salt restriction. Therefore, the only source for the ECF in the tumor mass was from nontumorous tissue. We conclude that during dietary sodium restriction solid tumor growth is retarded and can proceed only to the extent that ECF is released from cachectic body tissues.

Animals↗
PubMed1988

Molecular forms of atrial natriuretic peptides in dog atrium and plasma.

The level of immunoreactive ANP (iANP) as determined by radioimmunoassay, exhibits a fairly even distribution throughout the canine atria. However, the maximal concentration was found in the appendages of both the left and right atrium, and the level was significantly higher on the left side in all analyzed localizations. Reverse-phase HPLC of atrial extracts, coupled with RIA, revealed the presence of three iANP fractions. The dominant fraction (65% of iANP) has an estimated molecular weight 16,300, showing that it corresponds to the hormone precursor. By contrast, in the plasma extract, 92% of iANP coelutes with synthetic human ANP99-126, thus confirming the structural identity of dog and human ANP.

Animals↗
PubMed1988

Infantile subconjunctival and anterior orbital fibrous histiocytoma. Ultrastructural and immunohistochemical studies.

A fleshy, polypoidal and partially lobulated lesion that protruded between the eyelids from the medial caruncular region and that infiltrated the contiguous anterior orbital tissues developed over 1 month in a 9-month-old infant. The microscopic features of the tumor included a plump spindle cell population, more polygonal cells, early xanthoma cell transformation, infiltrating lymphocytes and eosinophils, and multinucleated giant cells, the last not exhibiting classic Touton characteristics. The histopathologic differential diagnosis ranged among fibrous histiocytoma, juvenile xanthogranuloma, and eosinophilic granuloma (histiocytosis-X). Results of electron microscopy disclosed abundant rough-surfaced endoplasmic reticulum, a paucity of lysosomes, and no Langerhans' (Birbeck) granules. Immunohistochemistry corroborated the fibrohistiocytic nature of the tumor, because histochemical stains for the enzymes alpha-1-antichymotrypsin and lysozyme, and monoclonal or polyclonal antibodies against common leukocytic antigen and S-100 protein, were negative--whereas they would have been expected to be positive in various combinations in the different histiocytic proliferations. Vimentin was identified in the tumor cells; this is an intermediate cytoplasmic filament almost always present in mesenchymal proliferations. The distinctions between fibrous histiocytomas of stromal cell origin and true histiocytic proliferations of bone marrow cell provenance are explored.

Conjunctival Neoplasms↗
PubMed1988

Euvolemic cirrhotic dogs in sodium balance maintain normal systemic hemodynamics.

Dogs with chronic biliary cirrhosis and portal hypertension commonly develop plasma volume expansion, urinary sodium retention, ascites, and perturbed systemic hemodynamics, i.e., a rise in cardiac output and a fall in peripheral vascular resistance. Our laboratory has previously demonstrated that creating a side-side portacaval anastomosis in such animals, and so venting hepatoportal pressure, will prevent sodium retention and ascites formation and will maintain the animals euvolemic. In the present study, in four cirrhotic dogs with such an anastomosis, observations made at 12 weeks postbiliary duct ligation, and in the presence of grossly disturbed liver function and morphology, failed to demonstrate any change from control conditions in arterial blood pressure, cardiac output, or peripheral vascular resistance. We conclude that venting hepatoportal pressure in cirrhotic dogs with markedly disturbed liver function prevents the advent of a hyperdynamic circulation, possibly by preventing volume expansion.

Animals↗
PubMed1988

Renal dose response and pharmacokinetics of atrial natriuretic factor in dogs.

The present studies investigated the dose-plasma level-response relationships with the use of increasing doses of atrial natriuretic factor [ANF-(99-126)] administered by constant infusion in conscious dogs. The preinfusion plasma immunoreactive ANF increased 12, 19, 23, and 35 times during 45-min consecutive infusions of 50, 75, 125, and 175 ng.kg-1.min-1, respectively. Over this pharmacological range, natriuresis increased linearly with the infused dose (r = 0.99, n = 5) to a maximum response of +1,550%, despite the significant gradual fall of blood pressure, which attained a minimum of 83 mmHg (-26%) at 125 ng.kg-1.min-1. There was no change of glomerular filtration rate (GFR) or renal plasma flow at any dose. A very similar renal response was found in 13 other dogs infused with the highest dose only in which the pharmacokinetic parameters of ANF-(99-126) were estimated. Metabolic clearance rate during the infusion was 1.09 +/- 0.19 l/min. The postinfusion decay curve of plasma immunoreactive ANF was best described by a biexponential function. Plasma disappearance half time was 1.44 min during the rapid phase and 10.3 min during the slow phase of elimination. The results show that 1) natriuretic response to ANF in the pharmacological range is dose dependent and occurs despite a pronounced hypotension, 2) increase in GFR is not a prerequisite of ANF-induced natriuresis, and 3) ANF is rapidly eliminated from the circulation, suggesting an intensive uptake and/or degradation in the target tissues.

Animals↗
PubMed1987

Primary prevention of gastrointestinal diseases.

In the belief that available information can provide reasonable guidance, we review the evidence identifying factors which increase or decrease the risk of developing several gastrointestinal diseases. In the absence of controlled studies, we review case control and other studies. As results from animal studies cannot be readily transferred to humans, we interpret them cautiously. We recommend appropriate personal behavior to reduce risk when they seem reasonably justified by the evidence.

Alcohol Drinking↗